RU2811403C2 - Gcn2 inhibitors and their use - Google Patents

Abstract

FIELD: organic chemistry and pharmaceuticals.

SUBSTANCE: group of inventions relates to compounds useful for inhibiting general amino acid regulating kinase 2 with constant repression (GCN2). The following is disclosed: a compound of one of the formulas XV-a, XV-b or XV-c or a pharmaceutically acceptable salt thereof, where the meanings of the radicals R¹, R are as presented in claim 1. In addition, a specific compound selected from the group, a pharmaceutical composition having a general amino acid regulatory kinase 2 (GCN2) inhibitory activity based on the disclosed compounds, is disclosed, and in addition, the use of these compounds or a pharmaceutical composition for inhibiting GCN2 in a biological sample and for obtaining a medicinal product for treating a GCN2-mediated disorder, disease or condition in a patient.

EFFECT: group of inventions provides effective inhibition of GCN2.

39 cl, 6 tbl, 26 ex

Description

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is subject to 35 U.S.C. §119(e) claims priority on a U.S. provisional application. No. 62/623312, filed January 29, 2018, the contents of which are incorporated herein by reference in their entirety.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0002] The present invention provides compounds and methods useful for inhibiting persistently repressed general amino acid regulatory kinase 2 ("GCN2"). The present invention also relates to pharmaceutically acceptable compositions containing the compounds of the present invention, and methods of using these compositions for the treatment of various disorders.

BACKGROUND OF THE ART

[0003] GCN2 (general amino acid regulatory kinase with constant repression 2) is a ubiquitously expressed protein kinase involved in cellular responses to amino acid starvation in eukaryotes (Castilho et al., 2014). The lack of one or more amino acids in cells leads to the accumulation of uncharged cognate transport RNAs (tRNAs), which are directly bound by GCN2, resulting in activation of the kinase and phosphorylation of eukaryotic initiation factor 2 α (eIF2α) at serine 51 (Wek et al., 1989; Dong et al., 2000). Phosphorylation of eIF2α results in the initiation of protein translation, which causes a decrease in the translation of most mRNAs, resulting in a decrease in overall amino acid utilization. Concomitantly, eIF2α phosphorylation enhances the translation of a specific subset of mRNAs containing some open reading frames in the reverse direction in their 5′ untranslated regions (5′-UTRs), such as the mammalian transcription factor ATF4 (Vattem and Wek, 2004), which stimulates restoration of protein homeostasis . Therefore, GCN2 is a critical determinant of cell death in response to amino acid depletion.

[0004] Induction of cellular responses to amino acid deficiency appears to be an important mechanism for regulating the mammalian immune system, particularly in certain diseases including cancer and autoimmunity. Different types of immunosuppressive cells involved in regulating immune responses in these cases, including tolerogenic dendritic cells, myeloid-derived suppressor cells (MDSCs), tolerogenic/M2 macrophages, and cancer cells themselves, have been reported to use amino acid depletion to suppress T cell responses ( Munn et al., 2004; Munn et al., 2005; Rodriguez et al., 2010; Whyte et al., 2011; Uyttenhove et al., 2003). This is accomplished by intracellular amino acid transport associated with the overexpression of amino acid catabolizing enzymes in these cells, such as the tryptophan catabolizing enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) and the arginine catabolizing enzymes arginase 1 and 2 (ARG1, ARG2). As a result, local intracellular concentrations of specific amino acids can be reduced in these cells, regardless of their location, and therefore GCN2 activity in nearby T cells is induced in an antigen-specific manner (Munn et al., 2004). In mice in vitro and in vivo, depletion of local tryptophan or arginine concentrations, for example by IDO- or ARG1-expressing dendritic cells, has been shown to induce proliferative block and tolerance in T cells in a GCN2-dependent manner (Munn et al., 2005; Rodriguez et al., 2007; Fletcher et al., 2015). In addition, the induction and/or maintenance of MDSCs and immunosuppressive regulatory T cells (T-regs) may also depend on GCN2 activity under conditions of amino acid depletion (Fletcher et al., 2015; Fallarino et al., 2006). In addition, another publication implicates GCN2 activation by IDO in tolerogenic macrophages as a key mechanism for suppressing systemic autoimmune responses to apoptotic cells (Ravishankar et al., 2015). These data indicate that GCN2 is a possible key effector of the immunosuppressive effects of amino acid depletion associated with various pathological conditions.

[0005] In order for nascent cancers to proliferate, it is necessary to bypass the host's anticancer immunity (Corthay, 2014). This can be accomplished by modulating tumor antigen presentation and/or by exploiting tumor immune evasion mechanisms to actively suppress immune attack. Significant expression of amino acid catabolizing enzymes such as IDO and ARG1 was observed in a significant proportion of cancer patients who had different types of tumors, in the cancer cells themselves and in the types of host immunosuppressive cells that accumulate in tumors, tumor-draining lymph nodes and/or peripheral blood flow (Uyttenhove et al., 2003; Pilotte et al., 2012; Zea et al., 2005). Therefore, amino acid depletion may be an effective and widespread mechanism for tumor evasion of immune surveillance, limiting anticancer immunity. Depletion of amino acids in tumors and tumor-draining lymph nodes has been shown to be a mechanism of resistance to available immuno-oncology agents, including checkpoint receptor blocking antibodies, in some syngeneic mouse tumor models (Holmgaard et al., 2013; Spranger et al., 2014 ). In this regard, IDO and TDO inhibitors are now increasingly used in cancer clinical trials, and additional amino acid catabolase inhibitors are in preclinical development. Accordingly, GCN2 inhibitors may also be useful for treating cancer by disrupting the nodal effector signal while depleting amino acids in the immune system and promoting an anti-cancer immune response. Genetic ablation of GCN2 is well tolerated in mice under standard growth conditions (Zhang et al., 2002), and GCN2 inhibitors may have broader applications than single amino acid catabolase inhibitors because GCN2 responds to depletion of several different amino acids.

[0006] Additionally, in contrast to normal tissues, activation and overexpression of GCN2 has been observed in various human tumors (Ye et al., 2010; Wang et al., 2013). Reducing GCN2 levels reduced the growth of embryonic fibroblasts in mice and cancer cells in humans in vitro under conditions of severe amino acid or glucose depletion, and blocked the growth of human tumor xenografts in mice (Ye et al., 2010). Therefore, GCN2 inhibitors may have direct anticancer effects due to frequent disruption of nutrient supply to the tumor microenvironment.

[0007] For these reasons, there is a need for the development of active and selective GCN2 inhibitors for the treatment of cancer, either as single agents or in combination, for example, with CTLA4 and PD1/PD-L1 checkpoint blocking antibodies.

SUMMARY OF THE INVENTION

[0008] The compounds of the present invention, and pharmaceutically acceptable compositions containing them, have been found to be effective as GCN2 kinase inhibitors. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described in the present invention.

[0009] The compounds of the present invention, and pharmaceutically acceptable compositions containing them, are useful for the treatment of various diseases, disorders or pathological conditions associated with the regulation of signaling pathways involving GCN2 kinase. Such diseases, disorders or pathological conditions include those described in the present invention.

[0010] The compounds of the present invention are also useful for studying the GCN2 enzyme in biological and pathological phenomena; studies of intracellular signal transmission pathways in body tissues; and comparative studies of novel GCN2 inhibitors or other regulators of kinases, signal transduction pathways, and cytokine content in vitro or in vivo.

DETAILED DESCRIPTION OF SOME IMPLEMENTATION OPTIONS

1. General description of some embodiments of the present invention:

[0011] The compounds of the present invention, and compositions containing them, are useful as GCN2 protein kinase inhibitors. In some embodiments, the compound of the invention inhibits GCN2.

[0012] In some embodiments, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, in which:

ring A is selected from the group consisting of a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms, whatever selected from the group consisting of nitrogen, oxygen or sulfur, optionally fused to a 5-6 membered aromatic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, 7-12 membered partially unsaturated spirocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12-membered partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, 7- 12-membered partially unsaturated bridged bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group including nitrogen , oxygen or sulfur, an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or

Het, where Het is a 4-8 membered saturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12 membered saturated spirocyclic heterocyclic ring containing 1-4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12 membered saturated bicyclic heterocyclic ring containing 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or a 7-12 membered saturated bridged bicyclic heterocyclic a ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;

Ring B represents

or ;

each R independently represents hydrogen or an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 -membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group including nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group including nitrogen , oxygen or sulfur, or an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; or

two R groups together do not necessarily form a divalent C_2-4 alkylene chain;

the two R groups, optionally together with the intervening atoms, form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;

each R' independently represents hydrogen or a C _1-3 aliphatic group, optionally substituted with halogen;

each of R¹ independently means hydrogen, halogen, -CN, -NO₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)NRS(O)₂R, -C(O)N=S(O)R₂, -NR₂, -NRC(O)R, -NRC(O)NR₂, -NRC(O)OR, -NRS(O)₂R, -NRS(O)₂NR₂, -OR, -ON(R)SO₂R, -P(O)R₂, -SR, -S(O)R, -S(O)₂R, -S(O)(NH)R, -S(O)₂N(R)₂, -S(NH₂)₂(O)OH, -N=S(O)R₂, -CH₃, -CH₂OH, -CH₂NHSO₂CH₃, -CH₃, -CH₂OH, -CH₂NHSO₂CH₃, -CD₃, -CD₂NRS(O)₂R, or R; or:

two R ¹ groups together optionally form =O, =NH or =NS(O) ₂ R; or

two R groups¹ together optionally form divalent C_2-4 alkylene chain;

each of R ² is independently hydrogen, halogen, -CN, -C(O)N(R') ₂ , -OR', -N(R') ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -O-phenyl or an optionally substituted group selected from the group consisting of a C _1-3 aliphatic group, phenyl, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group, comprising nitrogen, oxygen or sulfur, or a 4-8 membered saturated monocyclic heterocycle containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;

R ³ is hydrogen, halogen, -CN, -OR', -N(R') ₂ or an optionally substituted group selected from the group consisting of a C _1-3 aliphatic group, phenyl or a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;

R ⁴ is hydrogen, halogen, -CN, -OR, -N=S(O)R ₂ , -N(R) ₂ or an optionally substituted group selected from the group consisting of a C _1-3 aliphatic group, 4-8- a membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from a group comprising nitrogen, oxygen or sulfur;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

p is 0 or 1; And

q is equal to 0 or 1.

2. Connections and definitions:

[0013] The compounds proposed in the present invention include those described generally in the present invention and they are further illustrated by the classes, subclasses and types disclosed in the present invention. When used in the present invention, the following definitions apply unless otherwise noted. For purposes of the present invention, chemical elements are described in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, ^75th Ed. In addition, general principles of organic chemistry are described in the publications "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", ^5th Ed., Ed.: Smith, MB and March, J. , John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0014] The term "aliphatic" or "aliphatic group" as used in the present invention means a straight chain (i.e., straight) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more multiple bonds , or a monocyclic hydrocarbon or bicyclic hydrocarbon that is fully saturated or that contains one or more multiple bonds but is not aromatic (also referred to in the present invention as "carbocycle", "cycloaliphatic" or "cycloalkyl"), which contains one position of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") means a monocyclic C ₃ -C ₆ hydrocarbon that is fully saturated or that contains one or more multiple bonds but is not aromatic, that contains a single attachment position to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0015] As used herein, the term "bridged bicyclic" means any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, containing at least one bridge. By IUPAC definition, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridge heads, where a "bridge head" is any skeletal atom of a ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group contains 7-12 ring members and 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups listed below, where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bridging bicyclic group is optionally substituted with one or more substituents specified for aliphatic groups. Additionally or alternatively, any substitutable nitrogen atom of the bridging bicyclic group is optionally substituted. Typical bridged bicyclic systems include:

[0016] The term "lower alkyl" means a C _1-4 linear or branched alkyl group. Typical lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0017] The term "lower haloalkyl" means a C _1-4 linear or branched alkyl group that is substituted by one or more halogen atoms.

[0018] The term “heteroatom” means one or more oxygen, sulfur, nitrogen, phosphorus or silicon atoms (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen atom; or a substitutable nitrogen atom of a heterocyclic ring eg N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)).

[0019] The term "unsaturated" as used in the present invention means that the moiety contains one or more multiple bonds.

[0020] As used in the present invention, the term "divalent C _1-8 (or C _1-6 ) saturated or unsaturated, linear or branched, hydrocarbon chain" means divalent alkylene, alkenylene and alkynylene chains that are linear or branched, as defined in the present invention.

[0021] The term "alkylene" means a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e. -(CH ₂ ) _n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced by a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0022] The term "alkenylene" means a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms have been replaced by a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0023] As used in the present invention, the term "cyclopropylene" means a divalent cyclopropyl group of the following structure: .

[0024] The term "halogen" means F, Cl, Br or I.

[0025] The term “aryl,” when used alone or as part of a larger moiety such as “arylalkyl,” “arylalkoxy,” or “aryloxyalkyl,” means monocyclic or bicyclic ring systems containing a total of 5 to 14 ring units, where at least one ring in the system is aromatic and where each ring in the system contains from 3 to 7 ring elements. The term "aryl" can be used interchangeably with the term "aryl ring". In some embodiments of the present invention, "aryl" means an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may contain one or more substituents. The term "aryl" as used herein also includes a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl or tetrahydronaphthyl, and the like.

[0026] The terms "heteroaryl" and "heteroar-", when used alone or as part of a larger moiety, such as "heteroarylalkyl" or "heteroarylalkoxy", mean groups containing from 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms; containing 6, 10 or 14 π electrons, generalized in a cyclic system; and containing in addition to carbon atoms from 1 to 5 heteroatoms. The term "heteroatom" means nitrogen, oxygen or sulfur and includes any oxidized form of nitrogen or sulfur and any quaternized form of the basic nitrogen atom. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridine ill. The terms “heteroaryl” and “heteroar-” as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings wherein the radical or attachment position is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido [2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be mono- or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of which includes rings that are optionally substituted. The term “heteroarylalkyl” means an alkyl group substituted with heteroaryl, where the alkyl and heteroaryl moieties are independently optionally substituted.

[0027] As used in the present invention, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and mean a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and contains, in addition to carbon atoms, one or more, preferably 1 to 4 heteroatoms as defined above. When used in reference to the ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring containing 0-3 heteroatoms selected from the group consisting of oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or ⁺ NR (as in N-substituted pyrrolidinyl).

[0028] A heterocyclic ring may be attached to its side group at any heteroatom or carbon atom as long as this results in a stable structure and any of the ring atoms are optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, th azepinil, morpholinil and quinuclidinil. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably in the present invention and also include groups in which the heterocyclyl ring is fused to one or more aryl groups. , heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” means an alkyl group substituted with heterocyclyl, where the alkyl and heterocyclyl moieties are independently optionally substituted.

[0029] As used herein, the term "partially unsaturated" means a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" includes rings containing multiple multiple bonds, but does not include aryl or heteroaryl moieties as defined herein.

[0030] As indicated in the present invention, the compounds proposed in the present invention may contain "optionally substituted" moieties. Generally, the term “substituted,” whether or not preceded by the term “optional,” means that one or more hydrogen atoms of the moiety have been replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may contain a suitable substituent at each substitutable position of the group and, if more than one position in any given structure can be substituted by more than one substituent selected from a given group, substituents at different positions may be the same or different. The combinations of substituents provided in the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable” as used herein means compounds that do not change significantly under conditions allowing them to be produced, detected, and, in some embodiments, recovered, purified, and used for one or more purposes disclosed in the present invention.

[0031] Suitable monovalent substituents on the substitutable carbon atom of the "optionally substituted" group independently include halogen; -(CH ₂ ) _0-4 R°; -(CH ₂ ) _0-4 OR°; -O(CH ₂ ) _0-4 R ^o , -O-(CH ₂ ) _0-4 C(O)OR°; -(CH ₂ ) _0-4 CH(OR°) ₂ ; -(CH ₂ ) _0-4 SR°; -(CH ₂ ) _0-4 Ph, which may be substituted by the R° group; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph, which may be substituted by the R° group; -CH=CHPh, which may be substituted by an R° group; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridyl, which may be substituted by the R° group; -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) _0-4 N(R°) ₂ ; -(CH ₂ ) _0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH ₂ ) _0-4 N(R°)C(O)NR° ₂ ; -N(R°)C(S)NR° ₂ ; -(CH ₂ ) _0-4 N(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°; -(CH ₂ ) _0-4 C(O)R°; -C(S)R°; -(CH ₂ ) _0-4 C(O)OR°; -(CH ₂ ) _0-4 C(O)SR°; -(CH ₂ ) _0-4 C(O)OSiR° ₃ ; -(CH ₂ ) _0-4 OC(O)R°; -OC(O)(CH ₂ ) _0-4 SR-, —SC(S)SR°; -(CH ₂ ) _0-4 SC(O)R°; -(CH ₂ ) _0-4 C(O)NR° ₂ ; -C(S)NR° ₂ ; -C(S)SR°; -(CH ₂ ) _0-4 OC(O)NR° ₂ ; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH ₂ C(O)R°; -C(NOR°)R°; -(CH ₂ ) _0-4 SSR°; -(CH ₂ ) _0-4 S(O) ₂ R°; -(CH ₂ ) _0-4 S(O) ₂ OR°; -(CH ₂ ) _0-4 OS(O) ₂ R°; -S(O) ₂ NR° ₂ ; -(CH ₂ ) _0-4 S(O)R°; -(CH ₂ ) _0-4 S(O)(NR°)R°; -N(R°)S(O) ₂ NR° ₂ ; -N(R°)S(O) ₂ R°; -N(R°)S(O)(NR°)R° ₂ ; -N(OR°)R°; -N=S(O)R° ₂ ; -N(OR°)SO ₂ R°; -C(NH)NR° ₂ ; -P(O) ₂ R°; -P(O)R° ₂ ; -OP(O)R° ₂ ; -OP(O)(OR°) ₂ ; -SiR° ₃ ; -(C _1-4 linear or branched alkylene)ON(R°) ₂ ; or -(C _1-4 linear or branched alkylene)C(O)ON(R°) ₂ wherein each R° may be substituted as defined below and is independently hydrogen, a C _1-6 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -CH ₂ -(5-6 membered heteroaryl ring) or 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from the group , including nitrogen, oxygen or sulfur, or, regardless of the above definition, two independently contained R°, together with the atom(s) located between them, form a 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0032] Suitable monovalent substituents on R° (or on a ring formed from two independently contained R° together with intervening atoms) are independently halogen, -(CH ₂ ) _0-2 R ^λ , -(halogen-R ^λ ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^λ , -(CH ₂ ) _0-2 CH(OR ^λ ) ₂ ; -O(halogen-R ^λ ), -CN, -N ₃ , -(CH ₂ ) _0-2 C(O)R ^λ , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^λ , -(CH ₂ ) _0-2 SR ^λ , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^λ , -(CH ₂ ) _0-2 NR ^λ ₂ , -NO ₂ , -SiR ^λ ₃ , -OSiR ^λ ₃ , -C(O)SR ^λ _, -(C _1-4 linear or branched alkylene)C( O)OR ^λ or -SSR ^λ , wherein each R ^λ is unsubstituted or, if preceded by "halogen", substituted with only one or more halogens and independently selected from the group consisting of a C _1-4 aliphatic group, -CH ₂ Ph , -O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom in R° include =O and =S.

[0033] Suitable divalent substituents on a saturated carbon atom in an "optionally substituted" group include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O ) ₂ R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3 O-, or -S(C(R ^* ₂ )) _2-3 S-, where in each independent when R ^* appears, is selected from the group consisting of hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from group including nitrogen, oxygen or sulfur. Suitable divalent substituents that are bonded to the vicinal substitutable carbon atoms of the "optionally substituted" group include: -O(CR ^* ₂ ) _2-3 O- wherein, on each independent occurrence, R ^* is selected from the group consisting of hydrogen, C _{1 -6} aliphatic group which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[0034] Suitable aliphatic group substituents on R ^* include halogen, ^-Rλ , -(halogen- ^Rλ ), -OH, ^-ORλ , -O(halogen- ^Rλ ), -CN, -C(O)OH , -C(O)OR ^λ , -NH ₂ , -NHR ^λ , -NR ^λ ₂ , or -NO ₂ , wherein each R ^λ is unsubstituted or, if preceded by “halogen,” is substituted by only one or more halogens and independently means a C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from the group, including nitrogen, oxygen or sulfur.

[0035] Suitable substituents on the substitutable nitrogen atom in the "optionally substituted" group include -R ^† , -NR ^† ₂ , -C(O)R ^† , -C(O)OR ^† , -C(O)C( O)R ^† , -C(O)CH ₂ C(O)R ^† , -S(O) ₂ R ^† , -S(O) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , -C( NH)NR ^† ₂ or -N(R ^† )S(O) ₂ R ^† ; where each R ^† independently represents hydrogen, a C _1-6 aliphatic group which may be substituted, as defined below, unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from group including nitrogen, oxygen or sulfur, or, regardless of the above definition, two independently contained R ^† together with the intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring, containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[0036] Suitable aliphatic group substituents on R ^† are independently halogen, ^-Rλ , -(halogen- ^Rλ ), -OH, ^-ORλ , -O(halogen- ^Rλ ), -CN, -C(O) OH, -C(O)OR ^λ , -NH ₂ , -NHR ^λ , -NR ^λ ₂ , or -NO ₂ , where each R ^λ is unsubstituted or, if preceded by "halogen", is substituted by only one or more halogens and independently means a C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from the group containing nitrogen, oxygen or sulfur.

[0037] As used herein, the term "pharmaceutically acceptable salt" means salts that, based on careful medical clinical evaluation, are suitable for contact with the tissues of humans and lower animals without undesirable toxicity, irritation, allergic reaction, etc., and are within reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., described pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those formed from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amine salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid , tartaric acid, citric acid, succinic acid or malonic acid or by other techniques used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate , pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc.

[0038] Salts formed from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Typical alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like salts. Other pharmaceutically acceptable salts include, when appropriate, non-toxic ammonium, quaternary ammonium and amine salts formed with counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and arylsulfonate.

[0039] Unless otherwise indicated, the structures provided in the present invention also include all isomeric (eg, enantiomeric, diastereomeric and geometric (or conformational)) forms of the structure; for example, R and S configurations of each asymmetric center, Z and E isomers with respect to double bonds, and Z and E conformational isomers. Therefore, individual stereochemical isomers, as well as enantiomeric, diastereoisomeric and geometric (or conformational) mixtures of the compounds proposed in the present invention are included in the scope of the present invention. Unless otherwise indicated, all tautomeric forms of the compounds proposed in the present invention are included in the scope of the present invention. In addition, unless otherwise indicated, the structures provided in the present invention also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the proposed structures, including those where there is a replacement of hydrogen with deuterium or tritium, or a replacement of carbon with ¹³ C- or ¹⁴ C-rich carbon, are within the scope of the present invention. Such compounds are useful, for example, as analytical agents, as probes in biological research or as therapeutic agents in accordance with the present invention. In some embodiments, R ^x in the present compound includes one or more deuterium atoms.

[0040] As used herein, the term "inhibitor" is defined as a compound that binds to and/or inhibits GCN2 with measurable affinity. In some embodiments, the inhibitor has an IC ₅₀ and/or binding constant value of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0041] The compound of the present invention can be bound to a detectable moiety. It should be understood that such compounds are useful as imaging agents. One of ordinary skill in the art will understand that the detectable moiety can be attached to the compound of the invention using a suitable substituent. As used in the present invention, the term "suitable substituent" means a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, for example, a carboxylate moiety, an amine moiety, a thiol moiety, or a hydroxyl moiety, to name just a few examples. It should be understood that such moieties may be directly attached to the compound of the invention or via an attached group such as a divalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached using click chemistry. In some embodiments, such moieties may be added via 1,3-cycloaddition of an azide to an alkyne, optionally in the presence of a copper catalyst. Techniques for using click chemistry are known in the art and include those described in Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0042] As used in the present invention, the term "detectable fragment" is used interchangeably with the term "label" and refers to any fragment capable of detection, for example, primary marks and secondary marks. Primary labels such as radioisotopes (eg, tritium, ³² P, ³³ P, ³⁵ S, or ¹⁴ C), mass spectrometric labels, and fluorescent labels are signal-generating reporter groups that can be detected without additional modifications. Detectable moieties also include luminescent and phosphorescent groups.

[0043] The term "secondary label" as used herein refers to fragments, such as biotin and various protein antigens, in which the presence of a second intermediate is necessary to produce a detectable signal. For biotin, secondary intermediates may include streptavidin-enzyme conjugates. For antigenic tags, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in a non-radiative process. fluorescence resonance energy transfer (FRET) and the second group produces a detectable signal.

[0044] The terms "fluorescent label", "fluorescent dye" and "fluorophore" as used in the present invention mean moieties that absorb light energy at a certain excitation wavelength and emit light energy at another wavelength. Examples of fluorescent tags include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680 ), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630 /650, BODIPY 650/665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxyfluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, IRD dyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine Green, rhodamine Red, Rhodol Green, 2',4',5', 7'-tetrabromoulfonfluorescein, tetramethylrhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0045] The term “mass spectrometric tag” as used in the present invention means any fragment that can be unambiguously detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass spectrometric labels include electroform-releasing labels such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic acid, 4'-[2,3,5,6 -tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone and their derivatives. The synthesis and use of these mass spectrometry tags are described in U.S. patents. 4650750, 4709016, 53608191, 5516931, 5602273, 5604104, 5610020, and 5650270. Other examples of mass spectrometry tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying lengths and basic composition, oligopeptides, gosaccharides and other synthetic polymers of various lengths and with different compositions of monomers. A large number of organic molecules, neutral and charged (biomolecules or synthetic compounds) with a suitable molecular weight range (100-2000 Da) can also be used as mass spectrometric tags.

[0046] The terms “measurable affinity” and “measurable inhibition” as used herein mean a measurable change in GCN2 protein kinase activity from a sample containing a compound of the present invention, or a composition thereof and GCN2 protein kinase, to an equivalent sample containing protein kinase GCN2, in the absence of the specified compound or composition containing it.

3. Description of typical embodiments:

[0047] As stated above, in some embodiments, the present invention provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, in which:

ring A is selected from the group consisting of a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms, whatever selected from the group consisting of nitrogen, oxygen or sulfur, optionally fused to a 5-6 membered aromatic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, 7-12 membered partially unsaturated spirocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, 7- 12-membered partially unsaturated bridged bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group including nitrogen , oxygen or sulfur, an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or

Het, where Het is a 4-8 membered saturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12 membered saturated spirocyclic heterocyclic ring containing 1-4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12 membered saturated bicyclic heterocyclic ring containing 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or a 7-12 membered saturated bridged bicyclic heterocyclic a ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;

Ring B represents

or ;

each R independently represents hydrogen or an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 -membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group including nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group including nitrogen , oxygen or sulfur, or an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; or

two R groups together do not necessarily form a divalent C_2-4 alkylene chain;

the two R groups, optionally together with the intervening atoms, form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;

each R' independently represents hydrogen or a C _1-3 aliphatic group, optionally substituted with halogen;

each of R¹ independently means hydrogen, halogen, -CN, -NO₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)NRS(O)₂R, -C(O)N=S(O)R₂, -NR₂, -NRC(O)R, -NRC(O)NR₂, -NRC(O)OR, -NRS(O)₂R, -NRS(O)₂NR₂, -OR, -ON(R)SO₂R, -P(O)R₂, -SR, -S(O)R, -S(O)₂R, -S(O)(NH)R, -S(O)₂N(R)₂, -S(NH₂)₂(O)OH, -N=S(O)R₂, -CH₃, -CH₂OH, -CH₂NHSO₂CH₃, -CD₃, -CD₂NRS(O)₂R, or R; or:

two R ¹ groups together optionally form =O or =NH; or

two R groups¹ together optionally form divalent C_2-4 alkylene chain;

each of R ² is independently hydrogen, halogen, -CN, -C(O)N(R') ₂ , -OR', -N(R') ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -O-phenyl or an optionally substituted group selected from the group consisting of a C _1-3 aliphatic group, phenyl, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group, comprising nitrogen, oxygen or sulfur, or a 4-8 membered saturated monocyclic heterocycle containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;

R ³ is hydrogen, halogen, -CN, -OR', -N(R') ₂ or an optionally substituted group selected from the group consisting of a C _1-3 aliphatic group, phenyl, or a 5-6 membered monocyclic heteroaromatic ring, containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur;

R ⁴ is hydrogen, halogen, -CN, -OR, -N=S(O)R ₂ , -N(R) ₂ or an optionally substituted group selected from the group consisting of a C _1-3 aliphatic group, 4-8- a membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from a group comprising nitrogen, oxygen or sulfur;

m is 0, 1, 2, 3, 4 or 5;

n is 0, 1 or 2;

p is 0 or 1; And

q is equal to 0 or 1.

[0048] As defined above and described in the present invention, ring A is selected from the group consisting of 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered partially an unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, optionally fused to a 5-6 membered aromatic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12 membered partially unsaturated spirocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12 membered partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or Het, where Het is is a 4-8-membered saturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 7-12-membered saturated spirocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from the group, comprising nitrogen, oxygen or sulfur, a 7-12 membered saturated bicyclic heterocyclic ring containing 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or a 7-12 membered saturated bridged bicyclic heterocyclic ring containing 1- 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[0049] In some embodiments, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, ring A is phenyl. In some embodiments, Ring A is an 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, Ring A is a 4-8 membered partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, optionally fused to a 5-6 membered aromatic ring containing 0 -4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, Ring A is a 7-12 membered partially unsaturated spirocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, Ring A is a 7-12 membered partially unsaturated bicyclic heterocyclic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, Ring A is a 7-12 membered partially unsaturated bridged bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur.

[0050] In some embodiments, ring A is Het. In some embodiments, Ring A is a 4-8 membered saturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, Ring A is a 7-12 membered saturated spirocyclic heterocyclic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 7-12 membered saturated bicyclic heterocyclic ring containing 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, Ring A is a 7-12 membered saturated bridged bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[0051] In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is .

[0052] In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is .

[0053] In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is .

[0054] In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is .

[0055] In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is .

[0056] In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is . In some embodiments, ring A is .

[0057] In some embodiments, ring A is selected from among the structures shown in Table 1 below.

[0058] As defined above and described in the present invention, ring B is

or .

[0059] In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is . In some embodiments, ring B is .

[0060] In some embodiments, the B ring is selected from among the structures shown in Table 1 below.

[0061] As defined above and as defined herein, each R is independently hydrogen or an optionally substituted group selected from the group consisting of C_1-6 aliphatic group, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from group comprising nitrogen, oxygen or sulfur, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; or two R groups together optionally form a divalent C_2-4 alkylene chain; or two R groups, optionally together with the intervening atoms, form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[0062] In some embodiments, R is hydrogen. In some embodiments, R is optionally substituted with C_1-6 aliphatic group. In some embodiments, R is an optionally substituted 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is an optionally substituted 8-10 membered bicyclic aromatic carbocyclic ring. In some embodiments, R is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, R is an optionally substituted 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, R is an optionally substituted 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, two R groups together optionally form a divalent C_2-4 alkylene chain. In some embodiments, the two R groups, optionally together with the intervening atoms, form an optionally substituted 3-7 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[0063] In some embodiments, R is selected from among the structures shown in Table 1 below.

[0064] As defined above and described in the present invention, each of R' is independently hydrogen or a C _1-3 aliphatic group, optionally substituted with halogen.

[0065] In some embodiments, R' is hydrogen. In some embodiments, R' is a C _1-3 aliphatic group, optionally substituted with halogen.

[0066] In some embodiments, R' is selected from among the structures shown in Table 1 below.

[0067] As defined above and in the present invention, each of R¹ independently means hydrogen, halogen, -CN, -NO₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)NRS(O)₂R, -C(O)N=S(O)R₂, -NR₂, -NRC(O)R, -NRC(O)NR₂, -NRC(O)OR, -NRS(O)₂R, -NRS(O)₂NR₂, -OR, -ON(R)SO₂R, -P(O)R₂, -SR, -S(O)R, -S(O)₂R, -S(O)(NH)R, -S(O)₂N(R)₂, -S(NH₂)₂(O)OH, -N=S(O)R₂, -CH₃, -CH₂OH, -CH₂NHSO₂CH₃, -CD₃, -CD₂NRS(O)₂R, or R; or: two groups R¹ together optionally form =O or =NH; or two R groups¹ together optionally form divalent C_2-4 alkylene chain.

[0068] In some embodiments, R¹ means hydrogen. In some embodiments, R¹ means halogen. In some embodiments, R¹ means -CN. In some embodiments, R¹ means -NO₂. In some embodiments, R¹ means -C(O)R. In some embodiments, R¹ means -C(O)OR. In some embodiments, R¹ means -C(O)NR₂. In some embodiments, R¹ means -C(O)NRS(O)₂R. In some embodiments, R¹ means -C(O)N=S(O)R₂. In some embodiments, R¹ means -NR₂. In some embodiments, R¹ means -NRC(O)R. In some embodiments, R¹ means -NRC(O)NR₂. In some embodiments, R¹ means -NRC(O)OR. In some embodiments, R¹ means -NRS(O)₂R. In some embodiments, R¹ means -NRS(O)₂NR₂. In some embodiments, R¹ means -OR. In some embodiments, R¹ means -ON(R)SO₂R. In some embodiments, R¹ means -P(O)R₂. In some embodiments, R¹ means -SR. In some embodiments, R¹ means -S(O)R. In some embodiments, R¹ means -S(O)₂R. In some embodiments, R¹ means -S(O)(NH)R. In some embodiments, R¹ means -S(O)₂N(R)₂. In some embodiments, R¹ means -S(NH₂)₂(O)OH. In some embodiments, R¹ means -N=S(O)R₂. In some embodiments, R¹ means -CD₃. In some embodiments, R¹ means -CD₂NRS(O)₂R. In some embodiments, R¹ means R. In some embodiments, two R groups¹ together optionally form =O or =NH. In some embodiments, two R groups¹ together optionally form divalent C_2-4 alkylene chain.

[0069] In some embodiments, R ¹ is fluorine. In some embodiments, R ¹ is chlorine. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is ethyl. In some embodiments, R ¹ is -OH. In some embodiments, R ¹ is -OCH ₃ . In some embodiments, R ¹ is -CH ₂ OH. In some embodiments, R ¹ is -CH ₂ CN. In some embodiments, R ¹ is -CF ₃ . In some embodiments, R ¹ is -CH ₂ NH ₂ . In some embodiments, R ¹ is -COOH. In some embodiments, R ¹ is -NH ₂ .

[0070] In some embodiments, two R ¹ groups form =O. In some embodiments, two R ¹ groups form =NH. In some embodiments, two R ¹ groups form .

[0071] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0072] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0073] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0074] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0075] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0076] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0077] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0078] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0079] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0080] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0081] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0082] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0083] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0084] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0085] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0086] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0087] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0088] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0089] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0090] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0091] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0092] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0093] In some embodiments, R ¹ is selected from among the structures shown in Table 1 below.

[0094] As defined above and in the present invention, each of R ² is each of R ² independently is hydrogen, halogen, -CN, -C(O)N(R') ₂ , -OR', -N(R ') ₂ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -O-phenyl or an optionally substituted group selected from the group consisting of a C _1-3 aliphatic group, phenyl, 5-6 -membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or a 4-8 membered saturated monocyclic heterocycle containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur

[0095] In some embodiments, R ² is hydrogen. In some embodiments, R ² is halogen. In some embodiments, R ² is -CN. In some embodiments, R ² is -C(O)N(R') ₂ . In some embodiments, R ² is -OR'. In some embodiments, R ² is -N(R') ₂ . In some embodiments, R ² is -S(O) ₂ R. In some embodiments, R ² is -S(O) ₂ N(R) ₂ . In some embodiments, R ² is -O-phenyl. In some embodiments, R ² is an optionally substituted C _1-3 aliphatic group. In some embodiments, R ² is optionally substituted phenyl. In some embodiments, R ² is an optionally substituted 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, R ² is an optionally substituted 4-8 membered saturated monocyclic heterocycle containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[0096] In some embodiments, R ² is fluorine. In some embodiments, R ² is chlorine. In some embodiments, R ² is bromine. In some embodiments, R ² is methyl. In some embodiments, R ² is ethyl. In some embodiments, R ² is -CF ₃ . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is .

[0097] In some embodiments, R ² means . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is .

[0098] In some embodiments, R ² means . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is . In some embodiments, R ² is .

[0099] In some embodiments, R ² means . In some embodiments, R ² is . In some embodiments, R ² is .

[00100] In some embodiments, R ² is selected from among the structures shown in Table 1 below.

[00101] As defined above and in the present invention, R ³ is hydrogen, halogen, -CN, -OR', -N(R') ₂ or an optionally substituted group selected from the group consisting of a C _1-3 aliphatic group, phenyl or a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[00102] In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is halogen. In some embodiments, R ³ is -CN. In some embodiments, R ³ is -OR'. In some embodiments, R ³ is -N(R') ₂ . In some embodiments, R ³ is an optionally substituted C _1-3 aliphatic group. In some embodiments, R ³ is optionally substituted phenyl. In some embodiments, R ³ is an optionally substituted 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[00103] In some embodiments, R ³ is selected from among the structures shown in Table 1 below.

[00104] As defined above and in the present invention, R ⁴ is hydrogen, halogen, -CN, -OR, -N=S(O)R ₂ , -N(R) ₂ or an optionally substituted group selected from the group, comprising a C _1-3 aliphatic group, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or a 7-12 membered saturated or partially unsaturated spirocyclic a heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[00105] In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is halogen. In some embodiments, R ⁴ is -CN. In some embodiments, R ⁴ is -OR. In some embodiments, R ⁴ is -N=S(O)(R) ₂ . In some embodiments, R ⁴ is -N(R) ₂ . In some embodiments, R ⁴ is an optionally substituted C _1-3 aliphatic group. In some embodiments, R ⁴ is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. In some embodiments, R ⁴ is an optionally substituted 7-12 membered saturated or partially unsaturated spirocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[00106] In some embodiments, R ⁴ is fluorine. In some embodiments, R ⁴ is chlorine. In some embodiments, R ⁴ is methyl. In some embodiments, R ⁴ is -CF ₃ . In some embodiments, R ⁴ is -OH. In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is .

[00107] In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is .

[00108] In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is .

[00109] In some embodiments, R ⁴ is selected from among the structures shown in Table 1 below.

[00110] As defined above and specified in the present invention, m is 0, 1, 2, 3, 4 or 5.

[00111] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5 .

[00112] In some embodiments, m is 1, 2, or 3.

[00113] In some embodiments, m is selected from among the structures shown in Table 1 below.

[00114] As defined above and in the present invention, n is 0, 1, or 2.

[00115] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[00116] In some embodiments, n is selected from among the structures shown in Table 1 below.

[00117] As defined above and in the present invention, p is 0 or 1.

[00118] In some embodiments, p is 0. In some embodiments, p is 1.

[00119] In some embodiments, p is selected from among the structures shown in Table 1 below.

[00120] As defined above and in the present invention, q is 0 or 1.

[00121] In some embodiments, q is 0. In some embodiments, q is 1.

[00122] In some embodiments, q is selected from among the structures shown in Table 1 below.

[00123] In some embodiments, the present invention provides a compound of formula I wherein ring A is Het and thereby forms a compound of formula II:

or a pharmaceutically acceptable salt thereof, wherein each ring B, R ¹ , R ² , R ³ , R ⁴ , m, n, p and q is as defined above and described in the present embodiments, individually and in combination.

[00124] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring B is and thereby forms a compound of formula III:

or a pharmaceutically acceptable salt thereof, wherein Het, R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00125] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is and thereby forms a compound of formula IV-a, IV-b or IV-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00126] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring B is and thereby forms a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein Het, R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00127] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is and thereby forms a compound of formula VI-a, VI-b or VI-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00128] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring B is and thereby forms a compound of formula VII:

or a pharmaceutically acceptable salt thereof, wherein Het, R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00129] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is and thereby forms a compound of formula VIII-a, VIII-b or VIII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00130] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring B is and thereby forms a compound of formula IX:

or a pharmaceutically acceptable salt thereof, wherein Het, R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00131] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is and thereby forms a compound of formula Xa, Xb or Xc, respectively:

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00132] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring B is and thereby forms a compound of formula XI:

or a pharmaceutically acceptable salt thereof, wherein Het, R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00133] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl, or morpholinyl and ring B is and thereby forms a compound of formula XII-a, XII-b or XII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are each as defined above and described in the present embodiments, individually and in combination.

[00134] In some embodiments, the present invention provides a compound of formula I wherein n is 1, p is 1, q is 1, R ² is -CF ₃ , R ³ is hydrogen, R ⁴ is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl and ring B is and thereby forms a compound of formula XIII-a, XIII-b or XIII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00135] In some embodiments, the present invention provides a compound of formula I wherein n is 1, p is 1, q is 1, R ² is chlorine, R ³ is hydrogen, R ⁴ is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl and ring B represents and thereby forms a compound of formula XIV-a, XIV-b or XIV-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00136] In some embodiments, the present invention provides a compound of formula I wherein n is 1, p is 1, q is 1, R ² is -CHF ₂ , R ³ is hydrogen, R ⁴ is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl and ring B is and thereby forms a compound of formula XV-a, XV-b or XV-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00137] In some embodiments, the present invention provides a compound of Formula I wherein n is 1, p is 1, q is 1, R ² is -CF ₃ , R ³ is hydrogen, R ⁴ is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl and ring B is and thereby forms a compound of formula XVI-a, XVI-b or XVI-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00138] In some embodiments, the present invention provides a compound of formula I wherein n is 1, p is 1, q is 1, R ² is chlorine, R ³ is hydrogen, R ⁴ is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl and ring B represents and thereby forms a compound of formula XVII-a, XVII-b or XVII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00139] In some embodiments, the present invention provides a compound of formula I wherein n is 1, p is 1, q is 1, R ² is -CHF ₂ , R ³ is hydrogen, R ⁴ is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl and ring B is and thereby forms a compound of formula XVIII-a, XVIII-b or XVIII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00140] In some embodiments, the present invention provides a compound of formula I wherein n is 1, p is 1, q is 1, R ² is cyclopropyl, R ³ is hydrogen, R ⁴ is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl and ring B represents and thereby forms a compound of formula XIX-a, XIX-b or XIX-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00141] In some embodiments, the present invention provides a compound of formula I wherein n is 1, p is 1, q is 1, R ² is azetidinyl, R ³ is hydrogen, R ⁴ is hydrogen, ring A is piperidinyl, piperazinyl or morpholinyl and ring B is and thereby forms a compound of formula XX-a, XX-b or XX-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00142] In some embodiments, the present invention provides a compound of formula I, wherein n is 1, p is 1, q is 1, R ² is , R ³ is hydrogen, R ⁴ is methyl, ring A is piperidinyl, piperazinyl or morpholinyl and ring B is and thereby forms a compound of formula XXI-a, XXI-b or XXI-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each R ¹ and m is as defined above and described in the presented embodiments, individually and in combination.

[00143] Typical compounds proposed in the present invention are listed below in Table 1.

Table 1. Typical Compounds of Formula I

[00144] In some embodiments, the present invention provides the compounds listed in Table 1 above, or pharmaceutically acceptable salts thereof.

[00145] In some embodiments, the present invention provides a complex comprising GCN2 and an inhibitor.

4. General methods for preparing the compounds proposed in the present invention

[00146] The compounds proposed in the present invention can generally be prepared or isolated by synthetic and/or semi-synthetic methods known to those skilled in the art for the preparation of similar compounds and by methods described in detail in the examples in the present invention.

[00147] The following diagrams indicate specific protecting group ("PG"), leaving group ("LG"), or conversion conditions, and one of ordinary skill in the art will understand that other protecting groups, leaving groups, and conversion conditions are also are suitable and within the scope of the present invention. Such groups and transformations are described in detail from March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, ^5th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R.C. Larock, ^2nd Edition, John Wiley & Sons, 1999 and Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, which are incorporated by reference in their entirety.

[00148] As used herein, the term "leaving group" (LG) includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate , triflate), diazonium, etc.

[00149] As used herein, the term "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, and the like. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis , TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference in its entirety. Examples of suitable hydroxyl protecting groups include, but are not limited to, ester, allyl ether, ether, silyl ether, alkyl ether, arylalkyl ether and alkoxyalkyl ether. Examples of such ester groups include formates, acetates, carbonates and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivalate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate , p-benzyl benzoate, 2,4,6-trimethyl benzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl and p-nitrobenzyl. Examples of such silyl ether groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl and other trialkylsilyl ether groups. Alkyl ether groups include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, tert-butyl, allyl and allyloxycarbonyl ether groups or derivatives. Alkoxyalkyl ether groups include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl and tetrahydropyranyl ether groups. Examples of arylalkyl ether groups include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl .

[00150] Amine protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, ^3rd edition, John Wiley & Sons, 1999, which is incorporated herein in its entirety. as a reference. Suitable amino protecting groups include, but are not limited to, arylalkylamines, carbamates, cyclic imides, allylamines, amides, etc. Examples of such groups include tert-butyloxycarbonyl (BOC), ethoxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl-(Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, etc.

[00151] Scheme 1: General scheme for the preparation of compounds of formula I, in which ring B is a pyrimidine linked to a bicyclic ring at position 2, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00152] In the above diagram 1, each ring A, R ¹ , R ² , m and n is as defined above and below and in the classes of subclasses described in the present invention.

[00153] Scheme 2: General scheme for the preparation of compounds of formula I, in which ring B is a pyrimidine linked to a bicyclic ring at position 2, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1 .

[00154] In Scheme 2 above, each ring A, R ¹ , R ² , and m is as defined above and below and in the classes and subclasses described in the present invention.

[00155] Scheme 3: General scheme for the preparation of compounds of formula I, in which ring B is a pyrimidine linked to a bicyclic ring at position 2, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00156] In the above diagram 3, each ring A, R ¹ , R ² , m and n is as defined above and below and in the classes of subclasses described in the present invention.

[00157] Scheme 4: General scheme for the preparation of compounds of formula I, in which ring B is a pyrimidine linked to a bicyclic ring at position 4, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1 .

[00158] In Scheme 4 above, each ring A, R ¹ , R ² , and m is as defined above and below and in the classes and subclasses described in the present invention.

[00159] One skilled in the art will appreciate that compounds of Formula I may contain one or more stereocenters and may be present as a racemic mixture or a mixture of diastereoisomers. One skilled in the art will also understand that many techniques are known in the art for separating isomers and obtaining stereochemically enriched or stereochemically pure isomers of these compounds, including, but not limited to, HPLC, chiral HPLC, fractional crystallization of stereoisomeric salts, kinetic enzymatic separation (for example, using a lipase or esterase isolated from fungi, bacteria or animals) and the formation of covalent diastereomeric derivatives using an enantiomerically enriched reagent.

[00160] One skilled in the art will understand that the various functional groups contained in the compounds of the present invention, such as aliphatic groups, alcohol, carboxyl, ester, amide, aldehyde, halide and nitrile groups can be interconverted according to techniques well known in the art, including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration and hydrogenation. "March's Advanced Organic Chemistry", ^5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, which is incorporated herein by reference in its entirety. Such interconversions may require one or more of the above procedures, and certain procedures for the synthesis of the compounds of the present invention are described below in the examples section.

5. Application, preparation and administration

a. Pharmaceutically acceptable compositions

[00161] In another embodiment, the present invention provides a composition containing a compound of the present invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, excipient or diluent. The amount of compound in the compositions of the present invention is that which is effective to measurably inhibit GCN2 protein kinase or a mutant thereof in a biological sample or patient. In some embodiments, the amount of compound in the compositions of the present invention is such that it is effective to measurably inhibit GCN2 protein kinase or a mutant thereof in a biological sample or patient. In some embodiments, a composition of the present invention is prepared for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[00162] The term “patient” as used herein means an animal, preferably a mammal, and most preferably a human.

[00163] The term "pharmaceutically acceptable carrier, excipient or diluent" means a non-toxic carrier, excipient or diluent that does not interfere with the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, excipients or diluents that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering agents, such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone , cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol and lanolin.

[00164] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of a compound of the present invention which, when administered to a recipient, is capable, directly or indirectly, of forming the compound of the present invention or an inhibitor thereof. active metabolite or residue.

[00165] As used herein, the term “inhibitory active metabolite or residue thereof” means that the metabolite or residue thereof is also a GCN2 protein kinase inhibitor or mutant thereof.

[00166] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or by an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intraarticular, epigastric, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention may be an aqueous or oily suspension. These suspensions can be prepared by methods known in the art, using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable diluents and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are usually used as a solvent or suspending medium.

[00167] Any soft, fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glycerides are useful for the preparation of injection forms, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, their polyoxyethylated derivatives. These oily solutions or suspensions may also contain a long chain alcohol diluent or dispersant such as carboxymethylcellulose or similar dispersing agents that are commonly used to prepare pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers, which are commonly used for the preparation of pharmaceutically acceptable solid, liquid or other dosage forms, can also be used for the preparation.

[00168] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of an oral tablet, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, common diluents include lactose and dried corn starch. If aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, some sweeteners, flavoring or coloring agents may also be added.

[00169] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered as suppositories for rectal administration. They can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00170] The pharmaceutically acceptable compositions of the present invention can also be administered topically, particularly if the target for treatment includes sites or organs readily accessible through topical application, including diseases of the eye, skin, or lower gastrointestinal tract. Suitable topical preparations can easily be prepared for each of these sites or organs.

[00171] Topical administration to the lower gastrointestinal tract can be accomplished using a rectal suppository preparation (see above) or a suitable enema preparation. topical-transdermal patches can also be used.

[00172] For topical use, the pharmaceutically acceptable compositions of the invention may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifiable wax and water. Alternatively, the pharmaceutically acceptable compositions of the invention may be formulated as a suitable lotion or cream containing the active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00173] For ophthalmic use, the pharmaceutically acceptable compositions of the invention may be formulated as micronized suspensions in isotonic pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, with or without the use of a preservative such as benzylalkonium chloride . Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions may be formulated as an ointment such as petrolatum jelly.

[00174] Pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared by techniques well known in the art of pharmaceutical preparation and can be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to increase bioavailability, fluorinated hydrocarbons, and/or other conventional solubilizing or dispersing agents. .

[00175] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such drugs can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[00176] The amount of the compounds of the present invention that can be combined with carrier materials to formulate the composition in a single dosage form varies depending on the recipient being treated and the particular mode of administration. The present compositions should preferably be formulated so that a dose of inhibitor equal to 0.01-100 mg/kg body weight/day can be administered to a patient receiving these compositions.

[00177] It should also be understood that the specific dosage and treatment regimen for any particular patient depends on various factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, rate of elimination, drug combinations, and the decision of the attending physician and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition also depends on the particular compound in the composition.

b. Use of Compounds and Pharmaceutically Acceptable Compositions

[00178] The compounds and compositions described in the present invention are generally useful for inhibiting GCN2 kinase activity.

[00179] The activity of a compound used in the present invention as an inhibitor of GCN2 or its mutant can be tested in vitro, in vivo or using a cell line. In vitro studies include studies that determine the inhibition of phosphorylation activity and/or subsequent functional consequences or ATPase activity of activated GCN2 or its mutant. Alternative in vitro studies quantify the ability of the inhibitor to bind to GCN2. Inhibitor binding can be measured by introducing a radiolabel into the inhibitor prior to binding, isolating the inhibitor/GCN2 complex, and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by performing a comparative experiment in which new inhibitors are incubated with GCN2 bound to known radioligands. Detailed conditions for testing a compound used in the present invention as an inhibitor of GCN2 or its mutant are given below in the examples.

[00180] As used in the present invention, the terms “treating” or “treating” mean reversing, alleviating, delaying the onset of, or suppressing the progression of a disease or disorder or one or more symptoms thereof described in the present invention. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (eg, based on history of symptoms and/or genetic or other susceptibility factors). Treatment can also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[00181] The present compounds are inhibitors of one or more GCN2 and are therefore useful for the treatment of one or more disorders associated with GCN2 activity. Thus, in some embodiments, the present invention provides a method of treating a GCN2-mediated disorder, comprising the step of administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[00182] As used herein, the terms “GCN2-mediated” disorders, diseases and/or pathological conditions as used herein means any disease or other disease-causing pathological condition for which GCN2 or a mutant thereof is known to play a role. Accordingly, another embodiment of the present invention relates to the treatment or amelioration of one or more diseases for which GCN2 or a mutant thereof is known to play a role.

[00183] In some embodiments, the present invention relates to a method of treating one or more disorders, diseases and/or pathological conditions, where the disorder, disease or pathological condition is selected from the group consisting of inflammatory pathological conditions, immunological pathological conditions, autoimmune pathological conditions, allergic disease conditions, rheumatic disease conditions, thrombotic disease conditions, cancer, infections, neurodegenerative diseases, degenerative diseases, neuroinflammatory diseases, cardiovascular diseases and metabolic disease conditions.

[00184] In some embodiments, the cancer being treated is a solid tumor or a tumor of the blood and immune system.

[00185] In some embodiments, the cancer is a solid tumor, wherein the solid tumor is from a group of tumors of the epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid, intestine, liver, brain, prostate , genitourinary tract, lymphatic system, stomach, larynx, bones, including chondrosarcoma and Ewing's sarcoma, germ cells, including embryonal tissue tumors, and/or lungs selected from the group consisting of monocytic leukemia, lung adenocarcinoma, small cell lung carcinomas, pancreatic cancer , glioblastoma, neurofibroma, angiosarcoma, breast carcinoma and/or malignant melanoma.

[00186] In some embodiments, the autoimmune condition is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjögren's syndrome, or organ transplant rejection.

[00187] In some embodiments, the metabolic disease state is diabetes.

[00188] In some embodiments, the degenerative disease is osteoarthritis.

[00189] In some embodiments, the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arteritis.

[00190] In some embodiments, the cardiovascular disease is ischemic injury.

[00191] In some embodiments, the neurodegenerative disease is Alzheimer's disease, Down syndrome, hereditary cerebral hemorrhage with Dutch type amyloidosis, amyloid cerebral angiopathy, Creutzfeldt-Jakob disease, frontotemporal dementias, Huntington's disease, or Parkinson's disease.

[00192] In some embodiments, the infection is caused by Leishmania, mycobacteria, including M. leprae, M. tuberculosis and/or M. avium, Plasmodium, human immunodeficiency virus, Epstein-Barr virus, herpes simplex virus, or hepatitis C virus.

[00193] In addition, the present invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt or hydrate or solvate thereof, for the preparation of a medicament for the treatment of inflammatory pathological conditions, immunological pathological conditions, autoimmune pathological conditions, allergic pathological conditions, rheumatic pathological conditions, thrombotic pathological conditions, cancer, infections, neurodegenerative diseases, degenerative diseases, neuroinflammatory diseases, cardiovascular diseases or metabolic pathological conditions.

c. Combination Therapeutics

[00194] Depending on the particular pathological condition or disease being treated, additional therapeutic agents that are typically administered to treat such pathological condition can be administered in combination with the compounds and compositions of the present invention. When used in the present invention, additional therapeutic agents that are typically administered to treat a particular disease or condition are known as "suitable for the disease or condition being treated."

[00195] In some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and co-administering, simultaneously or sequentially, an effective amount of one or more additional therapeutic agents such as those described in the present invention. In some embodiments, the method includes coadministration of one additional therapeutic agent. In some embodiments, the method includes coadministration of two additional therapeutic agents. In some embodiments, the combination of a disclosed compound and an additional therapeutic agent or agents acts synergistically.

[00196] The compound of the present invention can also be used in combination with known therapeutic procedures, such as hormonal administration or radiation. In some embodiments, the present compound is used as a radiosensitizer, particularly for the treatment of tumors that have low sensitivity to radiotherapy.

[00197] A compound of the present invention may be administered alone or in combination with one or more other therapeutic compounds, possible combination therapeutics being in the form of fixed combinations or administration of a compound of the present invention and one or more other therapeutic compounds. compounds sequentially or independently of one another, or combined administration of fixed combinations and one or more other therapeutic compounds. The compound of the present invention may also or additionally be administered specifically for antitumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgery, or a combination thereof. Long-term therapy is also possible as adjuvant therapy in the context of other treatment strategies as described above. Other possible treatment options include maintenance therapy after tumor regression or even chemopreventive therapy, for example in at-risk patients.

[00198] In some embodiments, the proposed combination or a composition containing it is administered in combination with another therapeutic agent.

[00199] Examples of combination agents provided by the present invention that may also be combined include, without limitation: Alzheimer's disease treatments such as ^Aricept® and ^Exelon® ; HIV treatments such as ritonavir; Parkinson's disease treatments such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexefendyl and amantadine; multiple sclerosis (MS) treatments such as interferon beta (eg, Avonex ^® and Rebif ^® ), Copaxone ^® and mitoxantrone; asthma treatments such as albuterol and Singulair ^® ; schizophrenia treatments such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory drugs such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and antiparkinsonian drugs; cardiovascular medications such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; liver disease treatments such as corticosteroids, cholestyramine, interferons and antivirals; blood disorder treatments such as corticosteroids, anti-leukemia agents and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., metabolic breakdown inhibitors) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) and drugs for treating immunodeficiency disorders, such as gamma globulin.

[00200] In some embodiments, a combination of therapeutic agents provided by the present invention, or a pharmaceutically acceptable composition comprising them, is administered in combination with a monoclonal antibody or therapeutic siRNA.

[00201] These additional agents can be administered separately from the proposed combination therapeutic agent, as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form mixed with a compound of the present invention in a single composition. If administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially, or with an interval of usually no more than 5 hours between them.

[00202] As used herein, the term “combined,” “combined,” and related terms mean simultaneous or sequential administration of the therapeutic agents of the present invention. For example, the combination of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.

[00203] The amount of one or more additional therapeutic agents contained in the compositions of the present invention may be no more than the amount that is typically administered in a composition containing that therapeutic agent as the sole active agent. The preferred amount of one or more additional therapeutic agents in the compositions disclosed herein ranges from about 50% to 100% of the amount typically contained in a composition containing that agent as the sole therapeutically active agent. In some embodiments, one or more additional therapeutic agents are administered at a dose equal to about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90 % or approximately 95% of the normally administered amount of this agent. As used herein, the expression "usually administered" means the FDA-approved amount of therapeutic agent for administration as specified in the package insert.

[00204] In one embodiment, the present invention provides a composition comprising a compound of Formula I and one or more additional therapeutic agents. The therapeutic agent may be administered concomitantly with a compound of Formula I, or may be administered before or after administration of a compound of Formula I. Suitable therapeutic agents are described in detail below. In some embodiments, a compound of formula I can be administered over 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours before the therapeutic agent. In other embodiments, a compound of Formula I may be administered at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours or 18 hours after the therapeutic agent.

[00205] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder or condition by administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodin®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostat (Yuloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucoside (Solganal®), gold thiomalate (Myochrysin®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide ( Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arkalist®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T-cell" agents such as abatacept (Orenzia®), "anti-IL-6" agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparin® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®) , bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as magnesium suspension, polyethylene glycol (Miralax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as such as dicyclomine (Bentyl®), Singular®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate ( Bretair®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Quar® and Vanceril ®), triamcinolone acetonide (Azmacort®), mometasone (Astmanex®), budesonide (Pulmicort®) and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (theo-dur®, theolair®, slow-bid®, unifil®, theo-24®) and aminophylline, anti-IgE antibodies such as omalizumab (xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®) and zalcitabine (Khivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®) and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selsentri®), integrase inhibitors such as raltegravir ( isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®) and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®) or any combination(s) thereof.

[00206] In another embodiment, the present invention relates to a method of treating gout, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodin®) and celecoxib, colchicine (Colcris®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol and febuxostat (Yuloric®).

[00207] In another embodiment, the present invention relates to a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin , ibuprofen, naproxen, etodolac (Lodin®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen ®), methotrexate (Rheumatrex®), gold salts such as gold thioglucoside (Solganal®), gold thiomalate (Myochrysin®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®) , cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” drugs such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi® ), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalist®), antibodies such as rituximab (Rituxan®), “anti "T-cell" agents such as abatacept (Orenzia®) and "anti-IL-6" agents such as tocilizumab (Actemra®).

[00208] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodin®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®) and monoclonal antibodies such as tanezumab.

[00209] In some embodiments, the present invention relates to the treatment of lupus, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin , ibuprofen, naproxen, etodolac (Lodin®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan ®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparin® or Liquaemin®) and warfarin (Coumadin®).

[00210] In some embodiments, the present invention provides a method of treating inflammatory bowel disease, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of mesalamine (azakol®) sulfasalazine (azulfidine®) , antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiz®), laxatives such as magnesium suspension, polyethylene glycol (Miralax® ), Dulcolax®, Correctol® and Senokot® and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapeutics, steroids and antibiotics such as Flagyl or ciprofloxacin.

[00211] In some embodiments, the present invention provides a method of treating asthma, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of Singular®, beta-2 agonists, such as albuterol ( ventolin® HFA, proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Bretair®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics , such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Quar® and Vanceryl®), triamcinolone acetonide (Azmacort®), mometasone (Astmanex®) , budesonide (Pulmicort®), flunisolide (Aerobid®), Afviar®, Symbicort® and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Teolair®, Slow-Bid®, Unifil ®, theo-24®) and aminophylline and anti-IgE antibodies such as omalizumab (Xolair®).

[00212] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of beta-2 agonists, such as albuterol (Ventolin® HFA , proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Bretair®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slow-Bid®, Unifil®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Quar® and Vanzeril®), triamcinolone acetonide (Azmacort®), mometasone (Astmanex®), budesonide (Pulmicort®), flunisolide (Aerobid®), Afviar®, Symbicort® and Dulera®.

[00213] In some embodiments, the present invention provides a method of treating HIV, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of nucleoside reverse transcriptase inhibitors, such as zidovudine (Retrovir®) , abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®) , stavudine (Zerit®) and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®) and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selsentri®), integrase inhibitors such as raltegravir (isentress®) and their combinations.

[00214] In another embodiment, the present invention relates to a method of treating hematologic malignancies, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitor, BTK inhibitor, JAK/pan-JAK inhibitor, TYK2 inhibitor, PI3K inhibitor, SYK inhibitor and combinations thereof.

[00215] In another embodiment, the present invention relates to a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of rituximab (Rituxan®), cyclophosphamide (Cytoxan®) , doxorubicin (hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitor, BTK inhibitor, JAK/pan-JAK inhibitor, TYK2 inhibitor, PI3K inhibitor, SYK inhibitor and combinations thereof.

[00216] In another embodiment, the present invention provides a method of treating hematologic malignancies comprising administering to a patient in need thereof a compound of Formula I and an inhibitor of the Hedgehog (Hh) signaling pathway. In some embodiments, the hematologic malignancy is DLBCL (Ramirez et al "Defining causative factors contributing to the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012), published online July 17, and which in its entirety incorporated herein by reference).

[00217] In another embodiment, the present invention relates to a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of rituximab (Rituxan ®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, hedgehog signaling inhibitor, and combinations thereof.

[00218] In another embodiment, the present invention relates to a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of bortezomib (Velcade®) and dexamethasone (Decadron®) , hedgehog signaling inhibitor, BTK inhibitor, JAK/pan-JAK inhibitor, TYK2 inhibitor, PI3K inhibitor, SYK inhibitor in combination with lenalidomide (Revlimid®).

[00219] In another embodiment, the present invention relates to a method of treating Waldenström's macroglobulinemia, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, neosar®), fludarabine (Fludara®), cladribine (Leistatin®), rituximab (Rituxan®), hedgehog signaling inhibitor, BTK inhibitor, JAK/pan-JAK inhibitor, TYK2 inhibitor, PI3K inhibitor and SYK inhibitor.

[00220] In some embodiments, the present invention provides a method of treating Alzheimer's disease, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of donepezil ( ^Aricept® ), rivastigmine ( ^Exelon® ) , galantamine (Razadine ^® ), tacrine (Cognex ^® ) and memantine (Namenda ^® ).

[00221] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of a steroid, cyclosporine , FK506, rapamycin, hedgehog signaling inhibitor, BTK inhibitor, JAK/pan-JAK inhibitor, TYK2 inhibitor, PI3K inhibitor and SYK inhibitor.

[00222] In another embodiment, the present invention provides a method of treating or alleviating a disease, comprising administering to a patient in need thereof a compound of formula I and a BTK inhibitor, wherein the disease is selected from the following: inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE) , vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis nerve, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's syndrome, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized alopecia, Behçet's disease, chronic fatigue, autonomic dystonia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, both knovenous pemphigus, bullous pemphigoid, neuromyotomy, scleroderma, vulvodynia, hyperproliferative disease, organ or tissue transplant rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, transfusion, anaphylaxis, allergies (eg , allergies to pollen, milky sap, drugs, food, insect poisons, animal dander, fear of animals, house dust mites or cup-shaped parts of cockroaches), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin-A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis , otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-proliferative cell disorder, eg, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, prolymphocytic B-cell leukemia, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, splenic marginal zone cell lymphoma , multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer, or mast cell cancer (eg, mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis) , bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases including, but not limited to, rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, cancer bone, bone metastasis, thromboembolic disorder (eg, myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis ), pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, disease Crohn's, irritable bowel syndrome, ulcerative colitis, Sjögren's disease, tissue transplant rejection, hyperacute organ transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune pluriglandular disease (also known as autoimmune pluriglandular syndrome), autoimmune alopecia , pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic conditions, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, my fungoides goats, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia/reperfusion injury) and Graves' disease.

[00223] In another embodiment, the present invention provides a method of treating or alleviating a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from the following: cancer, neurodegenerative disorder, angiogenic disorder, viral disease, autoimmune disease, inflammatory disorder, hormone-related disease, organ transplant-related conditions, immunodeficiency conditions, destructive bone disorder, proliferative disorder, infectious disease, cell death condition, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune conditions including T-cell activation, cardiovascular disorder and CNS disorder.

[00224] In another embodiment, the present invention provides a method of treating or alleviating a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumor, carcinoma or solid brain tumor, kidney (eg, renal cell carcinoma (RCC)), liver, adrenal, bladder, breast, stomach, intestinal tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testicle , genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastomas, multiple myeloma or gastrointestinal cancer, especially colon carcinoma or colorectal adenoma or tumor of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia glands, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin's disease)), breast carcinoma , follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia, diseases include Cowden syndrome, Lhermitte-Dodos disease and Banayan-Zonan syndrome or diseases in which the PI3K/PKB pathway is aberrantly activated, asthma of any type or origin including hereditary ( non-allergic) asthma and acquired (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, stress asthma, occupational asthma and asthma caused by bacterial infection, acute lung injury (ALI), acute respiratory distress syndrome in adults ( ARDS), chronic obstructive pulmonary disease, airway or lung disease (COPD, COAD or COLD), including associated chronic bronchitis or shortness of breath, emphysema, and exacerbation of airway hyperresponsiveness after another drug, particularly another inhaled drug , bronchitis of any type or origin, including, but not limited to, acute, arachnoid, catarrhal, croupous, chronic or purulent tuberculous bronchitis, pneumoconiosis (an inflammatory, usually occupational, lung disease, often accompanied by airway obstruction, chronic or acute and emerging due to repeated inhalation of dust) of any type or origin, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis, Loeffler's syndrome, eosinophilic pneumonia, parasite infestation (in particular metazoans) (including tropical eosinophilia ), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related airway disorders caused by drug allergies, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma , vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis and inflammatory disease involving autoimmune reactions or having an autoimmune component or etiology, including autoimmune hematologic disorders (eg, hemolytic anemia, aplastic anemia, true erythrocyte anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondria, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens syndrome - Johnson, idiopathic sprue, autoimmune inflammatory bowel disease (eg, ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, for example, including idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and cerebral ischemia and neurodegenerative disease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

[00225] Compounds and compositions according to the method of the present invention can be administered in any amount and by any route of administration effective for treating or reducing the severity of cancer, autoimmune disorder, proliferative disorder, inflammatory disorder, neurodegenerative or neurological disorder, schizophrenia, related with bone disorders, liver disease or heart disorders. The exact amount required varies from subject to subject depending on the species, age and general health of the subject, the severity of the infection, the specific agent, its mode of administration, etc. The compounds of the present invention are preferably formulated in unit dosage form for ensuring ease of administration and uniformity of dosage. The expression "unit dosage form" as used in the present invention means a single portion of the drug suitable for the patient being treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician based on the results of a thorough medical clinical evaluation. The specific effective dose for any particular patient or organism depends on various factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the specific composition used; the age, body weight, general health, gender and diet of the patient; time of administration, route of administration, and rate of elimination of the particular compound used; duration of treatment; drugs used in combination or together with the particular compound used, and similar factors well known in medicine. The term "patient" as used herein means an animal, preferably a mammal and most preferably a human.

[00226] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccally, as an oral or nasal spray and etc. depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention can be administered orally or parenterally in doses of from about 0.01 mg/kg to about 50 mg/kg, and preferably from about 1 mg/kg to about 25 mg/kg body weight subject per day, one or more times per day, and provide the desired therapeutic effect.

[00227] Oral liquid dosage forms include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, 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, dimethylformamide, oils (especially cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include excipients such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents and fragrances.

[00228] Injectable preparations, such as sterile aqueous or oleaginous injectable suspensions, can be prepared by techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable diluents and solvents that may be used include water, Ringer's solution U.S.P. and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are usually used as a solvent or suspending medium. Any soft, fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are useful for preparing injection forms.

[00229] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[00230] To prolong the effect of a compound of the present invention, it is often desirable to slow down the absorption of the compound by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous substance having poor solubility in water. The rate of absorption of the compound then depends on the rate of its dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered form of the compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming microencapsulated matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of the amount of compound to the amount of polymer and the nature of the particular polymer used, the rate of release of the compound can be adjusted. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot preparations are also prepared by incorporating the compound into liposomes or microemulsions that are compatible with body tissues.

[00231] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or suppository wax, which are solid at ambient temperature. environment, but liquid at body temperature, and therefore melt in the rectum or vaginal cavity and release the active compound.

[00232] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or bulking agents such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) humectants such as glycerin, d) leavening agents such as agar-agar, calcium carbonate, potato or cassava starch, alginic acid, some silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h ) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

[00233] Solid compositions of a similar type can also be used to fill soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols, etc. Solid dosage forms of tablets, dragees, pills, pills and granules can be formulated with coatings or shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also be of a composition from which the active ingredient(s) are released only or preferably in some part of the intestine, optionally with a delay. Examples of comprising compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used to fill soft and hard gelatin capsules using excipients such as lactose or milk sugar, high molecular weight polyethylene glycols, etc.

[00234] The active compounds may also be in microencapsulated form with one or more of the excipients listed above. Solid dosage forms of tablets, dragees, pills, pellets and granules can be formulated with coatings or coatings, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also contain, as is common practice, additional substances other than inert diluents, such as tabletting lubricants and other tabletting agents such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents and may also be of a composition from which the active ingredient(s) are released only or preferably in some part of the intestine, optionally with a delay. Examples of comprising compositions that can be used include polymeric substances and waxes.

[00235] Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic preparation, ear drops and eye drops are also considered to be within the scope of the present invention. In addition, the present invention includes the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Suction enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by using a rate control membrane or by dispersing the compound in a polymer matrix or gel.

[00236] In one embodiment, the present invention provides a method of inhibiting protein kinase activity in a biological sample, comprising the step of reacting said biological sample with a compound of the present invention or a composition containing said compound.

[00237] In another embodiment, the present invention provides a method of inhibiting the activity of GCN2 or a mutant thereof in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention or a composition containing said compound.

[0100] The term "biological sample" as used in the present invention includes, without limitation, cell cultures or extracts thereof; bioptic material obtained from a mammal or its extracts; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[00238] Inhibiting the activity of protein kinase or GCN2 protein kinase, or a mutant thereof, in a biological sample is useful for a variety of purposes that are known to one skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological research.

[00239] Another embodiment of the present invention relates to a method of inhibiting protein kinase activity in a patient, comprising the step of administering to the patient a compound of the present invention or a composition containing the compound.

[00240] In another embodiment, the present invention provides a method of inhibiting the activity of GCN2 or a mutant thereof in a patient, comprising the step of administering to the patient a compound of the present invention or a composition containing the compound. In other embodiments, the present invention provides a method of treating a disorder mediated by GCN2, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound of the present invention, or a pharmaceutically acceptable composition thereof. Such disorders are described in detail in the present invention.

[00241] Depending on the particular pathological condition or disease being treated, additional therapeutic agents that are typically administered to treat such pathological condition may also be contained in the compositions of the present invention. When used in the present invention, additional therapeutic agents that are typically administered to treat a particular disease or condition are known as "suitable for the disease or condition being treated."

[00242] The compound of the present invention may also be used to provide benefit in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; compounds active towards microtubules; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antitumor antimetabolites; platinum compounds; compounds that target/reduce protein or lipid kinase activity and additional antiangiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of oncogenic Ras isoforms; telomerase inhibitors; proteasome inhibitors; compounds used for the treatment of malignant blood diseases; compounds that target, reduce or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal ^® ); kinesin spindle protein inhibitors such as SB715992 or SB743921 from GlaxoSmithKline or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as Array BioPharma's ARRY142886, AstraZeneca's AZD6244, Pfizer's PD181461, and leucovorin. The term "aromatase inhibitor" as used herein refers to a compound that inhibits the production of estrogen, eg, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, preferably atamestane, exemestane and formestane, and in particular non-steroids, preferably aminoglutethimide, rogletimide, pyroglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is sold under the trade name Aromasin™. Formestane is sold under the trade name Lentaron™. Fadrozole is sold under the trade name Afema™. Anastrozole is sold under the trade name Arimidex™. Letrozole is sold under the trade names Femara™ or Femar™. Aminoglutethimide is sold under the trade name orimethene™. The combination of the present invention containing a chemotherapeutic agent that is an aromatase inhibitor is particularly suitable for the treatment of hormone receptor-positive tumors, such as breast tumors.

[00243] The term "anti-estrogen" as used herein refers to a compound that antagonizes the effects of estrogens at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex™. Raloxifene hydrochloride is sold under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention containing a chemotherapeutic agent that is an antiestrogen is particularly suitable for the treatment of estrogen receptor-positive tumors, such as breast tumors.

[00244] The term "antiandrogen" as used herein refers to any substance that is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[00245] In some embodiments, the one or more other therapeutic agents is an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (xtandi®, Astellas/Medivation); approved androgen synthesis inhibitors include abiraterone (Zitiga®, Centocor/Ortho); an approved gonadotropin-releasing hormone (GnRH) receptor antagonist (Degaralix, Firmagon®, Ferring Pharmaceuticals).

[00246] In some embodiments, the one or more other therapeutic agents are a selective estrogen receptor modulator (SERM) that interferes with the synthesis or activity of estrogens. Validated SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[00247] The term “topoisomerase I inhibitor” as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and analogs thereof, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form in which it is sold, for example, under the trade name Camptosar™. Topotecan is sold under the trade name Hycamptin™.

[00248] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including a liposomal formulation such as Kaelix™), daunorubicin, epirubicin, idarubicin and nerubicin, the anthraquinones mitoxantrone and loxantrone, and podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name etopophos™. Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade names acriblastin™ or adriamycin™. Epirubicin is sold under the trade name Pharmarubicin™. Idarubicin is sold under the trade name Zavedos™. Mitoxantrone is sold under the trade name Novantrone.

[00249] The term “microtubule active agent” refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubulin polymerization inhibitors, including, but not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate and vinorelbine; discodermolides; colchicine and epothilones and their derivatives. Paclitaxel is sold under the trade name Taxol™. Docetaxel is sold under the trade name Taxotere™. Vinblastine sulfate is sold under the trade name Vinblastine R.P™. Vincristine sulfate is sold under the trade name Farmistin™.

[00250] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostine™. Ifosfamide is sold under the trade name Holoxan™.

[00251] The term “histone deacetylase inhibitors” or “HDAC inhibitors” refers to compounds that inhibit histone deacetylase and that have antiproliferative activity. These include, but are not limited to, hydroxamic acid suberoylanilide (SAHA).

[00252] The term "antitumor antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is sold under the trade name Xeloda™. Gemcitabine is sold under the trade name Gemzar™.

[00253] The term "platinum compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, for example, in the form in which it is sold, for example, under the trade name carboplat™. Oxaliplatin can be administered, for example, in the form in which it is sold, for example, under the trade name Eloxanthin™.

[00254] The term "compounds that target/reduce protein or lipid kinase activity; or protein or lipid phosphatase activity; or other antiangiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase inhibitors and/or serine and /or threonine kinases or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFR), such as compounds that target, reduce or inhibit the activity of PDGFR, preferably compounds that inhibit the PDGF receptor, such as N-phenyl-2-pyrimidinamine derivative such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFR); c) compounds that target, reduce or inhibit the activity of the insulin-like growth factor I receptor (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, preferably compounds that inhibit the kinase activity of the IGF-I receptor or antibodies that target the extracellular domain of the IGF-I receptor or its growth factors; d) compounds that target, reduce or inhibit the activity of the Trk receptor family of tyrosine kinases or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor family of tyrosine kinases; f) compounds targeted to reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinases that are part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the c-Kit receptor family of tyrosine kinases, preferably compounds that inhibit the c-Kit receptor family Kit such as imatinib; i) compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds that target, reduce or inhibit the activity of c-Abl family members and gene fusion products thereof, such as N-phenyl-2-pyrimidinamine derivative such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from Parke Davis; or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of members of the protein kinase C (PKC) family and Raf serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K family, SYK, TYK2, BTK and TEC, and/or members of the cyclin-dependent kinase (CDK) family, including staurosporine derivatives such as midostaurin; examples of additional compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531/LY379196; isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, including imatinib mesylate (Gleevec™) or tyrphostin, such as tyrphostin A23/RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor tyrosine kinase family (EGFR ₁ ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds that target, reduce or inhibit the activity of the receptor family epidermal growth factor are preferably compounds, proteins or antibodies that inhibit members of the EGF family of tyrosine kinases such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbutux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6, 4, E2,11, E6,3 or E7,6,3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, reduce or inhibit the activity of the c-Met receptor, such as compounds that target, reduce or inhibit the activity of c-Met, preferably compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target extracellular domain of the c-Met receptor or bind to HGF, n) compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) compounds targeted to reduce or inhibit the kinase activity of PI3 kinase (PI3K) including, but not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib , pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; And; and q) compounds that target, reduce or inhibit the signaling effects of hedgehog protein (Hh) or smoothed receptor pathway (SMO), including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridgegib).

[00255] The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against one or more enzymes of the phosphatidylinositol 3-kinase family, including but not limited to PI3Kα, PI3Kγ , PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101 and p87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL -719, dactolisib, XL-147, XL-765 and idelalisib.

[00256] The term "BTK inhibitor" as used herein includes, but is not limited to, compounds having Bruton's tyrosine kinase (BTK) inhibitory activity, including, but not limited to, AVL-292 and ibrutinib.

[00257] The term "SYK inhibitor" as used herein includes, but is not limited to, compounds having spleen tyrosine kinase (SYK) inhibitory activity, including, but not limited to, PRT-062070, R-343, R-333, excellar, PRT-062607 and fostamatinib.

[00258] Additional examples of BTK inhibitory compounds and pathological conditions that can be treated with such compounds in combination with the compounds of the present invention are provided in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entirety.

[00259] Additional examples of SYK inhibitory compounds and pathological conditions that can be treated with such compounds in combination with the compounds of the present invention are provided in WO2003063794, WO2005007623 and WO2006078846, which are incorporated herein by reference in their entirety.

[00260] Additional examples of PI3Ky inhibitory compounds and pathological conditions that are treated with such compounds in combination with the compounds of the present invention are provided in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO20 07129161, WO2006122806, WO2005113554 and WO2007044729, which are incorporated herein by reference in their entirety.

[00261] Additional examples of JAK inhibitory compounds and pathological conditions that are treated with such compounds in combination with the compounds of the present invention are provided in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, which are incorporated herein by reference in their entirety. .

[00262] Other anti-angiogenic compounds include compounds that have a different mechanism of activity, such as those not associated with protein or lipid kinase inhibition, such as thalidomide (Thalomide™) and TNP-470.

[00263] Examples of proteasome inhibitors useful in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinsporamide A, carfilzomib, ONX-0912, CEP-18770 and MLN9708.

[00264] Compounds that target, reduce or inhibit protein or lipid phosphatase activity are, for example, phosphatase 1, phosphatase 2A or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[00265] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ-, or δ-tocopherol, or α-, γ-, or δ-tocotrienol.

[00266] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-2-arylaminophenylacetic acid and derivatives such as celecoxib (Celebrex™), rofecoxib (Viox™), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[00267] The term “bisphosphonates” as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridronic acid is sold under the trade name Didronel™. Clodronic acid is sold under the trade name Bonefos™. Tiludronic acid is sold under the trade name Skelid™. Pamidronic acid is sold under the trade name Aredia™. Alendronic acid is sold under the trade name Fosamax™. Ibandronic acid is sold under the trade name Bondranate™. Risedronic acid is sold under the trade name Actonel™. Zoledronic acid is sold under the trade name Zometa™. The term “mTOR inhibitors” refers to compounds that inhibit mammalian target of rapamycin (mTOR) and that have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[00268] The term “heparanase inhibitor” as used in the present invention means compounds that target, reduce or inhibit the degradation of heparin sulfate. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used in the present invention means lymphokine or interferons.

[00269] The term "oncogenic Ras isoform inhibitor" such as H-Ras, K-Ras or N-Ras as used herein means compounds that target, reduce or inhibit the oncogenic activity of Ras; for example, a "farnesyltransferase inhibitor" such as L-744832, DK8G557 or R115777 (Zarnestra™). The term "telomerase inhibitor" as used in the present invention means compounds that target, reduce or inhibit the activity of telomerase. Compounds that target, reduce or inhibit telomerase activity are preferably compounds that inhibit the telomerase receptor, such as telomestatin.

[00270] The term “methionine aminopeptidase inhibitor” as used in the present invention means compounds that target, reduce or inhibit the activity of methionine aminopertidase. Compounds that target, reduce or inhibit the activity of methionine aminopertidase include, but are not limited to, benhamide or a derivative thereof.

[00271] The term "proteasome inhibitor" as used in the present invention means compounds that target, reduce or inhibit the activity of the proteasome. Compounds that target, reduce or inhibit proteasome activity include, but are not limited to, bortezomib (Velcade™) and MLN 341.

[00272] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, peptidomimetic and non-peptidomimetic collagen inhibitors, tetracycline derivatives, for example, the peptidomimetic hydroxamate inhibitor batimastat and its orally bioavailable analog marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[00273] The term "compounds useful for the treatment of hematological malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-β-D-arabinofuranzylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, reduce or inhibit anaplastic lymphoma kinase.

[00274] Compounds that target, reduce or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are preferably compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a derivative staurosporine, SU11248 and MLN518.

[00275] The term “HSP90 inhibitors” as used herein includes, but is not limited to, compounds that target to reduce or inhibit the intrinsic ATPase activity of HSP90; degrading, targeting, reducing, or inhibiting HSP90 client proteins along the ubiquitin-proteasome pathway. Compounds targeted to reduce or inhibit the intrinsic ATPase activity of HSP90 are preferably compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino-17-demethoxygeldanamycin (17AAG), a derivative of geldanamycin; other geldanamycin-related compounds; radicicol and HDAC inhibitors.

[00276] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbutux, bevacizumab (Avastin™), rituximab ( ^Rituxan® ), PRO64553 (anti-CD40 ) and 2C4 antibodies. By antibodies are meant, for example, intact monoclonal antibodies, polyclonal antibodies, multivalent antibodies formed from at least two intact antibodies, and antibody fragments, if they have the necessary biological activity.

[00276] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard anti-leukemia therapeutic agents, preferably in combination with therapeutic agents used for the treatment of AML. In particular, the compounds of the present invention may be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs used to treat AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone , idarubicin, carboplatin and PKC412.

[00278] Other antileukemic compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2' ^- alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included is a purine analogue of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A and the compounds disclosed in US 6552065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl -1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-( 1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, preferably lactate. Somatostatin receptor antagonists, as used in the present invention, mean compounds that target, process or inhibit the somatostatin receptor, such as octreotide and SOM230. Techniques for damaging tumor cells include techniques such as those using ionizing radiation. The term “ionizing radiation” as defined above and below in the present invention means ionizing radiation that appears in the form of electromagnetic radiation (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is used, but not limited to, in radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., ^4th Edition, Vol. 1, pp. 248-275 (1993).

[00279] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recycling, such as FTY720. The term "ribonucleotide reductase inhibitors" means pyrimidine or purine nucleoside analogues, including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (preferably in combination with ara-C relative to ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are preferably hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[00280] Also included in particular are compounds, proteins or monoclonal antibodies to VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4 -(4-pyridylmethyl)phthalazine succinate; angiostatin™; endostatin™; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies such as rhuMAb and RHUFab, a VEGF aptamer such as Macugone; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin™).

[00281] Photodynamic therapy as used in the present invention means a therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as visudin™ and sodium porfimer.

[00282] Angiostatic steroids as used herein means compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone and dexamethasone.

[00283] Implants containing corticosteroids are compounds such as fluocinolone and dexamethasone.

[00283] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or different compounds or compounds with a different or unknown mechanism of action.

[00285] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drugs, such as anti-inflammatory, bronchodilator or antihistamine drugs, especially for the treatment of obstructive or inflammatory airway diseases such as mentioned above in the present invention, for example, as enhancers of the therapeutic activity of such drugs or as a means of reducing the required doses or reducing possible side effects of such drugs. The compound of the present invention can be mixed with another drug in a fixed pharmaceutical composition or it can be administered separately, before, simultaneously or after another drug. Accordingly, the present invention includes a combination of a compound of the present invention described above in the present invention with an anti-inflammatory, bronchodilator, antihistamine or antitussive drug, said compound of the present invention and said drugs are in the same or different pharmaceutical compositions.

[00286] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; nonsteroidal glucocorticoid receptor antagonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), arophylline (Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12- 281 (Asta Medica), CDC-801 (Celgene), SeICID(TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW- 4490 (Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenergic agonists such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol fenoterol, procaterol and preferably formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or athymuscarinic compounds, in particular ipratropium bromide, oxytropium bromide, tiotropium salts and CHF 4226 (Chiesi) and glycopyrrolate.

[00287] Suitable antihistamine drugs include cetirizine hydrochloride, acetaminophen, clemastin fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[00288] Other useful combinations of compounds of the present invention with anti-inflammatory drugs are combinations with chemokine receptor antagonists, for example, CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D and Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzocyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N, N-dimethyl-2H-pyran-4-amine chloride (TAK-770).

[00289] In some embodiments, the one or more other therapeutic agents is a poly(ADP-ribose) polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is selected from the group consisting of olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zedjula®, Tesaro); talazoparib (MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[00290] The term "Bcl-2 inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma protein 2 (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogosypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and its analogs), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genesense (G3139) , HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan) and venetoclax. In some embodiments, the Bcl-2 inhibitor is a therapeutic small molecule. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[00291] In some embodiments, the one or more other therapeutic agents is an inhibitor of anti-apoptotic proteins, such as BCL-2. Approved antiapoptotic agents that can be used in the present invention include venetoclax (Venclexta®, AbbVie/Genentech); and blinatumomab (blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins that have undergone clinical trials and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[00292] The structure of active agents that have code numbers, generic or trade names is given in the latest edition of the standard reference book "The Merck Index" and in databases, for example, Patents International, (for example, IMS World Publications).

[00293] The compound of the present invention can also be used in combination with known therapeutic procedures, such as hormonal administration or radiation. In some embodiments, the present compound is used as a radiosensitizer, particularly for the treatment of tumors that have low sensitivity to radiotherapy.

[00294] A compound of the present invention may be administered alone or in combination with one or more other therapeutic compounds, possible combination therapeutics being in the form of fixed combinations or administration of a compound of the present invention and one or more other therapeutic compounds. compounds sequentially or independently of one another, or combined administration of fixed combinations and one or more other therapeutic compounds. The compound of the present invention may also or additionally be administered specifically for antitumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgery, or a combination thereof. Long-term therapy is also possible as adjuvant therapy in the context of other treatment strategies as described above. Other possible treatment options include maintenance therapy after tumor regression or even chemopreventive therapy, for example in at-risk patients.

[00295] These additional agents can be administered separately from a composition containing a compound of the present invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form mixed with a compound of the present invention in a single composition. When administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially, or with an interval of usually no more than 5 hours between them.

[00296] As used herein, the term “combined,” “combined,” and related terms mean simultaneous or sequential administration of the therapeutic agents of the present invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate dosage units or together in a single dosage unit. Accordingly, the present invention provides a single unit dosage form containing a compound of the present invention, an additional therapeutic agent and a pharmaceutically acceptable carrier, excipient or diluent.

[00297] The amount of the compound of the present invention and the additional therapeutic agent (in those compositions that contain the additional therapeutic agent described above) that can be combined with the carrier materials to form a single dosage form varies depending on the recipient being treated , and the specific mode of administration. The compositions of the present invention should preferably be formulated to allow administration of a compound of the present invention at a dose of 0.01-100 mg/kg body weight/day.

[00298] In such compositions that contain an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required for monotherapy using only that therapeutic agent. In such compositions, a dose of additional therapeutic agent of 0.01-1,000 μg/kg body weight/day can be administered.

[00299] The amount of additional therapeutic agent contained in the compositions of the present invention should be no more than the amount that would normally be administered in a composition containing that therapeutic agent as the sole active agent. The preferred amount of additional therapeutic agent in the compositions disclosed herein ranges from about 50% to 100% of the amount typically contained in a composition containing that agent as the sole therapeutically active agent.

[00300] The compounds of the present invention, or pharmaceutical compositions containing them, can also be formulated for application to an implantable medical device such as a prosthesis, prosthetic valve, vascular grafts, stents and catheters. For example, vascular stents have been used to overcome restenosis (re-narrowing of the vessel wall after a lesion). However, patients using stents or other implantable devices are at risk of developing a blood clot or activating platelets. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. Implantable devices coated with the compound of the present invention are another embodiment of the present invention.

Typical immuno-oncology agents

[00301] In some embodiments, the one or more other therapeutic agents are an immuno-oncology agent. As used herein, the term “immuno-oncology agent” means an agent that is effective for enhancing, stimulating and/or up-regulating immune responses in a subject. In some embodiments, administration of an immuno-oncology agent with a compound of the present invention has a synergistic effect in the treatment of cancer.

[00302] The immuno-oncology agent may be, for example, a small molecule drug, antibody, or biological agent or small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibodies are monoclonal antibodies. In some embodiments, the monoclonal antibodies are humanized or human.

[00303] In some embodiments, the immuno-oncology agent is (i) a stimulatory (including co-stimulatory) receptor agonist or (ii) an inhibitory (including co-inhibitory) T cell signal antagonist, both leading to amplification of antigen-specific T cell responses.

[00304] Some of the stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7- H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules, which bind to members of the related TNF receptor family, which include CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR/Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL , BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6 ,TROY,NGFR.

[00305] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate the immune response.

[00306] In some embodiments, the combination of a compound of the present invention and an immuno-oncology agent can stimulate T cell responses. In some embodiments, the immuno-oncology agent is: (i) a protein antagonist that inhibits T cell activation (eg, immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG- 3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1 and TIM-4; or (ii) a protein agonist that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL , CD70, CD27, CD40, DR3 and CD28H.

[00307] In some embodiments, the immuno-oncology agent is an inhibitory receptor antagonist on NK cells or an activating receptor agonist on NK cells. In some embodiments, the immuno-oncology agent is a KIR antagonist, such as lirilumab.

[00308] In some embodiments, the immuno-oncology agent is an agent that inhibits or reduces the number of macrophages or monocytes, including, but not limited to, CSF-1R antagonists, such as anti-CSF-1R antagonist antibodies, including RG7155 (WO11/70024 , WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

[00309] In some embodiments, the immuno-oncology agent is selected from the group consisting of agonists that bind to positive co-stimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase antitumor T- cells, agents that overcome direct immune suppressive pathways in the tumor microenvironment (eg, block the inhibitory effects of the receptor (eg, PD-L1/PD-1 interactions), eliminate or inhibit Tregs (eg, using anti-CD25 monoclonal antibodies (eg, daclizumab) ) or by ex vivo elimination of anti-CD25 antibodies), inhibit metabolic enzymes such as IDO or reverse/prevent energy or T-cell decline) and agents that trigger innate immune activation and/or inflammation at tumor sites.

[00310] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is a CTLA-4 antagonist antibody. In some embodiments, the CTLA-4 antagonist antibodies are YERVOY (ipilimumab) or tremelimumab.

[00311] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or an antigen-binding portion thereof that specifically binds to programmed cell death receptor-1 (PD-1) and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is a PD-1 antagonist antibody. In some embodiments, the PD-1 antagonist antibodies are OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein consisting of a PD-L2 extracellular domain (B7-DC) fused to the Fc portion of IgG1, called AMP-224.

[00312] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is a PD-L1 antagonist antibody. In some embodiments, the PD-L1 antibodies are MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).

[00313] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is a LAG-3 antagonist antibody. In some embodiments, the LAG3 antibodies are BMS-986016 (WO10/19570, WO14/08218) or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

[00314] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 agonist (4-1BB) is a CD137 agonist antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12/32433).

[00315] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is a GITR agonist antibody. In some embodiments, the GITR antibodies are BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116) or MK-4166 (WO11/028683).

[00316] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from the group consisting of epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

[00317] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an OX40 agonist antibody. In some embodiments, the OX40 antibodies are MEDI-6383 or MEDI-6469.

[00318] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an OX40 antagonist antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06/029879).

[00319] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is a CD40 agonist antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is a CD40 antagonist antibody. In some embodiments, the CD40 antibodies are lucatumumab or dacetuzumab.

[00320] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is a CD27 agonist antibody. In some embodiments, the CD27 antibody is varilumab.

[00321] In some embodiments, the immuno-oncology agent is MGA271 (to B7H3) (WO11/109400).

[00322] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzum ab ozogamicin, intelumumab, ipilimumab, isatuximam, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumabil tremelimumab.

[00323] In some embodiments, the immuno-oncology agent is an immunostimulant agent. For example, antibodies that block the PD-1 and PD-L1 axis of inhibition can release activated tumor-reactive T cells and have been shown in clinical studies to induce durable antitumor responses in an increasing number of histological tumor samples, including some tumor types that were not generally considered sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558) has been shown to prolong overall survival in patients with RCC who have progressed during or after prior antiangiogenic therapy.

[00324] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (picato®, LEO Pharma).

[00325] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from the group consisting of sipuleucel-T (Provenge®, Dendreon/Valeant Pharmaceuticals), which is approved for use in the treatment of asymptomatic or minimally symptomatic metastatic castration-refractory (hormone-resistant) prostate cancer; and talimogene laherparepvec (Imligic®, BioVex/Amgen, formerly known as T-VEC), a genetically engineered oncolytic viral therapy approved for the treatment of unresectable cutaneous, subcutaneous and nodular lesions in melanoma. In some embodiments, the immuno-oncology agent is selected from the group consisting of an oncolytic viral therapeutic agent, such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase-deficient (TK) viral vaccine that has been genetically engineered to conferred the ability to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a respiratory enteric orphan virus (reovirus) variant that does not replicate in cells that are not activated by RAS, in numerous cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); squamous cell carcinoma of the head and neck (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotukirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express full-length CD80 and antibody fragments specific for the T-cell receptor protein CD3 in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676); and peritoneal disease, colorectal or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68/GLV-1h153, Genelux GmbH), viral vaccines that have been genetically engineered to express beta-galactosidase (beta-gal)/beta-glucuronidase or the beta-gal/sodium iodide symporter in humans ( hNIS), respectively, were studied for peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus genetically engineered to express GM-CSF, in bladder cancer (NCT02365818).

[00326] In some embodiments, the immuno-oncology agent is selected from the group consisting of JX-929 (SillaJen/formerly Jennerex Biotherapeutics), viral vaccines for TK- and growth factor-deficient vaccine disease, which are genetically engineered to express a cytosine deaminase that is capable of convert the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos), peptide-based immunotherapies targeting difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), a genetically engineered adenovirus designated: Ad5/3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics) vesicular stomatitis virus (VSV), which can be genetically engineered to express glycoprotein (GP), lymphocytic choriomeningitis virus (LCMV), which can be further genetically engineered to express antigens designed to enhance antigen-specific CD8+ T cell response.

[00327] In some embodiments, the immuno-oncology agent is T cells that have been genetically engineered to express a chimeric antigen receptor or CAR. T cells that are genetically engineered to express such a chimeric receptor antigen are called CAR-T cells.

[00328] CARs are prepared that consist of binding domains that can be derived from natural ligands, single chain variable fragments (scFvs) derived from monoclonal antibodies specific for cell surface antigens fused to endodomains that are the functional end of the T cell receptor (TCR), such as the CD3-zeta signaling domain in TCRs, which is capable of generating an activation signal in T lymphocytes. When bound to antigen, such CARs bind to endogenous signaling pathways in effector cells and generate activating signals similar to those initiated by the TCR complex.

[00329] For example, in some embodiments, the CAR-T cells are those described in the U.S. patent. No. 8,906,682 (June; incorporated herein by reference in its entirety), which discloses CAR-T cells that have been genetically engineered to include an extracellular domain containing an antigen-binding domain (such as a domain that binds CD19 ), fused to the intracellular signaling domain of a T cell receptor antigen complex zeta chain (such as CD3 zeta). When expressed in T cells, CAR is capable of redirecting antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed in malignant B cells. There are currently more than 200 clinical trials in which CAR-T is used in a wide range of indications. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

[00330] In some embodiments, the immunostimulant agent is an activator of retinoic acid receptor-related orphan receptor γ (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17-expressing subsets of innate immune cells such as NK cells. In some embodiments, the RORγt activator is LYC-55716 (Lycera), which is currently being studied in clinical trials for the treatment of solid tumors (NCT02929862).

[00331] In some embodiments, the immunostimulant agent is a toll-like receptor (TLR) agonist or activator. Suitable activators of TLRs include a TLR9 agonist or activator such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG being studied for B-cell, follicular and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[00332] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), monoclonal antibody to OX40; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) monoclonal antibodies to NKG2A; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), monoclonal antibody to GITR.

[00333] In some embodiments, the immunostimulatory agent is selected from the group consisting of elotuzumab, mifamurtide, a toll-like receptor agonist or activator, and a RORγt activator.

[00334] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been investigated in the clinic as a therapeutic agent for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15 immunotherapy is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex consisting of a synthetic form of endogenous IL-15 complexed with the soluble IL-15 binding protein IL-15 alpha chain receptor (IL15:sIL-15RA), which was investigated in phase 1 clinical trials in melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724 or NCT02542124.

[00335] In some embodiments, the immuno-oncology agent is selected from the group including those described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology", Cancer Therapy 2015, Vol. 14, pages 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is selected from the group consisting of the examples described in Table 1 in Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[00336] In some embodiments, the immuno-oncology agent is selected from the group consisting of a small molecule immuno-oncology agent described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents", Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent that targets pathways described in Peter L. Toogood.

[00337] In some embodiments, the immuno-oncology agent is selected from the group including those described in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing,” PLoS ONE 12(8) : e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T-cell activator antibody (BiTE®) construct. In some embodiments, the bispecific T-cell activator antibody (BiTE®) construct is a bispecific CD19/CD3 antibody construct. In some embodiments, the bispecific anti-T cell activator (BiTE®) antibody construct is an anti-EGFR/CD3 bispecific antibody construct. In some embodiments, the bispecific T cell activator antibody (BiTE®) construct activates T cells. In some embodiments, a bispecific T-cell activator antibody construct (BiTE®) activates T cells that release cytokines that induce up-regulation of intercellular adhesion molecule 1 (ICAM-1) and FAS in nearby cells. In some embodiments, the bispecific T cell activator antibody (BiTE®) construct activates T cells, resulting in induced lysis of nearby cells. In some embodiments, the adjacent cells are located in solid tumors. In some embodiments, the adjacent cells being lysed are in proximity to the BiTE® activated T cells. In one embodiment, the adjacent cells include tumor associated antigen (TAA) negative cancer cells. In one embodiment, the adjacent cells include EGFR negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1/PD1 and/or CTLA4 axis. In some embodiments, the immuno-oncology agent is ex-vivo expanded tumor-infiltrating T cells. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or chimeric antigen receptor (CARs) that directly binds T cells to tumor-associated cell surface antigens (TAAs).

Typical immune checkpoint inhibitors

[00338] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor described in the present invention.

[00339] The term "checkpoint inhibitor" as used herein refers to agents useful in preventing cancer cells from entering a patient's immune system. Subversion of one of the main mechanisms of antitumor immunity, known as “T-cell exhaustion,” is caused by prolonged exposure to antigens that lead to up-regulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune reactions.

[00340] PD-1 and co-inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA-4, B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3) , lymphocyte activation gene-3 (Lag-3; CD223), etc., are often called checkpoint regulators.They act as molecular “dispatchers” that allow extracellular information to decide whether cell cycle progression and other intracellular signaling processes will occur.

[00341] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody. PD-1 binds to the programmed cell death receptor 1 (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby modulating the ability of tumors to suppress the host's antitumor immune response.

[00342] In one aspect, the checkpoint inhibitor is a biological therapeutic agent or small molecule. In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a full human antibody, a fusion protein, or a combination thereof. In another aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from the group consisting of CTLA-4, PDLl, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In a further aspect, the checkpoint inhibitor interacts with a checkpoint protein ligand selected from the group consisting of CTLA-4, PDLl, PDL2, PDl, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In one aspect, the checkpoint inhibitor is an immune stimulant, T-cell growth factor, interleukin, antibody, vaccine, or a combination thereof. In another subject, interleukin is a combination of IL-7 or IL-15. In a preferred aspect, the interleukin is glycosylated IL-7. In a further aspect, the vaccine is a dendritic cell (DC) vaccine.

[00343] Checkpoint inhibitors include any agent that statistically significantly blocks or inhibits inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies or antigen binding fragments thereof that bind to and block or inhibit immune checkpoint receptors or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary checkpoint molecules that can be targeted to block or inhibit include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA , KIR, 2B4 (belongs to the CD2 family of molecules and is expressed in all NK, γδ and CD8+ (αβ) memory T cells), CD160 (also called BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7 . Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biological therapeutics, or small molecules that bind to and block or inhibit the activity of one or more CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3 , GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibodies), anti-OX40, PD-Ll monoclonal antibodies (anti-B7-Hl antibodies; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PDl antibodies) , CT-011 (anti-PDL), monoclonal antibodies BY55, AMP224 (anti-PDL), BMS-936559 (anti-PDL), MPLDL3280A (anti-PDL), MSB0010718C (anti-PDL), and ipilimumab (anti-CTLA- 4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-Ll, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[00344] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Ervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (anti-PD-1, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1, Keytruda®, Merck); ipilimumab (anti-CTLA-4, Ervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1, Imfinzi®, AstraZeneca); and atezolizumab (anti-PD-L1, Tecentriq®, Genentech).

[00345] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS- 936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[00346] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody studied in patients who have basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1, studied in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), also known as MSB0010718C), a full human IgG1 anti-PD-L1 antibody, in clinical studies examining non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, kidney cancer , ovarian cancer, bladder cancer, head and neck cancer and stomach cancer; or PDR001 (Novartis), inhibitory antibodies that bind to PD-1, in clinical trials examining non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a complete human monoclonal antibody to CTLA-4 that has been studied in clinical trials for a number of indications, including the following: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer. pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic liver cancer, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer , metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being studied in a phase 1 clinical trial in advanced solid tumors (NCT02694822).

[00347] In some embodiments, the checkpoint inhibitor is a T-cell immunoglobulin mucin containing protein-3 (TIM-3) inhibitor. TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody being studied in advanced cancers (NCT02608268).

[00348] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor for certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and monoclonal antibodies to TIGIT (NCT03119428).

[00349] In some embodiments, the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. LAG-3 inhibitors that can be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), also an anti-LAG-3 antibody, is being studied in cancer (NCT03005782). IMP321 (Immutep S.A.) is a LAG-3-Ig fusion protein and is being studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[00350] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include PF-04518600/PF-8600 (Pfizer), an OX40 agonist antibody in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasia (NCT02554812; NCT05082566); GSK3174998 (Merck), an OX40 agonist antibody, in phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, for advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonistic anti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475).

[00351] Checkpoint inhibitors that can be used in the present invention include CD137 agonists (also called 4-1BB). CD137 agonists being studied in clinical trials include utomilumab (PF-05082566, Pfizer), an anti-CD137 agonist antibody, in diffuse large B-cell lymphoma (NCT02951156) and i in advanced cancers and neoplasia (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[00352] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists being studied in clinical trials include varilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 agonist antibody, in head and neck squamous cell carcinoma, ovarian carcinoma, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).

[00353] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic antibody to GITR, in malignant melanoma and other solid tumor malignancies (NCT01239134 and NCT02628574); GWN323 (Novartis), an anti-GITR agonist antibody for solid tumors and lymphoma (NCT 02740270); INCAGN01876 (Incyte/Agenus), agonistic anti-GITR antibodies, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistic hexameric GITR ligand molecule with a human IgG1 Fc domain, in advanced solid tumors (NCT02583165).

[00354] Checkpoint inhibitors that can be used in the present invention include inducible T cell costimulator (ICOS, also known as CD278 agonists). ICOS agonists being studied in clinical trials include MEDI-570 (Medimmune), an ICOS agonist antibody in lymphoma (NCT02520791); GSK3359609 (Merck), an anti-ICOS agonist antibody in phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an anti-ICOS agonist antibody in phase 1 (NCT02904226).

[00355] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include lirilumab (IPH2102/BMS-986015, Innate Pharma/Bristol-Myers Squibb), anti-KIR antibodies in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263) and lymphoma ( NCT01592370); IPH2101 (1-7F9, Innate Pharma) for myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three long cytoplasmic tail domains (KIR3DL2), in lymphoma (NCT02593045).

[00356] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47/SIRPa inhibitors being studied in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant (SIRPa), which binds to CD47 and prevents CD47/SIRPa-mediated signaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein formed by binding the N-terminal CD47 binding domain of SIRPa to the Fc domain of human IgG1, acts by binding human CD47 and preventing the production of a "do not kill" signal to macrophages, used in phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), anti-CD47, for leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), for colorectal neoplasia and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[00357] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody for solid tumors (NCT02754141).

[00358] Checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes (STING, also known as transmembrane protein 173 or TMEM173). STING agonists being studied in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclic dinucleotide, in phase 1 (NCT02675439 and NCT03172936).

[00359] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a small molecule CSF1R inhibitor in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, gastrointestinal tract - intestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxy]-pyridin-2-carboxylic acid methylamide, Novartis), an orally available CSF1R inhibitor, in advanced solid tumors (NCT02829723).

[00360] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody in head and neck neoplasia (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[00361] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

EXAMPLES

[00362] As shown in the examples below, in some exemplary embodiments, compounds are prepared in accordance with the general procedures below. It should be understood that while general procedures describe the synthesis of some of the compounds of this invention, the following general procedures and other procedures known to one of ordinary skill in the art can be used for all compounds and subclasses and types of each of these compounds. described in the present invention.

Synthesis 1: 3-(4-Methylsulfanylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine

[00363] NBS (165.2 mg, 0.928 mmol) was added to a solution of 2-[( E )-2-ethoxyvinyl]-4-methylsulfanylpyrimidine (181.4 mg, 0.924 mmol) in 1,4-dioxane (5.5 ml) and water (2 ml) and the reaction mixture was stirred at ambient temperature for 15 min. 5-(Trifluoromethyl)pyridin-2-amine (150 mg, 0.925 mmol) was added and the reaction mixture was heated at 65-75°C for 7 hours. The mixture was cooled to ambient temperature and diluted with saturated aqueous NaHCO ₃ and extracted with DCM. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc/petroleum ether, gradient) to give 3-(4-methylsulfanylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine (165 mg , 58%); ESV-MS m/z 311.1 (M+H).

[00364] The following compounds were prepared using a methodology similar to that described in Synthesis 1:

6-Chloro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2- a ]pyridine using 5-chloropyridin-2-amine;

6-Chloro-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2- a ]pyridine using 5-chloro-4-fluoropyridin-2-amine;

6-Bromo-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2- a ]pyridine using 5-bromo-4-fluoropyridin-2-amine;

6-Chloro-7-fluoro-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2- a ]pyridine using 5-chloro-4-fluoropyridin-2-amine.

Synthesis 2: 3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine

[00365] Sulfuryl chloride (174.9 μl, 2.160 mmol) was added to a solution of 3-(4-methylsulfanylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine (165 mg, 0.532 mmol) and concentrated HCl (47.1 µl 37% w/w, 0.860 mmol) in MeCN (13 ml) and the reaction mixture was stirred for 5 min. Cooled saturated aqueous NaHCO ₃ solution was added dropwise and the mixture was stirred for 10 minutes. The resulting precipitate was isolated by filtration, washed with water and dried to give 3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine (125 mg, 79%).

[00366] The following compounds were prepared using a methodology similar to that described in Synthesis 2:

6-Chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine using 6-chloro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2- a ]pyridine ;

6-Chloro-3-(4-chloropyrimidin-2-yl)-7-fluorimidazo[1,2- a ]pyridine using 6-chloro-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[ 1,2- a ]pyridine;

6-Bromo-3-(4-chloropyrimidin-2-yl)-7-fluoromidazo[1,2- a ]pyridine using 6-bromo-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[ 1,2- a ]pyridine;

6-Chloro-3-(4-chloropyrimidin-2-yl)-7-fluorimidazo[1,2- a ]pyridine using 6-chloro-7-fluoro-3-(4-(methylthio)pyrimidin-2-yl )imidazo[1,2- a ]pyridine.

4-Chloro-2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}pyrimidine

4-Chloro-2-{6-methanesulfonylimidazo[1,2-a]pyridin-3-yl}pyrimidine

3-(4-Chloropyrimidin-2-yl)-N-cyclopropylimidazo[1,2-a]pyridine-6-sulfonamide

3-(4-Chloropyrimidin-2-yl)imidazo[1,2-a]pyridine-6-sulfonamide

Synthesis 3: 3-Bromo-6-(difluoromethyl)imidazo[1,2- a ]pyridine

[00367] (Diethylamino)sulfur trifluoride (528.5 μL, 4.00 mmol) was added dropwise to 3-bromimidazo[1,2- a ]pyridine-6-carbaldehyde (450 mg, 2.00 mmol) in DCM ( 4.5 ml) at 0°C. After 2.5 hours, additional sulfur (diethylamino)trifluoride (150 μL, 1.135 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The crude mixture was diluted with methanol and purified using an SCX-2 ion exchange cartridge to give 3-bromo- 6-(difluoromethyl)imidazo[1,2- a ]pyridine (310 mg, 63%); ESV-MS m/z 247.0 (M+H).

Synthesis 4: 2-[6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-ol

Step 1: 6-(Difluoromethyl)-3-(4-methoxypyrimidin-2-yl)imidazo[1,2- a ]pyridine

[00368] 3-Bromo-6-(difluoromethyl)imidazo[1,2- a ]pyridine (120 mg, 0.486 mmol), tributyl-(4-methoxypyrimidin-2-yl)stannane (200 μl, 0.583 mmol) and PdCl ₂ (PPh ₃ ) ₂ (102.3 mg, 0.146 mmol) were combined in DMF (4 ml) and degassed with nitrogen and heated at 120°C for 16 hours. The mixture was allowed to cool, filtered and then purified using reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to obtain 6-(difluoromethyl)-3-(4-methoxypyrimidin-2-yl)imidazo[1,2- a ]pyridine trifluoroacetate (97 mg, 72 %); ESV-MS m/z 277.1 (M+H).

Step 2: 2-[6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-ol

[00369] Chlorotrimethylsilane (267 μL, 2.107 mmol) was added to a solution of 6-(difluoromethyl)-3-(4-methoxypyrimidin-2-yl)imidazo[1,2- a ]pyridine (97 mg, 0.351 mmol) and NaI ( 315.8 mg, 2.107 mmol) in MeCN (4 ml) and the mixture was heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was suspended in water and washed with saturated aqueous sodium thiosulfate. The solid was filtered, washed with water and dried in vacuo to give 2-[6-(difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-ol (75 mg, 81%); ESV-MS m/z 263.1 (M+H). The substance was used without additional purification.

Synthesis 5: 3-(2-Chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine

[00370] NBS (241 mg, 1.354 mmol) was added to a solution of 2-chloro-4-(2-ethoxyvinyl)pyrimidine (250 mg, 1.354 mmol) in 1,4-dioxane (8 ml)/water (3 ml) and the reaction mixture was stirred for 15 minutes. 5-(trifluoromethyl)pyridin-2-amine (220 mg, 1.357 mmol) was added and the reaction mixture was heated at 80°C for 3 hours. The mixture was cooled to room temperature and diluted with saturated aqueous NaHCO ₃ and extracted with DCM. The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, EtOAc/petroleum ether, gradient followed by MeOH/DCM, gradient) to give 3-(2-chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo [1,2- a ]pyridine (234.5 mg, 58%) as a beige solid.; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.95 (s, 1H), 8.78 (d, 1H), 8.19 (d, 1H), 8 .05 (d, 1H), 7.84 (dd, 1H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -60.86; ESV-MS m/z 299.1 (M+H).

Synthesis 6: N -[[( 2S )-Morpholin-2-yl]methyl]methanesulfonamide

Step 1: tert-Butyl-( S )-2-(methylsulfonamidomethyl)morpholine-4-carboxylate

[00371] Add tert-butyl-( 2R )-2-(aminomethyl)morpholine-4-carboxylate (5 g, 23 mmol) and Et ₃ N (16.1 mL, 115 mmol) to the round bottom flask, then add THF (100 ml). DCM (50 ml) and the mixture was cooled to 0°C. Methanesulfonyl chloride (2.4 ml, 30.5 mmol) was added dropwise and the mixture was stirred for 0.5 h, then kept at ambient temperature for 16 h under N ₂ atmosphere. The reaction was stopped with saturated aqueous NaHCO ₃ solution (100 ml) and most of the volatiles were removed in vacuo. The aqueous layer was extracted with ethyl acetate (3×50 ml). The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica; 70-100% EtOAc/petroleum ether gradient elution). The product fractions were combined and concentrated in vacuo. The residue was dried overnight in vacuo to give tert-butyl( S )-2-(methylsulfonamidomethyl)morpholine-4-carboxylate (3.61 g, 53%) as a white solid; ¹ H NMR (500 MHz, chloroform-d) δ 4.71-4.59 (m, 1H), 3.98-3.82 (m, 2H), 3.63-3.49 (m, 2H) , 3.38-3.24 (m, 1H), 3.20-3.11 (m, 1H), 3.04-2.90 (m, 4H), 2.73 (s, 1H), 1 .49 (s, 9H).

Step 2: N -[[( 2S )-Morpholin-2-yl]methyl]methanesulfonamide

[00372] TFA (9 mL, 115 mmol) was added to a solution of tert-butyl ( 2S )-2-(methanesulfonamidomethyl)morpholine-4-carboxylate (3.6 g, 12 mmol) in DCM (60 mL) with stirring. and the reaction mixture was stirred at ambient temperature for 6 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was transferred to methanol and passed through an ion exchange cartridge, eluting with methanol (discarded), then 2 M methanol ammonia. The filtrate was concentrated in vacuo to give N -[[( 2S )-morpholin-2-yl]methyl]methanesulfonamide (2.3 g, 97%); ¹ H NMR (500 MHz, chloroform-d) δ 4.73 (s, 1H), 3.90-3.87 (m, 1H), 3.65-3.60 (m, 2H), 3.26 (dd, 1H), 3.09 (dd, 1H), 2.99 (s, 3H), 2.92-2.84 (m, 3H), 2.66 (dd, 1H); MS m/z : 195 (M+H) ⁺ .

Synthesis 7: 2-( 1H -Pyrazol-4-yl)morpholine

Step 1: tert-Butyl-2-( 1H- pyrazol-4-yl)morpholine-4-carboxylate

[00373] A mixture of tert-butyl 2-(2-oxoethyl)morpholine-4-carboxylate (5.77 g, 25 mmol) and DMF-DMA (6.7 mL, 50 mmol) in DMF (50 mL) was stirred at 80°C for 17 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was taken up in EtOH (100 ml) and hydrazine hydrate (1.3 ml, 26.5 mmol) was added at ambient temperature with stirring. After 3 h, the solvent was removed in vacuo and the residue was purified by chromatography (silica, PE/EtOAc gradient elution) to give tert-butyl-2-( 1H- pyrazol-4-yl)morpholine-4-carboxylate ( 2.35 g, 37%) as a yellow solid. ¹ H NMR (500 MHz, chloroform-d) δ 7.63 (s, 2H), 4.52 (dd, 1H), 4.12 (br s, 1H), 3.97-3.90 (m, 2H), 3.68 (td, 1H), 3.05 (d, 2H), 1.51 (s, 9H); MS m/z : 254.1 (M+H) ⁺ .

Step 2: 2-( 1H -Pyrazol-4-yl)morpholine

[00374] 3M HCl in methanol (45 ml of 3M, 135 mmol) was added to a solution of tert-butyl 2-( 1H- pyrazol-4-yl)morpholine-4-carboxylate (2.35 g, 9.3 mmol) in DCM (75 ml) and the reaction mixture was refluxed for 5 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was dissolved in a minimal amount of DCM/MeOH and loaded into an ion exchange cartridge. The cartridge was washed with MeOH/DCM mixtures, which were discarded. The product was eluted by washing with 2M NH ₃ in MeOH/DCM. The solvent was removed in vacuo to give 2-( 1H -pyrazol-4-yl)morpholine (1.27 g, 89%) as an orange solid, which was used in the next reaction without further purification; ¹ H NMR (500 MHz, chloroform-d) δ 7.60 (s, 2H), 4.56 (dd, 1H), 3.98 (ddd, 1H), 3.77 (td, 1H), 3, 11 (dd, 1H), 3.00 (td, 1H), 2x.93-2.88 (m, 2H); MS m/z : 154.2 [M+H] ⁺ .

Synthesis 8: 2-Methyl-6-(1H - pyrazol-4-yl)morpholine.

[00375] Et ₃ N (150 μL, 1.1 mmol) was added to a solution of 1-benzylpyrazole-4-carbaldehyde (2 g, 10.7 mmol) and nitromethane (7 mL, 129 mmol) cooled in an ice bath. . The mixture was stirred with cooling for 15 minutes, then at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography (silica, EtOAc/petroleum ether gradient elution). The appropriate fractions were combined and concentrated in vacuo to give a colorless oil (1 g, 37%); MS m/z: 248 (M+H) ⁺ . This substance was immediately used in the next reaction.

[00376] Mixture of 1-(1-benzylpyrazol-4-yl)-2-nitroethanol (100 mg, 0.4 mmol), Pd at C, wet, Degussa (20 mg, 0.2 mmol) in methanol (4 ml ) was stirred at ambient temperature for 18 hours in an atmosphere of H ₂ at a pressure of 1 atm. The reaction mixture was filtered and the filtrate was concentrated in vacuo to obtain a colorless resinous substance (90 mg); MS m/z: 218 (M+H) ⁺ . This substance was immediately used in the next reaction.

[00377] 2-Bromopropanoyl bromide (114 mg, 0.5 mmol) was added to an ice-cold solution of 2-amino-1-(1-benzylpyrazol-4-yl)ethanol (100 mg, 0.5 mmol) and Et ₃ N ( 83 µl, 0.6 mmol) in DCM (4 ml) under N ₂ atmosphere. The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with DCM, washed with 2M aqueous HCl, saturated aqueous NaHCO ₃ and brine. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give a colorless oil. This material was taken up in THF (3 ml) and the solution was cooled in an ice bath. Sodium hydride (37 mg of 60% dispersion in mineral oil, 0.9 mmol) was added and the resulting suspension was stirred at ambient temperature for 2 hours. The reaction was quenched with methanol then diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over MgSO ₄ , filtered and concentrated in vacuo to give a pale yellow gum (100 mg), MS m/z: 272 (M+H) ⁺ , which was immediately used in the next reaction without purification.

[00378] A mixture of 6-(1-benzylpyrazol-4-yl)-2-methylmorpholin-3-one (100 mg, 0.4 mmol) and LiAlH ₄ (184 μl 2M, 0.4 mmol) in THF (3 ml ) was stirred at 60°C for 1 hour. The resulting suspension was neutralized with Na ₂ SO ₄ .10H ₂ O granules and stirred for 30 minutes, then filtered. The filtrate was concentrated in vacuo and the residue was taken up in methanol (2 ml). Three drops of concentrated HCl and Pd at C, wet, Degussa (20 mg, 0.02 mmol) were added to the solution. The reaction mixture was stirred at ambient temperature in an H ₂ atmosphere at a pressure of 1 atm. for 18 hours. The reaction mixture was poured into an ion exchange cartridge and eluted with methanol (the filtrate was discarded), then with a 2 M methanol solution of NH ₃ . The filtrate was concentrated in vacuo to give 2-methyl-6-( 1H- pyrazol-4-yl)morpholine (23 mg), MS m/z: 168 (M+H) ⁺ . This substance was immediately used in the next reaction.

Synthesis 9: Imino(methyl)(piperidin-3-ylmethyl)-λ ⁶ -sulfanone

[00379] Mixture of tert-butyl-3-(chloromethyl)piperidine-1-carboxylate (500 mg, 2.14 mmol), NaSMe (3 mL 20% w/v, 8.56 mmol), KI (355 mg , 2.14 mmol) in ethanol (10 ml) was stirred at 80°C for 22 hours. The reaction mixture was cooled to ambient temperature then concentrated in vacuo . The residue was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give the product as a pale brown oil (460 mg 88%), which was used in the next step without further purification or testing.

[00380]m-CPBA (324 mg, 1.88 mmol) was added to an ice-cold solution of tert-butyl 3-(methylsulfanylmethyl)piperidine-1-carboxylate (460 mg, 1.88 mmol) in DCM (7 mL) under N₂. The reaction mixture was stirred for 20 hours and the temperature was raised to ambient temperature. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over MgSO₄, filtered and concentrated in vacuo to give a pale brown oil (460 mg); MSm/z: 262 (M+H)⁺, which was used in the next step without further purification or testing. tert-Butyl-3-(methylsulfinylmethyl)piperidine-1-carboxylate (5.5 g, 21.0 mmol), 2,2,2-trifluoroacetamide (5.2 g, 46.3 mmol), diacetoxyiodobenzene (10.2 g, 31.6 mmol) and MgO (3.39 g, 84.2 mmol) were combined in DCM (250 ml) under N₂. Added Rh₂(OAc)₆ (0.9 g, 2.0 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through celite, washed with methanol and DCM. The filtrate was concentrated in vacuo and the remainder transferred to methanol (5 ml) and added MeCN/water (3:1) (5 ml). K₂CO₃ (17.4 g, 126.0 mmol) and the mixture was stirred at 90°C for 2 hours. The mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na₂SO₄), filtered and concentrated in vacuo to give tert-butyl 3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (5.96 g, quantitative yield) as an amber oil; MSm/z: 277 (M+H)⁺, which was immediately used in the next reaction.

[00381] tert-Butyl-3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (600 mg, 2.17 mmol) in DCM (3 ml) was treated with TFA (1.7 ml, 21.7 mmol) . The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The residue was transferred to methanol and loaded into an ion exchange cartridge. The cartridge was eluted with MeOH/DCM (the filtrate was discarded), then with methanol ammonia. The filtrate was concentrated in vacuo to give imino(methyl)(piperidin-3-ylmethyl)-λ ⁶ -sulfanone (250 mg, 65%); ¹ H NMR (500 MHz, methanol _-d4 ) δ 3.34-3.24 (m, 1H), 3.19-3.10 (m, 2H), 3.10-3.07 (m, 3H ), 3.05-2.97 (m, 1H), 2.60 (ddd, 1H), 2.52-2.43 (m, 1H), 2.30-2.18 (m, 1H), 2.08 (ddtd, 1H), 1.75 (dq, 1H), 1.61 (dtq, 1H), 1.37 (dtd, 1H).

Synthesis 10: Imino(methyl)(piperidin-3-ylmethyl)-λ ⁶ -sulfanone

[00382] Sodium thiomethoxide (4.06 g, 58 mmol) was added to a solution of tert-butyl 3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (8.5 g, 29 mmol) in ethanol (170 ml). The mixture was stirred at ambient temperature for 6 hours then concentrated in vacuo. The residue was partitioned between DCM and saturated aqueous NaHCO ₃ solution. The organic phase was dried and concentrated in vacuo. The residue was purified by chromatography (silica, MeOH/DCM gradient elution) to give a pale yellow oil (6.9 g). This substance was dissolved in DCM (100 ml) and the solution was cooled in an ice bath. m- CPBA (6.93 g, 70% w/w purity, 28 mmol) was added in portions. After addition was complete, the reaction mixture was stirred for 10 minutes, then partitioned between DCM, saturated aqueous sodium bicarbonate, and saturated aqueous sodium thiosulfate. The organic phase was dried and concentrated in vacuo. The residue was purified by chromatography (silica, DCM/MeOH gradient elution) to give the product as a colorless oil.

[00383] tert-Butyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate (5.5 g, 21.0 mmol), 2,2,2-trifluoroacetamide (5.23 g, 46.3 mmol) , (diacetoxyiodo)benzene (10.17 g, 31.6 mmol) and magnesium oxide (3.39 g, 84.2 mmol) were dissolved in DCM (250 ml) and diacetoxy(diacetoxyrodio)rhodium (0.9 g, 2.04 mmol). The mixture was stirred at ambient temperature overnight, then filtered through celite and concentrated in vacuo. The residue was dissolved in methanol (50 ml) and water (10 ml) and K was added₂CO₃ (17.44 g, 126.2 mmol). The mixture was stirred at ambient temperature for 3 hours, then heated at 50°C for 3 days. The mixture was concentrated in vacuo and the residue was dissolved in methanol (5 ml) and acetonitrile/water (3:1 mixture, 5 ml). After 1.5 h at 90°C, the mixture was cooled, diluted in EtOAc and washed with brine and saturated aqueous NaHCO₃. The organic layer was dried (Na₂SO₄) and concentrated in vacuo to obtain tert-butyl-3-((S-methylsulfonimidoyl)methyl)piperidine-1-carboxylate (5.96 g) as an amber oil, which was used without further purification.

[00384] A solution of tert-butyl-3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (600 mg, 2.17 mmol) and TFA (1.67 mL, 21.71 mmol) in DCM (3 mL) was stirred at ambient temperature for 16 hours, then concentrated in vacuo and the residue was passed through an SCX-2 cartridge. The product was eluted with methanolic ammonia to give imino(methyl)(piperidin-3-ylmethyl)-λ ⁶ -sulfanone (250 mg, 65%); ¹ H NMR (500 MHz, methanol _-d4 ) δ 3.34-3.24 (m, 1H), 3.19-3.10 (m, 2H), 3.10-3.07 (m, 3H ), 3.05-2.97 (m, 1H), 2.60 (ddd, J= 12.4, 11.5, 3.1 Hz, 1H), 2.52-2.43 (m, 1H ), 2.30-2.18 (m, 1H), 2.08 (ddtd, J= 30.1, 10.9, 3.8, 1.8 Hz, 1H), 1.75 (dq, J = 13.8, 3.3 Hz, 1H), 1.61 (dtq, J= 13.6, 11.5, 3.8 Hz, 1H), 1.37 (dtd, J= 12.8, 11 ,3, 3.9 Hz, 1H).

Synthesis 11: 2,5-Dimethyl-3-((methylsulfinyl)methyl)piperidine

Step 1: 1-(tert-Butyl)3-methyl-2,5-dimethylpiperidine-1,3-dicarboxylate

[00385] A mixture of methyl 2,5-dimethylpyridine-3-carboxylate (2.6 g, 15.74 mmol) and PtO ₂ (713 mg, 3.14 mmol) in HCl (57 ml of 3M solution in MeOH, 171, 1 mmol) was stirred with H ₂ supplied from a cylinder. The reaction mixture was stirred for 16 hours at ambient temperature, then filtered through celite and the filtrate was concentrated in vacuo. The residue was dissolved in THF (27 ml) and triethylamine (6.6 ml, 47.3 mmol), DMAP (96 mg, 0.79 mmol) and di-tert-butyl dicarbonate (17.4 ml of a 1M solution in THF, 17.4 ml) were added sequentially. 17.4 mmol). The reaction mixture was stirred for 16 hours, then partitioned between EtOAc and water. The organic layer was separated and washed with NH ₄ Cl solution, water (1×), brine (1×), then dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 0-10% EtOAc/petroleum ether gradient elution) to give 1-(tert-butyl)3-methyl-2,5-dimethylpiperidine-1,3-dicarboxylate (1,4 g, 33%) in the form of a colorless oil containing a mixture of diastereoisomers; ¹ H NMR (400 MHz, methanol-d ₄ ) δ 4.80-4.62 (m, 1H), 3.95-3.78 (m, 1H), 3.71 (d, 3H), 2, 71 (dq, 1H), 2.46 (dt, 1H), 1.89-1.77 (m, 1H), 1.48 (q, 10H), 1.10-0.92 (m, 7H) .

Step 2: tert-Butyl 3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate

[00386] O 1-tert-Butyl-O3-methyl-2,5-dimethylpiperidine-1,3-dicarboxylate (1.40 g, 5.16 mmol) was dissolved in THF (42 ml) and cooled to 0°C. Lithium borohydride (10.3 mL of 2M solution in THF, 20.6 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was heated to 50°C and stirred for 16 hours. The reaction mixture was cooled to ambient temperature and then the reaction was stopped with water. The mixture was extracted with EtOAc (×3). The combined organics were dried and concentrated in vacuo to give tert-butyl 3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate (1.25 g, 100%) as a colorless oil, which was immediately used in the next reaction without additional cleaning; ¹ H NMR (400 MHz, methanol-d ₄ ) δ 4.42-4.27 (m, 1H), 3.82-3.68 (m, 1H), 3.34-3.23 (m, 2H ), 2.33 (dt, 1H), 1.91 (s, 1H), 1.82-1.68 (m, 1H), 1.54-1.37 (m, 2H), 1.35 ( s, 9H), 0.95-0.87 (m, 3H), 0.86-0.76 (m, 4H).

Step 3: tert-Butyl 2,5-dimethyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

[00387] Methanesulfonyl chloride (2.77 ml, 35.7 mmol) was added to a solution of tert-butyl 3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate (5.80 g, 23.8 mmol) and triethylamine (6.64 ml, 47.7 mmol) in DCM (116 ml) and stirred at 0°C. After 30 min, the reaction was stopped with saturated aqueous NaHCO ₃ solution, stirred for 5 min and then the layers were separated using a phase separation cartridge. The organic phase was evaporated in vacuo to give tert-butyl 2,5-dimethyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (7.6 g), which was immediately used in the next step without further purification.

Step 4: tert-Butyl 2,5-dimethyl-3-((methylthio)methyl)piperidine-1-carboxylate

[00388] Sodium thiomethoxide (9.94 g, 141.8 mmol) was added to a solution of tert-butyl 2,5-dimethyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (7.6 g , 23.6 mmol) in EtOH (100 ml), stirred at 0°C. After addition, cooling was stopped and the reaction mixture was heated at 60°C for 16 hours. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by column chromatography (silica, eluting with 0-12.5% MeOH in DCM, gradient mode) to obtain tert-butyl 2,5-dimethyl-3-((methylthio)methyl)piperidine-1-carboxylate (3.4 g, 66%) as a colorless oil; ¹ H NMR (500 MHz, methanol-d ₄ ) δ 4.53-4.43 (m, 1H), 3.86 (td, J= 13.3, 4.4 Hz, 1H), 2.53- 2.31 (m, 3H), 2.10 (s, 3H), 1.91-1.81 (m, 1H), 1.74-1.63 (m, 1H), 1.61-1, 50 (m, 1H), 1.48 (s, 9H), 1.10-0.99 (m, 4H), 0.93 (t, J= 6.4 Hz, 3H).

Step 5: tert-Butyl 2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate

[00389] tert-Butyl 2,5-dimethyl-3-((methylthio)methyl)piperidine-1-carboxylate (2 g, 7.31 mmol) was dissolved in DCM (73 ml) and the solution was cooled to 0°C. m -CPBA (1.80 g, 7.31 mmol) was added in portions over 5 min and the reaction mixture was stirred for an additional 5 min, then the reaction was stopped by adding saturated aqueous sodium thiosulfate (40 ml) and stirred for 5 min , then extracted with DCM (3x50 ml). The combined organics were washed with saturated aqueous NaHCO ₃ (2 x 40 ml), filtered through a phase separation cartridge and concentrated in vacuo to give tert - butyl-2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1- carboxylate (2.1 g, 100%) as a colorless oil, which was used without further purification.

Step 6: 2,5-Dimethyl-3-((methylsulfinyl)methyl)piperidine

[00390] tert - Butyl 2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate (2.1 g, 7.26 mmol) was dissolved in methanol (36 ml) and 4M HCl in dioxane was added (9.1 ml, 36.3 mmol). The reaction mixture was stirred for 16 hours at ambient temperature, then concentrated in vacuo to give 2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine (1.85 g, 97%) as a white solid; MS m/z : 190.1 (M+H) ⁺ .

Synthesis 12: 2-(1H-Pyrazol-4-yl)piperazine

[00391] A mixture of 2-(1H-pyrazol-4-yl)pyrazine (400 mg, 2.7 mmol), PtO2 (100 mg, 0.4 mmol) in methanol (15 ml) was shaken at ambient temperature under pressure H ₂ equal to 60 lbf/in ² for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2-( 1H -pyrazol-4-yl)piperazine as a colorless oil, which was immediately used in the next reaction without cleaning; MS m/z : 153 (M+H) ⁺ .

Synthesis 13: 2,5-Dimethyl-3-(1H - pyrazol-4-yl)piperazine

[00392] In a 3-neck flask equipped with a reflux condenser and thermometer, place 3-chloro-2,5-dimethylpyrazine (5 ml, 40 mmol), tert-butyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyrazol-1-carboxylate (10 g, 34 mmol) in 1,4-dioxane (100 ml). Pd(PPh ₃ ) ₄ (2 g, 2 mmol), and Na ₂ CO ₃ (60 ml 2M, 100 mmol) were added and the solution was evacuated and refilled with N ₂ (×2). The solution was heated at 100°C and stirred overnight. The reaction mixture was cooled to ambient temperature and filtered, washed with diethyl ether. The filtrate was concentrated in vacuo and the residue was purified by chromatography (silica, 0-100% [EtOAc+2% 2M methanol ammonia]-petroleum ether gradient elution). The product fractions were combined and concentrated in vacuo to give 2,5-dimethyl-3-( 1H- pyrazol-4-yl)pyrazine as a white solid (4.5 g, 64%); MS m/z : 175 (M+H) ⁺ .

[00393] A mixture of 2,5-dimethyl-3-( 1H- pyrazol-4-yl)pyrazine (4.5 g, 26 mmol), PtO ₂ (1 g, 4 mmol) and HCl (60 ml of 3M solution in MeOH, 200 mmol) was shaken in a Parr hydrogenator for 24 hours at 60 psi ^{H 2} _pressure . The reaction mixture was filtered and the filtrate concentrated in vacuo to give the product 2,5-dimethyl-3-( 1H -pyrazol-4-yl)piperazine as an off-white solid (4.0 g, 61%); MS m/z : 181 (M+H) ⁺ . This substance was used in the following reaction, assuming the release of dihydrochloride.

[00394] The following compounds were prepared using a methodology similar to that described in Synthesis 213:

2-Methyl-6-( 1H -pyrazol-4-yl)piperazine;

3-( 1H -Imidazol-4-yl)-2,5-dimethylpiperazine.

Synthesis 14: Dimethyl((5-methylpiperidin-3-yl)imino)-λ⁶-sulfanone

Step 1: Dimethyl((5-methylpyridin-3-yl)imino)-λ ⁶ -sulfanone

[00395] 3-Bromo-5-methylpyridine (250 g, 1.439 mol), iminodimethyl-λ ⁶ -sulfane (142.6 g, 1.454 mol), Xantphos (24.976 g, 43.16 mmol), K ₂ CO ₃ ( 218.8 g, 1.583 mol) and tris(benzylideneacetone)dipalladium(0) (19.76 g, 21.58 mmol) were suspended in 1,4-dioxane (2.4 L). The reaction mixture was degassed (3 vacuum/nitrogen cycles) and stirred at reflux at 125°C for 16 hours. The reaction mixture was allowed to cool to ambient temperature then filtered through celite, washed with EtOAc. The oil was diluted with a small amount of MTBE (enough to detect slight precipitation; ~150 ml), seeded with a few crystals of the authentic sample and stirred at ambient temperature for 2 hours. The solid was filtered and washed with a minimal amount of MTBE to obtain a light pink solid, which dried at 30°C in a vacuum oven and obtained the desired product (105.9 g, 40%). The mother liquors were concentrated in vacuo to give 247.4 g of a dark brown oil. 247.4 g of the crude mixture was purified by column chromatography (3 kg silica column; product adsorbed onto a 350 g silica bed; 0 to 10% MeOH in EtOAc). The product containing fractions were combined and concentrated in vacuo to give the product (106.4 g 40%) after trituration with diethyl ether. Total yield 212.3 g (80%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (d, J= 2.4 Hz, 1H), 7.92 (dd, J= 1.9, 0.9 Hz, 1H), 7 .13 (dq, J= 2.8, 0.9 Hz, 1H), 3.25 (s, 6H), 2.22 (d, J= 0.8 Hz, 3H); ESV-MS m/z 185.0 (M+1) ⁺ .

Step 2: 1-Benzyl-3-((dimethyl(oxo)-λ ⁶ -sulfanylidene)amino)-5-methylpyridinium-1-ium bromide

[00396] To a solution of dimethyl((5-methylpyridin-3-yl)imino)-λ ⁶ -sulfanone (105.9 g, 574.73 mmol) in MeCN (900 mL) was added BnBr (69 mL, 580 mmol). The mixture was stirred at 100°C for 4 hours. The reaction mixture was allowed to cool to ambient temperature and the resulting precipitate was collected by filtration and washed with cold MeCN. The product was obtained as an off-white solid (158.8 g, 78%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.55 (s, 1H), 8.48 (t, J= 1.8 Hz, 1H), 7.87 (t, J= 1.5 Hz , 1H), 7.58-7.49 (m, 2H), 7.49-7.37 (m, 3H), 5.67 (s, 2H), 3.44 (s, 6H), 2, 41 (s, 3H). ESV-MS m/z 275.1 (M+1)+.

Step 3: ((1-benzyl-,5-methyl-1,2,5,6-tetrahydropyridin-3-yl)imino)dimethyl-λ ⁶ -sulfanone

[00397] A solution of NaBH ₄ (43 g, 1.137 mol) in sodium hydroxide (1.6 L 0.01 M 16.00 mmol) was added dropwise to the solution of 1-benzyl-3-((dimethyl) over 2 hours using a syringe pump (oxo)-λ ⁶ -sulfanylidene)amino)-5-methylpyridinium-1-ium bromide (200 g, 562.9 mmol) in ethanol (600 ml)/water (600 ml) at 0°C under N ₂ atmosphere. The mixture was extracted with MTBE (3x1.6 L), the organics were combined and washed with brine (1x600 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo to give the desired product (142 g, 91%); 1H NMR (400 MHz, chloroform-d) δ 7.40-7.17 (m, 5H), 5.18-5.10 (m, 1H), 3.58 (s, 2H), 3.08 ( d, J= 1.9 Hz, 6H), 3.04-2.93 (m, 1H), 2.86-2.68 (m, 3H), 2.55-2.40 (m, 1H) , 1.92 (dd, J= 11.0, 8.2 Hz, 1H), 0.95 (d, J= 6.9 Hz, 3H).ESV-MS m/z 279.1 (M+1 )+.

Step 4: Dimethyl((5-methylpiperidin-3-yl)imino)-λ ⁶ -sulfanone

[00398] Pd(OH)₂, (59 g, 20% w/w, Degussa, 84.03 mmol) was transferred to a nitrogen-filled vial and the vial was evacuated and refilled with nitrogen. Then a solution of ((1-benzyl-,5-methyl-1,2,5,6-tetrahydropyridin-3-yl)imino)dimethyl-λ was added⁶-sulfanone (117 g, 420.2 mmol) in methanol (700 ml) and the resulting solution was degassed using vacuum/nitrogen cycles (×3). The atmosphere was changed using vacuum/hydrogen cycles and the reaction mixture was shaken in a Parr hydrogenator for 16 hours. The reaction mixture was cooled to ambient temperature then filtered through celite and concentrated in vacuo to give an orange oil, which was analyzed and found to be incomplete. The product was redissolved in methanol (700 ml) and added to a Parr vial containing dihydroxypalladium (59 g 20% w/w, 84.03 mmol). The mixture was then shaken at 50°C and a molecular hydrogen pressure of 30 lbf/in.², during the night. The reaction mixture was cooled to ambient temperature then filtered through celite and the filtrate was concentrated in vacuo to give an orange oil which was analyzed by UPLC-MS and found to be incomplete. The mixture was redissolved in methanol (700 ml) and added to a Parr vial containing dihydroxypalladium (59 g 20% w/w, 84.03 mmol). The mixture was shaken at 50°C and at a molecular hydrogen pressure of 30 lbf/in.², in a Parr hydrogenator overnight. The mixture was cooled to ambient temperature, then filtered through celite, then concentrated in vacuo to give dimethyl((5-methylpiperidin-3-yl)imino)-λ⁶-sulfanone (56.7 g, 71%); 1H NMR (500 MHz, DMSO-d₆) δ 3.54 (masked signal, 1H), 3.09 (tt,J=10.8, 4.4 Hz, 1H), 2.95 (s, 6H), 2.89-2.74 (m, 2H), 2.11 (dd,J=12.0, 10.3 Hz, 1H), 1.92 (dd,J=12.1, 11.0 Hz, 1H), 1.84-1.73 (m, 1H), 1.58-1.44 (m, 1H), 0.89 (d,J=12.4 Hz, 1H), 0.77 (d,J=6.6 Hz, 3H).

[00399] The following compound was prepared using a methodology similar to that described in synthesis 214:

Dimethyl((piperidin-3-yl)imino)-λ ⁶ -sulfanone.

Synthesis 15: 2,5-Dimethylpiperidine-3-carboxamide

Step 1: 2,5-Dimethylnicotinamide

[00400] Methyl 2,5-dimethylpyridine-3-carboxylate (100 mg, 0.61 mmol) was dissolved in ammonium hydroxide (480 μl, 12.3 mmol) and the mixture was heated at 70°C in a sealed tube. After 16 hours, the reaction mixture was diluted in water and the mixture was concentrated in vacuo to give 2,5-dimethylpyridine-3-carboxamide (91 mg, 100%) as a white solid; MS m/z : 151.0 (M+H) ⁺ .

Step 2: 2,5-Dimethylpiperidine-3-carboxamide

[00401] 2,5-Dimethylnicotinamide (99 mg, 0.66 mmol) and PtO₂ (30.4 mg, 0.13 mmol) was dissolved in methanol (3 ml) and 3M HCl (1.1 ml, 3.30 mmol). The mixture was degassed and stirred with a supply of H₂ from a cylinder for 90 min, then passed through celite and the filtrate was concentrated in vacuo and obtained 2,5-dimethylpiperidine-3-carboxamide (dihydrochloride) (150 mg, 99%); MSm/z: 157.0 (M+H)⁺.

Synthesis 16: N-(((3S,5S) -4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

Step 1: Benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4-oxopiperidine-1-carboxylate

[00402] Benzyl 3-methyl-4-oxopiperidine-1-carboxylate (20 g, 0.08 mol) was dissolved in THF (300 ml) under N ₂ atmosphere. The solution was cooled to -78°C and LiHMDS (1M in THF, 101.1 ml, 0.1 mol) was added dropwise over 20 min, maintaining the temperature below -70°C. After stirring at -78°C for 90 min, a solution of 2-(chloromethyl)isoindoline-1,3-dione (23.7 g, 0.12 mol) in THF (200 ml) was added dropwise over 25 min, maintaining temperature below -70°C. The reaction mixture was stirred at -78°C for 1 hour, then the reaction was stopped at -78°C by adding saturated aqueous ammonium chloride (65 ml) and the mixture was allowed to warm to ambient temperature. The reaction was repeated and the two resulting mixtures were combined and extracted with EtOAc (300 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (300 ml) and brine (300 ml), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, eluting with EtOAc/petroleum ether). The product fractions were combined and concentrated in vacuo and the residue was recrystallized from EtOAc to give the product as a white solid (7.56 g, 23%).

Step 2: Benzyl-( 3R , 5S )-3-[(1,3-Dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methylpiperidine-1-carboxylate

[00403] Benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4-oxopiperidine-1-carboxylate (60 g, 0.15 mol) was placed in the flask and cooled in an ice bath /water. DAST (325 mL, 2.5 mol) was added in one portion and the mixture was stirred at ambient temperature for 3 days. The resulting yellow solution was diluted with DCM (1 L) and slowly added to the ice/water/solid sodium bicarbonate mixture while stirring with an overhead mixer. The temperature remained below 0°C and additional sodium bicarbonate was added to maintain the pH at 7-8. The mixture was heated to ambient temperature and the layers were separated. The aqueous phase was extracted with DCM (2 L). The combined organic substances were washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The residue was purified by chromatography (silica, eluting with EtOAc/petroleum ether). The product fractions were combined and concentrated in vacuo. The product, benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate, was obtained as a glass (32.5 g, 51%);¹H NMR (400 MHz, chloroform-d) δ 7.89-7.64 (4H, m), 7.42-7.11 (5H, m), 5.15-5.03 (2H, m), 4.39-4.07 (3H, m ), 3.83-3.66 (1H, m), 2.97-2.60 (2H, m), 2.56-2.31 (1H, m), 2.08-1.89 (1H , m), 1.05 (3H, d) as a mixture of isomers.

[00404] Preparative chiral supercritical liquid chromatography (conditions: ^Chiralpak® IC 5 μm, CO ₂ /iPrOH 90/10, 230 nm) was used to isolate one enantiomer benzyl-( 3R , 5S )-3-[(1,3 -dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methylpiperidin-1-carboxylate (98.7% ee ).

Step 3: Benzyl-( 3R , 5S )-3-(aminomethyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[00405] To a suspension of benzyl-( 3R , 5S )-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methylpiperidine-1-carboxylate (9.6 g , 22.4 mmol) in ethanol (144 ml) was added hydrazine hydrate (8.5 ml, 112 mmol). The reaction mixture was refluxed for 5 hours and then allowed to cool to ambient temperature overnight. The resulting suspension was filtered and the precipitate was washed with EtOH (×2). The filtrate was loaded into ion exchange cartridges (50 g×10). The cartridges were washed with MeOH/DCM mixtures (filtrates were discarded), then with 2 M methanolic ammonia solution. The filtrates were combined and concentrated in vacuo. The residue was taken into methanol and concentrated in vacuo (×2), then treated with heptane and concentrated in vacuo . The resulting yellow oil was dried in vacuo overnight to give the product as a solid (6.77 g) which was immediately used in the next reaction; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.48-7.17 (m, 5H), 5.11 (s, 2H), 4.41 (ddt, 1H), 4.02 (d, 1H), 2.98 (dd, 1H), 2.64 (s, 2H), 2.41 (dd, 1H), 2.15-1.78 (m, 2H), 1.50 (s, 2H ), 0.93 (d, 3H); MS m/z : 299 (M+H) ⁺ .

Step 4: Benzyl-( 3S , 5S )-4,4-difluoro-3-(methanesulfonamidomethyl)-5-methylpiperidine-1-carboxylate

[00406] Benzyl ( 3R.5S )-3-( aminomethyl )-4,4-difluoro-5-methylpiperidine-1-carboxylate (6.6 g, 22 mmol) was dissolved in DCM (66 ml) and cooled in an ice bath. The internal temperature reached 3°C. Et ₃ N (3.4 ml, 24 mmol) was added with stirring. Methanesulfonyl chloride (1.88 ml, 24 mmol) was added over 5 minutes at a rate such that the internal temperature remained below 10°C. After 30 min, the ice bath was removed. The solution was warmed to ambient temperature and the reaction was stopped with saturated aqueous NaHCO ₃ solution (66 ml). The layers were separated and the aqueous phase was extracted with DCM (33 ml). The combined organics were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by chromatography (silica; 0 to 100% EtOAc/petroleum ether gradient elution). The product fractions were combined and concentrated in vacuo. The residue was dried overnight under vacuum to give a white solid (7.92 g; 95%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.45-7.31 (m, 5H), 7.31-7.19 (m, 1H), 5.12 (s, 2H), 4, 37 (d, 1H), 4.18-3.94 (m, 1H), 3.38 (ddd, 1H), 3.00-2.80 (m, 4H), 2.68 (s, 2H) , 2.15 (s, 2H), 0.95 (d, 3H); MS m/z : 377 (M+H) ⁺ .

Step 5: N-((( 3S , 5S )-4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

[00407] To a solution of benzyl-( 3S , 5S )-4,4-difluoro-3-(methanesulfonamidomethyl)-5-methylpiperidine-1-carboxylate (7.54 g, 20 mmol) in DCM (113 ml) Et ₃ N (8.38 ml, 60 mmol), then Pd(OAc) ₂ (1.799 g, 8 mmol). Et ₃ SiH (19.20 mL, 120 mmol) was added over 5 minutes. The solution was stirred at ambient temperature for 1 hour, then divided into 6 equal portions and loaded into ion exchange cartridges (50 g). The cartridges were washed with DCM, 1:1 MeOH:DCM and methanol. The filtrates were discarded. The cartridges were washed with 2 M methanolic ammonia solution. The filtrates were combined and concentrated in vacuo. The residue was azeotroped with DCM, then taken into methanol (45 ml) and stirred with SPM32 (3-mercaptopropylethyl sulfide-silica) for 2 hours at ambient temperature, then at 50°C for 1 hour. The mixture was cooled and filtered through celite and the filtrate was concentrated in vacuo. The residue was taken up in DCM and concentrated in vacuo. The residue was dried overnight in vacuo to give N-(((3S,5S)-4,4- difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide as a white solid (4.40 g, 91%) ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.10 (t, 1H), 3.43-3.33 (m, 1H), 3.26-3.10 (m, 1H), 2, 93-2.88 (m, 4H), 2.79 (dtd, 1H), 2.38-2.20 (m, 2H), 2.13-1.78 (m, 2H), 0.89 ( d, 3H); MS m/z : 243.0 (M+H) ⁺ .

Synthesis 17: N- (Pyrrolidin-3-ylmethyl)methanesulfonamide

Step 1: tert-Butyl 3-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate

[00408] Methanesulfonyl chloride (222 mg, 150 μl, 1.938 mmol) was added to a solution of tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (300 mg, 1.498 mmol) and triethylamine (232.3 mg, 320 μl) with stirring , 2.296 mmol) in THF (10 ml) under nitrogen atmosphere and the reaction mixture was stirred at ambient temperature for 1.5 h. The reaction mixture was diluted with DCM and saturated aqueous NaHCO₃ and the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with DCM (×2). The combined organic extracts were dried (MgSO₄), filtered and concentrated in vacuo to obtain tert-butyl 3-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate as a pale yellow oil, which was deprotected assuming 100% yield and purity;¹H NMR (500 MHz, DMSO-d₆) δ 7.11 (t,J=6.2 Hz, 1H), 3.40-3.35 (m, 1H), 3.32-3.28 (m, 1H), 3.23-3.15 (m, 1H), 2.95 -2.93 (m, 3H), 2.89 (s, 3H), 2.31-2.26 (m, 1H), 1.93-1.88 (m, 1H), 1.65-1 .52 (m, 1H), 1.40 (s, 9H); ESV-MSm/z calculated 278.13004, found 223.1 (M+1)⁺.

Step 2: N- (Pyrrolidin-3-ylmethyl)methanesulfonamide

[00409] TFA (2.960 g, 2 mL, 25.96 mmol) was added to a solution of tert-butyl 3-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate (417 mg, 1.498 mmol) in DCM (20 mL) with stirring and reaction the mixture was stirred at ambient temperature for 15 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was passed through a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with mixtures of 2M NH ₃ in MeOH/DCM. The solvent was removed in vacuo to give N- (pyrrolidin-3-ylmethyl)methanesulfonamide (227.4 mg, 85%) as a pale yellow solid; ¹ H NMR (500 MHz, chloroform-d) δ 3.16 (qd, J= 12.3, 6.5 Hz, 2H), 3.09-3.03 (m, 2H), 2.98 (s , 3H), 2.94-2.89 (m, 1H), 2.75 (dd, J= 10.7, 5.0 Hz, 1H), 2.40-2.32 (m, 1H), 2.04-1.96 (m, 1H), 1.55-1.48 (m, 1H). ; ESV-MS m/z 179.2 (M+1) ⁺ .

Synthesis 18: 4-Pyrrolidin-3-yl-1H-pyrazole

Step 1: tert-Butyl 3-( 1H -pyrazol-4-yl)-2,5-dihydropyrrole-1-carboxylate

[00410] tert-Butyl-4-bromopyrazole-1-carboxylate (230 mg, 0.931 mmol), tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-2,5-dihydropyrrole-1-carboxylate (250 mg, 0.847 mmol) and potassium carbonate (1.3 mL 2M, 2.60 mmol) were combined in dioxane (3 mL) and the mixture was degassed (×2 vacuum cycles). Pd(dppf)Cl ₂ DCM (70 mg, 0.086 mmol) was added and the mixture was degassed (×2 vacuum cycles), then heated at 90°C overnight. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, 0-100% EtOAc/petroleum ether gradient elution). The product fractions were combined and concentrated to give the product as a pale yellow film-like substance (65 mg, 33%), which was used in the next reaction. ESV-MS m/z 236.0 (M+1) ⁺ .

Steps 2 and 3: 4-Pyrrolidin-3-yl- 1H -pyrazole

[00411] tert-Butyl-3-( 1H- pyrazol-4-yl)-2,5-dihydropyrrole-1-carboxylate (550 mg, 2.338 mmol) was dissolved in DCM (10 ml) and TFA was added. After 1 hour, the reaction mixture was concentrated in vacuo and the residue was subjected to azeotropic distillation with DCM (×2). The residue was transferred to methanol (10 ml) and the solution was degassed (×3 cycles of vacuum - N ₂ ). Pd at C, wet, Degussa (200 mg 10% w/w, 0.188 mmol) was added and the mixture was degassed (×3 cycles). The N ₂ atmosphere was replaced with hydrogen (×3 cycles) and the mixture was stirred at ambient temperature. After 90 min, the reaction mixture was filtered through celite and washed with methanol. The filtrate was concentrated in vacuo (cold water bath) to give crude 4-pyrrolidin-3-yl- 1H -pyrazole (trifluoroacetate) (600 mg, quantitative yield); ESV-MS m/z 136.0 (M+1) ⁺ .

Synthesis 19: ( E )-2-(2-Ethoxyvinyl)-4-(methylthio)pyrimidine

[00412] To a suspension of 2-chloro-4-(methylthio)pyrimidine (56.1 g, 349.3 mmol) and 2 M aqueous Na₂CO₃ (524 ml, 1.05 mol) in 1,2-dimethoxyethane (730 ml) was added 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76.1 g, 384 mmol). Pd(PPh) was added₃)₄ (20.2 g, 17.5 mmol) and the mixture was degassed. The reaction mixture was placed under a nitrogen atmosphere and refluxed for 4 hours. The mixture was cooled to ambient temperature and partitioned between EtOAc (1.1 L) and water (560 ml). The organic layer was washed with water (2×560 ml), the combined organic layers were re-extracted with EtOAc (280 ml) and the combined organic phases were washed with brine (×1), dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0 to 25% EtOAc/petroleum ether) to give (E)-2-(2-ethoxyvinyl)-4-(methylthio)pyrimidine as a pale yellow crystalline solid (62.4 g, 91%);¹H NMR (500 MHz, chloroform-d) δ 8.18 (d,J=5.5 Hz, 1H), 7.95 (d,J=12.6 Hz, 1H), 6.85 (d,J=5.5 Hz, 1H), 5.91 (d,J=12.6 Hz, 1H), 4.02 (q,J=7.0 Hz, 2H), 2.56 (s, 3H), 1.40 (t,J=7.0 Hz, 3H); ES+ [M+H]= 197.1.

Synthesis 20: 2-chloro-4-{6-cyclopropylimidazo[1,2-a]pyridin-3-yl}pyrimidine

[00413] Step 1: 6-Cyclopropylimidazo[1,2-a]pyridine. 6-bromimidazo[1,2-a]pyridine (5 g, 22.84 mmol, 1 eq., 90%), cyclopropylboronic acid (3.1 g, 34.26 mmol, 1. 50 equiv., 95%), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (2.0 g, 2.33 mmol, 0.10 equiv., 95%), dioxane (20 ml, 224.28 mmol, 9.82 eq., 95%), K ₃ PO ₄ (10.2 g, 45.68 mmol, 2.00 eq., 95%). The resulting solution was stirred overnight at 100°C in an oil bath. The resulting mixture was concentrated. The residue was applied to a silica gel column, ethyl acetate/petroleum ether (1/5). This gave 3.6 g (89.67%) 6-cyclopropylimidazo[1,2-a]pyridine as a white solid.

[00414] Step 2: 3-Bromo-6-cyclopropylimidazo[1,2-a]pyridine. Place 6-cyclopropylimidazo[1,2-a]pyridine (3.6 g, 20.48 mmol, 1 eq., 90%), NBS (3.8 g, 20.28 mmol, 0) into a 150 mL round bottom flask. .99 eq., 95%), DCM (20 ml, 298.87 mmol, 14.59 eq., 95%). The resulting solution was stirred for 3 hours at 25°C. The resulting mixture was concentrated. The residue was applied to a silica gel column, ethyl acetate/petroleum ether (1/5). This gave 4.3 g (79.70%) 3-bromo-6-cyclopropylimidazo[1,2-a]pyridine as a white solid.

[00415] Step 3: 2-Chloro-4-{6-cyclopropylimidazo[1,2-a]pyridin-3-yl}pyrimidine. With stirring, to a solution of 3-bromo-6-cyclopropylimidazo[1,2-a]pyridine (1.5 g, 5.694 mmol, 1 eq., 90%) in THF (10 ml, 117.259 mmol, 21.0 eq., 95%) iPrMgCl.LiCl (1.74 g, 11.388 mmol, 2 eq., 95%) was added dropwise at -10°C under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at 0°C under a nitrogen atmosphere. The above mixture was added with stirring to a mixture of 2,4-dichloropyrimidine (1.07 g, 6.824 mmol, 1.20 eq., 95%) and Pd(PPh ₃ ) ₄ (0.35 g, 0.285 mmol, 0.05 eq., 95%) in THF (10 ml, 117.259 mmol, 21.0 eq., 95%) at room temperature. The resulting mixture was stirred for another 4 hours at 70°C. The resulting mixture was concentrated. The residue was applied to a silica gel column, ethyl acetate/petroleum ether (1/10). This gave 1 g (58.39%) of 2-chloro-4-[6-cyclopropylimidazo[1,2-a]pyridin-3-yl]pyrimidine as a white solid.

[00416] The following compounds were prepared using a methodology similar to that described in Synthesis 20:

2-Chloro-4-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidine

Synthesis 21: 2-chloro-4-[(E)-2-ethoxyethenyl]-6-methylpyrimidine

[00417] With stirring, to a solution of 2,4-dichloro-6-methylpyrimidine (246.88 mg, 1.439 mmol, 1.20 eq., 95%), 2-[(E)-2-ethoxyethenyl]-4,4 ,5,5-tetramethyl-1,3,2-dioxaborolane (250 mg, 1.199 mmol, 1 equiv., 95%) and K ₃ PO ₄ (535.84 mg, 2.398 mmol, 2.00 equiv., 95% ) SPhos (36.27 mg, 0.084 mmol, 0.07 eq., 95%) and Pd(AcO)2 (8.50 mg, 0.036 mmol, 0.03 eq., 95%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated to a small volume. The resulting mixture was diluted with brine (20 ml). The resulting mixture was extracted with EtOAc (3×50 ml). The combined organic layers were washed with brine (2×20 ml), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to give 2-chloro-4-[(E)-2-ethoxyethenyl]-6-methylpyrimidine (100 mg, 37.78%) in the form of a light yellow oil.

Synthesis 22: 2-chloro-4-[6-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-6-methylpyrimidine

[00418] Step 1: 5-(3,3-difluoroazetidin-1-yl)-2-nitropyridine. With stirring to a solution of 5-bromo-2-nitropyridine (500 mg, 2.340 mmol, 1 equiv., 95%), 3,3-difluoroazetidin hydrochloride (350.95 mg, 2.574 mmol, 1.1 equiv., 95%) and Cs2CO3 (4012.66 mg, 11.700 mmol, 5.00 eq., 95%) in dioxane (37.50 ml, 425.622 mmol, 179.71 eq., 95%) was added Pd2(dba)3 (112.78 mg , 0.117 mmol, 0.05 eq., 95%) and XantPhos (142.52 mg, 0.234 mmol, 0.10 eq., 95%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to give 5-(3,3-difluoroazetidin-1-yl)-2-nitropyridine (200 mg, 27.81%) as light yellow solid.

[00419] Step 2: 5-(3,3-difluoroazetidin-1-yl)pyridin-2-amine. With stirring, to a solution of 5-(3,3-difluoroazetidin-1-yl)-2-nitropyridine (175 mg, 0.569 mmol, 1 eq., 70%) in MeOH (56.00 ml, 1747.713 mmol, 2307. 89 eq., 95%) Pd/C (318.89 mg, 2.847 mmol, 5 eq., 95%) was added in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3×30 ml). The filtrate was concentrated under reduced pressure. The crude product/resulting mixture was used in the next step without treatment without further purification.

[00420] Step 3: 2-chloro-4-[6-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-6-methylpyrimidine. With stirring, to a solution of 2-chloro-4-[(E)-2-ethoxyethenyl]-6-methylpyrimidine (550 mg, 2.630 mmol, 1 eq., 95%) in H2O (18 ml, 999.151 mmol, 379.87 eq. ., 9%) and H2O (18 ml, 999.151 mmol, 379.87 eq., 9%) NBS (492.78 mg, 2.630 mmol, 1 eq., 95%) was added at room temperature. The resulting mixture was stirred for 1 hour at room temperature. To the above mixture was added 5-(3,3-difluoroazetidin-1-yl)pyridin-2-amine (666.51 mg, 3.419 mmol, 1.3 eq., 95%). The resulting mixture was stirred for another 2.5 hours at 85°C. The resulting mixture was diluted with EtOAc (20 ml). The mixture was neutralized to pH 7 with saturated Na2CO3 (aq). The resulting mixture was extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine (2×50 ml), dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (20:1). This gave 2-chloro-4-[6-(3,3-difluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-6-methylpyrimidine (290 mg, 31.85%) in as a light yellow solid.

[00421] The following compounds were prepared using a methodology similar to that described in synthesis 22:

2-Chloro-4-[6-(3-fluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]pyrimidine

Synthesis 23: 5-[6-(azetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2-chloropyrimidine

[00422] Step 1: 1-{imidazo[1,2-a]pyridin-6-yl}azetidine. 6-bromimidazo[1,2-a]pyridine (3.5 g, 15.99 mmol, 1 eq, 90%), azetidine (1441.3 mg, 23.98) was added to a 500 mL round bottom flask at room temperature. mmol, 1.50 eq., 95%), toluene (300 ml, 2678.69 mmol, 167.55 eq., 95%), BINAP (1047.9 mg, 1.60 mmol, 0.10 eq., 95%) and t-BuONa(3234.5 mg, 31.97 mmol, 2.00 eq., 95%). The resulting mixture was stirred overnight at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to give 1-[imidazo[1,2-a]pyridin-6-yl]azetidine (2.5g,78.72%) as a green solid.

[00423] Step 2: 1-{3-bromimidazo[1,2-a]pyridin-6-yl}azetidine. 1-[Imidazo[1,2-a]pyridin-6-yl]azetidine (1 g, 5.03 mmol, 1 eq, 87.2%), NBS (896) was added to a 25 mL round bottom flask at room temperature. .0 mg, 4.78 mmol, 0.95 eq., 95%) and DCM (60 ml, 896.61 mmol, 178.11 eq., 95%). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to give 1-[3-bromimidazo[1,2-a]pyridin-6-yl]azetidine (1.1 g, 56. 25%) as a green solid.

[00424] Step 3: 5-[6-(azetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2-chloropyrimidine. With stirring, to a solution of 1-[3-bromimidazo[1,2-a]pyridin-6-yl]azetidine (200 mg, 0.777 mmol, 1 eq., 98%) in THF (20 ml, 234.517 mmol, 301.66 eq., 95%) chloro(propan-2-yl)magnesium chloride lithium (1 ml, 1.084 mmol, 1.39 eq., 17.5%) was added dropwise at -10°C under N ₂ atmosphere. The resulting mixture was stirred for 2 hours at 0°C under N ₂ atmosphere. The above mixture was added with stirring to a mixture of 2,4-dichloropyrimidine (182.86 mg, 1.166 mmol, 1.50 eq., 95%) and Pd(PPh ₃ ) ₄ (47.28 mg, 0.039 mmol, 0.05 eq., 95%) in THF at room temperature. The resulting mixture was stirred for another 4 hours at 80°C. The reaction was stopped with a saturated solution of NH ₄ Cl (aq.) at room temperature. The aqueous layer was extracted with EtOAc (3×20 ml). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA:PE (1:1) to give 4-[6-(azetidin-1-yl)imidazo[1,2-a]pyridin-3-yl]-2 -chloropyrimidine (120 mg, 19.61%) as a green solid.

Synthesis 24: 5-(3-methyl-1H-pyrazol-4-yl)piperidin-3-ol

[00425] Step 1: 5-(3-Methyl-1H-pyrazol-4-yl)pyridin-3-ol. A mixture of 5-bromopyridin-3-ol (10 g, 54.599 mmol, 1 eq., 95%), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (2.35 g, 2.730 mmol, 0.05 eq., 95 %), K ₂ CO ₃ (11.91 g, 81.898 mmol, 1.50 eq., 95%) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-pyrazole (14.35 g, 65.518 mmol, 1.2 eq., 95%) in dioxane (150.01 ml, 1682.194 mmol, 30.81 eq., 95%) and H2O (29.99 mL, 1664.971 mmol, 28.97 eq., 95%) was stirred overnight at 100°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /MeOH (10:1) to give 5-(3-methyl-1H-pyrazol-4-yl)pyridin-3-ol (6.5g, 61.16%) as a brown solid.

[00426] Step 2: 1-Benzyl-3-hydroxy-5-(3-methyl-1H-pyrazol-4-yl)pyridin-1-ium bromide. A mixture of 5-(3-methyl-1H-pyrazol-4-yl)pyridin-3-ol (6.2 g, 31.851 mmol, 1 eq., 90%) and BnBr (6.88 g, 0.038 mmol, 1. 2 eq., 95%) in MeCN (300.00 ml, 6942.365 mmol, 170.23 eq., 95%) was stirred overnight at 60°C under hydrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /MeOH (85:15) to give 1-benzyl-3-hydroxy-5-(3-methyl-1H-pyrazol-4-yl)pyridin- 1-Ibromide (9 g, 73.45%) as a brown solid.

[00427] Step 3: 1-Benzyl-5-(3-methyl-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridin-3-ol. A mixture of 1-benzyl-3-hydroxy-5-(3-methyl-1H-pyrazol-4-yl)pyridin-1-ium bromide (6.5 g, 16.896 mmol, 1 eq., 90%) and NaBH4 (2. 68 g, 67.296 mmol, 3.98 eq, 95%) in EtOH (260.00 mL, 5643.864 mmol, 251.64 eq, 95%) was stirred overnight at room temperature under nitrogen. The reaction was stopped with a saturated solution of NH4Cl (aqueous) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (10:1) to give 1-benzyl-5-(3-methyl-1H-pyrazol-4-yl)-1,2,3,6- tetrahydropyridin-3-ol (5 g, 98.88%) as a yellow oil.

[00428] Step 4: 5-(3-Methyl-1H-pyrazol-4-yl)piperidin-3-ol. 1-Benzyl-5-(3-methyl-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridin-3-ol mixture (3.2 g, 10.692 mmol, 1 eq., 90%) and Pd/C (1137.89 mg, 1.069 mmol, 0.10 eq., 10%) in MeOH (200.00 ml, 5929.777 mmol, 438.89 eq., 95%) were stirred for 4 h at room temperature in a hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3×5 ml). The filtrate was concentrated under reduced pressure to obtain 5-(3-methyl-1H-pyrazol-4-yl)piperidin-3-ol (2 g, 92.88%) as a colorless semi-solid.

[00429] The following compounds were prepared using a methodology similar to that described in Synthesis 24:

3-(3-Fluoro-1H-pyrazol-4-yl)-5-methylpiperidine

Example 1: 3-(4-(3-(( S -Methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine, I-4

[00430] 3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine (13.2 mg, 0.05 mmol), 3-(( S -methylsulfonimidoyl)methyl )piperidine (8 mg, 0.045 mmol), diisopropylethylamine (8 μl, 0.045 mmol) in DMF was heated at 80°C. After 20 min, the reaction mixture was cooled to room temperature and the mixture was filtered and purified by reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to give 3-(4-(3-(( S -methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine (12.7 mg, 40%).

[00431] The following compounds were prepared using a methodology similar to that described in Example 1:

8-Methylsulfonyl-1-[2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]-1,8-diazaspiro[4.5]decane, I-7

N -[[-4,4-Difluoro-5-methyl-1-[2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]-3-piperidyl ]methyl]methanesulfonamide, I-8

N -[[(2 S )-4-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide, I-19 (using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine)

4-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]-2-(1H - pyrazol-4-yl)morpholine, I-20 (using 6 -chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine)

6-Chloro-3-(4-(3-((methylsulfonimidoyl)methyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2- a ]pyridine, I-21 (using 6-chloro- 3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine)

4-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]-2-(1 H -pyrazol-4-yl)morpholine, I-23 (using 6-chloro-3-(4-chloropyrimidin-2-yl)-7-fluorimidazo[1,2- a ]pyridine)

4-[2-(6-Bromo-7-fluorimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]-2-(1 H -pyrazol-4-yl)morpholine, I-24 (using 6-bromo-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2- a ]pyridine)

N -[[1-[2-(6-Bromo-7-fluorimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]pyrrolidin-3-yl]methyl]methanesulfonamide I-25 (c using 6-bromo-7-fluoro-3-(4-methylsulfanylpyrimidin-2-yl)imidazo[1,2- a ]pyridine)

1-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]-1,4-diazepan-5-one I-26 (using 6-chloro-3- (4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine);

6-Chloro-3-[4-[3-(1 H -pyrazol-4-yl)pyrrolidin-1-yl]pyrimidin-2-yl]imidazo[1,2- a ]pyridine I-27 (using 6 -chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine)

6-Chloro-3-[4-[3-(1 H -pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]imidazo[1,2- a ]pyridine I-28 (using 6 -chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine)

6-Chloro-3-[4-[3-dimethylphosphoryl-5-( 1H -pyrazol-4-yl)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2- a ]pyridine I-29 ( using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine)

((1-(2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)dimethyl-λ ^6- sulfanone I-30 (using 6-chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine)

N -[[-1-[4-[6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-2-yl]-4,4-difluoro-5-methyl-3-piperidyl ]methyl]methanesulfonamide, I-41 (using 3-(2-chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2- a ]pyridine);

6-Chloro-7-fluoro-3-[4-[3-(1 H -imidazol-4-yl)-2,5-dimethylpiperazin-1-yl]pyrimidin-2-yl]imidazo[1,2- a ]pyridine I-42 (using 6-chloro-3-(4-chloropyrimidin-2-yl)-7-fluorimidazo[1,2- a ]pyridine)

7-[2-[6-(Trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]-1,2,5,6,8,8a-hexahydroimidazo[1,5- a ]pyrazin-3-one I-43 (using 3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine)

2-( 1H -Pyrazol-4-yl)-4-[4-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-2-yl]morpholine I-44 (c using 3-(2-chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine)

( 3S )-1-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]piperidin-3-carboxamide I-48 (using 6- chloro-3-(4-chloropyrimidin-2-yl)-7-fluorimidazo[1,2- a ]pyridine)

((1-(2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)dimethyl-λ ⁶ -sulfanone I- 49 (using 6-chloro-3-(4-chloropyrimidin-2-yl)-7-fluorimidazo[1,2- a ]pyridine)

1-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]-2,5-dimethylpiperidine-3-carboxamide I-50 (using 6-chloro-3- (4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine);

1-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]-2,5-dimethylpiperidine-3-carboxamide I-51 (using 6-chloro-3- (4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine)

1-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]-2,5-dimethylpiperidin-3-carboxamide I-52 and 1-[2 -(6-chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl]-2,5-dimethylpiperidine-3-carboxamide I-53

Example 2: 1 H -Pyrazol-4-yl-4-[2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]morpholine and 1 H -pyrazol- 4-yl-4-[2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]morpholine, I-2 and I-3

[00432] Racemic mixture of 2-(1H-pyrazol-4-yl)-4-[2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]morpholine ( prepared using a methodology similar to that described in Example 107) were separated using chiral supercritical liquid chromatography (conditions: OD-H, 45% MeOH, 20 mM NH3, 290 nm). The first compound to elute was I-2 (99.3% ee); ESV-MS m/z 416.8 (M+H). The second compound to elute was I-3 (98.2% ee); ESV-MS m/z 416.4 (M+H).

[00433] The following compounds were prepared using a methodology similar to that described in Example 2:

7-(2-(6-(Trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)hexahydroimidazo[1,5- a ]pyrazin-3( 2H )-one I- 5

7-(2-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)hexahydroimidazo[1,5- a ]pyrazin-3( 2H )-one, I -6

2-( 1H -Pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)pyrimidin-2-yl)morpholine, I-9

2-( 1H- pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)pyrimidin-2-yl)morpholine, I-10

Dimethyl((5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ ⁶ - sulfanone I-31 and dimethyl((5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino )-λ ⁶ -sulfanone I-32

3-[2-[2,5-Dimethyl-3-(1 H -pyrazol-4-yl)piperazin-1-yl]pyrimidin-4-yl]-6-(trifluoromethyl)imidazo[1,2- a ] pyridine I-33 and 3-[2-[2,5-dimethyl-3-(1 H -pyrazol-4-yl)piperazin-1-yl]pyrimidin-4-yl]-6-(trifluoromethyl)imidazo[1 ,2- a ]pyridine I-34

6-Chloro-3-[4-[2,5-dimethyl-3-(1 H -pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]imidazo[1,2- a ]pyridine I -35 and 6-chloro-3-[4-[2,5-dimethyl-3-(1 H -pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]imidazo[1,2- a ]pyridine I-36

3-[4-[2,5-Dimethyl-3-( 1H- pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2- a ] pyridine I-37 and 3-[4-[2,5-dimethyl-3-(1 H -pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1 ,2- a ]pyridine I-38

3-[4-[3-Methyl-5-( 1H- pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2- a ]pyridine I -39 and 3-[4-[3-methyl-5-(1 H -pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2- a ]pyridine I-40

Example 3: N -[[( 2S )-4-[2-[6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl ]methanesulfonamide, I-13

[00434] DBU (79.8 μl, 0.534 mmol) and PyBroP (124.5 mg, 0.267 mmol) were added to the 2-[6-(difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidine solution -4-ol (35 mg, 0.134 mmol) in MeCN (700 µl). After 5 min, N -[[( 2S )-morpholin-2-yl]methyl]methanesulfonamide (31.1 mg, 0.160 mmol) was added and the mixture was heated to 40°C. After 2 h, the reaction mixture was cooled to room temperature and the mixture was filtered and purified by reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to give trifluoroacetate N -[[( 2S )-4- [2-[6-(difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide (28.2 mg, 45%).

[00435] The following compounds were prepared using a methodology similar to that described in Example 3:

N -[[(2 S )-4-[2-[6-(Trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide, I-1 (using 2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl] -1H- pyrimidin-6-one)

1-[4-[2-[6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethanone, I-14

4-[2-[6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl]-2-(1 H -pyrazol-4-yl)morpholine, I-15

N -(((3 S ,5 S )-1-(2-(6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)-4,4-difluoro- 5-methylpiperidin-3-yl)methyl)methanesulfonamide, I-16

2-( 1H -Pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)morpholine, I-45

Example 4: N -[[( 2S )-4-[4-[6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-2-yl]morpholin-2-yl]methyl ]methanesulfonamide, I-17

[00436] 3-Bromo-6-(difluoromethyl)imidazo[1,2- a ]pyridine (70 mg, 0.283 mmol), tributyl-(2-chloropyrimidin-4-yl)stannane (137.3 mg, 0.340 mmol) and PdCl ₂ (PPh ₃ ) ₂ (59.7 mg, 0.085 mmol) were combined in DMF (2.1 ml) and degassed with nitrogen, then heated at 120°C. N -[[( 2S )-morpholin-2-yl]methyl]methanesulfonamide (27.7 mg, 0.143 mmol) and diisopropylethylamine (49.6 μL, 0.285 mmol) were added to the mixture and the reaction mixture was heated at 150°C. After 16 h, the reaction mixture was cooled to room temperature and the mixture was filtered and purified by reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to give trifluoroacetate N -[[( 2S )-4- [4-[6-(difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-2-yl]morpholin-2-yl]methyl]methanesulfonamide (6.5 mg, 5%).

[00437] The following compound was prepared using a methodology similar to that described in Example 4:

4-[4-[6-(Difluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-2-yl]-2-(1 H -pyrazol-4-yl)morpholine, I-18

Example 5: 1-[4-[6-[6-(Trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]-2-pyridyl]piperazin-1-yl]ethanone, I-11

Step 1: tert-Butyl 4-[6-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]-2-pyridyl]piperazine-1-carboxylate

[00438] Mixture of 3-iodo-6-(trifluoromethyl)imidazo[1,2- a ]pyridine (50 mg, 0.160 mmol), tert - butyl-4-[6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine-1-carboxylate (62.4 mg, 0.160 mmol), dppf (8.8 mg, 0.016 mmol), Pd(OAc) ₂ (1 .8 mg, 0.008 mmol), CuCl (15.9 mg, 0.160 mmol) and Cs ₂ CO ₃ (156.6 mg, 0.481 mmol) in DMF (1 ml) were degassed with nitrogen and heated at 90°C for 16 h The reaction mixture was cooled to ambient temperature, filtered through a pad of silica gel and concentrated under reduced pressure to give tert - butyl-4-[6-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]- 2-pyridyl]piperazine-1-carboxylate; ESV-MS m/z 448.2 (M+H). The substance was used without additional purification.

Step 2: 3-(6-Piperazin-1-yl-2-pyridyl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine

[00439] tert - Butyl 4-[6-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]-2-pyridyl]piperazine-1-carboxylate was dissolved in DCM (2 ml) and TFA (1 ml, 12.98 mmol) was added. The mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in methanol and purified using an SCX-2 ion exchange cartridge to give 3-(6-piperazin-1-yl-2-pyridyl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine; ESV-MS m/z 348.1 (M+H).

Step 3: 1-[4-[6-[6-(Trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]-2-pyridyl]piperazin-1-yl]ethanone

[00440] Acetyl chloride (15 μL, 0.208 mmol) and triethylamine (67 μL, 0.481 mmol) were added to a solution of 3-(6-piperazin-1-yl-2-pyridyl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine in CH ₂ Cl ₂ (1 ml) and stirred for 20 minutes. The mixture was concentrated and purified by reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to give 1-[4-[6-[6-(trifluoromethyl)imidazo[1,2- a] trifluoroacetate ]pyridin-3-yl]-2-pyridyl]piperazin-1-yl]ethanone (5.5 mg, 5%).

Example 6: 2-( 1H -Pyrazol-4-yl)-4-[6-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]-2-pyridyl]morpholine, I- 12

[00441] 3-Bromo-6-(trifluoromethyl)imidazo[1,2- a ]pyridine (100 mg, 0.377 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyridine (84.2 mg, 0.377 mmol), dppf (20.6 mg, 0.038 mmol), Pd(OAc) ₂ (4.2 mg, 0.0189 mmol), CuCl (37 .4 mg, 0.377 mmol) and Cs ₂ CO ₃ (368.8 mg, 1.132 mmol) in DMF (2 ml) were degassed with nitrogen and heated at 90°C for 16 hours. The reaction mixture was cooled to ambient temperature and filtered through layer of silica gel. Diisopropylethylamine (48.8 mg, 66 μl, 0.377 mmol) and 2-( 1H -pyrazol-4-yl)morpholine (57.8 mg, 0.377 mmol) were added directly to the filtrate and the mixture was heated at 120°C for 16 The reaction mixture was cooled to ambient temperature, filtered and purified by reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to give 2-( 1H -pyrazol-4-yl) trifluoroacetate. -4-[6-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]-2-pyridyl]morpholine (3.1 mg, 2%).

Example 7: 4-[4-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)-1,3,5-triazin-2-yl]-2-(1H - pyrazol-4-yl )morpholine, I-22

Step 1: 4-(4-Chloro-1,3,5-triazin-2-yl)-2-( 1H- pyrazol-4-yl)morpholine

[00442] 2-( 1H -pyrazol-4-yl)morpholine (51.1 mg, 0.333 mmol). The reaction mixture was stirred for 90 minutes and then partitioned between DCM and water, the organics were extracted, dried (MgSO ₄ ), filtered and concentrated to give 4-(4-chloro-1,3,5-triazin-2-yl) -2-( 1H- pyrazol-4-yl)morpholine; ESV-MS m/z 267.1 (M+H). The substance was used without additional purification.

Step 2: 4-[4-[( E )-2-Ethoxyvinyl]-1,3,5-triazin-2-yl]-2-( 1H- pyrazol-4-yl)morpholine

[00443] 4-(4-Chloro-1,3,5-triazin-2-yl)-2-( 1H- pyrazol-4-yl)morpholine was dissolved in DME (750 μl) and 2-(2-ethoxyvinyl )-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (99 mg, 0.5 mmol) and Na ₂ CO ₃ (500 μl 2M, 1 mmol) were added. The mixture was degassed using vacuum/nitrogen cycles (×3), then Pd(PPh ₃ ) ₄ (38.5 mg, 0.033 mmol) was added and the mixture was degassed again using vacuum/nitrogen cycles (x3). The mixture was heated at 40°C for 2 hours. The reaction mixture was purified by column chromatography (silica, EtOAc/petroleum ether, gradient) to give 4-[4-[( E )-2-ethoxyvinyl]-1. 3,5-triazin-2-yl]-2-(1H - pyrazol-4-yl)morpholine; ESV-MS m/z 303.2 (M+H).

Step 3: 4-[4-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)-1,3,5-triazin-2-yl]-2-(1H - pyrazol-4-yl )morpholine

[00444] NBS (5.9 mg, 0.033 mmol) was added to a solution of 4-[4-[( E )-2-ethoxyvinyl]-1,3,5-triazin-2-yl]-2-( 1H - pyrazol-4-yl)morpholine (10 mg, 0.033 mmol) in 1,4-dioxane (300 µl)/water (100 µl) and the reaction mixture was stirred for 15 min. 5-Chloropyridin-2-amine (5.1 mg, 0.040 mmol) was then added and the reaction mixture was heated to 65°C. After 16 h, the reaction mixture was cooled to ambient temperature, filtered and purified by reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) to give 4-[4-(6-chloroimidazo[1] trifluoroacetate ,2- a ]pyridin-3-yl)-1,3,5-triazin-2-yl]-2-( 1H -pyrazol-4-yl)morpholine (4.9 mg, 26%).

Example 8: ((1-(2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)( methyl)-λ ⁶ -sulfanone ( trans-diastereoisomer ), I-46

Step 1: 6-Chloro-3-[4-[2,5-dimethyl-3-(methylsulfinylmethyl)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2- a ]pyridine (trans-diastereoisomer)

[00445] 6-Chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine (30 mg, 0.113 mmol), 2,5-dimethyl-3-( methylsulfinylmethyl)piperidine (dihydrochloride) (42 mg, 0.160 mmol), DIPEA (60 µl, 0.345 mmol) and NMP (900 µl), then sealed and heated at 100°C for 16 hours. The reaction mixture was allowed to cool, then purified with using reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to obtain 6-chloro-3-[4-[2,5-dimethyl-3-(methylsulfinylmethyl)-1-piperidyl] pyrimidin-2-yl]imidazo[1,2- a ]pyridine (11 mg, 45%).

Step 2: ((1-(2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)( methyl)-λ ⁶ -sulfanone (trans-diastereoisomer)

[00446] Methanol (375 μl) was added to a mixture of 6-chloro-3-[4-[2,5-dimethyl-3-(methylsulfinylmethyl)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyridine (11.2 mg, 0.144 mmol) and (diacetoxyiodo)benzene (34.7 mg, 0.108 mmol), then DCM (375 μl) was added. The reaction mixture was stirred at ambient temperature for 3 hours. The crude reaction mixture was filtered, then purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give ((1-(2 -(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)(methyl)- λ⁶-sulfanone (3 mg, 19%, trans-diastereoisomer) I-46.

[00447] The following compound was prepared using a methodology similar to that described in Example 8:

((1-(2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)(methyl)- ^λ6 -sulfanone ( cis-diastereoisomer ), I-47

Example 9: 6-chloro-3-{4-cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl]-pyrimidin-2- yl}-imidazo[1,2- a ]pyridine, I-54

[00448] Into a microwave-safe container containing 6-chloro-3-(4-chloropyrimidin-2-yl)-imidazo[1,2- a ]pyridine (50.00 mg; 0.19 mmol; 1.00 eq. .) and rac-(2r,6r)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholine hydrochloride (41.43 mg; 0.19 mmol; 1.00 equiv .), DIPEA (0.11 ml; 0.66 mmol; 3.50 eq.) and acetonitrile (2.00 ml) were added. The reaction mixture was stirred at 85°C for 2 hours, then the mixture was diluted in 5 ml DMSO (partial dissolution), filtered and purified in an alkaline environment using preparative HPLC (C18.10-90% ACN/H ₂ O/0.1 % NH ₄ OH as eluent) and obtained 6-chloro-3-{4-cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholine-4- yl]-pyrimidin-2-yl}-imidazo[1,2- a ]pyridine (5.0 mg, 6.4%)

[00449] The following compounds were prepared using a methodology similar to that described in Example 9:

6-Chloro-3-{4-[3-(1H-imidazol-4-yl)-piperidin-1-yl]-pyrimidin-2-yl}-imidazo[1,2- a ]pyridine, I-55

3-(2-((3R,5R)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-136 (after chiral separation)

3-(2-((3S,5S)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-137 (after chiral separation)

5-methyl-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid amide, I-149

( S )-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid amide, I-154

5,5-difluoro-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid methyl ester, I-570

[00450] 2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a] pyridin-3-yl]pyrimidin I-136 and 3-(2-((3S,5S)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-137 was purified by preparative chiral HPLC as described below:

[00451] (2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a ]pyridin-3-yl]pyrimidine (200 mg, 0.42 mmol, 1 equiv., 90%) was purified using preparative chiral HPLC under the following conditions (Column: Chiralpak IA, 2*25 cm, 5 µm; Mobile phase A : Hex(8 mmol/l NH3.MeOH)--HPLC, Mobile phase B: IPA--HPLC; Flow rate: 20 ml/min; Gradient mode: from 20 V to 20 V in 25 min; 254/220 nm; RT1:11.829) This gave 116.2 mg (63.86%) 2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4- [6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine I-136 as a white solid.

[00452] 2-[(3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2-a] pyridin-3-yl]pyrimidine 200 mg, 0.42 mmol, 1 equiv, 90%) was purified using preparative chiral HPLC under the following conditions (Column: Chiralpak IA, 2*25 cm, 5 µm; Mobile phase A: Hex (8 mmol/l NH3.MeOH)--HPLC, Mobile phase B: IPA--HPLC; Flow rate: 20 ml/min; Gradient mode: from 20 V to 20 V in 25 min; 254/220 nm; RT2: 19.149). This gave 117.8 mg 2-[(3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2 -a]pyridin-3-yl]pyrimidine I-137 as a white solid

Example 10: 6-Chloro-7-fluoro-3-{4-[cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl] -pyrimidin-2-yl}-imidazo[1,2- a ]pyridine, I-56

[00453] Into a microwave-safe container containing 6-chloro-3-(4-chloropyrimidin-2-yl)-7-fluorimidazo[1,2- a ]pyridine (50.00 mg; 0.18 mmol; 1. 00 equiv.) and rac-(2r,6r)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl) morpholin hydrochloride (38.80 mg; 0.18 mmol; 1, 00 eq.), DIPEA (0.10 ml; 0.62 mmol; 3.50 eq.) and acetonitrile (2.00 ml) were added. The reaction mixture was stirred at 85°C for 2 hours. The white precipitate was filtered off, washed with H ₂ O (2 ml×2), dried to obtain 6-chloro-7-fluoro-3-{4-[cis-2- methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl]-pyrimidin-2-yl}-imidazo[1,2- a ]pyridine (75.9 mg, 79.2%).

[00454] The following compounds were prepared using a methodology similar to that described in Example 10:

6-Chloro-7-fluoro-3-{4-[3-(1H-imidazol-4-yl)-piperidin-1-yl]-pyrimidin-2-yl}-imidazo[1,2- a ]pyridine, I-57

3-{4-[(3S,5S)-3-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-piperidin-1-yl]-pyrimidin-2-yl}-6-trifluoromethylimidazo[ 1,2- a ]pyridine (racemic mixture), I-60

3-{4-[(3R,5S)-3-Methyl-5-(1-methyl-1H-pyrazol-4-yl)-piperidin-1-yl]-pyrimidin-2-yl}-6-trifluoromethylimidazo[ 1,2- a ]pyridine (racemic mixture), I-61

1-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-(3-methyl-[1,2,4]oxadiazol-5-yl) -pyrrolidin-3-ol, I-64

6-Chloro-3-[4-(3-isoxazol-4-ylpiperidin-1-yl)-pyrimidin-2-yl]-imidazo[1,2- a ]pyridine, I-65

6-Chloro-3-[4-(3-isoxazol-3-ylpiperidin-1-yl)-pyrimidin-2-yl]-imidazo[1,2- a ]pyridine, I-66

3-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-azabicyclo[4.1.0]heptan-6-ol, I-67

4-{1-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-yl}-4-methyloxazolidin-2-one, I- 68

1-Methyl-4-[2-(6-trifluoromethylimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-[1,4]diazepan-2-one, I-69

3-{4-[(3aR,6aR)-3a-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-hexahydrocyclopenta[c]pyrrol-2-yl]-pyrimidin-2-yl} -6-trifluoromethylimidazo[1,2- a ]pyridine, I-70

3-[4-(3-Methylpiperidin-1-yl)-pyrimidin-2-yl]-6-trifluoromethylimidazo[1,2- a ]pyridine, I-71

1-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-(1-isopropyl-1H-[1,2,3]triazol-4- yl)-pyrrolidin-3-ol, I-72

6-Chloro-3-{4-[(2S,3S)-2-(3-chlorophenyl)-3-methylmorpholin-4-yl]-pyrimidin-2-yl}-7-fluorimidazo[1,2- a ] pyridine (racemic mixture), I-73

3-[2-(6-Trifluoromethylimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-azabicyclo[4.1.0]heptan-1-ol, I-74

6-Chloro-3-{4-[(3aR,6aR)-3a-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-hexahydrocyclopenta[c]pyrrol-2-yl]-pyrimidin- 2-yl}-imidazo[1,2- a ]pyridine (racemic mixture), I-75

1-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-(1-isopropyl-1H-[1,2,3]triazol-4- yl)-piperidin-3-ol, I-76

( S )-1-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic acid (1-methyl-1H -pyrazol-4-yl)-amide, I-77

5-[2-(6-Chloroimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-5-azaspiro2.5]octane-1-carboxylic acid, I-78

6-Chloro-3-[4-(7,7-difluoro-6-methyl-3-azabicyclo[4.1.0]hept-3-yl)-pyrimidin-2-yl]-imidazo[1,2- a ] pyridine, I-79

4-[2-(6-Trifluoromethylimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-[1,4]diazepan-2-one, I-80

1-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-phenylpiperidin-3-ol, I-81

1-{1-[2-(6-chloroimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-hydroxypiperidin-3-yl}-cyclobutanecarboxylic acid methyl ester, I-82

{1-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-phenylpiperidin-4-yl}-methanol, I-83

6-Chloro-3-[4-(1-phenyl-3-azabicyclo[3.1.0]hex-3-yl)-pyrimidin-2-yl]-imidazo[1,2- a ]pyridine, I-84

{1-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-3-phenylpiperidin-3-yl}-methanol, I-85

Example 11: ( S )-1-[2-(6-Chloro-7-fluoroimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid, I- 58

Step 1: ( S )-1-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid

[00455] To a solution of 6-Chloro-3-(4-chloropyrimidin-2-yl)-7-fluoroimidazo[1,2- a ]pyridine (120.00 mg; 0.42 mmol; 1.00 eq.) and ( R )-(-)-nipenicotinic acid (54.75 mg; 0.42 mmol; 1.00 eq.) in acetonitrile (2.00 ml) was added TEA (0.15 ml; 1.06 mmol; 2. 50 eq.) and stirred at 85°C for 3 hours. The white precipitate was dried and used in the next step.

Step 2: ( 1H- Pyrazol-4-yl)-amide ( S )-1-[2-(6-chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4- yl]-piperidine-3-carboxylic acid

[00456] Into a round bottom flask containing ( S )-1-[2-(6-Chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3- carboxylic acid (50.00 mg; 0.10 mmol; 1.00 eq.) and 1H-pyrazol-4-ylamine (8.27 mg; 0.10 mmol; 1.00 eq.) in DCM (2.00 ml) TEA (0.03 ml; 0.22 mmol; 2.20 eq.) was added. After stirring at RT for 2 min, 1-propanephosphonic anhydride (63.37 mg; 0.20 mmol; 2.00 eq.) was added in two portions. The reaction mixture was stirred at RT for 15 min, then it was concentrated, diluted with 2 ml MeOH/1 ml DMSO, filtered and purified in an alkaline medium using preparative HPLC (10-90% I/H ₂ O/0.1% NH ₄ OH as eluent) and obtained (1H-pyrazol-4-yl)-amide ( S )-1-[2-(6-chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)- pyrimidin-4-yl]-piperidin-3-carboxylic acid (43.9 mg, 15.6%).

[00457] The following compounds were prepared using a methodology similar to that described in Example 11:

(1-methyl-1H-pyrazol-4-yl)-amide ( S )-1-[2-(6-chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4- yl]-piperidine-3-carboxylic acid, I-59

pyridin-4-ylamide ( S )-1-[2-(6-chloro-7-fluorimidazo[1,2- a ]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid, I-86

Example 12: (3S)-1-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)piperidin-3-amine, I-87

Step 1: tert-butyl-N-[( 3S )-1-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)piperidin-3-yl]carbamate

[00458] To a mixture of tert-butyl-N-[(3S)-piperidin-3-yl]carbamate (195.3 mg, 0.98 mmol) and 6-chloro-3-(4-chloropyrimidin-2-yl) imidazo[1,2- a ]pyridine (198.8 mg, 0.75 mmol) in DCM (3.75 ml) was added triethylamine (0.21 ml, 1.50 mmol). After stirring overnight at room temperature, the reaction was quenched with water (3 ml) and extracted with DCM (2 x 5 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and the solvent was removed in vacuo to give tert-butyl-N-[(3S)-1-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl} pyrimidin-4-yl)piperidin-3-yl]carbamate; ESI-MS m/z 429.2 (M+H). The substance was used without additional purification.

Step 2: ( 3S )-1-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)piperidin-3-amine

[00459] N-[(3S)-1-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)piperidin-3-yl]carbamate was dissolved in 1.4 -dioxane (3 ml) and added 4 N. HCl in 1,4-dioxane (3 ml, 35.2 mmol). The mixture was stirred for 1 hour at 40°C and then concentrated under reduced pressure. The residue was dissolved in DMSO and purified by reverse phase chromatography (C18; MeCN/water/0.01% NH ₄ OH as eluent) to give (3S)-1-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)piperidin-3-amine (72.7 mg, 29%).

Example 13: 6-Chloro-7-fluoro-3-[4-(2-pyridin-2-ylmorpholin-4-yl)-pyrimidin-2-yl]-imidazo[1,2- a ]pyridine, I-88

[00460] 6-Chloro-4-(4-chloropyrimidin-2-yl)-7-fluoromidazo[1,2- a ]pyridine (50.0 mg, 0.18 mmol), 2-(pyridin-2-yl )morpholine (35.0 mg, 0.21 mmol), triethylamine (20 μl, 0.18 mmol) in DMF (1.0 ml) was heated at 80°C. After 14 h, the reaction mixture was cooled to room temperature and the mixture was filtered and purified by reverse phase chromatography (C18; MeCN/water/0.01% NH ₄ OH as eluent) to give 6-chloro-7-fluoro-3- [4-(2-pyridin-2-ylmorpholin-4-yl)-pyrimidin-2-yl]-imidazo[1,2- a ]pyridine (11.1 mg, 16%).

[00461] The following compounds were prepared using a methodology similar to that described in Example 13:

cis-2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-4-{2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl ]pyrimidin-4-yl}morpholine, I-93 (using 3-(4-xchloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine)

3-{4-[cis-2-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)morpholin-4-yl]pyrimidin-2-yl}imidazo[1,2- a ]pyridine-6-carbonitrile, I-94 (using 3-(4-chloropyrimidin-2-yl)imidazo[1,2- a ]pyridine-6-carbonitrile)

cis-4-(2-{6-chlorimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)-2-methyl-6-(5-methyl-1,3,4-oxadiazol- 2-yl)morpholine, I-95 (using 4-chloro-2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidine)

2-(2-{6-chlorimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)-octahydro-1H-pyrazino[1,2-c]pyrimidin-6-one, I-96 (using 4-chloro-2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidine)

7-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)-octahydroimidazo[1,5- a ]pyrazin-3-one, I-97 (using 4 -chloro-2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidine)

2-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)-octahydropyrazino[1,2-c][1,3]oxazin-6-one, I- 98 (using 4-chloro-2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidine)

7-(2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidin-4-yl)-hexahydro-1H-[1,3]oxazolo[3,4- a ]pyrazin-3- he, I-99 (using 4-chloro-2-{6-chloroimidazo[1,2- a ]pyridin-3-yl}pyrimidine)

2-{6-chlorimidazo[1,2- a ]pyridin-3-yl}-4-[3-(1H-pyrazol-4-yl)piperidin-1-yl]pyrimidine, I-100 (using 4- chloro-2-{6-chlorimidazo[1,2- a ]pyridin-3-yl}pyrimidine)

4-[3-(1H-pyrazol-4-yl)piperidin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidine, I-101 (c using 3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a ]pyridine)

Example 14: 2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3- yl]pyrimidin-4-yl}morpholine, I-89 and I-90

[00462] Racemic mixture of cis-(2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-4-{2-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-4-yl}morpholine (prepared using a methodology similar to that described in example 1) was separated using chiral supercritical liquid chromatography (conditions: IA-H, MeOH + 0.5% DMEA, 2 ml/ min, 220 nm) The first compound to elute was I-89 (98% ee); ESI-MS m/z 446.2 (M+H). The second compound to elute was I-90 (98% ee); ESI -MS m/z 446.2 (M+H).

[00463] The following compounds were prepared using a methodology similar to that described in Example 14:

3-{4-[(2S,6S)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)morpholin-4-yl]pyrimidin-2-yl}imidazo[1 ,2- a ]pyridine-6-carbonitrile, I-91 and 3-{4-[(2R,6R)-2-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl) morpholin-4-yl]pyrimidin-2-yl}imidazo[1,2- a ]pyridin-6-carbonitrile, I-92

Example 15: Typical connections I-102 - I-113.

[00464] Additional compounds were prepared using methodologies similar to those described above in Examples 1-14:

( S )-1-(2-(6-chloroimidazo[1,2- a ]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-102

N -((( 3S , 5S )-1-(3-(6-(difluoromethyl)imidazo[1,2- a ]pyridin-3-yl)-1,2,4-thiadiazol-5-yl) -4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide, I-103

2-(1 H -pyrazol-4-yl)-4-(3-(6-(trifluoromethyl)imidazo[1,2 -a ]pyridin-3-yl)-1,2,4-thiadiazol-5-yl )morpholine, I-104

4-(3-(6-(difluoromethyl)imidazo[1,2- a ]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)-2-(1 H -pyrazol-4-yl )morpholine, I-105

( S )- N -((4-(3-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)morpholine-2- yl)methyl)methanesulfonamide, I-106

( S )- N -((4-(3-(6-(difluoromethyl)imidazo[1,2- a ]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)morpholine-2- yl)methyl)methanesulfonamide, I-107

2-( 1H- pyrazol-4-yl)-4-(5-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)-1,2,4-thiadiazol-3-yl )morpholine, I-108

( S )- N -((4-(5-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)-1,2,4-thiadiazol-3-yl)morpholine-2- yl)methyl)methanesulfonamide, I-109

N -((1-(5-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)-1,2,4-thiadiazol-3-yl)piperidin-3-yl)methyl) methanesulfonamide, I-110

( S )- N -((4-(4-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)thiazol-2-yl)morpholin-2-yl)methyl)methanesulfonamide, I -111

N -((1-(3-(6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl)-1,2,4-thiadiazol-5-yl)piperidin-3-yl)methyl) methanesulfonamide, I-112

( S ) -N -((4-(6-(6-chloroimidazo[1,2- a ]pyridin-3-yl)pyrazin-2-yl)morpholin-2-yl)methyl)methanesulfonamide, I-113

Example 16: 6-chloro-3-{4-cis-2-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-yl)-morpholin-4-yl]-pyrimidin-2- yl}-imidazo[1,2- a ]pyridine, I-114

[00465] Place 2-chloro-4-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidine (200,000 mg, 0.60 mmol, 1.00 eq) into a 25 mL sealed tube ., 90%), 3-methyl-5-(1H-pyrazol-4-yl)piperidine (110.658 mg, 0.60 mmol, 1.00 eq., 90%), DIEA (163.993 mg, 1.21 mmol , 2.00 eq., 95%), isopropanol (10,000 ml, 124.30 mmol, 206.24 eq., 95%). The resulting solution was stirred overnight at 100°C. The resulting mixture was concentrated in vacuo. The crude product (300 mg) was purified using preparative HPLC under the following conditions (Prep-HPLC-015): Column, XBridge Shield RP18 OBD Column, 30*150 mm, 5 µm; mobile phase, water (10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O) and ACN (from 43.0% ACN to 47.0% in 9 min); Detector, uv 254 nm. This gave 23.9 mg (9%) 2-[3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl]-4-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidine I-114 as a white solid.

[00466] The following compounds were prepared using a methodology similar to that described in Example 16:

cis-2-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-2 -yl}morpholine, I-115

cis-2-Methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2- a ]pyridin-3-yl]pyrimidin-2-yl}morpholine , I-117

3-{4-[cis-2-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-2-yl}-6-trifluoromethylimidazo[1,2- a ]pyridine, I-119

Table 2: Analysis data for compounds of formula I

[00467] The purity and retention time of the compounds of the present invention were determined using HPLC.

[00468] HPLC Procedure: Analytical reverse phase UPLC-MS was performed using a Waters Acquity UPLC-MS system equipped with a Waters BEH 1.7 mm C-18 reverse phase column (2.1 mm x 50 mm, 1.7 µm ). The mobile phases were acetonitrile and water/acetonitrile (95:5 with 10 mM ammonium formate, pH 9). Study duration 5 min

Connection No. LCMS (ES+) LCMS (rt, min) ^1H NMR I-1 457.2 2.46 (500 MHz, methanol-d4) δ 10.40 (s, 1H), 8.71 (s, 1H), 8.34 (d, 1H), 8.03 (d, 1H), 7.93 (dd , 1H), 6.91 (d, 1H), 4.58-4.34 (m, 1H), 4.13 (ddd, 1H), 3.80-3.68 (m, 2H), 3, 22-3.12 (m, 1H), 2.99 (s, 3H) I-2 416.8 2.37 (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 8.42 (d, 1H), 7.99 (d, 1H), 7.75 (dd , 1H), 7.69 (s, 2H), 6.95 (d, 1H), 4.60 (dd, 1H), 4.08-4.01 (m, 1H), 3.23 (dd, 2H) I-3 416.4 2.37 (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.65 (s, 1H), 8.42 (d, 1H), 7.99 (d, 1H), 7.75 (dd , 1H), 7.69 (s, 2H), 6.95 (d, 1H), 4.60 (dd, 1H), 4.08-4.01 (m, 1H), 3.23 (dd, J= 13.1, 10.6 Hz, 2H) I-4 439.2 2.41 (500 MHz, DMSO-d6) δ 10.43-10.36 (m, 1H), 8.61 (d, 1H), 8.40 (dd, 1H), 7.97 (dt, 1H), 7 .72 (dd, 1H), 6.79 (d, 1H), 3.90-3.66 (m, 2H), 3.62 (d, 3H), 3.37-3.08 (m, 2H ), 2.36 (d, 1H), 2.02 (s, 1H), 1.79 (s, 1H), 1.68-1.47 (m, 2H) I-5 404.5 2.24 (500 MHz, methanol-d4) δ 10.38-10.32 (m, 1H), 8.75 (s, 1H), 8.34 (d, 1H), 8.04 (d, 1H), 7 .94 (dd, 1H), 6.99 (d, 1H), 4.79-4.65 (m, 1H), 4.65-4.47 (m, 1H), 4.01-3.88 (m, 2H), 3.65 (dd, 1H), 3.29-3.17 (m, 3H), 3.12 (ddd, 1H) I-6 404.4 2.24 (500 MHz, methanol-d4) δ 10.38-10.32 (m, 1H), 8.75 (s, 1H), 8.34 (d, 1H), 8.04 (d, 1H), 7 .94 (dd, 1H), 6.99 (d, 1H), 4.79-4.65 (m, 1H), 4.65-4.47 (m, 1H), 4.01-3.88 (m, 2H), 3.65 (dd, 1H), 3.29-3.17 (m, 3H), 3.12 (ddd, 1H) I-7 481.2 3.13 (500 MHz, DMSO- d 6) δ 10.47 (d, 1H), 8.47 (s, 1H), 8.36 (d, 1H), 7.96 (d, 1H), 7.70 ( dd, 1H), 6.48 (s, 2H), 3.72-3.65 (m, 6H), 2.95 (s, 3H), 2.88 (dd, 2H), 2.16-2 .08 (m, 2H), 1.96 (p, 2H), 1.51 (d, 2H) I-8 398.1 1.47 (400 MHz, d4-MeOH) δ 8.81 (d, 1H), 7.16 (d, 1H), 3.98 (dd, 1H), 3.76 (dt, 1H), 3.50 (dd , 1H), 3.35 (ddd, 1H), 2.68 (tt, 1H), 2.05 (dt, 1H), 1.88-1.58 (m, 3H) I-9 416.1 2.39 (500 MHz, methanol-d4) δ 10.50 (s, 1H), 8.56 (s, 1H), 8.44 (d, 1H), 7.89 (d, 1H), 7.73 (br s, 2H) 7.70 (dd, 1H), 7.26 (d, 1H), 4.74-4.70 (m, 2H), 4.58 (d, 1H), 4.13 (ddd, 1H), 3.87 (td, 1H), 3.37-3.28 (m, 2H) I-10 416.3 2.38 (500 MHz, methanol-d4) δ 10.50 (s, 1H), 8.56 (s, 1H), 8.44 (d, 1H), 7.89 (d, 1H), 7.74 (br s, 2H), 7.70 (dd, 1H), 7.26 (d, 1H), 4.74-4.70 (m, 2H), 4.58 (d, 1H), 4.13 (ddd , 1H), 3.87 (td, 1H), 3.37-3.28 (m, 2H) I-11 390.1 2.65 (500 MHz, methanol-d4) δ 10.66 (s, 1H), 8.58 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H), 7.77 (dd , 1H), 7.37 (d, 1H), 6.94 (d, 1H), 3.84-3.68 (m, 8H), 2.20 (s, 3H) I-12 415.2 2.6 (500 MHz, DMSO-d6) δ 10.35 (dt, 1H), 8.47 (s, 1H), 7.89 (dt, 1H), 7.76 (s, 1H), 7.72 (dd , 1H), 7.58 (dd, 1H), 7.53 (s, 1H), 7.39 (d, 1H), 6.92 (d, 1H), 4.63 (dd, 1H), 4 .30-4.22 (m, 1H), 4.13-4.00 (m, 2H), 3.78 (td, 1H), 3.10 (td, 1H), 3.05 (dd, 1H ) I-13 439.1 2.18 (500 MHz, methanol-d4) δ 10.18 (tt, 1H), 8.45 (s, 1H), 8.30 (d, 1H), 7.78 (dd, 1H), 7.60 (dd , 1H), 7.03 (t, 1H), 6.65 (d, 1H), 4.41 (s, 1H), 4.27 (d, 1H), 4.12 (ddd, 1H), 3 .78-3.66 (m, 2H), 3.30 (dd, 1H), 3.22-3.14 (m, 2H), 3.05 (s, 3H), 2.95 (dd, 1H ) I-14 373.1 2.12 (500 MHz, DMSO-d6) δ 10.17 (d, 1H), 8.65 (s, 1H), 8.40 (d, 1H), 7.96 (dd, 1H), 7.72 (dd , 1H), 7.31 (t, 1H), 6.87 (d, 1H), 3.88-3.81 (m, 2H), 3.81-3.74 (m, 2H), 3, 65-3.60 (m, 4H), 2.08 (s, 3H) I-15 398.1 2.16 (500 MHz, DMSO-d6) δ 10.18 (d, 1H), 8.64 (s, 1H), 8.40 (d, 1H), 7.94 (d, 1H), 7.75-7 .64 (m, 3H), 7.24 (t, 1H), 6.93 (d, 1H), 4.60 (dd, 1H), 4.09-4.00 (m, 1H), 3, 72 (td, 1H), 3.26-3.16 (m, 1H) I-16 487.2 2.71 ---- I-17 439.1 2.25 (500 MHz, methanol-d4) δ 10.38 (dd, 1H), 8.83 (s, 1H), 8.47 (d, 1H), 8.11-7.99 (m, 2H), 7 .27 (d, 1H), 7.15 (td, 1H), 4.60 (ddd, 1H), 4.50 (dt, 1H), 4.10 (ddd, 1H), 3.77-3, 64 (m, 2H), 3.30-3.22 (m, 2H), 3.05 (dd, 1H), 2.99 (s, 3H) I-18 398.1 2.2 (500 MHz, methanol-d4) δ 10.38 (d, 1H), 8.86 (s, 1H), 8.50 (d, 1H), 8.13-7.98 (m, 2H), 7 .76 (s, 2H), 7.29 (d, 1H), 7.01 (t, 1H), 4.71 (dt, 2H), 4.59-4.51 (m, 1H), 4, 14 (ddd, 1H), 3.86 (td, 1H), 3.43-3.32 (m, -2H) I-19 423.1 2.3 (500 MHz, methanol-d4) δ 10.13 (dd, 1H), 8.73 (s, 1H), 8.33 (d, 1H), 7.95 (dd, 1H), 7.92 (dd , 1H), 6.91 (d, 1H), 4.54 (s, 1H), 4.36 (s, 1H), 4.19-4.08 (m, 1H), 3.79-3, 66 (m, 2H), 3.34 (d, 3H), 3.13 (dd, 1H), 2.99 (s, 3H) I-20 382.1 2.24 (500 MHz, DMSO-d6) δ 10.02 (d, 1H), 8.60 (s, 1H), 8.41 (d, 1H), 7.87 (d, 1H), 7.70 (s , 2H), 7.63 (dd, 1H), 6.92 (d, 1H), 4.60 (dd, 1H), 4.05 (dd, 1H), 3.71 (td, 1H), 3 .22 (td, 2H) I-21 405.1 2.26 (500 MHz, DMSO-d6) δ 10.03 (dd, 1H), 8.56 (d, 1H), 8.38 (dd, 1H), 7.86 (d, 1H), 7.61 (dd , 1H), 6.80 (dd1H), 3.94-3.68 (m, 2H), 3.64 (d, 3H), 3.23 (dd, 2H), 2.44-2.32 ( m, 1H), 2.02 (d, 1H), 1.85-1.73 (m, 1H), 1.67-1.45 (m, 2H) I-22 383.1 2.23 (500 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.74 (s, 1H), 8.66 (d, 1H), 7.87 (d, 1H), 7.69 (d , 2H), 7.63 (d, 1H), 4.80-4.65 (m, 1H), 4.65-4.48 (m, 2H), 4.11-3.96 (m, 1H ), 3.68 (d, 1H) I-23 400.1 2.36 (500 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.14 (d, 1H), 8.45 (d, 1H), 8.38 (dd, 1H), 7.91 (d , 1H), 7.70 (s, 2H), 6.86 (d, 1H), 4.59 (dd, 1H), 4.56-4.15 (m, 2H), 4.12-4, 01 (m, 1H), 3.71 (td, 1H), 3.24-3.09 (m, 2H) I-24 446 2.35 (500 MHz, DMSO-d6) δ 10.20 (d, 1H), 8.51 (s, 1H), 8.40 (d, 1H), 7.92 (d, 1H), 7.70 (s , 2H), 6.90 (d, 1H), 4.59 (dd, 1H), 4.09-4.00 (m, 1H), 3.70 (dd, 1H), 3.28-3, 12 (m, 2H) I-25 469.1 2.5 (500 MHz, DMSO-d6) δ 10.35 (d, 1H), 8.39 (s, 1H), 8.29 (d, 1H), 7.88 (d, 1H), 7.22 (d , 1H), 6.43 (s, 1H), 3.81-3.42 (m, 5H), 3.10-3.02 (m, 2H), 2.93 (s, 3H), 2, 17 (s, 1H), 1.84 (s, 1H) I-26 343.1 2.0 (400 MHz, DMSO-d6) δ 10.04-9.98 (m, 1H), 8.47 (s, 1H), 8.37 (d, J= 6.2 Hz, 1H), 7.85 -7.77 (m, 1H), 7.69 (t, J= 5.6 Hz, 1H), 7.52 (dd, J= 9.5, 2.1 Hz, 1H), 6.80 ( d, J= 6.3 Hz, 1H), 3.91 (s, 4H), 3.30 (s, 3H), 2.62 (d, J= 6.8 Hz, 2H). I-27 366.1 2.42 (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.13 (dd, J= 2.2, 0.9 Hz, 1H), 8.42 (s, 1H), 8.28 (d, J= 5.9 Hz, 1H), 7.79 (dd, J= 9.5, 0.9 Hz, 1H), 7.69 (s, 1H), 7.49 (dd, J= 9.6, 2.1 Hz, 2H), 6.43 (d, J= 6.1 Hz, 1H), 3.85 (d, J= 30.4 Hz, 1H), 3.63 (d, J= 35.1 Hz, 1H), 3.49 (d, J= 8.0 Hz, 2H), 2.42 (d, J= 18.1 Hz, 1H), 2.05 (s, 1H) , 0.99-0.90 (m, 1H). I-28 381.1 2.0 ---- I-29 456.1 1.89 ---- I-30 405.1 2.25 (400 MHz, DMSO-d6) δ 10.04 (dd, J= 2.1, 0.8 Hz, 1H), 8.42 (s, 1H), 8.31 (d, J= 6.3 Hz , 1H), 7.79 (dd, J= 9.5, 0.8 Hz, 1H), 7.49 (dd, J= 9.5, 2.2 Hz, 1H), 6.71 (d, J= 6.3 Hz, 1H), 3.30 (s, 2H), 3.05 (d, J= 0.9 Hz, 3H), 3.02 (d, J= 1.0 Hz, 3H) , 2.97 (d, J= 3.4 Hz, 1H), 2.86 (s, 2H), 1.91 (dd, J= 9.1, 4.9 Hz, 1H), 1.77 ( d, J= 11.5 Hz, 1H), 1.50 (t, J= 9.4 Hz, 2H). I-31 453.1 2.55 (500 MHz, methanol-d4) δ 10.33 (s, 1H), 8.39 (s, 1H), 8.15 (d, 1H), 7.74 (d, 1H), 7.54 (dd , 1H), 6.56 (d, 1H), 4.40 (br s, 2H), 3.22 (masked, 1H), 3.04 (d, 6H), 2.98 (s, 1H), 2.60 (m, 1H), 2.43 (m, 1H), 1.93 (m, 1H), 1.67 (m, 1H), 1.27 (d, 1H), 1.18 (qd , 1H), 0.93 (d, 3H). I-32 453.1 2.55 (500 MHz, methanol-d4) δ 10.33 (s, 1H), 8.39 (s, 1H), 8.15 (d, 1H), 7.74 (d, 1H), 7.54 (dd , 1H), 6.56 (d, 1H), 4.40 (br s, 2H), 3.22 (masked, 1H), 3.04 (d, 6H), 2.98 (s, 1H), 2.60 (m, 1H), 2.43 (m, 1H), 1.93 (m, 1H), 1.67 (m, 1H), 1.27 (d, 1H), 1.18 (qd , 1H), 0.93 (d, 3H). I-33 443.1 2.37 ---- I-34 443.1 2.37 (500 MHz, methanol-d4) δ 10.60-10.22 (m, 1H), 8.53 (s, 1H), 8.41 (d, J= 5.2 Hz, 1H), 7.86 (d, J= 9.5 Hz, 1H), 7.73 (s, 2H), 7.68 (d, J= 9.3 Hz, 1H), 7.22 (d, J= 5.2 Hz , 1H), 5.05 (s, 1H), 4.64 (s, 1H), 4.50 (s, 1H), 3.29-3.19 (m, 1H), 2.99 (s, 1H), 1.38 (d, J= 6.3 Hz, 3H), 1.32-0.97 (m, 3H). I-35 409.1 2.29 (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.05 (m, 1H), 8.45 (m, 1H), 8.36 (m, 1H), 7.95 (d , 1H), 7.80 (d, 1H), 7.61 (d, 1H), 6.79 (m, 1H), 5.03-4.60 (m, 1H), 4.23-3, 83 (m, 2H), 2.92 (m, 1H), 2.76 (m, 1H), 2.51 (m, 1H), 1.19 (m, 3H), 0.99 (m, 3H ). I-36 409.3 2.48 (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 10.05 (m, 1H), 8.45 (m, 1H), 8.36 (m, 1H), 7.95 (d , 1H), 7.80 (d, 1H), 7.61 (d, 1H), 6.79 (m, 1H), 5.03-4.60 (m, 1H), 4.23-3, 83 (m, 2H), 2.92 (m, 1H), 2.76 (m, 1H), 2.51 (m, 1H), 1.19 (m, 3H), 0.99 (m, 3H ). I-37 443.4 2.45 (500 MHz, DMSO-d6) δ 10.41 (m, 1H), 8.54 (s, 1H), 8.35 (d, 1H), 7.96 (d, 1H), 7.66-7 .61 (m, 3H), 6.85 (m, 1H), 5.92-5.45 (m, 1H), 4.06 (m, 1H), 2.89 (m, 1H), 2, 80-2.65 (m, 1H), 2.55 (m, 1H), 1.18 (m, 3H), 0.98 (m, 3H). I-38 443.4 2.45 ---- I-39 429.4 2.35 (500 MHz, methanol-d4) δ 10.37 (s, 1H), 8.47 (s, 1H), 8.27 (d, 1H), 7.82 (d, 1H), 7.76 (s , 1H), 7.64 (d, 1H), 6.72 (d, 1H), 4.47 (s, 2H), 4.00 (d, 1H), 3.07-2.97 (m, 2H), 1.26 (d, 3H). I-40 429.4 2.35 ---- I-41 487.3 2.79 (500 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.67 (s, 1H), 8.48 (d, J= 5.3 Hz, 1H), 7.92 (d, J = 9.6 Hz, 1H), 7.62 (dd, J= 9.3, 1.7 Hz, 1H), 7.33 (d, J= 5.3 Hz, 1H), 7.25 (t , J= 55.8 Hz, 1H), 7.25 (s, 1H), 5.12 (d, J= 15.6 Hz, 1H), 4.73 (d, J= 15.0 Hz, 1H ), 3.47-3.42 (m, 1H), 3.01-2.84 (m, 3H), 2.96 (s, 3H), 2.23 (s, 2H), 1.07 ( d, J= 6.6 Hz, 3H). I-42 427.8 2.2 (500 MHz, methanol-d4) δ 10.39-10.32 (m, 1H), 8.72 (d, J= 7.0 Hz, 1H), 8.53-8.38 (m, 2H) , 7.84-7.78 (m, 1H), 7.59 (d, J= 18.5 Hz, 1H), 6.94 (dd, J= 18.3, 6.5 Hz, 1H), 5.33 (s, 1H), 5.14 (d, J= 4.4 Hz, 1H), 4.89 (d, J= 4.1 Hz, 1H), 4.45 (d, J= 14 ,7 Hz, 1H), 4.09 (dq, J= 6.7, 3.8 Hz, 1H), 3.80 (dd, J= 14.8, 3.4 Hz, 1H), 3.65 -3.54 (m, 1H), 3.29 (d, J= 14.1 Hz, 1H), 1.56 (dd, J= 6.7, 2.1 Hz, 3H), 1.31 ( dd, J= 12.3, 7.0 Hz, 3H). I-43 404.1 2.24 (500 MHz, methanol-d4) δ 10.38-10.32 (m, 1H), 8.75 (s, 1H), 8.34 (d, J= 6.9 Hz, 1H), 8.04 (d, J= 9.4 Hz, 1H), 7.94 (dd, J= 9.4, 1.8 Hz, 1H), 6.99 (d, J= 6.9 Hz, 1H), 4 .79-4.65 (m, 1H), 4.65-4.47 (m, 1H), 4.01-3.88 (m, 2H), 3.65 (dd, J= 9.5, 8.4 Hz, 1H), 3.29-3.17 (m, 3H), 3.12 (ddd, J= 13.3, 12.0, 3.4 Hz, 1H). I-44 416.1 2.37 (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.73 (s, 1H), 8.47 (d, J= 5.2 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.74-7.68 (m, 1H), 7.65 (s, 2H), 7.34 (d, J= 5.3 Hz, 1H), 4.63 -4.54 (m, 2H), 4.46 (d, J= 13.3 Hz, 1H), 4.07-3.99 (m, 1H), 3.72 (td, J= 11.6 , 2.9 Hz, 1H), 3.22 (d, J= 11.8 Hz, 1H). I-45 416.2 2.33 (500 MHz, methanol-d4) δ 10.29 (s, 1H), 8.77 (s, 1H), 8.33 (d, J= 7.2 Hz, 1H), 8.06 (dt, J = 9.5, 0.8 Hz, 1H), 7.97 (dd, J= 9.4, 1.8 Hz, 1H), 7.76 (s, 2H), 7.05 (d, J= 7.2 Hz, 1H), 4.76 (dd, J= 10.6, 2.7 Hz, 1H), 4.19 (ddd, J= 11.8, 3.8, 1.6 Hz, 1H ), 3.88 (td, J= 11.8, 2.8 Hz, 1H), 3.59-3.41 (m, 2H). I-46 433.3 2.53 ---- I-47 433.2 2.53 ---- I-48 377.1 2.19 (500 MHz, methanol-d4) δ 10.01 (d, J= 7.0 Hz, 1H), 8.62 (s, 1H), 8.22 (d, J= 7.3 Hz, 1H), 7.82 (dd, J= 8.7, 0.6 Hz, 1H), 7.02 (d, J= 7.3 Hz, 1H), 4.58 (s, 1H), 4.30 (s , 1H), 3.76 (dd, J= 13.5, 9.4 Hz, 1H), 3.60 (t, J= 11.7 Hz, 1H), 2.71 (tt, J= 9, 4, 4.1 Hz, 1H), 2.21-2.12 (m, 1H), 2.08-1.94 (m, 2H), 1.83-1.71 (m, 1H). I-49 423.0 2.29 (500 MHz, methanol-d4) δ 10.12 (d, J= 6.9 Hz, 1H), 8.63 (s, 1H), 8.29 (dd, J= 7.0, 0.6 Hz , 1H), 7.84 (d, J= 8.7 Hz, 1H), 6.96 (d, J= 7.1 Hz, 1H), 4.50 (s, 1H), 4.19 (s , 1H), 3.89 (tt, J= 8.5, 3.9 Hz, 1H), 3.61-3.59 (m, 7H), 3.55 (dd, J= 13.2, 8 ,6 Hz, 1H), 2.25-2.16 (m, 1H), 2.05 (ddq, J= 13.4, 6.9, 3.9, 3.4 Hz, 1H), 1, 90-1.76 (m, 2H). I-50 385.1 2.32 (500 MHz, methanol-d4) δ 10.05 (dd, J= 2.0, 0.9 Hz, 1H), 8.70 (s, 1H), 8.27 (d, J= 7.2 Hz , 1H), 7.93 (dd, J= 9.5, 0.8 Hz, 1H), 7.85 (dd, J= 9.5, 2.0 Hz, 1H), 7.00 (d, J= 7.2 Hz, 1H), 5.37 (s, 1H), 4.06 (s, 1H), 3.59 (dd, J= 13.9, 3.2 Hz, 1H), 3, 04 (dt, J= 12.7, 4.5 Hz, 1H), 2.40-2.29 (m, 2H), 1.68-1.61 (m, 1H), 1.39 (d, J= 6.9 Hz, 3H), 1.14 (d, J= 6.8 Hz, 3H). I-51 385.1 2.38 (500 MHz, methanol-d4) δ 10.04 (s, 1H), 8.71 (s, 1H), 8.29 (d, J= 7.1 Hz, 1H), 7.94 (dd, J = 9.7, 0.9 Hz, 1H), 7.87 (dd, J= 9.5, 2.0 Hz, 1H), 7.03 (d, J= 7.2 Hz, 1H), 2 .96 (s, 1H), 2.80 (d, J= 11.6 Hz, 1H), 1.89 (s, 1H), 1.77 (t, J= 11.9 Hz, 2H), 1 .35 (d, J= 6.9 Hz, 3H), 1.17 (s, 3H). I-52 403.1 2.41 (500 MHz, methanol-d4) δ 10.06 (d, J= 7.0 Hz, 1H), 8.65 (s, 1H), 8.25 (d, J= 7.3 Hz, 1H), 7.84 (dd, J= 8.7, 0.6 Hz, 1H), 7.02 (d, J= 7.3 Hz, 1H), 5.39 (s, 1H), 4.07 (s , 1H), 3.62 (dd, J= 13.7, 3.3 Hz, 1H), 3.04 (dt, J= 12.8, 4.7 Hz, 1H), 2.43-2, 27 (m, 2H), 1.71-1.61 (m, 1H), 1.40 (d, J= 7.0 Hz, 3H), 1.14 (d, J= 6.8 Hz, 3H ). I-53 403.1 2.47 1H NMR (500 MHz, methanol-d4) δ 10.06 (d, J= 7.0 Hz, 1H), 8.66 (s, 1H), 8.26 (d, J= 7.2 Hz, 1H ), 7.84 (dd, J= 8.8, 0.6 Hz, 1H), 7.05 (d, J= 7.3 Hz, 1H), 5.66 (s, 1H), 4.06 (s, 1H), 2.99 (s, 2H), 2.87-2.77 (m, 1H), 1.89 (s, 1H), 1.77 (q, J= 12.0 Hz, 2H), 1.36 (s, 3H), 1.17 (s, 3H). I-54 412 1.92 (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.61-8.37 (m, 2H), 7.81 (d, 1H), 7.52 (d, 1H), 6 .89 (d, 1H), 5.08 (dd, 1H), 3.92 (t, 2H), 2.86 (t, 1H), 2.41 (s, 3H), 1.44 (s, 1H), 1.28 (d, 3H). I-55 380 0.89 (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 10.0 (s, 1H), 8.43 (m, 2H), 7.76 (d, 1H), 7.51 (m , 2H), 6.88 (m, 2H), 3.07 (m, 2H), 2.76 (s, 1H), 2.03 (m, 1H), 1.55 (m, 3H). I-56 430 2.22 (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.41 (d, 1H), 7.92 (d, 1H), 6.89 (d, 1H), 5.07 (dd , 1H), 4.01-3.70 (m, 1H), 2.84 (dd, 1H), 2.41 (s, 3H), 2.08 (s, 1H), 1.28 (d, 3H). I-57 398 0.98 (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 10.12 (d, 1H), 8.50-8.16 (m, 2H), 7.89 (d, 1H), 7 .58 (s, 1H), 6.96-6.59 (m, 2H), 3.11 (dd, 2H), 2.77 (dq, 1H), 2.15-2.01 (m, 1H ), 1.89-1.67 (m, 2H), 1.60 (dd, 1H). I-58 441 1.27 (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.02 (s, 1H), 8.52-8.11 (m, 2H), 7.90 (d, 1H), 7 .68 (s, 2H), 6.83 (d, 1H), 3.22 (dd, 1H), 3.07 (t, 1H), 2.63-2.52 (m, 1H), 1, 99 (d, 1H), 1.92-1.65 (m, 2H), 1.50 (d, 1H). I-59 455 1.40 (400 MHz, DMSO-d6) δ 10.14 (d, 1H), 10.01 (s, 1H), 8.41 (s, 1H), 8.32 (d, 1H), 7.97-7 .72 (m, 2H), 7.39 (s, 1H), 6.83 (d, 1H), 3.78 (s, 3H), 3.22 (dd, 1H), 3.08 (t, 1H), 1.98 (d, 1H), 1.82 (s, 2H), 1.51 (t, 1H). I-60 442 1.84 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.53 (s, 1H), 8.30 (d, J= 6.2 Hz, 1H), 7.95 (d , J= 9.4 Hz, 1H), 7.67 (d, J= 9.4 Hz, 1H), 7.49 (d, J= 39.5 Hz, 1H), 7.39-7.19 (m, 2H), 6.82 (d, J= 6.1 Hz, 1H), 3.74 (s, 4H), 3.47 (s, 1H), 3.05 (s, 1H), 2 .05-1.87 (m, 2H), 1.72 (d, J= 10.6 Hz, 1H), 0.99 (d, J= 6.7 Hz, 3H). I-61 442 1.91 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.52 (s, 1H), 8.32 (d, J= 6.2 Hz, 1H), 7.94 (d , J= 9.4 Hz, 1H), 7.82-7.54 (m, 2H), 7.40 (s, 1H), 6.87 (d, J= 6.3 Hz, 1H), 3 .80 (s, 3H), 2.79 (t, J= 12.1 Hz, 1H), 2.68 (t, J= 13.1 Hz, 1H), 2.58 (t, J= 12, 3 Hz, 1H), 2.05 (d, J= 12.8 Hz, 1H), 1.71 (s, 1H), 1.31 (q, J= 11.9 Hz, 1H), 1.00 (d, J= 6.4 Hz, 3H). I-62 412 I-63 412 I-64 398 1.65 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 7.80 (d, J= 9.9 Hz , 1H), 7.51 (d, J= 9.5 Hz, 1H), 6.64 (s, 1H), 6.50 (s, 1H), 4.27-3.56 (m, 5H) , 2.56 (s, 1H), 2.39 (s, 3H). I-65 381 1.59 1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.42 (d, J= 5.9 Hz, 1H), 8.33 (d, J= 6.2 Hz, 1H ), 7.79 (d, J= 9.5 Hz, 1H), 7.49 (d, J= 10.1 Hz, 2H), 6.78 (dd, J= 16.5, 6.3 Hz , 1H), 4.43 (s, 2H), 3.00 (q, J= 16.5, 14.9 Hz, 1H), 2.94-2.76 (m, 1H), 1.82 ( d, J= 12.5 Hz, 2H), 1.68-1.42 (m, 2H). I-66 381 1.65 1H NMR (400 MHz, DMSO-d6) δ 9.98 (dd, J= 2.2, 0.9 Hz, 1H), 8.86 (d, J= 1.6 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J= 6.3 Hz, 1H), 7.78 (dd, J= 9.5, 0.8 Hz, 1H), 7.48 (dd, J= 9.5, 2.2 Hz, 1H), 6.83 (d, J= 6.3 Hz, 1H), 6.68 (d, J= 1.7 Hz, 1H), 4.58 (s, 1H), 4.34 (s, 1H), 3.22 (ddd, J= 13.6, 11.4, 2.8 Hz, 1H), 3.03 (tt, J= 10.4, 3, 9 Hz, 1H), 2.12 (d, J= 10.0 Hz, 1H), 1.84 (dtd, J= 13.9, 10.3, 9.3, 4.2 Hz, 2H), 1.63 (q, J= 12.9 Hz, 1H). I-67 342 1.22 1H NMR (400 MHz, DMSO-d6) δ 10.13-9.94 (m, 1H), 8.41 (d, J= 3.0 Hz, 1H), 8.31 (d, J= 6, 2 Hz, 1H), 7.79 (d, J= 9.9 Hz, 1H), 7.50 (d, J= 9.2 Hz, 1H), 6.63 (d, J= 6.3 Hz , 1H), 5.70 (d, J= 2.5 Hz, 1H), 4.37 (s, 1H), 3.68 (d, J= 13.1 Hz, 2H), 2.13 (s , 1H), 1.68 (d, J= 10.3 Hz, 1H), 1.21 (s, 1H), 0.75 (d, J= 9.4 Hz, 1H), 0.36 (d , J= 5.0 Hz, 1H). I-68 413 1.38 1H NMR (400 MHz, DMSO-d6) δ 10.04 (d, J= 8.7 Hz, 1H), 8.52 (s, 1H), 8.35 (d, J= 6.3 Hz, 1H ), 8.06 (s, 1H), 7.80 (d, J= 9.4 Hz, 1H), 7.55-7.43 (m, 1H), 6.77 (d, J= 6, 4 Hz, 1H), 4.45 (s, 2H), 4.25 (d, J= 8.7 Hz, 1H), 3.98 (t, J= 9.9 Hz, 1H), 2.92 (t, J= 12.3 Hz, 1H), 2.74 (t, J= 12.5 Hz, 1H), 1.79 (dd, J= 21.9, 11.6 Hz, 2H), 1 .58 (d, J= 11.5 Hz, 1H), 1.39 (dt, J= 23.5, 14.1 Hz, 2H), 1.29 (d, J= 11.8 Hz, 3H) . I-69 390 1.57 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.55 (d, J= 2.9 Hz, 1H), 8.38 (d, J= 5.9 Hz, 1H ), 7.95 (d, J= 9.5 Hz, 1H), 7.68 (d, J= 9.5 Hz, 1H), 6.72 (s, 1H), 4.41 (s, 2H ), 3.94 (dd, J= 47.0, 23.2 Hz, 2H), 3.57 (s, 2H), 2.81 (s, 3H), 1.85 (s, 2H). I-70 484 2.65 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.50 (s, 1H), 8.52 (d, J= 1.5 Hz, 1H), 8.34 (dd, J= 6.1, 1.5 Hz, 1H), 7.94 (d, J= 9.4 Hz, 1H), 7.67 (d, J= 9.5 Hz, 1H), 6.52 (d, J= 6, 1 Hz, 1H), 4.25 (s, 1H), 3.89 (s, 2H), 3.19 (s, 1H), 3.12-2.94 (m, 1H), 2.30 ( dt, J= 14.3, 7.7 Hz, 1H), 2.12 (dq, J= 16.2, 8.8, 7.9 Hz, 2H), 1.92 (ddp, J= 34, 3, 13.4, 7.0, 6.5 Hz, 2H), 1.72 (dt, J= 13.0, 6.4 Hz, 1H), 1.26 (s, 6H). I-71 362 2.43 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.51 (d, J= 1.3 Hz, 1H), 8.30 (dd, J= 6.4, 1, 4 Hz, 1H), 7.94 (d, J= 9.4 Hz, 1H), 7.67 (d, J= 9.3 Hz, 1H), 6.78 (d, J= 6.3 Hz , 1H), 4.33 (s, 1H), 3.02 (t, J= 12.0 Hz, 1H), 1.79 (dd, J= 33.2, 13.3 Hz, 2H), 1 .70-1.41 (m, 2H), 1.41-1.17 (m, 1H), 0.95 (d, J= 6.5 Hz, 3H). I-72 425 1.6 1H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J= 19.7 Hz, 1H), 8.43 (d, J= 8.7 Hz, 1H), 8.31 (dd, J = 16.7, 6.1 Hz, 1H), 8.17 (d, J= 1.5 Hz, 1H), 7.79 (s, 1H), 7.50 (s, 1H), 6.46 (dd, J= 19.6, 6.0 Hz, 1H), 5.80 (d, J= 20.5 Hz, 1H), 4.84 (p, J= 6.9 Hz, 1H), 3 .89 (dt, J= 45.7, 12.7 Hz, 3H), 3.66 (d, J= 10.1 Hz, 2H), 2.31 (s, 1H), 1.51 (d, J= 6.7 Hz, 7H). I-73 459 2.8 1H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J= 7.5 Hz, 1H), 8.47 (s, 1H), 8.40 (d, J= 6.2 Hz, 1H ), 7.90 (d, J= 9.8 Hz, 1H), 7.48 (s, 1H), 7.44-7.25 (m, 3H), 6.84 (d, J= 6, 3 Hz, 1H), 5.14 (d, J= 7.1 Hz, 1H), 4.85 (d, J= 2.2 Hz, 1H), 4.21-3.97 (m, 1H) , 3.78 (dd, J= 11.2, 4.1 Hz, 1H), 3.55 (td, J= 11.5, 3.7 Hz, 1H), 3.42 (td, J= 12 ,6, 4.3 Hz, 1H), 1.41 (d, J= 6.6 Hz, 3H). I-74 376 1.44 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.51 (s, 1H), 8.31 (d, J= 6.1 Hz, 1H), 7.94 (d , J= 9.4 Hz, 1H), 7.67 (d, J= 9.5 Hz, 1H), 6.66 (d, J= 6.2 Hz, 1H), 5.69 (d, J = 2.6 Hz, 1H), 4.34 (s, 1H), 3.68 (d, J= 13.1 Hz, 2H), 2.22-2.04 (m, 1H), 1.76 -1.50 (m, 1H), 1.22 (s, 1H), 0.76 (dd, J= 10.3, 5.1 Hz, 1H), 0.36 (t, J= 5.1 Hz, 1H). I-75 450 2.29 1H NMR (400 MHz, DMSO-d6) δ 10.03 (d, J= 4.9 Hz, 1H), 8.40 (d, J= 5.2 Hz, 1H), 7.77 (d, J = 9.4 Hz, 1H), 7.61-7.31 (m, 1H), 6.48 (d, J= 6.0 Hz, 1H), 4.18 (d, J= 35.3 Hz , 1H), 3.86 (s, 2H), 3.17 (d, J= 8.8 Hz, 1H), 3.04 (p, J= 7.1 Hz, 1H), 2.30 (dt , J= 14.7, 7.7 Hz, 1H), 2.12 (dp, J= 16.1, 8.0, 7.5 Hz, 2H), 2.04-1.76 (m, 2H ), 1.72 (dt, J= 13.1, 6.6 Hz, 1H), 1.36-1.13 (m, 6H). I-76 439 1.3 1H NMR (400 MHz, DMSO-d6) δ 10.0 (s, 1H), 8.4 (s, 1H), 8.25 (d, 1H), 8.16 (s, 1H), 7.76 (d, 1H), 7.51 (d, 1H), 6.77 (d, 1H), 5.25 (s, 1H), 4.75 (m, 1H), 3.70 (m, 1H) , 2.22 (m, 1H), 1.92 (m, 2H), 1.61 (m, 1H), 1.46 (m, 6H). I-77 455 1.4 1H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J= 7.6 Hz, 1H), 10.01 (s, 1H), 8.41 (s, 1H), 8.32 (d , J= 6.3 Hz, 1H), 7.97-7.72 (m, 2H), 7.39 (s, 1H), 6.83 (d, J= 6.3 Hz, 1H), 3 .78 (s, 3H), 3.22 (dd, J= 13.2, 10.9 Hz, 1H), 3.08 (t, J= 12.4 Hz, 1H), 1.98 (d, J= 11.8 Hz, 1H), 1.82 (s, 2H), 1.51 (t, J= 12.9 Hz, 1H). I-78 384 1.39 1H NMR (400 MHz, DMSO-d6) δ 10.03 (d, J= 13.8 Hz, 1H), 8.45 (s, 1H), 8.29 (t, J= 6.5 Hz, 1H ), 7.78 (dd, J= 9.8, 5.5 Hz, 1H), 7.49 (d, J= 9.6 Hz, 1H), 6.84-6.47 (m, 1H) , 1.93-1.46 (m, 5H), 1.22-0.98 (m, 1H), 0.91 (dt, J= 13.2, 4.6 Hz, 1H). Several peaks overlap with the solvent peak. I-79 376 2.0 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.51-8.16 (m, 2H), 7.78 (d, J= 9.5 Hz, 1H), 7 ,64-7.36 (m, 1H), 6.67 (d, J= 6.3 Hz, 1H), 4.40-4.06 (m, 1H), 3.80-3.54 (m , 2H), 2.01-1.64 (m, 3H), 1.26 (s, 3H). I-80 377 1.46 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.55 (s, 1H), 8.40 (d, J= 6.1 Hz, 1H), 7.95 (d , J= 9.4 Hz, 1H), 7.68 (d, J= 9.5 Hz, 2H), 6.72 (s, 1H), 4.31 (s, 2H), 4.19-3 .63 (m, 2H), 1.77 (d, J= 6.6 Hz, 2H). I-81 424 1.79 1H NMR (400 MHz, DMSO-d6) δ 10.15 (d, J= 7.6 Hz, 1H), 8.46-8.16 (m, 2H), 7.90 (d, J= 9, 9 Hz, 1H), 7.63 (d, J= 7.7 Hz, 2H), 7.33 (dt, J= 40.4, 7.4 Hz, 2H), 6.76 (d, J= 6.3 Hz, 1H), 5.06 (s, 1H), 3.44 (d, J= 13.4 Hz, 1H), 3.15 (t, J= 12.2 Hz, 1H), 2 .16 (td, J= 12.6, 4.1 Hz, 1H), 1.84 (d, J= 13.1 Hz, 1H), 1.65 (d, J= 12.9 Hz, 1H) . I-82 442 1.9 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.38 (s, 1H), 8.26 (d, J= 6.3 Hz, 1H), 7.79 (d , J= 9.5 Hz, 1H), 7.49 (d, J= 9.2 Hz, 1H), 6.69 (d, J= 6.4 Hz, 1H), 4.73 (s, 1H ), 2.96 (d, J= 12.9 Hz, 1H), 2.84 (t, J= 13.5 Hz, 1H), 2.61 (d, J= 9.3 Hz, 1H), 2.43 (t, J= 9.9 Hz, 1H), 2.36-2.15 (m, 2H), 1.87 (d, J= 12.6 Hz, 1H), 1.72 (dt , J= 24.0, 11.6 Hz, 3H), 1.55 (q, J= 13.0, 12.2 Hz, 2H). I-83 438 1.7 1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.44-8.21 (m, 2H), 7.87 (d, J= 9.9 Hz, 1H), 7 .44-7.13 (m, 5H), 6.79 (d, J= 6.1 Hz, 1H), 4.46 (s, 1H), 4.17 (s, 1H), 3.90 ( s, 1H), 3.65 (s, 1H), 2.14 (s, 1H), 1.75 (s, 2H). I-84 388 2.2 1H NMR (400 MHz, DMSO-d6) δ
10.16 (m, 1H), 8.47 (s, 1H), 8.25 (d, 1H), 7.79 (d, 1H), 7.50 (d, 1H), 7.31 (m , 4H), 7.24 (m, 1H), 6.5 (m, 1H), 4.07 (m, 1H), 2.22 (m, 1H), 1.25 (m, 1H), 1 ,0 (m, 1H). Several peaks overlap with the solvent peak. I-85 438 1.95 1H NMR (400 MHz, DMSO-d6) δ 10.20 (d, J= 7.5 Hz, 1H), 8.45 (s, 1H), 8.28 (d, J= 6.2 Hz, 1H ), 7.91 (d, J= 9.8 Hz, 1H), 7.49 (d, J= 7.8 Hz, 2H), 7.27 (t, J= 7.6 Hz, 2H), 7.15 (t, J= 7.3 Hz, 1H), 6.80 (s, 1H), 4.69 (s, 1H), 3.78 (d, J= 13.5 Hz, 2H), 3.51 (s, 3H), 2.07 (s, 2H), 1.70 (s, 1H). I-86 452 1.0 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.12 (d, J= 7.5 Hz, 1H), 8.48-8.22 (m, 4H), 7 .89 (d, J= 9.9 Hz, 1H), 7.65-7.44 (m, 2H), 6.85 (d, J= 6.3 Hz, 1H), 3.12 (t, J= 12.5 Hz, 1H), 2.66 (d, J= 5.6 Hz, 1H), 2.06 (d, J= 12.3 Hz, 1H), 1.84 (t, J= 12.4 Hz, 2H), 1.53 (t, J= 12.4 Hz, 1H). I-87 329.1 0.80 (500 MHz, methanol-d4) δ 10.17-10.04 (m, 1H), 8.44 (s, 1H), 8.28 (d, 1H), 7.70 (d, 1H), 7 .49 (d, 1H), 6.69 (d, 1H), 4.43 (s, 1H), 4.31 (s, 1H), 3.18 (t, 1H), 3.04-2, 92 (m, 1H), 2.92-2.81 (m, 1H), 2.16-2.02 (m, 1H), 1.95-1.84 (m, 1H), 1.64 ( q, 1H), 1.59-1.40 (m, 1H). I-88 411.1 1.49 (400 MHz, DMSO-d6) δ 10.11 (d, 1H), 8.66-8.55 (m, 1H), 8.46-8.33 (m, 2H), 7.95-7, 80 (m, 2H), 7.56 (d, 1H), 7.38 (dd, 1H), 6.83 (d, 1H), 4.74 (s, 1H), 4.66 (dd, 1H ), 4.35 (s, 1H), 4.26-4.13 (m, 1H), 3.81 (td, 1H), 3.28-3.16 (m, 1H), 3.16- 3.06 (m, 1H). I-89 446.2 1.46 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.37 (s,1H), 8.60 (s, 1H), 8.44 (d, J= 6.2 Hz, 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.68 (dd, J= 9.4, 2.0 Hz, 1H), 6.92 (d, J= 6.3 Hz, 1H), 5 .09 (dd, J= 11.0, 2.8 Hz, 1H), 4.80 (s, 1H), 4.49 (s, 1H), 3.92 (s, 1H), 2.92- 2.81 (m, 1H), 2.41 (s, 3H), 1.28 (d, J= 6.2 Hz, 3H). I-90 446.2 1.46 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.37 (s, 1H), 8.60 (s, 1H), 8.44 (d, J= 6.2 Hz, 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.68 (dd, J= 9.4, 2.0 Hz, 1H), 6.92 (d, J= 6.3 Hz, 1H), 5 .09 (dd, J= 11.0, 2.8 Hz, 1H), 4.80 (s, 1H), 4.49 (s, 1H), 3.92 (s, 1H), 2.92- 2.81 (m, 1H), 2.41 (s, 3H), 1.28 (d, J= 6.2 Hz, 3H). I-91 403.2 1.24 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (d, J= 1.4 Hz, 1H), 8.61 (s, 1H), 8.44 (d, J= 6.2 Hz , 1H), 7.92 (dd, J= 9.3, 1.0 Hz, 1H), 7.70 (dd, J= 9.3, 1.8 Hz, 1H), 6.92 (d, J= 6.3 Hz, 1H), 5.07 (dd, J= 11.0, 2.8 Hz, 1H), 4.50 (s, 1H), 3.92 (ddd, J= 10.9 , 6.3, 2.7 Hz, 1H), 2.91-2.80 (m, 1H), 2.41 (s, 3H), 1.28 (d, J= 6.2 Hz, 3H) . I-92 403.2 1.26 1H NMR (400 MHz, DMSO- d ₆ ) δ 10.40 (d, J= 1.4 Hz, 1H), 8.61 (s, 1H), 8.44 (d, J= 6.2 Hz, 1H), 7.92 (dd, J= 9.3, 1.0 Hz, 1H), 7.70 (dd, J= 9.3, 1.8 Hz, 1H), 6.92 (d, J = 6.3 Hz, 1H), 5.07 (dd, J= 11.0, 2.8 Hz, 1H), 4.50 (s, 1H), 3.92 (ddd, J= 10.9, 6.3, 2.7 Hz, 1H), 2.91-2.80 (m, 1H), 2.41 (s, 3H), 1.28 (d, J= 6.2 Hz, 3H). I-93 446.3 1.28 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.36 (s, 1H), 8.58 (s, 1H), 8.42 (d, J= 6.1 Hz, 1H), 7.95 (d, J= 9.4 Hz, 1H), 7.67 (dd, J= 9.4, 1.9 Hz, 1H), 6.89 (d, J= 6.3 Hz, 1H), 5 .01 (dd, J= 11.1, 2.7 Hz, 1H), 4.61 (d, J= 103.5 Hz, 2H), 4.07-3.83 (m, 1H), 2, 85 (dd, J= 13.2, 10.8 Hz, 1H), 1.26 (d, J= 6.2 Hz, 3H). I-94 403.2 1.07 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.42 (s, 1H), 8.61 (s, 1H), 8.44 (d, J= 6.3 Hz, 1H), 7.91 (d, J= 9.3 Hz, 1H), 7.70 (dd, J= 9.3, 1.8 Hz, 1H), 6.92 (d, J= 6.3 Hz, 1H), 4 .99 (dd, J= 11.1, 2.7 Hz, 1H), 4.66 (d, J= 106.3 Hz, 2H), 3.98-3.83 (m, 1H), 2, 94-2.76 (m, 1H), 1.27 (d, J= 6.2 Hz, 3H). I-95 412.2 1.11 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.00 (s, 1H), 8.49 (d, J= 2.3 Hz, 1H), 8.44-8.37 (m, 1H) , 7.79 (dd, J= 9.6, 2.2 Hz, 1H), 7.49 (dd, J= 9.5, 2.5 Hz, 1H), 6.90-6.83 (m , 1H), 4.99 (dd, J= 11.1, 2.7 Hz, 1H), 4.78 (s, 1H), 4.48 (s, 1H), 3.90 (t, J= 8.4 Hz, 1H), 2.84 (t, J= 12.0 Hz, 1H), 2.53 (d, J= 23.2 Hz, 3H), 1.26 (d, J= 5, 9 Hz, 3H). I-96 384.1 1.29 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.98 (d, J= 2.6 Hz, 1H), 8.49 (d, J= 2.2 Hz, 1H), 8.36 (dd , J= 6.4, 2.2 Hz, 1H), 7.78 (dd, J= 9.5, 2.2 Hz, 1H), 7.57-7.43 (m, 1H), 6, 79 (dd, J= 6.5, 2.1 Hz, 1H), 4.48 (d, J= 40.8 Hz, 2H), 4.33-4.07 (m, 4H), 3.60 (d, J= 7.8 Hz, 1H), 3.10 (t, J= 12.3 Hz, 1H), 2.92 (dt, J= 37.3, 12.3 Hz, 2H), 2 .20 (d, J= 14.0 Hz, 1H), 1.82 (q, J= 11.5 Hz, 1H). I-97 370.1 0.82 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.04 (s, 1H), 8.51 (d, J= 2.9 Hz, 1H), 8.43-8.31 (m, 1H) , 7.81 (d, J= 9.6 Hz, 1H), 7.52 (d, J= 9.6 Hz, 1H), 6.83 (d, J= 6.3 Hz, 1H), 6 .59 (s, 1H), 4.55 (d, J= 55.4 Hz, 2H), 3.71 (d, J= 11.1 Hz, 2H), 3.47 (t, J= 9, 0 Hz, 1H), 3.15-2.79 (m, 4H). I-98 385.1 1.35 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.00 (s, 1H), 8.51 (d, J= 2.1 Hz, 1H), 8.35 (dd, J= 6.3, 2.2 Hz, 1H), 7.80 (dd, J= 9.7, 2.3 Hz, 1H), 7.52 (d, J= 9.3 Hz, 1H), 7.34-6, 97 (m, 2H), 6.80 (d, J= 6.4 Hz, 1H), 6.44 (s, 1H), 4.46 (d, J= 44.9 Hz, 2H), 4, 26-4.12 (m, 1H), 3.22-2.90 (m, 4H), 2.77 (dt, J= 23.4, 12.1 Hz, 2H), 2.05 (d, J= 12.3 Hz, 1H), 1.69 (d, J= 11.9 Hz, 1H). I-99 371.1 0.91 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.04 (s, 1H), 8.54 (d, J= 1.7 Hz, 1H), 8.48-8.37 (m, 1H) , 7.83 (d, J= 9.6 Hz, 1H), 7.53 (d, J= 9.8 Hz, 1H), 6.85 (d, J= 6.3 Hz, 1H), 4 .79 (s, 1H), 4.56 (s, 1H), 4.48 (t, J= 8.6 Hz, 1H), 4.12-4.05 (m, 1H), 3.96 ( dd, J= 11.5, 8.3 Hz, 1H), 3.71 (d, J= 11.3 Hz, 1H), 3.05 (dt, J= 40.0, 12.6 Hz, 3H ). I-100 380.2 0.97 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.65 (s, 1H), 10.03 (d, J= 2.1 Hz, 1H), 8.44 (d, J= 1.8 Hz , 1H), 8.33 (dd, J= 6.3, 1.9 Hz, 1H), 7.80 (dd, J= 9.7, 1.8 Hz, 1H), 7.74-7, 39 (m, 3H), 6.84 (dd, J= 6.4, 1.9 Hz, 1H), 4.53 (s, 2H), 3.18-2.98 (m, 2H), 2 .76 (t, J= 10.9 Hz, 1H), 2.10 (d, J= 12.4 Hz, 1H), 1.84 (d, J= 13.0 Hz, 1H), 1.77 -1.50 (m, 2H). I-101 414.2 1.05 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.36 (s, 1H), 8.51 (d, J= 1.8 Hz, 1H), 8.31 (dd, J= 6.4, 1.8 Hz, 1H), 7.93 (d, J= 9.4 Hz, 1H), 7.65 (d, J= 9.4 Hz, 1H), 7.56 (s, 2H), 6 .84 (d, J= 6.3 Hz, 1H), 4.45 (s, 2H), 3.09 (q, J= 11.9 Hz, 3H), 2.85-2.60 (m, 1H), 2.12-1.96 (m, 1H), 1.81 (d, J= 12.7 Hz, 1H), 1.65 (tq, J= 24.5, 12.3, 11, 5 Hz, 2H), 1.20 (t, J= 7.4 Hz, 1H). I-102 357.1 1.1 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.43 (d, J= 2.2 Hz, 1H), 8.33 (d, J= 6.2 Hz, 1H ), 7.80 (d, J= 9.3 Hz, 1H), 7.50 (d, J= 9.6 Hz, 1H), 7.41 (s, 1H), 6.91 (s, 1H ), 6.80 (d, J= 6.4 Hz, 1H), 4.42 (s, 2H), 3.09 (dt, J= 32.0, 12.4 Hz, 2H), 2.37 (s, 1H), 1.93 (d, J= 13.4 Hz, 1H), 1.74 (dt, J= 24.2, 13.3 Hz, 2H), 1.48 (t, J= 13.1 Hz, 1H). I-114 441 1.1 1H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.41 (s, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 7.98 (d, J= 9.0 Hz, 1H), 7.71 (s, 1H), 7.47 (s, 1H), 6.87 (s, 1H), 2.73 (d, J= 50, 4Hz, 4H), 2.16 (d, J= 31.7Hz, 3H), 1.98 (s, 1H), 1.75 (s, 1H), 1.43 (s, 1H), 1.26 (s, 1H), 1.02 (d, J= 6.3Hz, 3H). I-115 443 1.2 1H NMR (300 MHz, DMSO-d6) δ 12.49 (d, J= 28.6 Hz, 1H), 10.36 (s, 1H), 8.73 (s, 1H), 8.44 (d , J= 5.3 Hz, 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.70 (d, J= 9.4 Hz, 1H), 7.60-7.16 (m, 2H), 4.55 (d, J= 10.1 Hz, 3H), 3.80 (s, 1H), 3.09 (t, 1H), 2.78 (t, 1H), 2 ,37-2.05 (m, 3H), 1.23 (d, J= 6.1 Hz, 3H), 1.2 min, 443). I-116 443 1.2 1H NMR (300 MHz, DMSO-d6) δ 12.49 (d, J= 28.6 Hz, 1H), 10.36 (s, 1H), 8.73 (s, 1H), 8.44 (d , J= 5.3 Hz, 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.70 (d, J= 9.4 Hz, 1H), 7.60-7.16 (m, 2H), 4.55 (d, J= 10.1 Hz, 3H), 3.80 (s, 1H), 3.09 (t, 1H), 2.78 (t, 1H), 2 ,37-2.05 (m, 3H), 1.23 (d, J= 6.1 Hz, 3H), 1.2 min, 443). I-117 429 1.4 1H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s, 1H), 8.45 (d, J= 5.3 Hz , 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.79 (s, 1H), 7.74-7.65 (m, 1H), 7.55 (s, 1H) , 7.33 (d, J= 5.3 Hz, 1H), 4.57 (dd, J= 25.6, 12.1 Hz, 3H), 3.79 (d, J= 7.2 Hz, 1H), 3.06 (t, J= 12.3 Hz, 1H), 2.79 (t, J= 11.8 Hz, 1H), 1.24 (d, J= 6.2 Hz, 3H) . I-118 429 1.4 1H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s, 1H), 8.45 (d, J= 5.3 Hz , 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.79 (s, 1H), 7.74-7.65 (m, 1H), 7.55 (s, 1H) , 7.33 (d, J= 5.3 Hz, 1H), 4.57 (dd, J= 25.6, 12.1 Hz, 3H), 3.79 (d, J= 7.2 Hz, 1H), 3.06 (t, J= 12.3 Hz, 1H), 2.79 (t, J= 11.8 Hz, 1H), 1.24 (d, J= 6.2 Hz, 3H) . I-119 443 1.1 1H NMR (300 MHz, DMSO-d6) δ 12.52(s,1H),10.38(s,1H),8.56(s,1H),8.38(d, J= 6.2Hz, 1H), 7.96(d, J= 9.4Hz,1H), 7.76-7.49(m,2H), 6.89(d, J= 6.3Hz,1H), 4.63- 4.22(m,3H), 3.79(s,1H), 3.10(t, J= 12.0Hz,1H), 2.84-2.69(m,1H), 2.25( s,3H), 1.25(d, J= 6.2Hz,3H). I-120 443 1.1 1H NMR (300 MHz, DMSO-d6) δ 12.52 (s,1H), 10.38(s,1H), 8.56(s,1H), 8.38(d, J= 6.2Hz, 1H), 7.96(d, J= 9.4Hz,1H), 7.76-7.49(m,2H), 6.89(d, J= 6.3Hz,1H), 4.63- 4.22(m,3H), 3.79(s,1H), 3.10(t, J= 12.0Hz,1H), 2.84-2.69(m,1H), 2.25( s,3H), 1.25(d, J= 6.2Hz,3H). I-123 452.90 1.825 1H NMR (400 MHz, DMSO-d6) d 10.41 (s, 1H), 8.53 (s, 1H), 8.33 (d, J= 6.2 Hz, 1H), 7.95 (d , J= 9.5 Hz, 1H), 7.72-7.62 (m, 1H), 6.75 (d, J= 6.4 Hz, 1H), 3.03 (d, J= 11, 1 Hz, 6H), 2.34-2.26 (m, 1H), 2.01-1.82 (m, 2H), 1.28-1.08 (m, 2H), 0.96 (d , J= 6.6 Hz, 3H). I-126 430.1 1.47 (300MHz, DMSO, ppm): 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s, 1H), 8.45 (d, J= 5.3 Hz , 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.79 (s, 1H), 7.74-7.65 (m, 1H), 7.55 (s, 1H) , 7.33 (d, J= 5.3 Hz, 1H), 4.57 (dd, J= 25.6, 12.1 Hz, 3H), 3.79 (d, J= 7.2 Hz, 1H), 3.06 (t, J= 12.3 Hz, 1H), 2.79 (t, J= 11.8 Hz, 1H), 1.24 (d, J= 6.2 Hz, 3H) . I-127 430.1 1.47 (300MHz, DMSO, ppm): 12.84 (s, 1H), 10.37 (s, 1H), 8.73 (s, 1H), 8.45 (d, J= 5.3 Hz , 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.79 (s, 1H), 7.74-7.65 (m, 1H), 7.55 (s, 1H) , 7.33 (d, J= 5.3 Hz, 1H), 4.57 (dd, J= 25.6, 12.1 Hz, 3H), 3.79 (d, J= 7.2 Hz, 1H), 3.06 (t, J= 12.3 Hz, 1H), 2.79 (t, J= 11.8 Hz, 1H), 1.24 (d, J= 6.2 Hz, 3H) . I-136 407.1 1.59 (300MHz, DMSO, ppm): 12.65 (s, 1H), 10.35 (s, 1H), 8.70 (s, 1H), 8.40 (d, J= 5.3 Hz , 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.82-7.67 (m, 1H), 7.61 (s, 1H), 7.43 (s, 1H) , 7.23 (d, J= 5.3 Hz, 1H), 4.86 (d, J= 10.2 Hz, 1H), 4.68 (d, J= 12.8 Hz, 1H), 2 .72 (d, J= 9.4 Hz, 2H), 2.59 (d, J= 12.0 Hz, 1H), 2.15-1.90 (m, 1H), 1.71 (s, 1H), 1.31 (q, J= 12.0 Hz, 1H), 0.98 (d, J= 6.5 Hz, 3H). I-137 407.1 1.46 (300MHz, DMSO, ppm): 12.64 (s, 1H), 10.36 (s, 1H), 8.70 (s, 1H), 8.41 (d, J= 5.2 Hz , 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.70 (dd, J= 9.4, 1.9 Hz, 1H), 7.61 (s, 1H), 7 .43 (s, 1H), 7.24 (d, J= 5.4 Hz, 1H), 4.86 (d, J= 9.1 Hz, 1H), 4.69 (d, J= 12, 7 Hz, 1H), 2.73 (d, J= 9.4 Hz, 2H), 2.59 (d, J= 12.1 Hz, 1H), 2.06 (d, J= 12.9 Hz , 1H), 1.73 (s, 1H), 1.31 (q, J= 11.9 Hz, 1H), 0.99 (d, J= 6.5 Hz, 3H). I-149 405.2 1.38 1H NMR (400 MHz, DMSO-d6) δ 10.39 (d, J= 15.2 Hz, 1H), 8.53 (d, J= 2.3 Hz, 1H), 8.31 (ddd, J = 15.4, 6.3, 2.1 Hz, 1H), 7.95 (d, J= 9.5 Hz, 1H), 7.84-7.54 (m, 1H), 7.40 ( s, 1H), 7.03-6.73 (m, 2H), 3.78-3.50 (m, 2H), 2.93 (m, 1H), 2.45-2.0 (m, 2H), 1.58-1.35 (m, 2H), 1.02-0.74 (m, 3H). I-154 391.2 1.31 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.53 (s, 1H), 8.34 (dd, J= 6.3, 2.3 Hz, 1H), 7 .96 (d, J= 9.4 Hz, 1H), 7.68 (d, J= 9.5 Hz, 1H), 7.40 (s, 1H), 7.00-6.74 (m, 2H), 4.50 (m, 2H), 3.11 (dt, J= 35.7, 12.4 Hz, 2H), 2.42-2.25 (m, 2H), 1.94 (d , J= 12.9 Hz, 1H), 1.76 (dd, J= 24.5, 13.2 Hz, 2H), 1.48 (d, J= 12.7 Hz, 1H). I-202 427.1 1.76 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.59 (s, 1H), 8.44 (d, J= 6.2 Hz, 1H), 7.97 (d , J= 9.4 Hz, 1H), 7.73-7.61 (m, 2H), 7.15 (s, 1H), 7.01 (d, J= 6.3 Hz, 1H), 2 .75-2.64 (m, 3H). I-214 444.1 1.67 (400 MHz, DMSO-d6) δ 12.48 (d, J= 37.9 Hz, 1H), 10.38 (s, 1H), 8.55 (s, 1H), 8.38 (d, J = 6.2 Hz, 1H), 7.95 (d, J= 9.4 Hz, 1H), 7.67 (dd, J= 9.4, 2.0 Hz, 1H), 7.45 (s , 1H), 6.87 (d, J= 6.3 Hz, 1H), 4.55 (dd, J= 11.0, 2.7 Hz, 1H), 4.49-4.19 (m, 2H), 3.85-3.67 (m, 1H), 3.09 (t, J= 12.1 Hz, 1H), 2.85-2.69 (m, 1H), 2.25 (s , 3H), 1.24 (d, J= 6.2 Hz, 3H). I-247 396.0 1.11 (300 MHz, DMSO, ppm): 12.84 (s, 1H), 9.94 (s, 1H), 8.73-8.54 (m, 1H), 8.40 (d, J = 3.8 Hz, 1H), 7.91-7.70 (m, 2H), 7.53 (d, J= 10.5 Hz, 2H), 7.26 (d, J= 4.9 Hz , 1H), 4.57 (d, J= 32.9 Hz, 3H), 3.80 (d, J= 10.8 Hz, 1H), 3.17-2.63 (m, 2H), 1 .26 (d, J= 6.4 Hz, 3H). I-248 396.0 1.10 (300 MHz, DMSO, ppm): 12.84 (s, 1H), 9.96 (s, 1H), 8.62 (s, 1H), 8.42 (s, 1H), 7. 82 (d, J= 8.6 Hz, 2H), 7.54 (d, J= 10.6 Hz, 2H), 7.28 (s, 1H), 4.63 (d, J= 11.5 Hz, 3H), 3.81 (s, 1H), 3.23-2.68 (m, 2H), 1.26 (d, J= 6.0 Hz, 3H). I-249 400.1 1.71 (300 MHz, DMSO, ppm): 12.64 (s, 1H), 9.62 (s, 1H), 8.46 (s, 1H), 8.32 (d, J= 5.3 Hz, 1H), 7.87-7.36 (m, 3H), 7.14 (t, J= 7.2 Hz, 2H), 4.80 (dd, J= 37.2, 11.9 Hz , 2H), 3.45 (qd, J= 7.0, 5.1 Hz, 1H), 2.89-2.66 (m, 2H), 2.03 (d, J= 12.7 Hz, 1H), 1.71 (s, 2H), 1.26 (dd, J= 20.9, 8.9 Hz, 1H), 1.09-0.85 (m, 5H), 0.64 (s , 2H). I-259 451.1 2.11 1H NMR (400 MHz, DMSO-d6, ppm) 12.66 (s, 1H), 9.05 (s, 1H), 8.44 (s, 1H), 8.33 (d, J= 5.3 Hz, 1H), 7.69 (d, J= 9.5 Hz, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.15 (d, J= 5.3 Hz, 1H), 7.04 (d, J= 9.5 Hz, 1H), 4.80-4.77 (m, 2H), 4.14-3.71 (m, 4H), 2.87-2.83 (m, 1H), 2.78-2.73 (m, 1H), 2.59-2.55 (m, 1H), 2.00-1.98 (m, 1H ), 1.72-1.70 (m, 1H), 1.34-1.30 (m, 1H), 0.98 (d, J= 6.5 Hz, 3H). I-261 451.2 1.19 1H NMR (300 MHz, DMSO-d6, ppm) 12.53 (s, 1H), 9.10 (s, 1H), 8.43 (s, 1H), 8.31 (d, J= 5.3 Hz, 1H), 7.68 (d, J= 9.6 Hz, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.12 (d, J= 5.3 Hz, 1H), 7.08-7.04 (m, 1H), 4.32-4.08 (m, 4H), 4.02-3.90 (m, 3H), 3.59 -3.56 (m, 1H), 3.15-3.10 (m, 1H), 1.94-1.90 (m, 2H), 1.72-1.62 (m, 1H), 0 .96 (d, J= 6.6 Hz, 3H). I-271 415.0 1.15 1H NMR (300 MHz, DMSO-d6, ppm) 12.62 (s, 1H), 8.86 (s, 1H), 8.37 (s, 1H), 8.28 (d, J= 5.3 Hz, 1H), 7.57 (d, J= 9.5 Hz, 3H), 7.10 (d, J= 5.3 Hz, 1H), 6.88 (dd, J= 9, 5, 2.1 Hz, 1H), 4.76 (d, J= 11.7 Hz, 2H), 3.56 (br s, 4H), 2.76 (t, J= 12.7 Hz, 2H ), 2.44 (s, 1H), 2.12 (s, 2H), 1.95 (d, J= 12.7 Hz, 1H), 1.67 (s, 1H), 1.26 (q , J= 11.7 Hz, 1H), 0.94 (d, J= 6.5 Hz, 3H). I-287 465.1 1.24 1H NMR (400 MHz, DMSO-d6, ppm) 12.55 (s, 1H), 9.13 (s, 1H), 8.40 (s, 1H), 7.68 (d, J= 9.5 Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 7.10-7.01 (m, 2H), 4.14 (s, 4H), 4, 02 (s, 1H), 3.98 (d, J= 12.8 Hz, 2H), 3.52 (s, 1H), 3.11 (s, 1H), 2.32 (s, 3H), 1.89 (d, J= 9.3 Hz, 2H), 1.67 (s, 1H), 0.97 (d, J= 6.5 Hz, 3H). I-288 465.1 1.23 (400 MHz, DMSO-d6. ppm) 12.67 (s, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 7.67 (d, J= 9, 6 Hz, 2H), 7.45 (s, 1H), 7.08 (s, 1H), 7.02 (d, J= 9.5 Hz, 1H), 4.82 (d, J= 10, 4 Hz, 2H), 4.07 (s, 4H), 2.77 (d, J= 11.5 Hz, 2H), 2.55 (d, J= 17.2 Hz, 1H), 2.32 (s, 3H), 1.98 (d, J= 12.7 Hz, 1H), 1.71 (s, 1H), 1.28 (q, J= 12.1 Hz, 1H), 0.98 (d, J= 6.5 Hz, 3H). I-272 415.0 1.16 (300 MHz, DMSO-d6, ppm) 12.62 (s, 1H), 8.86 (s, 1H), 8.37 (s, 1H), 8.28 (d, J= 5, 3 Hz, 1H), 7.65-7.33 (m, 3H), 7.10 (d, J= 5.3 Hz, 1H), 6.88 (dd, J= 9.5, 2.1 Hz, 1H), 4.85-4.72 (m, 2H), 3.72-3.3 5(m, 4H), 2.87-2.73 (m, 2H), 2.57-2 .43 (m, 1H), 2.20-2.03 (m, 2H), 2.01-1.90 (m, 1H), 1.80-1.63 (m, 1H), 1.32 -1.09 (m, 1H), 0.94 (d, J= 6.5 Hz, 3H). I-310 429 1,392 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57 (1H), 7.46 (1H), 6 .84 (1H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42 (1H), 1.13 (3H) I-312 463.1 1.08 1H NMR (400 MHz, DMSO-d6) d 10.50 (dd, J= 1.9, 0.9 Hz, 1H), 8.54 (s, 1H), 8.33 (d, J= 6, 3 Hz, 1H), 7.95 (dd, J= 9.4, 0.9 Hz, 1H), 7.81 (dd, J= 9.4, 1.9 Hz, 1H), 6.73 ( d, J= 6.4 Hz, 1H), 5.14-3.91 (m, 3H), 3.37 (s, 3H), 3.22 (td, J= 10.4, 9.8, 5.1 Hz, 1H), 3.06 (d, J= 0.9 Hz, 3H), 3.02 (d, J= 0.9 Hz, 3H), 2.55 (s, 1H), 1 .93 (d, J= 12.8 Hz, 1H), 1.76-1.58 (m, 1H), 1.17 (q, J= 11.9 Hz, 1H), 0.97 (d, J= 6.5 Hz, 3H). I-313 424.2 1.19 1H NMR (400 MHz, DMSO-d6) d 12.61 (s, 1H), 10.54 (dd, J= 2.0, 0.9 Hz, 1H), 8.54 (s, 1H), 8 .34 (d, J= 6.3 Hz, 1H), 7.95 (dd, J= 9.4, 0.9 Hz, 1H), 7.81 (dd, J= 9.4, 1.9 Hz, 1H), 7.68 (s, 1H), 7.49 (s, 1H), 6.87 (d, J= 6.3 Hz, 1H), 4.49 (d, J= 54.0 Hz, 4H), 3.11 (d, J= 23.8 Hz, 2H), 2.71 (d, J= 24.5 Hz, 2H), 2.16-2.03 (m, 1H), 1.85 (d, J= 5.6 Hz, 1H), 1.79-1.55 (m, 2H). I-314 444.0 0.93 (300MHz, DMSO, ppm) 12.34 (d, J= 35.0 Hz, 1H), 10.35 (s, 1H), 8.48 (s, 1H), 8.33 (d, J= 6.3 Hz, 1H), 7.92 (d, J= 9.4 Hz, 1H), 7.65 (m, 1H), 7.36 (s, 1H), 6.79 (d, J= 6.4 Hz, 1H), 5.12 (d, J= 4.6 Hz, 1H), 4.46 (s, 1H), 3.31 (m, 1H), 3.56 (d, J= 4.9 Hz, 1H), 2.67 (d, J= 26.7 Hz, 3H), 2.16 (s, 4H), 1.60 (s, 1H). I-315 444.0 0.93 (300MHz, DMSO, ppm) 12.33 (d, J= 36.2 Hz, 1H), 10.35 (s, 1H), 8.48 (s, 1H), 8.33 (d, J= 6.3 Hz, 1H), 7.92 (d, J= 9.4 Hz, 1H), 7.78-7.25 (m, 2H), 6.79 (d, J= 6.4 Hz, 1H), 5.12 (d, J= 4.5 Hz, 1H), 4.82-4.01 (s, 1H), 3.56 (s, 1H), 3.31 (m, 1H ), 2.87-2.54 (m, 3H), 2.17 (m, 4H), 1.59 (s, 1H). I-318 465.5 1.29 1H NMR (400 MHz, DMSO-d6) d 12.61 (s, 1H), 10.50 (dd, J= 2.0, 0.9 Hz, 1H), 8.52 (s, 1H), 8 .33 (d, J= 6.3 Hz, 1H), 8.17 (s, 1H), 7.94 (dd, J= 9.4, 0.8 Hz, 1H), 7.64 (dd, J= 9.4, 1.9 Hz, 2H), 7.53 (s, 1H), 6.86 (d, J= 6.3 Hz, 1H), 4.47 (d, J= 66.6 Hz, 2H), 3.20-3.04 (m, 2H), 2.75 (dd, J= 9.7, 5.1 Hz, 1H), 2.21 (dt, J= 6.7, 3.4 Hz, 1H), 2.09 (dd, J= 11.2, 3.5 Hz, 1H), 1.89-1.78 (m, 1H), 1.79-1.67 (m , 1H), 1.67-1.56 (m, 1H), 0.60-0.45 (m, 2H), 0.41 (qd, J= 5.4, 2.4 Hz, 2H). I-319 504.2 1.23 1H NMR (400 MHz, DMSO-d6) d 10.46 (dd, J= 2.0, 0.9 Hz, 1H), 8.52 (s, 1H), 8.33 (d, J= 6, 3 Hz, 1H), 8.19 (s, 1H), 7.94 (dd, J= 9.5, 0.9 Hz, 1H), 7.65 (dd, J= 9.4, 1.9 Hz, 1H), 6.73 (d, J= 6.4 Hz, 1H), 4.94-4.07 (m, 3H), 3.23 (s, 1H), 3.05 (dd, J = 13.6, 0.9 Hz, 6H), 2.70-2.59 (m, 1H), 2.26 (dt, J= 6.8, 3.4 Hz, 1H), 1.94 ( d, J= 12.8 Hz, 1H), 1.75-1.57 (m, 1H), 1.17 (q, J= 12.0 Hz, 1H), 0.98 (d, J= 6 .5 Hz, 3H), 0.60-0.46 (m, 2H), 0.47-0.34 (m, 2H). I-320 425.1 1.09 1H NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 10.49 (dd, J= 1.9, 0.9 Hz, 1H), 8.51 (s, 1H), 8 .32 (d, J= 6.3 Hz, 1H), 7.93 (dd, J= 9.4, 0.9 Hz, 1H), 7.72 (dd, J= 9.4, 1.9 Hz, 1H), 7.70-7.41 (m, 4H), 6.86 (d, J= 6.4 Hz, 1H), 4.48 (d, J= 59.9 Hz, 2H), 3.11 (tt, J= 10.6, 4.5 Hz, 2H), 2.73 (dd, J= 9.1, 5.0 Hz, 1H), 2.14-2.05 (m, 1H), 1.83 (d, J= 13.4 Hz, 1H), 1.70 (ddd, J= 22.7, 11.5, 2.9 Hz, 1H), 1.65-1.55 (m, 1H). I-322 485 2.037 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57 (1H), 7.46 (1H), 6 .84 (1H), 4.72 (1H), 4.47 (4H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42 (1H), 1. 13 (3H) I-325 477.25 1,392 ¹ H NMR (400 MHz, chloroform- d ) δ 9.90 (d, J= 2.3 Hz, 1H), 8.54 (s, 1H), 8.24 (d, J= 6.2 Hz, 1H), 7.73 (d, J= 9.7 Hz, 1H), 7.40-7.34 (m, 2H), 7.23-7.09 (m, 2H), 7.09-7 .01 (m, 2H), 6.41 (d, J= 6.2 Hz, 1H), 4.51 (s, 2H), 3.29 (dq, J= 10.5, 5.3, 4 ,4 Hz, 1H), 3.05 (d, J= 13.3 Hz, 7H), 2.73 (t, J= 11.9 Hz, 1H), 2.47 (t, J= 12.4 Hz, 1H), 2.07 (d, J= 13.1 Hz, 1H), 1.31 (q, J= 12.0 Hz, 1H), 0.97 (d, J= 6.6 Hz, 3H). I-328 464.2 1.00 1H NMR (400 MHz, DMSO-d6) δ 10.45 (dd, J= 2.0, 0.9 Hz, 1H), 8.51 (s, 1H), 8.31 (d, J= 6, 3 Hz, 1H), 7.92 (dd, J= 9.4, 0.9 Hz, 1H), 7.72 (dd, J= 9.4, 1.9 Hz, 1H), 7.63 ( s, 2H), 6.73 (d, J= 6.4 Hz, 1H), 4.51 (s, 3H), 3.29-3.16 (m, 1H), 3.06 (d, J = 0.9 Hz, 3H), 3.03 (d, J= 0.9 Hz, 3H), 2.68-2.56 (m, 1H), 1.93 (d, J= 12.6 Hz , 1H), 1.76-1.59 (m, 1H), 1.17 (q, J= 11.9 Hz, 1H), 0.97 (d, J= 6.5 Hz, 3H). I-329 437.90 1.857 1H NMR (400 MHz, chloroform-d) d 9.88 (dd, J= 2.4, 0.8 Hz, 1H), 8.56 (s, 1H), 8.26 (d, J= 6, 2 Hz, 1H), 7.74 (dd, J= 9.7, 0.8 Hz, 1H), 7.50 (s, 2H), 7.41-7.33 (m, 2H), 7, 20 (dd, J= 9.6, 2.3 Hz, 1H), 7.18-7.12 (m, 1H), 7.09-7.04 (m, 2H), 6.40 (d, J= 6.2 Hz, 1H), 4.25 (s, 1H), 3.20-2.93 (m, 2H), 1.91-1.79 (m, 2H), 1.78-1 .63 (m, 2H), 1.60-1.40 (m, 2H). Spectra I-330 458.2 1.16 ¹ H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.41 (s, 1H), 8.30 (d, J= 5.3 Hz, 1H), 7.66 ( d, J= 9.5 Hz, 1H), 7.13 (d, J= 5.3 Hz, 1H), 7.03 (dd, J= 9.5, 2.1 Hz, 1H), 5, 55 (d, J= 57.5 Hz, 1H), 4.70 (d, J= 12.6 Hz, 2H), 4.26 (d, J= 6.7 Hz, 2H), 4.03 ( ddd, J= 34.5, 23.2, 9.1 Hz, 2H), 3.01 (d, J= 6.1 Hz, 7H), 2.65 (d, J= 14.6 Hz, 1H ), 1.99 (d, J= 12.7 Hz, 1H), 1.68 (s, 1H), 1.13 (q, J= 11.9 Hz, 1H), 0.94 (d, J = 6.5 Hz, 3H). I-340 434.90 1,546 ¹ H NMR (400 MHz, chloroform- d ) δ 10.22 (dd, J= 2.5, 1.5 Hz, 1H), 8.59 (s, 1H), 8.29 (d, J= 6 ,3 Hz, 1H), 7.85-7.75 (m, 1H), 7.45 (dd, J= 9.3, 1.8 Hz, 1H), 6.45 (d, J= 6, 3 Hz, 1H), 3.33 (tt, J= 10.9, 4.4 Hz, 1H), 3.10 (d, J= 0.9 Hz, 3H), 3.07 (d, J= 0.9 Hz, 3H), 2.76 (t, J= 13.0, 10.7 Hz, 1H), 2.53 (t, J= 12.3 Hz, 1H), 2.09 (ddt, J= 12.7, 4.0, 2.1 Hz, 1H), 1.79 (d, J= 12.8 Hz, 3H), 1.42-1.28 (m, 1H), 1.04 (d, J= 6.6 Hz, 3H). I-352 489 0.979 12.7 (1H), 10.36 (1H), 8.56 (1H), 8.36 (1H), 7.90 (2H), 7.42 (1H), 6.84 (1H), 4 .42 (1H), 4.25 (1H), 3.52 (1H), 3.43 (1H), 3.11 (1H), 2.32 (1H), 1.83 (1H) I-353 496 1.255 12.84 (1H), 10.36 (1H), 8.56 (1H), 8.36 (1H), 8.27 (1H), 7.90 (2H), 7.71 (1H), 7 .63 (1H), 7.01 (1H), 6.84 (1H), 4.27 (2H), 3.72 (2H), 3.43 (2H), 2.98 (2H), 2. 30 (1H) I-362 485 1.671 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57 (1H), 7.46 (1H), 6 .84 (1H), 4.72 (1H), 4.47 (4H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42 (1H), 1. 13 (3H) I-369 469 1.059 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57 (1H), 7.46 (1H), 6 .84 (1H), 4.32 (2H), 3.39 (2H), 3.22 (2H), 2.39 (2H), 1.95 (1H), 0.85 (1H), 0. 45 (2H), 0.04 (2H) I-380 406.1 1.0 1H NMR (400 MHz, DMSO-d6) δ 10.42 (d, J= 38.1 Hz, 1H), 8.53 (s, 1H), 8.38 (dd, J= 15.5, 6, 2 Hz, 1H), 7.95 (d, J= 9.4 Hz, 1H), 7.67 (dd, J= 9.4, 2.0 Hz, 1H), 7.27 (d, J= 43.5 Hz, 2H), 6.76 (d, J= 6.3 Hz, 1H), 3.08 (d, J= 12.7 Hz, 2H), 2.88-2.62 (m, 1H), 1.12 (d, J= 6.7 Hz, 3H). I-398 437.95 1,398 1H NMR (400 MHz, chloroform-d) d 9.87 (s, 1H), 8.54 (s, 1H), 8.23 (d, J= 6.0 Hz, 1H), 7.65 (d , J= 38.3 Hz, 2H), 7.37 (t, J= 7.8 Hz, 2H), 7.15 (q, J= 9.0, 7.5 Hz, 2H), 7.05 (d, J= 8.0 Hz, 2H), 6.87 (s, 1H), 6.43 (d, J= 6.2 Hz, 1H), 4.49 (d, J= 12.8 Hz , 1H), 4.22 (s, 1H), 3.28 (t, J= 11.6 Hz, 1H), 3.11 (t, J= 12.2 Hz, 1H), 2.95 (s , 1H), 2.20 (d, J= 12.8 Hz, 1H), 1.95-1.78 (m, 2H), 1.65 (d, J= 12.4 Hz, 1H). Spectra I-399 437.95 1.419 1H NMR (400 MHz, DMSO-d6) d 9.77-9.66 (m, 1H), 8.42 (d, J= 21.7 Hz, 1H), 8.24 (dd, J= 12, 9, 6.3 Hz, 1H), 7.80 (d, J= 9.6 Hz, 1H), 7.54 (d, J= 5.2 Hz, 1H), 7.47-7.29 ( m, 2H), 7.21-7.13 (m, 2H), 7.13-7.07 (m, 2H), 6.91 (s, 1H), 6.82-6.65 (m, 1H), 4.35 (d, J= 73.8 Hz, 2H), 3.01 (dt, J= 32.7, 12.0 Hz, 2H), 2.83-2.61 (m, 1H ), 2.05 (t, J= 10.5 Hz, 1H), 1.72 (q, J= 11.7 Hz, 2H), 1.49 (d, J= 12.4 Hz, 1H). Spectra I-461 497 2.101 12.84 (1H), 10.36 (1H), 8.56 (1H), 8.36 (1H), 8.27 (1H), 7.90 (2H), 7.71 (1H), 7 .63 (1H), 6.84 (1H), 4.27 (2H), 3.72 (2H), 3.43 (2H), 2.98 (2H), 2.30 (1H) I-476 538.85 1,469 1H NMR (400 MHz, chloroform-d) d 10.40 (s, 1H), 8.59 (s, 1H), 8.35 (dd, J= 6.2, 1.5 Hz, 1H), 7 .83 (d, J= 9.4 Hz, 1H), 7.64 (s, 2H), 7.46 (dd, J= 9.4, 1.9 Hz, 1H), 6.44 (dd, J= 6.3, 1.7 Hz, 1H), 4.29 (s, 2H), 3.79 (ddd, J= 20.2, 10.4, 4.4 Hz, 1H), 3.60 (tq, J= 21.0, 11.1, 9.7 Hz, 1H), 2.76-2.37 (m, 2H), 2.17 (d, J= 54.3 Hz, 1H), 1.84-1.53 (m, 1H), 1.22-0.96 (m, 2H), 0.78 (s, 1H), 0.62 (s, 1H). I-481 512.80 1.832 1H NMR (400 MHz, chloroform-d) d 10.35 (s, 1H), 8.73 (s, 1H), 8.35 (s, 1H), 7.90 (d, J= 9.9 Hz , 1H), 7.64-7.47 (m, 3H), 6.42 (s, 1H), 4.62 (s, 1H), 4.40 (d, J= 5.5 Hz, 1H) , 4.29 (d, J= 22.7 Hz, 3H), 3.66 (s, 1H), 3.43 (s, 2H), 2.26 (s, 2H), 1.54 (s, 3H), 1.34 (s, 3H). I-484 411.9 1.38 NMR was not taken due to limited quantity. I-490 547.2 0.085 (300 MHz, DMSO) 12.74 (s, 1H), 10.33 (s, 1H), 8.49 (s, 1H), 8.34 (d, J= 6.2 Hz, 1H), 7 .93 (d, J= 9.4 Hz, 1H), 7.65 (d, J= 9.4 Hz, 2H), 7.44 (br, 1H), 6.80 (d, J= 6, 4 Hz, 1H), 3.94 (br, 2H), 3.81-3.44 (m, 5H), 2.81 (s, 3H), 2.80-2.73 (m, 1H), 2.38-2.16 (m, 3H), 2.05-1.93(m, 1H), 1.83-1.72 (m, 1H). I-495 547.2 1.65 (300 MHz, DMSO) 12.74 (s, 1H), 10.32 (s, 1H), 8.49 (s, 1H), 8.33 (d, J= 6.3 Hz, 1H), 7 .93 (d, J= 9.4 Hz, 1H), 7.65 (d, J= 9.5 Hz, 2H), 7.46 (br, 1H), 6.80 (d, J= 6, 2 Hz, 1H), 3.93 (br, 2H), 3.71 (br, 2H), 3.63-3.51(m, 2H), 2.81 (s, 3H), 2.80- 2.73 (m, 1H), 2.38-2.16 (m, 3H), 2.05-1.93 (m, 1H), 1.83-1.72 (m, 1H). I-499 434.90 1.847 ¹ H NMR (400 MHz, chloroform- d ) δ 10.28-10.15 (m, 1H), 8.37-8.29 (m, 2H), 7.81 (d, J= 9.3 Hz , 1H), 7.49 (dd, J= 9.2, 1.8 Hz, 1H), 6.91 (d, J= 5.3 Hz, 1H), 4.92-4.82 (m, 1H), 4.82-4.70 (m, 1H), 3.37 (tt, J= 10.9, 4.5 Hz, 1H), 3.18-2.99 (m, 6H), 2 .78 (dd, J= 12.8, 10.7 Hz, 1H), 2.50 (t, J= 12.2 Hz, 1H), 2.15-2.04 (m, 1H), 1, 80 (dq, J= 10.6, 6.9 Hz, 1H), 1.34 (q, J= 12.0 Hz, 1H), 1.04 (d, J= 6.6 Hz, 3H). I-508 455.1 0.98 (300 MHz, chloroform-d, ppm) 10.36 (s, 1H), 8.41-8.29 (m, 2H), 7.80 (d, J= 9.4 Hz, 1H) , 7.59 (s, 2H), 7.45 (dd, J= 9.4, 1.9 Hz, 1H), 6.93 (d, J= 5.3 Hz, 1H), 4.22- 4.01 (m, 2H), 4.01-3.74 (m, 3H), 3.02 (br, 1H), 2.67 (br, 1H), 1.56 (br, 1H), 0 .52-0.18 (m, 4H).; I-511 540.90 1,849 ¹ H NMR (400 MHz, chloroform- d ) δ 12.34 (s,1H), 10.39 (s, 1H), 8.65 (d, J= 48.3 Hz, 1H), 8.40 ( d, J= 23.0 Hz, 1H), 8.04 (dd, J= 51.1, 38.0 Hz, 2H), 7.81-7.49 (m, 1H), 6.54 (s , 1H), 4.75 (s, 1H), 4.03-3.11 (m, 5H), 3.03 (s, 1H), 1.97 (s, 7H), 1.27 (s, 4H), 0.88 (d, J= 20.3 Hz, 2H), 0.10 (s, 3H). I-537 429 1.416 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57 (1H), 7.46 (1H), 6 .84 (1H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42 (1H), 1.13 (3H) I-543 510.2 1.67 (400 MHz, DMSO-d6): 10.39 (s, 1H), 8.71 (s, 1H), 8.48 (d, J= 5.2 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.72 (dd, J= 9.4, 1.9 Hz, 1H), 7.29 (d, J= 5.3 Hz, 1H), 7.17 (br , 1H), 5.00 (br, 1H), 4.36 (br, 1H), 3.71 (br, 1H), 3.26-3.17 (m, 1H), 3.06 (d, J= 11.4 Hz, 1H), 2.95 (s, 3H), 2.92-2.81 (m, 1H), 2.67-2.57 (m, 1H), 2.39 (t , J= 11.6 Hz, 1H), 1.62 (br, 1H), 1.08 (d, J= 6.6 Hz, 3H), 0.70 (q, J= 5.9 Hz, 1H ), 0.50 (p, J= 4.6, 4.2 Hz, 2H), 0.42-0.31 (m, 1H).;

Example 17: GCN2 Enzyme Inhibition Study

[00469] The ability of compounds to inhibit GCN2 kinase activity was screened using the ^{Transcreener®} ADP ² Fluorescence Polarization Assay, which measures ADP levels (BellBrook Labs, WI). Studies were carried out in a buffer containing 25 mM Tris-HCl (pH 7.5), 50 mM NaCl, 10 mM MgCl ₂ and 1 mM DTT. The final substrate concentrations were 280 μM ATP and 200 μM peptide substrate (H-Gly-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-Ser-Arg-OH [( RS) ₇ ], Bachem, Switzerland). Studies were performed at 25°C in the presence of GCN2 kinase at a (typical) final concentration of 4 nM.

[00470] An assay buffer containing GCN2 kinase and (RS) ₇ was prepared. 4.7 μl of this stock solution was placed into the wells of a black low-volume 384-well microtiter plate (eg, catalog number 3676, Corning Inc., NY). To this was added 0.65 μM DMSO-containing serial dilutions of the test compound (typical final concentrations of the test compound ranged from 0 to 8 μM). The plate was incubated for 10 min at 25°C and then 4.7 μl of ATP stock buffer was added to initiate the enzyme reaction. The reaction was allowed to proceed for 1 hour at 25°C, then 10 μl of detection buffer (containing appropriate concentrations of ADP ² antibodies and ADP Alexa633 labeled compound in 1× stop and detection buffer supplied by BellBrook Labs) was added. The reaction mixture was incubated for 1 h at 25°C, then the fluorescence polarization signal (mP) was measured for each well using a PHERAstar FS reader (BMG Labtech, Germany).

[00471] Fluorescence polarization values were normalized to the plate calibration curve for different ratios of ATP to ADP in the assay buffer to a final total concentration of 280 μM. 9.4 μL of buffer at each ATP:ADP ratio and 0.65 μL of DMSO were added to the plate before adding detection buffer to simulate assay volumes and conditions. The calibration curve was used to convert the mP values obtained for the test wells to the percentage of ATP converted to ADP. The percentage degree of inhibition of enzyme activity was then calculated for the dose of each compound. _IC50 and Ki _(app) values (using known assay and kinetic parameters) were calculated from the percentage inhibition data using a non-linear tight coupling algorithm. All analysis data were processed using Screener ^® software (Genedata, Switzerland).

Table 3: Enzyme activity of compounds of formula I

[00472] +++ for Ki<10 nM; ++ for Ki in the range of 10 nM-100 nM; and+ for Ki 100 nM-1 µM.

Compound GCN2(Ki) I-1 ++ I-2 +++ I-3 +++ I-4 ++ I-5 ++ I-6 ++ I-7 + I-8 ++ I-9 +++ I-10 +++ I-11 ++ I-12 +++ I-13 +++ I-14 ++ I-15 +++ I-16 +++ I-17 +++ I-18 +++ I-19 ++ I-20 +++ I-21 ++ I-22 +++ I-23 +++ I-24 +++ I-25 +++ I-26 + I-27 +++ I-28 +++ I-29 +++ I-30 + I-31 ++ I-32 ++ I-33 ++ I-34 +++ I-35 ++ I-36 +++ I-37 +++ I-38 ++ I-39 +++ I-40 +++ I-41 +++ I-42 +++ I-43 +++ I-44 +++ I-45 +++ I-46 ++ I-47 +++ I-48 +++ I-49 ++ I-50 +++ I-51 +++ I-52 +++ I-53 +++ I-54 ++ I-55 ++ I-56 ++ I-57 ++ I-58 ++ I-59 + I-62 ++ I-63 +++ I-65 ++ I-66 ++ I-76 + I-77 + I-81 ++ I-83 ++ I-84 + I-85 + I-86 ++ I-87 + I-88 + I-89 ++ I-90 +++ I-91 ++ I-92 +++ I-93 ++ I-94 + I-95 ++ I-96 +++ I-97 ++ I-98 ++ I-99 ++ I-100 +++ I-101 +++ I-102 +++ I-103 +++ I-104 ++ I-105 ++ I-106 ++ I-107 +++ I-108 +++ I-109 ++ I-110 +++ I-111 ++ I-112 +++ I-113 +++ I-114 +++ I-115 +++ I-116 +++ I-117 +++ I-118 +++ I-119 +++ I-120 +++ I-137 +++ I-154 +++ I-137 +++ I-149 +++ I-202 +++ I-380 +++ I-484 +++

Table 4: Enzyme activity of compounds of formula I

[00473] +++ for IC ₅₀ <10 nM; ++ for IC ₅₀ in the range of 10 nM-100 nM; + for IC ₅₀ 100 nM-1 µM.

Compound GCN2( _IC50 ) I-122 +++ I-123 ++ I-124 +++ I-125 +++ I-126 +++ I-127 +++ I-128 ++ I-129 ++ I-130 ++ I-131 + I-132 ++ I-133 + I-134 ++ I-135 +++ I-136 +++ I-137 +++ I-138 ++ I-139 + I-140 + I-141 + I-142 + I-143 ++ I-144 + I-145 + I-146 + I-147 ++ I-148 +++ I-149 +++ I-150 ++ I-151 + I-152 ++ I-153 +++ I-154 +++ I-155 + I-156 + I-157 + I-158 ++ I-159 ++ I-160 +++ I-161 ++ I-162 ++ I-163 ++ I-164 ++ I-165 ++ I-166 ++ I-167 + I-168 ++ I-169 ++ I-170 ++ I-171 ++ I-172 ++ I-173 + I-174 ++ I-175 +++ I-176 +++ I-177 ++ I-178 + I-179 +++ I-180 +++ I-181 ++ I-182 ++ I-183 ++ I-184 ++ I-185 ++ I-186 +++ I-187 ++ I-188 ++ I-189 ++ I-190 + I-191 ++ I-192 ++ I-193 +++ I-195 ++ I-196 +++ I-197 ++ I-198 +++ I-199 +++ I-200 +++ I-201 ++ I-202 +++ I-203 ++ I-204 ++ I-205 ++ I-206 ++ I-207 + I-208 ++ I-209 ++ I-210 + I-211 + I-212 + I-213 ++ I-214 + I-217 ++ I-218 ++ I-219 ++ I-220 ++ I-221 +++ I-222 ++ I-223 +++ I-224 + I-225 + I-226 + I-227 ++ I-228 + I-229 +++ I-230 ++ I-231 + I-232 + I-233 + I-234 ++ I-235 ++ I-236 ++ I-238 ++ I-239 + I-240 + I-241 ++ I-242 ++ I-243 + I-244 ++ I-245 ++ I-246 ++ I-247 +++ I-248 +++ I-249 +++ I-250 ++ I-251 ++ I-252 + I-253 + I-254 + I-255 + I-256 + I-257 + I-258 ++ I-259 +++ I-260 +++ I-261 +++ I-262 ++ I-263 ++ I-264 +++ I-265 ++ I-266 +++ I-267 ++ I-268 +++ I-269 ++ I-270 +++ I-271 ++ I-272 +++ I-273 +++ I-274 ++ I-275 +++ I-276 + I-277 ++ I-278 +++ I-279 ++ I-280 ++ I-281 ++ I-282 + I-283 ++ I-284 ++ I-285 + I-286 +++ I-287 ++ I-288 +++ I-289 ++ I-290 ++ I-291 ++ I-292 + I-293 +++ I-294 + I-295 ++ I-296 + I-297 ++ I-298 + I-299 + I-300 ++ I-301 + I-302 +++ I-303 ++ I-304 ++ I-305 + I-307 ++ I-308 ++ I-309 + I-310 +++ I-311 ++ I-312 + I-313 ++ I-314 +++ I-315 +++ I-316 +++ I-317 ++ I-318 + I-319 + I-320 ++ I-321 ++ I-322 ++ I-323 +++ I-324 + I-325 + I-326 +++ I-327 ++ I-328 + I-329 ++ I-330 + I-331 + I-332 + I-333 + I-334 + I-335 + I-336 ++ I-337 + I-338 + I-339 ++ I-340 +++ I-341 + I-342 ++ I-343 + I-344 + I-345 + I-346 ++ I-347 + I-348 ++ I-349 ++ I-350 + I-351 +++ I-352 +++ I-353 +++ I-354 +++ I-355 + I-356 ++ I-357 ++ I-358 +++ I-359 +++ I-360 +++ I-361 ++ I-362 +++ I-363 + I-364 + I-365 + I-366 +++ I-367 + I-368 + I-369 +++ I-370 +++ I-371 +++ I-372 +++ I-373 +++ I-374 +++ I-375 ++ I-376 ++ I-377 ++ I-378 ++ I-379 ++ I-380 +++ I-382 + I-383 +++ I-384 +++ I-385 +++ I-386 + I-387 + I-388 + I-389 ++ I-390 +++ I-391 + I-392 + I-393 + I-394 + I-395 + I-396 ++ I-397 ++ I-398 + I-399 ++ I-400 ++ I-401 + I-402 + I-403 + I-404 ++ I-405 ++ I-406 ++ I-407 ++ I-408 ++ I-409 ++ I-410 + I-411 + I-412 + I-413 + I-414 ++ I-415 + I-416 ++ I-417 + I-418 ++ I-419 ++ I-420 ++ I-421 ++ I-422 ++ I-423 + I-424 ++ I-425 + I-426 ++ I-427 ++ I-428 ++ I-429 +++ I-432 ++ I-433 ++ I-434 + I-435 +++ I-436 ++ I-437 + I-438 ++ I-439 + I-440 + I-441 ++ I-442 ++ I-443 ++ I-444 ++ I-445 ++ I-446 ++ I-447 ++ I-448 ++ I-449 +++ I-450 ++ I-451 ++ I-452 + I-454 ++ I-455 ++ I-456 ++ I-457 ++ I-458 ++ I-459 +++ I-460 ++ I-461 +++ I-462 + I-463 ++ I-464 + I-465 + I-466 ++ I-467 ++ I-468 + I-469 ++ I-470 +++ I-471 + I-472 ++ I-473 +++ I-474 + I-475 ++ I-476 +++ I-477 ++ I-478 ++ I-479 + I-480 + I-481 +++ I-482 ++ I-483 + I-484 +++ I-485 ++ I-486 + I-487 + I-488 ++ I-489 ++ I-490 +++ I-491 ++ I-492 ++ I-493 ++ I-494 + I-495 +++ I-496 + I-497 + I-498 ++ I-499 +++ I-500 + I-501 + I-502 ++ I-503 ++ I-504 +++ I-505 + I-506 ++ I-507 + I-508 +++ I-509 + I-510 +++ I-511 +++ I-512 + I-513 + I-514 + I-515 + I-516 +++ I-517 + I-518 ++ I-519 + I-520 ++ I-521 +++ I-522 +++ I-523 ++ I-524 ++ I-525 ++ I-526 ++ I-527 ++ I-528 ++ I-529 +++ I-530 ++ I-531 ++ I-532 ++ I-533 +++ I-534 + I-535 + I-536 + I-537 +++ I-538 ++ I-539 ++ I-540 +++ I-541 + I-542 +++ I-543 +++ I-544 +++ I-545 +++ I-546 +++ I-547 +++ I-548 ++ I-549 + I-550 + I-551 ++

Example 18: GCN2 Inhibition Study in Cells

[00474] The ability of compounds to inhibit intracellular GCN2 can be screened using the AlphaScreen assay (Perkin Elmer) to detect phosphorylation of the eIF2α substrate for GCN2 in borrelidin-treated cells. U2OS cells were plated at 5000 cells/well in 384-well white polystyrene plates (Corning 3570) in McCoy's 5A media (GIBCO 26600-023) supplemented with 10% fetal bovine serum (SAFC 12103C), penicillin/streptomycin diluted at a ratio of 1:100 (Sigma P0781) and 2 mM L-glutamine (Sigma G7513) and allowed to clump overnight at 37°C in 5% CO ₂ . Compounds were then added to cell media from a final concentration of 40 μM in 4-fold serial dilutions. Borrelidine (FluoroChem M01440) was immediately added to the wells to a final concentration of 10 μM, and cells were incubated for 1 h at 37°C in 5% CO ₂ . After treatment with borrelidine for 1 h, the media was removed and the cells were lysed in lysis buffer (TGR BioSceinces TGRLB) at ambient temperature.

[00475] The AlphaScreen SureFire P-eIF2α (Ser51) Assay Kit (Perkin Elmer TGREIF2S) was used to determine the content of eIF2α phosphorylated at serine 51. Anti-phosphorylated eIF2α Ser51 antibody-coupled acceptor beads (TGR BioScience 6760617) were added to the cell homogenizer (1 dilution :250 in a mixture of activator (TGR BioScience TGRAB) and reaction buffer (TGR BioScience TGREIF2S), prepared immediately before use). The plate was then incubated for 2 h at ambient temperature in the dark. Anti-eIF2α antibody-coupled donor beads (TGR BioScience 6760617) were then added (diluted 1:100 in dilution buffer (TGR BioScience TGRDB), prepared immediately before use). The plate was then incubated overnight at ambient temperature in the dark.

[00476] The plates were then probed using an Alpha Technology compatible PHERAstar FS plate reader (BMG Labtech Version 1.14) to quantify phosphorylated eIF2α Ser51 content. The percentage of inhibition of phosphorylated eIF2α was calculated based on comparison with control wells stimulated with borrelidin alone. The dependence of these data on the concentration of the compound was plotted and IC ₅₀ was determined using Genedata Analyzer software (Genedata AG Version 12.0.3).

Table 5: Cellular activity of compounds of formula II (biomarker assay)

[00477] +++ for IC ₅₀ <0.5 μM; ++ for IC ₅₀ in the range of 0.5 µM-5 µM; and+ for IC ₅₀ >5 µM.

Compound Biomarker GCN2(IC ₅₀ ) I-1 ++ I-2 +++ I-3 +++ I-4 ++ I-5 ++ I-6 ++ I-8 ++ I-9 +++ I-10 +++ I-11 + I-12 +++ I-13 ++ I-14 ++ I-15 +++ I-16 ++ I-17 +++ I-18 +++ I-19 ++ I-20 +++ I-21 ++ I-22 +++ I-23 +++ I-24 +++ I-25 ++ I-27 +++ I-28 ++ I-29 + I-31 ++ I-32 ++ I-33 + I-34 +++ I-35 ++ I-36 +++ I-37 +++ I-39 +++ I-41 ++ I-42 ++ I-43 ++ I-44 +++ I-45 +++ I-46 ++ I-47 ++ I-48 +++ I-49 + I-50 ++ I-54 ++ I-55 ++ I-56 ++ I-57 ++ I-58 ++ I-59 + I-62 ++ I-63 +++ I-65 ++ I-66 ++ I-76 + I-77 + I-81 ++ I-83 ++ I-84 + I-85 + I-86 ++ I-88 +++ I-90 +++ I-92 ++ I-102 +++ I-103 +++ I-104 ++ I-105 + I-106 + I-107 +++ I-108 +++ I-109 ++ I-110 ++ I-111 ++ I-112 ++ I-113 ++ I-114 +++ I-115 +++ I-116 ++ I-117 +++ I-118 +++ I-120 +++ I-123 +++ I-124 +++ I-125 +++ I-126 +++ I-127 +++ I-128 +++ I-130 ++ I-134 +++ I-135 +++ I-136 +++ I-137 +++ I-138 +++ I-143 +++ I-144 +++ I-145 +++ I-146 ++ I-147 +++ I-148 +++ I-149 +++ I-150 +++ I-153 +++ I-154 +++ I-157 +++ I-159 +++ I-169 ++ I-170 +++ I-171 +++ I-172 +++ I-175 +++ I-176 +++ I-177 +++ I-179 +++ I-180 +++ I-181 ++ I-182 +++ I-183 +++ I-184 +++ I-185 +++ I-186 +++ I-191 +++ I-193 +++ I-196 +++ I-197 +++ I-198 ++ I-199 +++ I-200 +++ I-201 ++ I-202 +++ I-203 ++ I-204 ++ I-208 +++ I-209 +++ I-213 ++ I-217 ++ I-218 ++ I-219 ++ I-220 ++ I-221 +++ I-222 +++ I-223 +++ I-224 +++ I-225 ++ I-226 ++ I-227 ++ I-232 ++ I-233 ++ I-235 +++ I-236 +++ I-238 ++ I-240 ++ I-241 ++ I-242 + I-244 ++ I-245 ++ I-246 ++ I-247 +++ I-248 +++ I-249 +++ I-250 +++ I-251 ++ I-252 ++ I-259 +++ I-260 +++ I-261 +++ I-262 + I-263 ++ I-266 +++ I-267 ++ I-268 ++ I-269 ++ I-270 +++ I-271 +++ I-272 +++ I-273 +++ I-274 ++ I-275 ++ I-277 ++ I-278 +++ I-279 ++ I-280 +++ I-281 +++ I-283 ++ I-284 + I-285 ++ I-286 ++ I-287 +++ I-288 +++ I-289 ++ I-290 ++ I-291 ++ I-293 +++ I-294 + I-295 ++ I-297 ++ I-298 + I-300 ++ I-301 ++ I-302 +++ I-303 ++ I-304 ++ I-307 ++ I-308 ++ I-310 +++ I-311 ++ I-313 ++ I-314 +++ I-315 +++ I-316 +++ I-317 ++ I-318 + I-320 ++ I-321 ++ I-322 +++ I-323 ++ I-324 + I-325 ++ I-326 +++ I-327 ++ I-329 +++ I-339 ++ I-340 +++ I-342 +++ I-343 ++ I-344 ++ I-345 ++ I-346 +++ I-347 ++ I-348 +++ I-349 ++ I-351 +++ I-352 ++ I-353 +++ I-354 +++ I-355 ++ I-356 ++ I-357 +++ I-358 +++ I-359 +++ I-360 +++ I-361 ++ I-362 +++ I-363 ++ I-363 ++ I-364 + I-365 ++ I-366 +++ I-368 ++ I-369 +++ I-370 +++ I-371 ++ I-372 ++ I-373 +++ I-383 ++ I-384 +++ I-385 ++ I-386 ++ I-387 ++ I-388 + I-389 ++ I-390 +++ I-391 ++ I-392 ++ I-393 ++ I-395 ++ I-396 + I-397 ++ I-398 ++ I-399 ++ I-400 ++ I-401 ++ I-402 ++ I-403 ++ I-404 ++ I-405 ++ I-406 ++ I-407 ++ I-408 ++ I-409 +++ I-413 + I-414 ++ I-416 ++ I-417 + I-418 ++ I-419 ++ I-420 ++ I-421 + I-422 + I-423 + I-424 ++ I-426 ++ I-440 + I-441 + I-442 ++ I-443 ++ I-444 ++ I-445 ++ I-446 ++ I-447 ++ I-448 ++ I-449 +++ I-450 +++ I-461 +++ I-464 ++ I-470 +++ I-472 +++ I-473 +++ I-476 +++ I-477 +++ I-478 +++ I-481 +++ I-490 +++ I-491 +++ I-492 ++ I-493 +++ I-494 ++ I-495 +++ I-499 +++ I-500 ++ I-501 ++ I-502 +++ I-503 +++ I-504 +++ I-505 + I-506 ++ I-507 ++ I-508 +++ I-510 +++ I-511 +++ I-512 ++ I-516 +++ I-517 ++ I-520 +++ I-521 +++ I-522 +++ I-523 +++ I-524 ++ I-525 ++ I-526 +++ I-527 ++ I-528 +++ I-529 +++ I-530 ++ I-531 +++ I-532 ++ I-533 +++ I-536 ++ I-537 +++ I-538 ++ I-540 +++ I-541 ++ I-543 +++ I-544 +++ I-545 +++ I-546 +++ I-552 +++ I-553 +++ I-554 +++ I-556 ++

Example 19: 4-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-3-methylpiperazin-2-carboxamide, I-484

[00478] To a solution of 4-(2-{6-chloroimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-3-methylpiperazin-2-carboxamide I-451 (49.00 mg; 0.13 mmol; 1.00 eq.) and 1-ethoxycyclopropoxy)trimethylsilane (0.13 ml; 0.66 mmol; 5.00 eq.) in methanol (2.50 ml; 61.72 mmol; 468.32 eq.) acetic acid (0.06 ml; 1.05 mmol; 8.00 eq.) and then sodium cyanoborohydride (66.25 mg; 1.05 mmol; 8.00 eq.) were added. The reaction mixture was stirred overnight at 70°C and purified by preparative HPLC (10-90% ACN/NH ₄ OH-H ₂ O for 12 min) to give 4-(2-{6-chloroimidazo[1,2- a]pyridin-3-yl}pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide (17.6 mg, 31%) as a white solid.

Example 20: 5,5-Difluoro-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid amide, I-202

[00479] Into a microwave-safe container containing 5,5-difluoro-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-methyl ester 3-carboxylic acid (118.23 mg; 0.27 mmol; 1.00 eq.), ammonia 7 N was added. in MeOH (2.00 ml). The reaction mixture was stirred at 100°C for 72 hours, then it was purified using preparative HPLC (10-90% ACN/0.1% NH4OH-H2O for 12 minutes) to obtain the amide 5,5-difluoro-1-[2 -(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic acid (2.2 mg, 1.9%) as a white solid.

Example 21: 3-{2-[(2R,6S)-2-Methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-6-trifluoromethylimidazo[1 ,2-a]pyridine I-127 and (2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a ]pyridin-3-yl]pyrimidin-2-yl}morpholine I-126

[00480] Step 1: 2-Methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2 -yl}morpholine. 2-Chloro-4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine solution (200 mg, 0.60 mmol, 1 eq., 90%), 2-methyl-6 -(1H-pyrazol-4-yl)morpholine (112.0 mg, 0.60 mmol, 1 equiv., 90%) and DIPEA (155.8 mg, 1.21 mmol, 2 equiv., 95%) in i-PrOH (10 mL, 124.30 mmol, 206.24 eq., 95%) was stirred for 16 h at 100°C under nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane/EtOAc (1:1) to give 2-methyl-6-(1H-pyrazol-4-yl)-4-[4-[6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3-yl]pyrimidin-2-yl]morpholine (100 mg, 34.77%) as a white solid.

[00481] Step 2: 3-{2-[(2R,6S)-2-Methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-6- trifluoromethylimidazo[1,2-a]pyridine and (2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a ]pyridin-3-yl]pyrimidin-2-yl}morpholine. Racemic mixture of 2-methyl-6-(1H-pyrazol-4-yl)-4-[4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-2-yl]morpholine purified using chiral preparative HPLC under the following conditions (Prep-HPLC-032): Column, Chiralpak IA, 2*25 cm, 20 µm; mobile phase, Hex(8 mmol/L NH3.MeOH)--HPLC and IPA--HPLC (15% IPA--HPLC for 29 min); Detector, UV 254/220 nm. Two pure compounds were obtained: peak 1 3-{2-[(2R,6S)-2-Methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-6 -trifluoromethylimidazo[1,2-a]pyridine I-127, retention time = 18.029 min, 10.6 mg (22%), white solid; peak 2 (2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-{4-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine -2-yl}morpholine I-126, retention time=25.76 min, 12.3 mg (25%), white solid.

Example 22: 3-{4-[(S)-4-(3-Methanesulfonylcyclobutyl)-3-(1H-pyrazol-4-yl)-piperazin-1-yl]-pyrimidin-2-yl}-6-trifluoromethylimidazo [1,2-a]pyridine I-495 and 3-{4-[(R)-4-(3-Methanesulfonylcyclobutyl)-3-(1H-pyrazol-4-yl)-piperazin-1-yl]-pyrimidine -2-yl}-6-trifluoromethylimidazo[1,2-a]pyridine I-490

[00482] Step 1: 4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine . With stirring, to a mixture of 4-chloro-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine (600.00 mg, 1.808 mmol, 1.00 eq., 90%) and 2-(1H-pyrazol-4-yl)piperazine (458.67 mg, 2.712 mmol, 1.50 eq., 90%) in i-PrOH (15.00 ml, 245.293 mmol, 271.32 eq., 95 %) DIEA (491.98 mg, 3.616 mmol, 2.00 eq., 95%) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 hours at 100°C under a nitrogen atmosphere. The desired product could be detected using LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2/MeOH (8:1) to give 4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl )imidazo[1,2-a]pyridin-3-yl]pyrimidine (510 mg, 61.26%) as a light yellow oil.

[00483] Step 2: 4-[4-(3-methanesulfonylcyclobutyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a ]pyridin-3-yl]pyrimidine. With stirring, to a mixture of 4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine (100 .00 mg, 0.217 mmol, 1.00 eq., 90%) and 3-methanosulfonylcyclobutan-1-one (169.38 mg, 1.086 mmol, 5.00 eq., 95%) in MeOH (2.50 ml, 74.121 mmol, 270.09 eq., 95%) CH3COOH (109.83 mg, 1.737 mmol, 8.00 eq., 95%) and NaBH ₃ CN (57.47 mg, 0.869 mmol, 4.00 eq., 95%). The resulting mixture was stirred for 3 hours at 70°C under a nitrogen atmosphere. The desired product could be detected using LCMS. The crude product (110 mg) was purified using preparative HPLC under the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Shield RP18 OBD Column, 30*150 mm, 5 µm; mobile phase, water (10 mmol/L NH4HCO3 + 0.1% NH3.H2O) and ACN (from 30% phase B to 35% in 8 min); Detector, UV 254 nm. 80 mg of racemic product was obtained. The racemic product (80) mg was separated using chiral preparative HPLC under the following conditions (Prep-HPLC-032): Column, CHIRAL ART Cellulose -SB, 2*25 cm, 5 µm; mobile phase, Hex(8 mmol/L NH3.MeOH)- and EtOH- (50% EtOH- for 17 min); Detector, UV 254 nm. This gave peak 1: 4-[(3S)-4-(3-methanesulfonylcyclobutyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1, 2-a]pyridin-3-yl]pyrimidine (11.0 mg 9.08%) as a white solid, retention time=4.501 min, ee:99; peak 2: 4-[(3R)-4-(3-methanesulfonylcyclobutyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2- a]pyridin-3-yl]pyrimidine (12.1 mg, 9.17%) as a white solid, retention time=5.529 min, ee:98.

Example 23: 4-[4-({6-oxaspiro2.5]octan-1-yl}methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl) )imidazo[1,2-a]pyridin-3-yl]pyrimidine I-476

[00484] Into a microwave-safe vessel containing a solution of 4-[3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin- 3-yl]pyrimidine (50.00 mg; 0.12 mmol; 1.00 eq.) and 6-oxaspiro2.5]octane-1-carbaldehyde (84.57 mg; 0.60 mmol; 5.00 eq. ) in methanol (2.50 ml; 61.72 mmol; 640.56 eq.), add acetic acid (0.01 ml; 0.24 mmol; 2.00 eq.) and then sodium cyanoborohydride (30.33 mg ; 0.48 mmol; 4.00 eq.). The reaction mixture was stirred overnight at 70C. LCMS-3 detected the mass of the desired product upon complete conversion. The reaction mixture was allowed to cool, then diluted with DCM. The reaction mixture was then added dropwise to a saturated NaHCO ₃ solution and washed 3 times with NaHCO ₃ and twice with brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was dissolved in DMSO, then purified using PuriFlash PF-C18HP 15 µl 10-90% MeCN in water (0.1% formic acid) 14 min gradient, then 90% over 3 min. The pure fractions were combined and lyophilized to give the product: 4-[4-({6-oxaspiro2.5]octan-1-yl}methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2 -[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine (46.60 mg; 0.09 mmol)

[00485] Example 24: 4-[2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo [1,2-a]pyridin-3-yl]pyrimidine, I-322

[00486] 4-[2-Methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl solution ]pyrimidine (150.00 mg; 0.35 mmol; 1.00 eq.), oxetan-3-one (30.28 mg; 0.42 mmol; 1.20 eq.) and acetic acid (210.26 mg ; 3.50 mmol; 10.00 eq.) in THF (3 ml) was treated with sodium triacetoxyborohydride (742.07 mg; 3.50 mmol; 10.00 eq.) and the mixture was stirred at room temperature overnight. LCMS-3 showed the presence of the desired product. The crude product was loaded into reverse phase HPLC and purified with 20% ACN in water containing 0.1% NH ₄ OH to 100% ACN in 10 minutes at a flow rate of 60 ml/min to give product 4- [2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridine -3-yl]pyrimidine with a yield of 16%. M/z (M+H): 485; H NMR (DMSO-d6): 12.70 (1H), 10.06 (1H), 8.46 (1H), 8.31 (1H), 7.80 (2H), 7.57 (1H), 7.46 (1H), 6.84 (1H), 3.82 (1H), 2.83 (2H), 2.58 (2H), 2.42 (1H), 1.13 (3H)

Example 25: Typical compounds I-122 - I-563.

[00487] Additional compounds were prepared using methodologies similar to those described in the examples above:

6-Chloro-3-(4-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine, I -122

Dimethyl(((3R,5S)-5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl) imino)-λ6-sulfanone, I-123

3-{4-[(2S,6R)-2-Methyl-6-(3-methyl-1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-2-yl}-6-trifluoromethylimidazo[ 1,2-a]pyridine, I-124

(2R,6S)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl )pyrimidin-4-yl)morpholine, I-125

(((3R,5S)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6 -sulfanone, I-128

(2R,6S)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide, I-129

N, N-dimethyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-130

pyrrolidin-1-yl(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanone, I-131

5-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-azaspiro2.5]octane-1-carboxamide, I-132

Methyl 5-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-azaspiro2.5]octane-1-carboxylate, I-133

(2S,6S)-2-methyl-6-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2 -yl)morpholine, I-134

(2R,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2 -yl)morpholine, I-135

3-(2-((3R,5R)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-136 (after chiral separation)

3-(2-((3S,5S)-3-Methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-137 (after chiral separation)

(2S,6R)-2-methyl-6-(1H-pyrazol-3-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2 -yl)morpholine, I-138

3-(2-((3R,5S)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl) imidazo[1,2-a]pyridine, I-139

3-(2-((3S,5R)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl) imidazo[1,2-a]pyridine, I-140

3-(2-((3S,5S)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl) imidazo[1,2-a]pyridine, I-141

3-(2-((3R,5R)-3-(1,3-dimethyl-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl) imidazo[1,2-a]pyridine, I-142

3-(2-((3R,5R)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-( trifluoromethyl)imidazo[1,2-a]pyridine, I-143

3-(2-((3R,5S)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-( trifluoromethyl)imidazo[1,2-a]pyridine, I-144

3-(2-((3S,5R)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-( trifluoromethyl)imidazo[1,2-a]pyridine, I-145

3-(2-((3S,5S)-3-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-( trifluoromethyl)imidazo[1,2-a]pyridine, I-146

(2S,6S)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl )pyrimidin-4-yl)morpholine, I-147

(3R,5S)-5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-148

5-Methyl-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid amide, I-149

(S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide, I-150

(R)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide, I-151

(R)-1-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidin-3-carboxamide, I-152

(S)-1-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidin-3-carboxamide, I-153

( S )-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid amide, I-154

(2R,6R)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-2-yl)morpholine, I-155

(2S,6S)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-2-yl)morpholine, I-156

(2R,6S)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-2-yl)morpholine, I-157

(2S,6R)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl)pyrimidin-2-yl)morpholine, I-158

(((3R,5S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6 -sulfanone, I-159

4-(4-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)morpholine, I-160

2-(1-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetic acid, I-161

2-(1-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide, I-162

4-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide, I-163

(R)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-164

2-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetic acid, I-165

2-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide, I-166

(((3S,5R)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-5-methylpyrimidin-2-yl)-5-methylpiperidin-3-yl)imino) dimethyl-λ6-sulfanone, I-167

(((3S,5R)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-5-methylpiperidin-3-yl)imino) dimethyl-λ6-sulfanone, I-168

dimethyl(((3S,5R)-5-methyl-1-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidin-3-yl) imino)-λ6-sulfanone, I-169

3-(2-((2S,5S)-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyridine, I-170

3-(2-((2R,5R)-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyridine, I-171

3-(2-((2S,5S)-2,5-dimethyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl )imidazo[1,2-a]pyridine, I-172

3-(2-((2R, 5R)-2,5-dimethyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl )imidazo[1,2-a]pyridine, I-173

(S)-1-(4-(6-chlorimidazo[1,2-a]pyridin-3-yl)-5-methylpyrimidin-2-yl)piperidin-3-carboxamide, I-174

(2S,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl) -6-methylmorpholine, I-175

(2R,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-(5-fluoro-1H-pyrazol-4-yl) -6-methylmorpholine, I-176

(2S,6R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-6-methylmorpholine-2-carboxamide, I-177

(2R,6R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-6-methylmorpholine-2-carboxamide, I-178

(2S,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol- 4-yl)morpholine, I-179

(2R,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol- 4-yl)morpholine, I-180

(2S,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol- 4-yl)morpholine, I-181

(2R,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(5-methyl-1H-pyrazol- 4-yl)morpholine, I-182

(S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidin-3-carboxamide, I-183

6-chloro-3-(5-methyl-2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-184

6-chloro-3-(5-methyl-2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-185

6-chloro-3-(5-methyl-2-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-186

N-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide, I-187

4-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-4-carboxamide, I-188

(2S,6S)-2-methyl-6-(2H-tetrazol-5-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2 -yl)morpholine, I-189

(2R,6R)-2-methyl-6-(2H-tetrazol-5-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2 -yl)morpholine, I-190

(((3S,5R)-1-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino )dimethyl-λ6-sulfanone, I-191

3-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-192

3-(4-(2-(5-(difluoromethyl)-1H-pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyridine-6-carbonitrile, I-193

6-chloro-3-(2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a ]pyridine, I-195

6-chloro-3-(2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a ]pyridine, I-196

6-chloro-3-(5-methyl-2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-197

6-chloro-3-(2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a ]pyridine, I-198

6-chloro-3-(2-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a ]pyridine, I-199

6-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-200

6-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxylic acid, I-201

(2S,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-5-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H -pyrazol-4-yl)morpholine, I-203

(2R,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-5-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H -pyrazol-4-yl)morpholine, I-204

5,5-Difluoro-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidin-3-carboxylic acid, I-205

5-fluoro-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl]-piperidine-3-carboxylic acid, I-206

tert-butyl-2-carbamoyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-carboxylate, I-207

6-chloro-3-(6-methyl-2-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-208

6-chloro-3-(6-methyl-2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-209

6-chloro-3-(6-methyl-2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-210

6-chloro-3-(6-methyl-2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-211

tert-butyl-3-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxylate, I-212

3-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-213

3-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidine-3-carboxylic acid, I-214

4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide, I-217

(2R,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H -pyrazol-4-yl)morpholine, I-218

(S)-1-(5-fluoro-4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidin-3-carboxamide, I-219

(2S,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H -pyrazol-4-yl)morpholine, I-220

(2S,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H -pyrazol-4-yl)morpholine, I-221

(2R,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)-6-methylpyrimidin-2-yl)-2-methyl-6-(5-methyl-1H -pyrazol-4-yl)morpholine, I-222

(R)-1-(5-fluoro-4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperidin-3-carboxamide, I-223

3-(4-(3,3-difluoropiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-224

2-(difluoromethyl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine, I-225

3-(4-(3-fluoro-3-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-226

(S)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carbonitrile, I-227

1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)azetidin-3-carboxamide, I-228

5-fluoro-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-229

2-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)azetidin-3-yl)acetamide, I-230

3-(4-(3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-231

(S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-carbonitrile, I-232

(S)-6-(trifluoromethyl)-3-(4-(3-(trifluoromethyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine, I-233

3-(4-(3,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I -234

6-cyclopropyl-3-(2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a ]pyridine, I-235

6-cyclopropyl-3-(2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-a ]pyridine, I-236

tert-butyl-((3S,5S)-5-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3- yl)carbamate, I-237

(3R,5S)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3,5-diol, I-238

(3S,5S)-5-amino-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-ol, I-239

3-(4-((3R,4R)-3-fluoro-4-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-240

3-(hydroxymethyl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol, I-241

1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-sulfonamide, I-242

tert-butyl-((3R,4R)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-4-hydroxypiperidin-3-yl)carbamate, I-243

(((3S,5R)-1-(4-(6,7-dichloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl -λ6-sulfanone, I-244

4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-(3,3,3-trifluoropropyl)piperazine-2-carboxamide, I -245

(2S,6S)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol-4-yl) morpholine, I-246

6-Chloro-3-{2-[(2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-imidazo[1, 2-a]pyridine, I-247

6-Chloro-3-{2-[(2R,6S)-2-methyl-6-(1H-pyrazol-4-yl)-morpholin-4-yl]-pyrimidin-4-yl}-imidazo[1, 2-a]pyridine, I-248

6-Cyclopropyl-3-{2-[(3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)-piperidin-1-yl]-pyrimidin-4-yl}-imidazo[1, 2-a]pyridine, I-249

6-Cyclopropyl-3-{2-[(3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)-piperidin-1-yl]-pyrimidin-4-yl}-imidazo[1, 2-a]pyridine, I-250

(2R,6R)-4-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol-4-yl) morpholine, I-251

tert-butyl-((3R,5R)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)carbamate, I-252

2-hydroxy-N-((3S,5S)-5-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin- 3-yl)acetamide, I-253

2-hydroxy-N-((3S,5S)-5-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin- 3-yl)propanamide, I-254

(3R,4R)-3-amino-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-4-ol, I-255

(3R,5R)-1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-amine, I-256

N-((3S,5S)-5-hydroxy-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl) -1H-pyrazole-4-carboxamide, I-257

1-(2-methoxyethyl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide, I-258

6-(3,3-difluoroazetidin-1-yl)-3-(2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4 -yl)imidazo[1,2-a]pyridine, I-259

(R)-1-(3-fluoro-6-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyridin-2-yl)piperidin-3-carboxamide, I-260

6-(3,3-difluoroazetidin-1-yl)-3-(2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4 -yl)imidazo[1,2-a]pyridine, I-261

3-(4-((3S,5R)-3-((dimethyl(oxo)-λ6-sulfanylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a] pyridine-6-carbonitrile, I-262

1-(oxetan-3-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide, I-263

(2S,6S)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide, I-264

(2S,6R)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide, I-265

6-chloro-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine, I-266

6-chloro-3-(4-(3-methyl-5-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine , I-267

6-chloro-3-(4-(3-methyl-5-(5-methyl-1H-pyrazol-4-yl)-4-(methylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1 ,2-a]pyridine, I-268

(((3S,5R)-1-(2-(6,7-dichloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl -λ6-sulfanone, I-269

(2S,6R)-4-(4-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol- 4-yl)morpholine, I-270

6-(azetidin-1-yl)-3-(2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo [1,2-a]pyridine, I-271

6-(azetidin-1-yl)-3-(2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo [1,2-a]pyridine, I-272

(2R,6S)-4-(4-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol- 4-yl)morpholine, I-273

(2R,6R)-4-(4-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol- 4-yl)morpholine, I-274

(2S,6S)-4-(4-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-2-methyl-6-(1H-pyrazol- 4-yl)morpholine, I-275

1-(4-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl )piperazin-1-yl)ethan-1-one, I-276

1-(4-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl)piperazin-1 -yl)ethan-1-one, I-277

(S)-1-(5-fluoro-2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-278

6-chloro-3-(6-methoxy-2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-279

6-chloro-3-(6-methoxy-2-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-280

6-chloro-3-(6-methoxy-2-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1 ,2-a]pyridine, I-281

(S)-1-(5-fluoro-2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-282

N-((1-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-N-methylmethanesulfonamide, I-283

2-(1-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-2-methylpropanoic acid, I-284

tert-butyl 6-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate, I-285

4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide, I-286

6-(3,3-difluoroazetidin-1-yl)-3-(6-methyl-2-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl )pyrimidin-4-yl)imidazo[1,2-a]pyridine, I-287

6-(3,3-difluoroazetidin-1-yl)-3-(6-methyl-2-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl )pyrimidin-4-yl)imidazo[1,2-a]pyridine, I-288

(((3S,5R)-1-(2-(6-bromimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6 -sulfanone, I-289

dimethyl(((3S,5R)-5-methyl-1-(2-(6-(trifluoromethoxy)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl) imino)-λ6-sulfanone, I-290

dimethyl(((3S,5R)-5-methyl-1-(2-(6-(difluoromethoxy)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl) imino)-λ6-sulfanone, I-291

tert-butyl 6,6-dimethyl-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro [3.5]nonane-2-carboxylate, I-292

(2R,6S)-2-methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethoxy)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)morpholine, I-293

6,6-dimethyl-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5] nonan, I-294

(R)-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one, I-295

(S)-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-1-one, I-296

1-(1-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)cyclopropan-1-carboxylic acid, I-297

2-(4-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)acetic acid, I-298

6-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane, I-299

(((3S,5R)-1-(2-(6-cyclopropylimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6 -sulfanone, I-300

6-chloro-3-(4-(3-methyl-4-(methylsulfonyl)-5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo [1,2-a]pyridine, I-301

1-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)piperidin-3-ol, I-302

1-(1-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)cyclopropan-1-carboxamide, I-303

6,6-dimethyl-2-(methylsulfonyl)-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2, 8-diazaspiro[3.5]nonane, I-304

2-((6,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methoxy)- N,N-dimethylacetamide, I-305

(3S,5R)-5-(5-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)piperidin-3-ol, I-307

(3R,5S)-5-(5-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)piperidin-3-ol, I-308

2-(1-(2-(6-chlorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-2-methylpropanamide, I-309

3-(4-((3R)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyridine, I-310

1-cyclopropyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide, I-311

dimethyl(((3R,5S)-5-methyl-1-(2-(6-(methylsulfonyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl) imino)-λ6-sulfanone, I-312

3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(methylsulfonyl)imidazo[1,2-a]pyridine, I-313

(3S,5S)-5-(3-Methyl-1H-pyrazol-4-yl)-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl ]-piperidin-3-ol I-314

(3R,5R)-5-(3-Methyl-1H-pyrazol-4-yl)-1-[2-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-4-yl ]-piperidin-3-ol I-315

(3S,5S)-1-(4-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-hydroxypiperidin-3-carboxamide, I-316

(((3S,5R)-1-(2-(6-bromo-7-fluoroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino )dimethyl-λ6-sulfanone, I-317

3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-N-cyclopropylimidazo[1,2-a]pyridin-6-sulfonamide, I-318

N-cyclopropyl-3-(4-((3R,5S)-3-((dimethyl(oxo)-λ6-sulfanylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1, 2-a]pyridine-6-sulfonamide, I-319,

3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridin-6-sulfonamide, I-320

3-(4-(2-methyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyridine, I-321

(R)-1-cyclopropyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide, I-323

(S)-1-cyclopropyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide, I-324

dimethyl({[(3S,5R)-5-methyl-1-(2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)piperidin-3-yl]imino} )-λ6-sulfanone I-325

3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-bromo-7-fluoroimidazo[1,2-a]pyridine, I-326

N-(1-(4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide, I-327

3-(4-((3R,5S)-3-((dimethyl(oxo)-λ6-sulfanylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a] pyridine-6-sulfonamide, I-328

2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}-4-[3-(1H-pyrazol-4-yl)piperidin-1-yl]pyrimidine I-329

(((3S,5R)-1-(2-(6-(3-fluoroazetidin-1-yl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin- 3-yl)imino)dimethyl-λ6-sulfanone, I-330

6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-carbonitrile, I-331

3-methyl-5-(1-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)-1 ,2,4-oxadiazole, I-332

3-(4-(3,3-dimethyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine , I-333

3-(4-(3,3-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-334

3-(4-(4-(2-methoxyethyl)-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-335

1-(2,2-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethane-1- he, I-336

3-(4-(3-(5-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-337

8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)octahydropyrazino[2,1-c][1,4]thiazine 2,2-dioxide , I-338

3-(4-(3,3-dimethyl-4-(methylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-339

(((3S,5R)-1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino) dimethyl-λ6-sulfanone, I-340

(2S,6S)-4-(2-(6-cyclopropyl-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl- 1,2,4-oxadiazol-5-yl)morpholine, I-341

dimethyl(((3R,5R)-5-(5-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl) pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone, I-342

(2R,6R)-2-methyl-6-(5-methylisoxazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)morpholine, I-343

dimethyl(((3S,5R)-5-(5-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl) pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone, I-344

(2S,6S)-2-methyl-6-(5-methylisoxazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)morpholine, I-345

(2S,6R)-2-methyl-6-(5-methylisoxazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)morpholine, I-346

(2R,6S)-2-methyl-6-(5-methylisoxazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)morpholine, I-347

3-(4-(4-(1-ethoxycyclopropyl)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyridine, I-348

(R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide, I-349

(s)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide, I-350

3-(4-(3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-351

3-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- yl)propane-1,2-diol, I-352

4-((2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1 -yl)methyl)oxazole, I-353

3-(4-(3-(1H-pyrazol-4-yl)-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)-6-( trifluoromethyl)imidazo[1,2-a]pyridine, I-354

6-(trifluoromethyl)-3-(4-(3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyridine , I-355

3-(4-(3-(1H-1,2,4-triazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine , I-356

3-(4-(3-fluoro-5-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyridine, I-357

2-methyl-6-(3-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl )morpholine, I-358

(2S,6R)-4-(2-(7-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3 -methyl-1H-pyrazol-4-yl)morpholine, I-359

(2R,6R)-4-(2-(7-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3 -methyl-1H-pyrazol-4-yl)morpholine, I-360

3-(4-((2S,3R)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-361

4-[(2R,3S)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo [1,2-a]pyridin-3-yl]pyrimidine, I-362

3-(4-((2R,3R)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-363

3-(4-((2S,3S)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-364

3-(4-(2S,3R)-2-methyl-3-(5-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2- yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-365

3-(4-(2R,3S)-2-methyl-3-(5-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2- yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-366

3-(4-(2S,3S)-2-methyl-3-(5-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2- yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-367

3-(4-(2R,3R)-2-methyl-3-(5-methyl-1H-pyrazol-4-yl)-4-(oxetan-3-yl)piperazin-1-yl)pyrimidin-2- yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-368

4-[4-(cyclopropylmethyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine , I-369

3-(4-(4-((3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-370

3-(4-(4-((1H-imidazol-2-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl) imidazo[1,2-a]pyridine, I-371

3-(4-(4-((2-methyl-1H-imidazol-5-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6 -(trifluoromethyl)imidazo[1,2-a]pyridine, I-372

3-(4-(4-((2-(tert-butyl)-1H-imidazol-5-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2- yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-373

3-(4-(4-(oxetan-3-ylmethyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-374

(2R,6R)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)morpholine, I-375

(((3S,5R)-1-(2-(6-cyclopropyl-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino )dimethyl-λ6-sulfanone, I-376

6-cyclopropyl-7-fluoro-3-(4-(3-fluoro-5-(5-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2 -a]pyridine, I-377

4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-carboxamide, I-378

3-(4-(3-methyl-4-(1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I -379

3-methyl-4-{2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidin-4-yl}piperazin-2-carboxamide, I-380

(1-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-1,2,3- triazol-4-yl)methanol, I-382

3-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- yl)cyclobutan-1-ol, I-383

3-(4-(4-((1-methyl-1H-pyrazol-4-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6 -(trifluoromethyl)imidazo[1,2-a]pyridine, I-384

3-(4-(4-((1H-imidazol-5-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl) imidazo[1,2-a]pyridine, I-385

tert-butyl 8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonan-2 -carboxylate, I-386

tert-butyl 6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate, I -387

tert-butyl 9,9-dimethyl-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro [3.5]nonane-2-carboxylate, I -388

4-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide, I-389

(3-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1 -yl)cyclobutyl)methanol, I-390

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1-isopropyl-1H-pyrazol-4-yl)methanone, I-391

3-(4-(4-cyclopropyl-3,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-392

2-(2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)acetonitrile, I- 393

N-(((1R,4S)-2-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-azabicyclo[2.2.2] octan-6-yl)methyl)methanesulfonamide, I-394

6-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonane, I- 395

8-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-6,6-dimethyl-2-(methylsulfonyl)-5-oxa-2, 8-diazaspiro[3.5]nonane, I-396

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (cyclopropyl)methanone, I-397

2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}-4-[(3R)-3-(1H-pyrazol-4-yl)piperidin-1-yl]pyrimidine I-398

2-{6-phenoxyimidazo[1,2-a]pyridin-3-yl}-4-[(3S)-3-(1H-pyrazol-4-yl)piperidin-1-yl]pyrimidine I-399

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (2,2-difluorocyclopropyl)methanone, I-400

(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-isopropyl -1H-pyrazol-3-yl)methanone, I-401

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (3,3-difluorocyclobutyl)methanone, I-402

cyclopropyl(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone, I -403

N-((R)-1-((S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl )ethyl)methanesulfonamide, I-404

N-((S)-1-((R)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl )ethyl)methanesulfonamide, I-405

N-((R)-1-((R)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl )ethyl)methanesulfonamide, I-406

N-((S)-1-((S)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholin-2-yl )ethyl)methanesulfonamide, I-407

3-(4-((3R,5S)-3-methyl-5-(5-methyl-2H-1,2,3-triazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-408

3-(4-((3S,5R)-3-methyl-5-(5-methyl-2H-1,2,3-triazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-409

3-(4-(cis-3,5-dimethyl-4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyridine, I-410

tert-butyl-3-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonan-9- carboxylate, I-411

8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane, I-412

6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane, I-413

1-(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethane- 1-on, I-414

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1-(2-hydroxyethyl)-1H-pyrazol-4-yl)methanone, I-415

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1-(2-methoxyethyl)-1H-pyrazol-4-yl)methanone, I-416

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1-(oxetan-3-yl)-1H-pyrazol-4-yl)methanone, I-417

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1-methyl-1H-pyrazol-4-yl)methanone, I-418

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1-methyl-1H-pyrazol-5-yl)methanone, I-419

1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- yl)-2-hydroxypropan-1-one, I-420

1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- yl)-2-hydroxyethan-1-one, I-421

1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- yl)-3-(1H-imidazol-1-yl)propan-1-one, I-422

1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- yl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)propan-1-one, I-423

(S)-4-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide, I-424

(R)-4-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropylpiperazine-2-carboxamide, I-425

6-chloro-7-fluoro-3-(4-(3-fluoro-5-(5-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2 -a]pyridine, I-426

4-(2-(6-cyclopropyl-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-carboxamide, I-427

(2S,6S)-4-(2-(6-cyclopropyl-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl- 1H-pyrazol-4-yl)morpholine, I-428

(2S,6R)-4-(2-(6-cyclopropyl-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl- 1H-pyrazol-4-yl)morpholine, I-429

1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- carbonyl)cyclopropane-1-carbonitrile, I-432

(R)-1-(4-(4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl)-1H- pyrazole-1-carbonyl)cyclopropane-1-carbonitrile, I-433

(2R,3R)-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide, I-434

(2S,3S)-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide, I-435

N-(((2R,3S)-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl )methyl)methanesulfonamide, I-436

(3,3-difluorocyclobutyl)(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1 -yl)methanone, I-437

(2,2-difluorocyclopropyl)(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1 -yl)methanone, I-438

3-(4-(cis-3,5-dimethyl-4-(methylsulfonyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-439

(1-cyclopropyl-1H-pyrazol-3-yl)(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)piperazin-1-yl)methanone, I-440

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1,2,5-oxadiazol-3-yl)methanone, I-441

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (2H-1,2,3-triazol-4-yl)methanone, I-442

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (oxazol-4-yl)methanone, I-443

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (isoxazol-4-yl)methanone, I-444

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1H-imidazol-4-yl)methanone, I-445

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1-methyl-1H-imidazol-4-yl)methanone, I-446

2-(methylsulfonyl)-8-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5] nonan, I-447

2-(methylsulfonyl)-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane, I- 448

3-(4-(3-(1H-pyrazol-4-yl)-4-(3,3,3-trifluoropropyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyridine, I-449

3-(4-(4-(3,4-difluorobenzyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-450

4-(2-{6-chlorimidazo[1,2-a]pyridin-3-yl}pyrimidin-4-yl)-3-methylpiperazine-2-carboxamide, I-451

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (2-methoxypyridin-4-yl)methanone, I-452

(2R,3S)-4-(2-(6-cyclopropyl-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-carboxamide, I-454

4-(2-(6-cyclopropyl-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-carboxamide, I-455

3-(4-(3-(1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo [1,2-a]pyridine, I-456

3-(4-(4-(4-fluorobenzyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyridine, I-457

3-(4-(4-(3-fluorobenzyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyridine, I-458

3-(4-(4-(2-fluorobenzyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyridine, I-459

3-(4-(4-(4,4-difluorocyclohexyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-460

4-{4-[(1,2,5-oxadiazol-3-yl)methyl]-3-(1H-pyrazol-4-yl)piperazin-1-yl}-2-[6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3-yl]pyrimidine, I-461

3-(4-(cis-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, I-462

3-(2-((3R,5S)-3-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-463

1-(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2 -(tetrahydro-2H-pyran-4-yl)ethan-1-one, I-464

3-(2-((3S,5S)-3-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-465

3-(2-((3S,5R)-3-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-466

3-(2-((3R,5R)-3-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-467

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (spiro[2.2]pentan-1-yl)methanone, I-468

5-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- carbonyl)pyrrolidin-2-one, I-469

3-(4-(4-((2,2-difluorocyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, I-470

N-(((2S,3S)-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-2-yl )methyl)methanesulfonamide, I-471

N-((1-cyclopropyl-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl) methanesulfonamide, I-472

3-(4-(4-((2-methylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1, 2-a]pyridine, I-473

(S)-6-((S)-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin- 4-yl)piperazin-1-carbonyl)piperidin-2-one, I-474

3-(4-(3-(1H-pyrazol-4-yl)-4-(spiro[2.2]pentan-1-ylmethyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo [1,2-a]pyridine, I-475

3-(4-(4-((2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyridine, I-477

N-(5-(trifluoromethyl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide, I- 478

(R)-(1,3-dimethyl-1H-pyrazol-4-yl)(2-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine -4-yl)piperazin-1-yl)methanone, I-479

(S)-(1,3-dimethyl-1H-pyrazol-4-yl)(2-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine -4-yl)piperazin-1-yl)methanone, I-480

3-(4-((2S,3R)-2-methyl-4-((3-methyloxetan-3-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin- 2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-481

3-(4-((2S,3S)-2-methyl-4-((3-methyloxetan-3-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin- 2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-482

(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(pyridin-4 -yl)methanone, I-483

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) ((1R,2R)-2-fluorocyclopropyl)methanone, I-485

(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)(1-methylcyclopropyl )methanone, I-486

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (tetrahydro-2H-pyran-4-yl)methanone, I-487

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (1-(difluoromethyl)cyclopropyl)methanone, I-488

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) ((1R,2R)-2-fluorocyclopropyl)methanone, I-489

N-(((2R,3S,6S)-1-cyclopropyl-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)piperazin-2-yl)methyl)methanesulfonamide, I-491

4-(2,2-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-carbonyl)cyclohexane-1- he, I-492

N-(((2R,3R,6R)-1-cyclopropyl-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)piperazin-2-yl)methyl)methanesulfonamide, I-493

N-(((2S,3R,6R)-1-cyclopropyl-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)piperazin-2-yl)methyl)methanesulfonamide, I-494

N-((4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-(trifluoromethyl)piperazin-2-yl)methyl)methanesulfonamide , I-496

(2R,6R)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)morpholine, I-497

(2S,6S)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(3-methyl-1 ,2,4-oxadiazol-5-yl)morpholine, I-498

(((3S,5R)-1-(4-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-methylpiperidin-3-yl)imino) dimethyl-λ6-sulfanone, I-499

N-((S)-1-((2S,3S)-1-cyclopropyl-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine -4-yl)piperazin-2-yl)ethyl)methanesulfonamide, I-500

1-(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)-2 -(oxetan-3-yl)ethan-1-one, I-501

(S)-3-(4-(3-(1H-pyrazol-4-yl)-4-(2-oxaspiro[3.3]heptan-6-yl)piperazin-1-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-502

(R)-3-(4-(4-cyclopropyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyridine, I-503

(R)-3-(4-(3-(1H-pyrazol-4-yl)-4-(2-oxaspiro[3.3]heptan-6-yl)piperazin-1-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-504

N-((R)-1-((2R,3R)-1-cyclopropyl-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine -4-yl)piperazin-2-yl)ethyl)methanesulfonamide, I-505

N-((R)-1-((2S,3S)-1-cyclopropyl-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine -4-yl)piperazin-2-yl)ethyl)methanesulfonamide, I-506

N-((S)-1-((2R,3R)-1-cyclopropyl-3-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine -4-yl)piperazin-2-yl)ethyl)methanesulfonamide, I-507

3-{2-[(R)-4-Cyclopropyl-3-(1H-pyrazol-4-yl)-piperazin-1-yl]-pyrimidin-4-yl}-6-trifluoromethylimidazo[1,2-a] pyridine, I-508,

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (3-hydroxy-3-methylcyclobutyl)methanone, I-509

3-(4-(4-((1-methylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1, 2-a]pyridine, I-510

4-[(2R,3S)-4-{[1-(methoxymethyl)cyclobutyl]methyl}-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6- (trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine, I-511

4-[(2S,3S)-4-{[1-(methoxymethyl)cyclobutyl]methyl}-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6- (trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]pyrimidine, I-512

(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-yl)(cis-2,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[ 1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl)methanone, I-513

1-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1- yl)-2-hydroxy-2-methylpropan-1-one, I-514

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (5-methylisoxazol-4-yl)methanone, I-515

N-(((2R,3S)-1-cyclopropyl-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin- 2-yl)methyl)methanesulfonamide, I-516

N-(((2S,3R)-1-cyclopropyl-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methylpiperazin- 2-yl)methyl)methanesulfonamide, I-517

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (4-methyl-1,2,5-oxadiazol-3-yl)methanone, I-518

(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin-1-yl) (3,5-dimethylisoxazol-4-yl)methanone, I-519

3-(4-((R)-4-(((R)-6-oxaspiro2.5]octan-1-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl) pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-520

3-(4-((S)-4-(((S)-6-oxaspiro2.5]octan-1-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl) pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-521

3-(4-((S)-4-(((R)-6-oxaspiro2.5]octan-1-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl) pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-522

3-(4-((R)-4-(((S)-6-oxaspiro2.5]octan-1-yl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl) pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-523

((2S,6S)-4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-6-methylmorpholin-2-yl)methanol, I -524

N-(1-(4-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)-5-(trifluoromethyl)piperidin-3-yl)methanesulfonamide, I- 525

3-(4-((R)-4-(((R)-2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-526

3-(4-((S)-4-(((S)-2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-527

3-(4-((S)-4-(((R)-2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-528

3-(4-((R)-4-(((S)-2,2-dimethylcyclopropyl)methyl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl) -6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-529

N-((4-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-3-methyl-1-(oxetan-3-yl)piperazine -2-yl)methyl)methanesulfonamide, I-530

N-(1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)methanesulfonamide, I- 531

(R)-3-(4-(3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I -532

(S)-3-(4-(3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I -533

3-(4-((2S,3R)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-534

3-(4-((2S,3S)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-535

3-(4-((2R,3R)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-536

4-[(2R,3S)-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]-2-[6-(trifluoromethyl)imidazo[1,2-a]pyridin-3 -yl]pyrimidine, I-537

(2R,6R)-4-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl- 1H-pyrazol-4-yl)morpholine, I-538

(2S,6S)-4-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl- 1H-pyrazol-4-yl)morpholine, I-539

(2R,6S)-4-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl- 1H-pyrazol-4-yl)morpholine, I-540

N-(((2R,3S)-1-cyclopropyl-3-methyl-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperazine -2-yl)methyl)methanesulfonamide, I-541

3-(2-((S)-3-(1H-pyrazol-4-yl)-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)pyrimidin- 4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-542

N-{(2S,3R)-1-Cyclopropyl-3-methyl-4-[4-(6-trifluoromethylimidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-yl]-piperazin-2 -ylmethyl}-methanesulfonamide, I-543

3-(2-((R)-3-(1H-pyrazol-4-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)pyrimidin- 4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-544

3-(2-((R)-3-(1H-pyrazol-4-yl)-4-(((R)-tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)pyrimidin- 4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-545

3-(2-((S)-3-(1H-pyrazol-4-yl)-4-(((S)-tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)pyrimidin- 4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-546

(2R,3R)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropyl-3-methylpiperazine-2-carboxamide, I-547

(2S,3S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-1-cyclopropyl-3-methylpiperazine-2-carboxamide, I-548

(S)-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin- 1-yl)(5-methylisoxazol-4-yl)methanone, I-549

(R)-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperazin- 1-yl)(5-methylisoxazol-4-yl)methanone, I-550

1-(2-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-2-yl)piperazin-1- carbonyl)cyclopropane-1-carbonitrile, I-551

3-(4-((R)-3-(1H-pyrazol-4-yl)-4-(((R)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-yl)pyrimidin- 2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-552

3-(4-((S)-3-(1H-pyrazol-4-yl)-4-(((S)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-yl)pyrimidin- 2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-553

3-(4-((S)-3-(1H-pyrazol-4-yl)-4-(((R)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-yl)pyrimidin- 2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-554

3-(4-((R)-3-(1H-pyrazol-4-yl)-4-(((S)-spiro[2.2]pentan-1-yl)methyl)piperazin-1-yl)pyrimidin- 2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-555

(S)-6-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl) piperazin-1-yl)-2-thiaspiro[3.3]heptane 2,2-dioxide, I-556

(R)-6-(2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl) piperazin-1-yl)-2-thiaspiro[3.3]heptane 2,2-dioxide, I-557

(S)-1-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, I-558

6-chloro-3-(4-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyridine, I-559

(2S,6R)-2-methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)morpholine, I-560

(2R,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(5-methyl-1H-pyrazol- 4-yl)morpholine, I-561

(2S,6S)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide, I-562

6-chloro-3-(4-((2S,3R,5S)-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1 ,2-a]pyridine, I-563

(2R,6S)-2-methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4 -yl)morpholine, I-564

3-(4-((2R,3S)-2-methyl-4-(oxetan-3-yl)-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyridine, I-565

(2R,6S)-4-(2-(6-chloroimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl) morpholine, I-566

3-(4-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyridine, I-567

(2S,6R)-4-(2-(6-chloro-7-fluorimidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol- 4-yl)morpholine, I-568

(((3R,5R)-1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyridin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino) dimethyl-λ6-sulfanone, I-569

Example 26: GCN2 Inhibition Study by Human IL-2

[00488] The tumor microenvironment is highly immunosuppressive. This can be attributed to a decrease in amino acids (such as arginine and tryptophan), which triggers GCN2 activation in immune cells, including T cells and myeloid cells. In T cells, activation of GCN2 leads to attenuation of CD8 T cell effector functions and the induction and/or maintenance of immunosuppressive T-regs. Inhibition of this immunosuppressive response by GCN2 inhibitors provides an anticancer immune response by activating effector T cells. The present invention describes an in-vitro system developed by us using human T cells stimulated under low amino acid conditions to exhibit the biological characteristics of GCN2. The described technique involves modulating the level of IL-2 secreted by human T cells in response to the GCN2 inhibitors disclosed in the present invention.

[00489] Amino acid-free RPMI medium was reconstituted with all amino acids except one found in standard RMPI (e.g., arginine, tryptophan), 10% charcoal-stripped fetal bovine serum, 100 U/mL penicillin, and 0.1 mg/mL streptomycin. Primary human pan-T cells were isolated using a human Pan T Cell Isolation kit (MACS Miltenyi biotech Cat# Order no. 130-096-535) from apheresis cones and 5x104 pan-T cells/well. Purified T cells were seeded into 96-well round bottom polystyrene Nunc™ 96-Well microtiter plates (cells were maintained in TRP-free media in a 15 mL Falcon tube in an incubator for 30-45 min while tryptophan was titrated and GCN2 inhibitory compounds). A plate matrix was developed to titrate GCN2 inhibitor and amino acid of interest ranging from “no amino acid” up to the concentration found in standard RPMI media (20 µM for TRP and 950 µM for arginine). Cells were incubated for 30 min at 37°C with GCN2 inhibitor and then stimulated with 5 x 104 anti-CD3/CD28 dynabeads® per well. After 96 hours of incubation, IL-2 content in the supernatant was measured using ELISA (R&D systems Cat# DY202 (Human IL-2 DuoSet ELISA). The data were plotted using GraphPad Prism software and EC ₅₀ was calculated.

Table 6. EC ₅₀ values based on IL-2 secretion by T cells

[00490] +++ for EC ₅₀ <100 nM; ++ for EC ₅₀ in the range of 100-500 nM; + for EC ₅₀ >500 nM; and "-" for inactive

Connection No. IL2/T cell EC ₅₀ (nM) I-102 ++ I-116 +++ I-123 +, - I-124 ++, +++ I-125 +++, ++, + I-126 ++ I-127 +++ I-128 + I-134 + I-135 ++ I-136 +++, ++ I-137 ++ I-148 ++ I-154 +++ I-160 ++ I-170 ++ I-176 +++ I-179 ++ I-185 - I-191 - I-200 ++ I-209 ++ I-223 ++ I-247 +++ I-248 ++ I-249 ++ I-250 - I-259 +++ I-293 +++ I-314 - I-315 ++ I-323 + I-354 ++ I-359 ++ I-366 +++ I-409 + I-473 ++ I-481 +++ I-482 + I-495 + I-499 + I-504 ++ I-547 ++ I-558 ++ I-559 +++ I-560 +++ I-561 ++ I-562 ++ I-563 ++ I-564 +++ I-565 +++ I-566 +++ I-567 +++ I-568 ++ I-569 ++ I-562 ++

[00491] Although a number of embodiments of the present invention have been described, it will be appreciated that the basic examples given can be modified to produce other embodiments that utilize the compounds and methods of the present invention. Therefore, it should be understood that the scope of the present invention is defined by the appended claims and not by the specific embodiments, which are given by way of example.

Claims (105)

1. Compound of one of the formulas XV-a, XV-b or XV-c: or a pharmaceutically acceptable salt thereof, where each of R¹ independently means hydrogen, halogen, -CN, -NO₂, -C(O)R, -C(O)OR, -C(O)NR₂, -C(O)NRS(O)₂R, -C(O)N=S(O)R₂, -NR₂, -NRC(O)R, -NRC(O)NR₂, -NRC(O)OR, -NRS(O)₂R, -NRS(O)₂NR₂, -OR, -ON(R)SO₂R, -P(O)R₂, -SR, -S(O)R, -S(O)₂R, -S(O)(NH)R, -S(O)₂N(R)₂, -S(NH₂)₂(O)OH, -N=S(O)R₂, -CH₃, -CH₂OH, -CH₂NHSO₂CH₃, -CD₃, -CD₂NRS(O)₂R, or R; or: two R ¹ groups together form =O or =NH; or two R groups¹ together form divalent C_2-4 alkylene chain; or each of R ¹ is independently selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And ; each R independently represents hydrogen or a group selected from the group consisting of C _1-6 aliphatic group, 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, 8-10 membered bicyclic aromatic carbocyclic ring, 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, 5-6-membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; or two R groups together form a divalent C_2-4 alkylene chain; two R groups together with the atoms located between them form a 3-7 membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur; m is 0, 1, 2, 3, 4 or 5. 2. Connection according to claim 1, where R¹ represents hydrogen, halogen, –CN, –C(O)R, –C(O)OR, –C(O)NR₂, –C(O)NRS(O)₂R, –C(O)N=S(O)R₂, –NR₂, –NRC(O)R, –NRC(O)NR₂, –NRC(O)OR, –NRS(O)₂R, –NRS(O)₂NR₂, –OR, –ON(R)SO₂R, –P(O)R₂, –SR, –S(O)R, –S(O)₂R, –S(O)(NH)R, –S(O)₂N(R)₂, –S(NH₂)₂(O)OH, –N=S(O)R₂, -CH₃, -CH₂OH, -CH₂NHSO₂CH₃, –CD₃, –CD₂NRS(O)₂R or R 3. The compound according to claim 1, where two groups R¹ together form divalent C_2-4 alkylene chain. 4. A compound according to claim 1, where the two R ¹ groups together form =O or =NH. 5. Connection according to any one of paragraphs. 1-4, in which m is 1, 2, 3, 4 or 5, preferably 1, 2 or 3. 6. A compound according to claim 2, wherein each R independently represents hydrogen or a group selected from the group consisting of a C _1-6 aliphatic group, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic an aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. 7. The compound according to claim 2, where R represents hydrogen. 8. The compound according to claim 2, where R represents a C _1-6 aliphatic group. 9. A compound according to claim 2, where R represents a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. 10. The compound according to claim 2, where R represents phenyl. 11. A compound according to claim 2, where R represents an 8-10 membered bicyclic aromatic carbocyclic ring. 12. A compound according to claim 2, where R represents a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. 13. The compound according to claim 2, where R represents a 5-6 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. 14. The compound according to claim 2, where R represents an 8-10 membered bicyclic heteroaromatic ring containing 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. 15. The compound according to claim 2, where two R groups together form a divalent C_2-4 alkylene chain. 16. The compound according to claim 2, where the two R groups together with the atoms located between them form a 3-7-membered saturated or partially unsaturated monocyclic ring containing 0-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur. 17. The compound according to claim 1, where R ¹ is selected from the group consisting of fluorine, chlorine, methyl, ethyl, –OH, –OCH ₃ , –CH ₂ OH, –CH ₂ CN, –CF ₃ , –CH ₂ NH ₂ , –COOH, _–NH2 , , , , , , , , , , , , , , , , , , , , And . 18. The connection according to claim 1, where R ¹ is selected from the group consisting of: , , , , , , , , , , , , , , , , And . 19. The connection according to claim 1, where R ¹ is selected from the group consisting of: , , , , , , , , , , , , , , , , , , And . 20. The connection according to claim 1, where R ¹ is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And . 21. The connection according to claim 1, where R ¹ is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , And . 22. The connection according to claim 1, where R ¹ is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , And . 23. The connection according to claim 1, where R ¹ is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , And . 24. The connection according to claim 1, where R ¹ is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , And . 25. A compound according to claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 26. A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition having inhibitory activity of general amino acid regulating kinase 2 with constant repression (GCN2), containing an effective amount of a compound according to any one of paragraphs. 1-26 and a pharmaceutically acceptable carrier, excipient or diluent. 28. Use of a compound according to any one of paragraphs. 1-26 or a pharmaceutical composition containing it for inhibiting GCN2 in a biological sample. 29. Use of a compound according to any one of paragraphs. 1-26 or a pharmaceutical composition containing the same for the preparation of a medicament for treating a GCN2-mediated disorder, disease or condition in a patient. 30. The use of claim 29, wherein the GCN2-mediated disorder, disease or condition is selected from the group consisting of inflammatory disease conditions, immunological disease conditions, autoimmune disease conditions, allergic disease conditions, rheumatic disease conditions, thrombotic disease conditions, cancer, infections, neurodegenerative diseases, degenerative diseases, neuroinflammatory diseases, cardiovascular diseases and metabolic pathological conditions. 31. Use according to claim 30, where the cancer is selected from the group consisting of a solid tumor, where the solid tumor comes from the group of tumors of the epithelium, bladder, stomach, kidney, head and neck, esophagus, cervix, thyroid gland, intestine, liver, brain, prostate, genitourinary tract, lymphatic system, stomach, larynx, bones, including chondrosarcoma and Ewing's sarcoma, germ cells, including embryonal tissue tumors, and/or lungs selected from the group consisting of monocytic leukemia, adenocarcinoma lung, small cell lung carcinoma, pancreatic cancer, glioblastoma, neurofibroma, angiosarcoma, breast carcinoma and/or malignant melanoma and tumor of the blood and immune system. 32. Use according to claim 30, wherein the autoimmune pathological condition is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjögren's syndrome or organ transplant rejection. 33. Use according to claim 30, wherein the metabolic pathological condition is diabetes. 34. Use according to claim 30, wherein the degenerative disease is osteoarthritis. 35. Use according to claim 30, wherein the inflammatory pathological condition is asthma, inflammatory bowel disease or giant cell arteritis. 36. Use according to claim 30, wherein the cardiovascular disease is ischemic damage. 37. Use according to claim 30, where the neurodegenerative disease is Alzheimer's disease, Down syndrome, hereditary cerebral hemorrhage with Dutch type amyloidosis, amyloid cerebral angiopathy, Creutzfeldt-Jakob disease, frontotemporal dementia, Huntington's disease or Parkinson's disease. 38. Use according to claim 29, where the infection is caused by leishmania, mycobacteria, including M. leprae, M. tuberculosis and/or M. avium, Plasmodium, human immunodeficiency virus, Epstein-Barr virus, herpes simplex virus or hepatitis C virus. 39. The use of claim 29, wherein the GCN2-mediated disorder, disease or condition is cancer and the method further comprises administering a second agent for treating the cancer.