RU2811408C2 - 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 formula I or a pharmaceutically acceptable salt thereof, wherein the meaning of the radicals is as disclosed in the claims. Besides, specific compounds selected from the group, a pharmaceutical composition based on the presented compounds are disclosed, and the use of the above compounds for inhibiting GCN2 in a biological sample and for obtaining a drug is also disclosed.

EFFECT: group of inventions provides effective inhibition of GCN2.

31 cl, 19 tbl, 115 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. 62/623299, 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 kinase activation 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- a 12-membered partially unsaturated bicyclic heteroaromatic 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, including 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 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 ;

The C ring 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)N(R)₂, -C(O)N(R)S(O)₂R, -C(O)N=S(O)(R)₂, -N(R)₂, -N(R)C(O)R, -N(R)C(O)N(R)₂, -N(R)C(O)OR, -N(R)S(O)₂R, -N(R)S(O)₂N(R)₂, -OR, -ON(R)SO₂R, -P(O)(R)₂, -SR, -S(O)R, -S(O)₂R, -S(O)(NH)R, -S(O)₂N(R)₂, -S(NH₂)₂(O)OH, -N=S(O)(R)₂, -C(R)₂S(=O)(=NH)R, -C(R)₂NHSO₂CH₃, -CD₃, -CD₂N(R)S(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- An 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 heterocyclic ring containing 1-2 heteroatoms, independently selected from the group consisting of 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 stated, 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)N(R°) ₂ ; -N(R°)C(S)N(R°) ₂ ; -(CH ₂ ) _0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)N(R°) 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)OSi(R°) 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)N(R°) ₂ ; -C(S)N(R°) ₂ ; -C(S)SR°; -(CH ₂ ) _0-4 OC(O)N(R°) 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 N(R°) ₂ ; -(CH ₂ ) _0-4 S(O)R°; -(CH ₂ ) _0-4 S(O)(NR°)R°; -N(R°)S(O) ₂ N(R°) 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)N(R°) ₂ ; -P(O) ₂ R°; -P(O)(R°) ₂ ; -OP(O)(R°) ₂ ; -OP(O)(OR°) ₂ ; -Si(R°) 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 N(R ^λ ) ₂ , -NO ₂ , -Si(R ^λ ) ₃ , -OSi(R ^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 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 ^* , =NSO ₂ R ^* , -O(C(R ^* ₂ )) _2-3 O- or -S(C(R ^* ₂ )) _2-3 S- wherein on each independent occurrence R ^* 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 heteroatom independently selected from the group consisting of 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 , -N(R ^λ ) ₂ or -NO ₂ , where each R ^λ is unsubstituted or, if preceded by "halogen", is substituted by only one or more number of 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 group including nitrogen, oxygen or sulfur.

[0035] Suitable substituents on the substitutable nitrogen atom in the "optionally substituted" group include -R ^† , -N(R ^† ) 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 N(R ^† ) ₂ , -C(S)N (R ^† ) ₂ , -C(NH)N(R ^† ) 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 , -N(R ^λ ) ₂ or -NO ₂ , where each R ^λ is unsubstituted or, if preceded by "halogen", is substituted by only one or a large number of 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 consisting of 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 tissues of humans and lower animals without undesirable toxicity, irritation, allergic reaction, or the like. and correspond to a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., describe 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. 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 in that they transfer energy to another group in the process of non-radiative 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- a 12-membered partially unsaturated bicyclic heteroaromatic 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, including 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 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 ;

The C ring 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)N(R)₂, -C(O)N(R)S(O)₂R, -C(O)N=S(O)(R)₂, -N(R)₂, -N(R)C(O)R, -N(R)C(O)N(R)₂, -N(R)C(O)OR, -N(R)S(O)₂R, -N(R)S(O)₂N(R)₂, -OR, -ON(R)SO₂R, -P(O)(R)₂, -SR, -S(O)R, -S(O)₂R, -S(O)(NH)R, -S(O)₂N(R)₂, -S(NH₂)₂(O)OH, -N=S(O)(R)₂, -C(R)₂S(=O)(=NH)R, -C(R)₂NHSO₂CH₃, -CD₃, -CD₂N(R)S(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- An 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 heterocyclic ring containing 1-2 heteroatoms, independently selected from the group consisting of 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 bicyclic heteroaromatic 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, 8-10- a membered bicyclic heteroaromatic ring containing 1-5 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 bicyclic heteroaromatic 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 . 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 Tables 1-4 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 .

[0060] In some embodiments, the B ring is selected from among the structures shown in Tables 1-4 below.

[0061] As defined above and described in the present invention, ring C is

or .

[0062] In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is . In some embodiments, ring C is .

[0063] In some embodiments, the C ring is selected from among the structures shown in Tables 1-4 below.

[0064] 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.

[0065] 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.

[0066] In some embodiments, R is selected from among the structures shown in Tables 1-4 below.

[0067] As defined above and described in the present invention, each of R' independently represents hydrogen or a C _1-3 aliphatic group, optionally substituted with halogen.

[0068] In some embodiments, R' is hydrogen. In some embodiments, R' is a C _1-3 aliphatic group, optionally substituted with halogen.

[0069] In some embodiments, R' is selected from among the structures shown in Tables 1-4 below.

[0070] 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)N(R)₂, -C(O)N(R)S(O)₂R, -C(O)N=S(O)(R)₂, -N(R)₂, -N(R)C(O)R, -N(R)C(O)N(R)₂, -N(R)C(O)OR, -N(R)S(O)₂R, -N(R)S(O)₂N(R)₂, -OR, -ON(R)SO₂R, -P(O)(R)₂, -SR, -S(O)R, -S(O)₂R, -S(O)(NH)R, -S(O)₂N(R)₂, -S(NH₂)₂(O)OH, -N=S(O)(R)₂, -C(R)₂S(=O)(=NH)R, -C(R)₂NHSO₂CH₃, -CD₃, -CD₂N(R)S(O)₂R or R; or: two groups R¹ together optionally form =O, =NH or =NS(O)₂R; or two R groups¹ together optionally form divalent C_2-4 alkylene chain.

[0071] 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)N(R)₂. In some embodiments, R¹ means -C(O)N(R)S(O)₂R. In some embodiments, R¹ means -C(O)N=S(O)(R)₂. In some embodiments, R¹ means -N(R)₂. In some embodiments, R¹ means -N(R)C(O)R. In some embodiments, R¹ means -N(R)C(O)N(R)₂. In some embodiments, R¹ means -N(R)C(O)OR. In some embodiments, R¹ means -N(R)S(O)₂R. In some embodiments, R¹ means -N(R)S(O)₂N(R)₂. In some embodiments, R¹ means -OR. In some embodiments, R¹ means -ON(R)SO₂R. In some embodiments, R¹ means -P(O)(R)₂. 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)(R)₂. In some embodiments, R¹ means -C(R)₂S(=O)(=NH)R. In some embodiments, R¹ means -C(R)₂NHSO₂CH₃. In some embodiments, R¹ means -CD₃. In some embodiments, R¹ means -CD₂N(R)S(O)₂R. In some embodiments, R¹ means R. In some embodiments, two R groups¹ together optionally form =O, =NH or =NS(O)₂R. In some embodiments, two R groups¹ together optionally form divalent C_2-4 alkylene chain.

[0072] 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 .

[0073] 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 =NSO ₂ CH ₃ . In some embodiments, two R ¹ groups form .

[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 . 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 . 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 .

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

[0093] 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 .

[0094] In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0095] 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 . 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 .

[0096] In some embodiments, R ¹ means . In some embodiments, R ¹ means .

[0097] 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 .

[0098] In some embodiments, R ¹ is selected from among the structures shown in Tables 1-4 below.

[0099] 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

[00100] 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.

[00101] 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 .

[00102] 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 .

[00103] 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 .

[00104] 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 .

[00105] In some embodiments, R ² is selected from among the structures shown in Tables 1-4 below.

[00106] 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.

[00107] 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.

[00108] In some embodiments, R ³ is selected from among the structures shown in Tables 1-4 below.

[00109] As defined above and as used herein, R ⁴ is hydrogen, halogen, -CN, -OR, -N=S(O)(R) ₂ , -N(R) ₂ or an optionally substituted group selected from 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 an unsaturated spirocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur.

[00110] 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.

[00111] 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 .

[00112] 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 .

[00113] In some embodiments, R ⁴ is . In some embodiments, R ⁴ is . In some embodiments, R ⁴ is .

[00114] In some embodiments, R ⁴ is selected from among the structures shown in Tables 1-4 below.

[00115] As defined above and specified in the present invention, m is 0, 1, 2, 3, 4 or 5.

[00116] 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 .

[00117] In some embodiments, m is 1, 2, or 3.

[00118] In some embodiments, m is selected from the values shown in Tables 1-4 below.

[00119] As defined above and described in the present invention, n is 0, 1 or 2.

[00120] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[00121] In some embodiments, n is selected from the values shown in Tables 1-4 below.

[00122] As defined above and in the present invention, p is 0 or 1.

[00123] In some embodiments, p is 0. In some embodiments, p is 1.

[00124] In some embodiments, p is selected from the values shown in Tables 1-4 below.

[00125] As defined above and described in the present invention, q is 0 or 1.

[00126] In some embodiments, q is 0. In some embodiments, q is 1.

[00127] In some embodiments, q is selected from the values shown in Tables 1-4 below.

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

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

[00129] In some embodiments, the present invention provides a compound of Formula I wherein ring B is and thereby forms a compound of formula III:

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

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

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

[00131] In some embodiments, the present invention provides a compound of Formula I wherein ring B is and thereby forms a compound of formula V:

or a pharmaceutically acceptable salt thereof, wherein each ring A, ring C, R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are as defined above and described in the presented 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 VI:

or a pharmaceutically acceptable salt thereof, wherein each ring C, 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.

[00133] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het, ring B is and ring C represents 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.

[00134] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl or morpholinyl, ring B is and ring C represents and thereby forms a compound of formula VIII-a, VIII-b or VIII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of 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.

[00135] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het, ring B is and ring C represents 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.

[00136] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl or morpholinyl, ring B is and ring C represents and thereby forms a compound of formula Xa, Xb or Xc, respectively:

X-c

or a pharmaceutically acceptable salt thereof, wherein each of 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.

[00137] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het, ring B is and ring C represents 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.

[00138] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl or morpholinyl, ring B is and ring C represents and thereby forms a compound of formula XII-a, XII-b or XII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of 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.

[00139] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het, ring B is and ring C represents and thereby forms a compound of formula XIII:

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.

[00140] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl or morpholinyl, ring B is and ring C represents and thereby forms a compound of formula XIV-a, XIV-b or XIV-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of 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.

[00141] 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 XV:

or a pharmaceutically acceptable salt thereof, wherein each ring C, 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.

[00142] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het, ring B is and ring C represents and thereby forms a compound of formula XVI:

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.

[00143] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl or morpholinyl, ring B is and ring C represents and thereby forms a compound of formula XVII-a, XVII-b or XVII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of 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.

[00144] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het, ring B is and ring C represents and thereby forms a compound of formula XVIII:

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.

[00145] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl or morpholinyl, ring B is and ring C represents and thereby forms a compound of formula XIX-a, XIX-b or XIX-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of 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.

[00146] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het, ring B is and ring C represents and thereby forms a compound of formula XX:

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.

[00147] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl or morpholinyl, ring B is and ring C represents and thereby forms a compound of formula XXI-a, XXI-b or XXI-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of 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.

[00148] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het, ring B is and ring C represents and thereby forms a compound of formula XXII:

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.

[00149] In some embodiments, the present invention provides a compound of formula I, wherein ring A is piperidinyl, piperazinyl or morpholinyl, ring B is and ring C represents and thereby forms a compound of formula XXIII-a, XXIII-b or XXIII-c, respectively:

or a pharmaceutically acceptable salt thereof, wherein each of 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.

[00150] In some embodiments, the present invention provides a compound of formula I wherein ring A is Het and thereby forms a compound of formula XXIV:

or a pharmaceutically acceptable salt thereof, wherein each Het, Ring B, Ring C, R ¹ , R ² , R ³ , R ⁴ , m, n, p and q are as defined above and described in the presented embodiments, according to separately and in combination.

[00151] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring C is and thereby forms a compound of formula XXV:

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

[00152] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring C is and thereby forms a compound of formula XXVI:

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

[00153] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring C is and thereby forms a compound of formula XXVII:

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

[00154] In some embodiments, the present invention provides a compound of formula I, wherein ring A is Het and ring C is and thereby forms a compound of formula XXVIII:

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

[00155] 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, ring B is and ring C represents and thereby forms a compound of formula XXIX-a, XXIX-b or XXIX-c, respectively:

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

[00156] Typical compounds proposed in the present invention are listed below in Table 1.

Table 1. Typical compounds of formula II

Table 2. Typical compounds of formula III

Table 3. Typical compounds of formula IV

Table 4. Typical compounds of formula V

[00157] In some embodiments, the present invention provides the compounds listed in Tables 1-4 above, or pharmaceutically acceptable salts thereof.

[00158] 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

[00159] 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.

[00160] The following diagrams indicate specific protecting group ("PG"), leaving group ("LG"), or conversion conditions, and one of ordinary skill in the art will appreciate 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.

[00161] 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.

[00162] As used in the present invention, 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 .

[00163] 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, and the like. 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.

[00164] In some embodiments, the compounds of Formula II of the present invention are typically prepared according to Schemes 1-17 below:

[00165] Scheme 1: General scheme for the preparation of compounds of formula II, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00166] In Scheme 1 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.

[00167] Scheme 2: General scheme for the preparation of compounds of formula II in which ring C is pyrimidine, R ² is -CHF ₂ , R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00168] In Scheme 2 above, each ring A, R ¹ and m is as defined above and below and in the classes and subclasses described in the present invention.

[00169] Scheme 3: General scheme for the preparation of compounds of formula II, in which ring C is pyridine, R ³ is hydrogen, n is 1 and q is 1.

[00170] In Scheme 3 above, each ring A, R ¹ , R ² , R ⁴ , m and p is as defined above and below and in the classes and subclasses described in the present invention.

[00171] Scheme 4: General scheme for the preparation of compounds of formula II, in which ring A is pyridine, R ³ is hydrogen, n is 1 and q is 1.

[00172] In the above diagram 4, each ring A, R ¹ , R ² , R ⁴ , m and p is as defined above and below and in the subclasses described in the present invention.

[00173] Scheme 5: General scheme for the preparation of compounds of formula II in which ring C is pyridine, R ² is -CHF ₂ , R ³ is hydrogen, n is 1 and q is 1.

[00174] In the above diagram 5, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00175] Scheme 6: General scheme for the preparation of compounds of formula II, in which ring C is pyridine, R ² is -CHF ₂ , R ³ is hydrogen, n is 1 and q is 1.

[00176] In Scheme 6 above, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes and subclasses described in the present invention.

[00177] Scheme 7: General scheme for the preparation of compounds of formula II in which ring C is pyridine, R ² is -CHF ₂ , R ³ is hydrogen, n is 1 and q is 1.

[00178] In the above diagram 7, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00179] Scheme 8: General scheme for the preparation of compounds of formula II in which ring C is pyridine, R ² is -CHF ₂ , R ³ is hydrogen, n is 1 and q is 1.

[00180] In the above diagram 8, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00181] Scheme 9: General scheme for the preparation of compounds of formula II in which ring C is pyridine, R ² is -CHF ₂ , R ³ is hydrogen, n is 1, p is 1 and q is 1.

[00182] In the above diagram 9, each ring A, R ¹ , R ⁴ and m is as defined above and below and in the classes and subclasses described in the present invention.

[00183] Scheme 10: General scheme for the preparation of compounds of formula II, in which ring C is pyridine, R ² is -CHF ₂ , R ³ is hydrogen, n is 1 and q is 1.

[00184] In the above diagram 10, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00185] Scheme 11: General scheme for the preparation of compounds of formula II in which ring C is phenyl, R ² is -CHF ₂ , R ³ is hydrogen, n is 1 and q is 1.

[00186] In the above diagram 11, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00187] Scheme 12: General scheme for the preparation of compounds of formula II in which ring C is phenyl, R ² is -CHF ₂ , R ³ is hydrogen, n is 1 and q is 1.

[00188] In the above diagram 12, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00189] Scheme 13: General scheme for the preparation of compounds of formula II, in which ring C is pyridine, R ² is -OCF ₂ H, R ³ is hydrogen, n is 1 and q is 1.

[00190] In the above diagram 13, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00191] Scheme 14: General scheme for the preparation of compounds of formula II in which ring C is pyridine, R ² is -CF ₃ , R ³ is hydrogen, n is 1 and q is 1.

[00192] In the above diagram 14, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00193] Scheme 15: General scheme for the preparation of compounds of formula II in which ring C is pyridine, R ² is -CHF ₂ , R ³ is hydrogen, n is 1 and q is 1.

[00194] In the above diagram 15, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00195] Scheme 16: General scheme for the preparation of compounds of formula II, in which ring C is pyrimidine, R ² is -Cl, R ³ is hydrogen, n is 1 and q is 1.

[00196] In the above diagram 16, each ring A, R ¹ , R ⁴ , m and p is as defined above and below and in the classes of subclasses described in the present invention.

[00197] Scheme 17: General scheme for the preparation of compounds of formula II in which ring C is pyrimidine, R ² is -CHF ₂ , R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00198] In the above diagram 17, each ring A, R ¹ and m is as defined above and below and in the classes and subclasses described in the present invention.

[00199] Scheme 18: General scheme for the preparation of compounds of formula III, in which ring C is a pyrimidine linked to a bicyclic ring at the 4 position, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00200] In the above diagram 18, 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.

[00201] Scheme 19: General scheme for the preparation of compounds of formula III, in which ring C is a pyrimidine linked to a bicyclic ring at position 4, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00202] In the above diagram 19, 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.

[00203] Scheme 20: General scheme for the preparation of compounds of formula III, in which ring C is a pyrimidine linked to a bicyclic ring at position 4, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00204] In the above diagram 20, 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.

[00205] Scheme 21: General scheme for the preparation of compounds of formula III, in which the C ring is pyridine bonded to a bicyclic ring at position 4, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00206] In the above diagram 21, each ring A, R ¹ , R ² , m and n is as defined above and below and in the subclasses described in the present invention.

[00207] Scheme 22: General scheme for the preparation of compounds of formula III, in which ring C is pyrimidine, R ³ is hydrogen and q is 1.

[00208] In the above diagram 22, each ring A, R ¹ , R ² , R ⁴ , m, n and p is as defined above and below and in the classes of subclasses described in the present invention.

[00209] Scheme 23: General scheme for the preparation of compounds of formula III in which ring C is pyridin-4-yl further substituted at position 2, R ³ is hydrogen and q is 1.

[00210] In the above diagram 23, each ring A, R ¹ , R ² , R ⁴ , m, n and p is as defined above and below and in the classes of subclasses described in the present invention.

[00211] Scheme 24: General scheme for the preparation of compounds of formula III, in which ring C is pyridine introduced by cross-coupling, R ³ is hydrogen and q is 1.

[00212] In the above diagram 24, each ring A, R ¹ , R ² , R ⁴ , m, n and p is as defined above and below and in the classes of subclasses described in the present invention.

[00213] Scheme 25: General scheme for the preparation of compounds of formula III, in which ring C is pyridine introduced by activation of CH, R ³ is hydrogen and q is 1.

[00214] In the above diagram 25, each ring A, R ¹ , R ² , R ⁴ , m, n and p is as defined above and below and in the classes of subclasses described in the present invention.

[00215] Scheme 26: General scheme for the preparation of compounds of formula IV, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00216] In the above diagram 26, 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.

[00217] Scheme 27: General scheme for the preparation of compounds of formula IV, in which ring C is pyridine, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00218] In the above diagram 27, 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.

[00219] Scheme 28: General scheme for the preparation of compounds of formula IV, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00220] In the above diagram 28, 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.

[00221] Scheme 29: General scheme for the preparation of compounds of formula IV in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00222] In the above diagram 29, 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.

[00223] Scheme 30: General scheme for the preparation of compounds of formula IV, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, p is 1 and q is 1.

[00224] In the above diagram 30, 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.

[00225] Scheme 31: General scheme for the preparation of compounds of formula IV, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00226] In the above diagram 31, each ring A, R ¹ , R ² and m is as defined above and below and in the classes of subclasses described in the present invention.

[00227] Scheme 32: General scheme for the preparation of compounds of formula IV in which ring C is pyrimidine, R ² is -C(O)NH ₂ , R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is equal to 1.

[00228] In the above diagram 32, each ring A, R ¹ and m is as defined above and below and in the classes and subclasses described in the present invention.

[00229] Scheme 33: General scheme for the preparation of compounds of formula IV, in which ring C is 5-fluoropyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00230] In the above diagram 33, 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.

[00231] Scheme 34: General scheme for the preparation of compounds of formula IV, in which ring C is 6-chloropyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00232] In the above diagram 34, 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.

[00233] Scheme 35: General scheme for the preparation of compounds of formula IV, in which ring C is a 6-substituted pyrimidine, R ³ is hydrogen, n is 1, p is 1 and q is 1.

[00234] In the above diagram 35, each ring A, R ¹ , R ² , R ⁴ and m is as defined above and below and in the classes of subclasses described in the present invention.

[00235] Scheme 36: General scheme for the preparation of compounds of formula IV, in which ring C is 6-methylpyrimidine, R ³ is hydrogen, R ⁴ is methyl, n is 1, p is 1 and q is 1.

[00236] In the above diagram 36, 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.

[00237] Scheme 37: General scheme for the preparation of compounds of formula IV, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00238] In the above diagram 37, 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.

[00239] Scheme 38: General scheme for the preparation of compounds of formula IV in which ring C is pyridine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00240] In the above diagram 38, 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.

[00241] Scheme 39: General scheme for the preparation of compounds of formula IV, in which ring C is pyridine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00242] In the above diagram 39, 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.

[00243] Scheme 40: General scheme for the preparation of compounds of formula IV, in which ring C is pyridine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00244] In the above diagram 40, 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.

[00245] Scheme 41: General scheme for the preparation of compounds of formula IV, in which ring C is pyridine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00246] In the above diagram 41, 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.

[00247] Scheme 42: General scheme for the preparation of compounds of formula IV, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00248] In the above diagram 42, 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.

[00249] Scheme 43: General scheme for the preparation of compounds of formula IV, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00250] In the above diagram 43, 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.

[00251] Scheme 44: General scheme for the preparation of compounds of formula IV, in which ring C is pyridazine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00252] In the above diagram 44, 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.

[00253] Scheme 45: General scheme for the preparation of compounds of formula IV, in which ring C is pyridazine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00254] In the above diagram 45, 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.

[00255] Scheme 46: General scheme for the preparation of compounds of formula IV in which ring C is pyridine, R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00256] In the above diagram 46, 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.

[00257] Scheme 47: General scheme for the preparation of compounds of formula IV, in which ring C is pyridine, R ³ is hydrogen, R ⁴ is fluorine, n is 1, p is 1 and q is 1.

[00258] In the above diagram 47, 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.

[00259] Scheme 48: General scheme for the preparation of compounds of formula IV, in which ring C is pyrimidine, R ³ is hydrogen, R ⁴ is fluorine, n is 1, p is 1 and q is 1.

[00260] In the above diagram 48, 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.

[00261] Scheme 49: General scheme for the preparation of compounds of formula IV in which ring C is pyrimidine, R ² is -CF ₂ CH ₃ , R ³ is hydrogen, R ⁴ is hydrogen, n is 1, p is 1 and q is 1.

[00262] In the above diagram 49, each ring A, R ¹ and m is as defined above and below and in the classes of subclasses described in the present invention.

[00263] Scheme 50: General scheme for the preparation of compounds of formula V in which ring C 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 .

[00264] In the above diagram 50, 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.

[00265] Scheme 51: General scheme for the preparation of compounds of formula V, in which ring C is a pyrimidine linked to a bicyclic ring at position 2, R ² is -CF ₂ H, R ³ is hydrogen, R ⁴ is hydrogen, n is 1 , p is 1 and q is 1.

[00266] In the above diagram 51, each ring A, R ¹ and m is as defined above and below and in the classes and subclasses described in the present invention.

[00267] One skilled in the art will understand that the compounds of formula I - V 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.

[00268] 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

[00269] 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.

[00270] The term “patient” as used herein means an animal, preferably a mammal, and most preferably a human.

[00271] 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.

[00272] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt, or other derivative of a compound of the present invention that, 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.

[00273] 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.

[00274] 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.

[00275] 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, which 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.

[00276] 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.

[00277] 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.

[00278] Pharmaceutically acceptable compositions of the present invention can also be administered topically, particularly if the target for treatment includes sites or organs that are easily accessible through topical application, including diseases of the eye, skin, or lower gastrointestinal tract. Suitable topical preparations can be easily prepared for each of these sites or organs.

[00279] 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.

[00280] 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.

[00281] 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.

[00282] 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. .

[00283] 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.

[00284] The amount of compounds of the present invention that can be combined with carrier materials to form a composition in a single dosage form varies depending on the recipient being treated and the particular mode of administration. The proposed 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 the patient receiving these compositions.

[00285] 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

[00286] The compounds and compositions described in the present invention are generally useful for inhibiting GCN2 kinase activity.

[00287] The activity of a compound used in the present invention as an inhibitor of GCN2 or its mutant can be studied 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.

[00288] 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.

[00289] 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.

[00290] 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.

[00291] 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.

[00292] In some embodiments, the cancer being treated is a solid tumor or a tumor of the blood and immune system.

[00293] 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.

[00294] In some embodiments, the autoimmune condition is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjögren's syndrome, or organ transplant rejection.

[00295] In some embodiments, the metabolic disease state is diabetes.

[00296] In some embodiments, the degenerative disease is osteoarthritis.

[00297] In some embodiments, the inflammatory condition is asthma, inflammatory bowel disease, or giant cell arteritis.

[00298] In some embodiments, the cardiovascular disease is ischemic injury.

[00299] 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.

[00300] 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.

[00301] 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

[00302] 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."

[00303] In some embodiments, the proposed combination or a composition containing it is administered in combination with another therapeutic agent.

[00304] 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.

[00305] 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.

[00306] 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.

[00307] 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.

[00308] 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.

[00309] 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 may 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.

[00310] 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 (Arcalist ^® ), 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 such as dicyclomine ( ^Bentyl® ), ^Singular® , beta-2 agonists such as albuterol ( ^Ventolin® HFA, Proventil® HFA), levalbuterol ( ^Xopenex® ), metaproterenol ( ^{Alupent® )} , pirbuterol acetate ( ^Maksair® ), 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 Vanzeril ^® ), 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.

[00311] 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 ^® ).

[00312] 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” 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 (Arcalist ^® ), antibodies such as rituximab (Rituxan ^® ), “anti "T-cell" agents such as abatacept (Orenzia ^® ) and "anti-IL-6" agents such as tocilizumab (Actemra ^® ).

[00313] 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.

[00314] 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 ^® ).

[00315] In some embodiments, the present invention relates to 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 (Amitiza ^® ), 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.

[00316] 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 Vanzeril ^® ), 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 ^® ).

[00317] 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 Vanceril ^® ), triamcinolone acetonide (Azmacort ^® ), mometasone (Astmanex ^® ), budesonide (Pulmicort ^® ), flunisolide (Aerobid ^® ), Afviar ^® , Symbicort ^® and Dulera ^® .

[00318] 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 ( ^Khivid® ), 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 ( ^Fuseon® ) and maraviroc ( ^Selsentri® ), integrase inhibitors such as raltegravir (isentress ^® ) and their combinations.

[00319] 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.

[00320] 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.

[00321] 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).

[00322] 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.

[00323] 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 ^® ).

[00324] In another embodiment, the present invention relates to a method of treating Waldenström 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.

[00325] 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 ^® ).

[00326] 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.

[00327] 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, tendinitis, 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.

[00328] 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.

[00329] In another embodiment, the present invention provides a method of treating or ameliorating 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, infestation by parasites (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 hematological 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.

[00330] 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, and the like. The compounds of the present invention are preferably formulated in unit dosage form to ensure 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.

[00331] 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.

[00332] 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.

[00333] 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.

[00334] 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.

[00335] 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.

[00336] 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.

[00337] 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.

[00338] 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 and the like. 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. 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, and the like.

[00339] 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.

[00340] 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.

[00341] 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.

[00342] 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 reacting said biological sample with a compound of the present invention or a composition containing said compound.

[00343] 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.

[00344] 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.

[00345] 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.

[00346] 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.

[00347] 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."

[00348] 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.

[00349] 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.

[00350] 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™.

[00351] 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).

[00352] 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).

[00353] 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™.

[00354] 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.

[00355] 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™.

[00356] 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™.

[00357] 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).

[00358] 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™.

[00359] 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™.

[00360] 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).

[00361] 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.

[00362] 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.

[00363] 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.

[00364] 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.

[00365] 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.

[00366] 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.

[00367] 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. .

[00368] 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.

[00369] 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.

[00370] 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.

[00371] 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.

[00372] 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.

[00373] 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 the mammalian target of rapamycin (mTOR) and that have antiproliferative activity, such as sirolimus ( ^Rapamune® ), everolimus (Certican™), CCI-779 and ABT578.

[00374] The term “heparanase inhibitor” as used in the present invention refers to 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.

[00375] 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.

[00376] 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.

[00377] 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.

[00378] 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.

[00379] 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.

[00380] 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.

[00381] 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.

[00382] The term "anti-proliferative 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.

[00383] 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.

[00384] 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).

[00385] 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.

[00386] 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™).

[00387] 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.

[00388] 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.

[00389] Implants containing corticosteroids are compounds such as fluocinolone and dexamethasone.

[00390] 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.

[00391] 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.

[00392] 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.

[00393] Suitable antihistamine drugs include cetirizine hydrochloride, acetaminophen, clemastifumate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[00394] Other useful combinations of the 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).

[00395] 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.).

[00396] 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.

[00397] 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).

[00398] 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).

[00399] 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.

[00400] 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.

[00401] 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.

[00402] 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.

[00403] 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.

[00404] 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.

[00405] 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.

[00406] 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

[00407] 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.

[00408] 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.

[00409] 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.

[00410] 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.

[00411] 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.

[00412] 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.

[00413] 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.

[00414] 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).

[00415] 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 ablation 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.

[00416] 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.

[00417] 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.

[00418] 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).

[00419] 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).

[00420] 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).

[00421] 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).

[00422] 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).

[00423] 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.

[00424] 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).

[00425] 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.

[00426] 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.

[00427] In some embodiments, the immuno-oncology agent is MGA271 (to B7H3) (WO11/109400).

[00428] 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.

[00429] 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 have the ability to prolong overall survival in patients with RCC who have progressed during or after prior antiangiogenic therapy.

[00430] 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).

[00431] 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 (Imligik ^® , 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 variant of a respiratory enteric orphan virus (reovirus) 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).

[00432] 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.

[00433] 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.

[00434] 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.

[00435] 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].

[00436] 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).

[00437] 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).

[00438] 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.

[00439] 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.

[00440] 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.

[00441] 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.

[00442] 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.

[00443] 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 construct ( ^BiTE® ). In some embodiments, the bispecific T-cell activator antibody construct ( ^BiTE® ) is a bispecific CD19/CD3 antibody construct. In some embodiments, the bispecific T-cell activator antibody construct ( ^BiTE® ) is an EGFR/CD3 bispecific antibody construct. In some embodiments, the design of bispecific T cell activator antibodies ( ^BiTE® ) 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, a 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

[00444] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor described in the present invention.

[00445] 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.

[00446] 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.

[00447] 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.

[00448] 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.

[00449] 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.

[00450] 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 antibodies, 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).

[00451] 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.

[00452] 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).

[00453] 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).

[00454] 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).

[00455] 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).

[00456] 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).

[00457] 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).

[00458] 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).

[00459] 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).

[00460] 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).

[00461] 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).

[00462] 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).

[00463] 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).

[00464] 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).

[00465] 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).

[00466] 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).

[00467] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

EXAMPLES

[00468] 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.

[00469] Synthesis 1: 2-(1H-Pyrazol-4-yl)morpholine A1.

[00470] 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 with stirring at ambient temperature. After 3 h, the solvent was removed in vacuo and the residue was purified by column 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) ⁺ .

[00471] 3M HCl in MeOH (45 ml of 3 M, 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 2 M NH ₃ in MeOH/DCM. The solvent was removed in vacuo to give 2-(1H-pyrazol-4-yl)morpholine A1 (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), 2.93-2.88 (m, 2H); MS m/z: 154.2 (M+H) ⁺ .

[00472] Synthesis 2: N-((6-Methylmorpholin-2-yl)methyl)methanesulfonamide A2.

[00473] Di-tert-butyl dicarbonate (600 mg, 2.75 mmol) was added with stirring to a solution of (6-methylmorpholin-2-yl)methanol (300 mg, 2.3 mmol) and Et ₃ N (835 μl, 6 mmol) in DCM (5 ml) at ambient temperature and the reaction mixture was stirred for 2 hours. The reaction mixture was washed with 0.5 M HCl (×1), water (×2) and brine (×1). The combined organics were dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography (silica, PE/EtOAc gradient elution) to give cis-tert-butyl 2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (225 mg, 42%) as colorless oils, ¹ H NMR (500 MHz, chloroform-d) δ 3.90 (s, 2H), 3.73-3.68 (m, 1H), 3.64-3.55 (m, 3H), 2 .67 (s, 1H), 2.49 (s, 1H), 1.94 (dd, 1H), 1.49 (s, 9H), 1.21 (d, 3H) and trans-tert-butyl- 2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (170 mg, 32%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 4.00-3.96 (m, 1H), 3.90 (s, 1H), 3.72 (s, 1H), 3.66-3.49 (m, 3H), 3.38 (ddd, 1H), 3.15 (s, 1H), 1.98-1.82 (m, 1H), 1.49 (s, 9H), 1.23 ( d, 3H).

[00474] To a solution of cis-tert-butyl-2-(hydroxymethyl)-6-methylmorpholine-4-carboxylate (225 mg, 1 mmol), tert-butyl-N-methylsulfonylcarbamate (280 mg, 1.4 mmol) and PPh ₃ (760 mg, 3 mmol) in THF (10 ml), DEAD (330 μl, 2 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature under N ₂ for 18 h. The reaction mixture was concentrated in vacuo and purified with Using column chromatography, cis-tert-butyl-2-[[tert-butoxycarbonyl(methylsulfonyl)amino]methyl]-6-methylmorpholine-4-carboxylate was obtained as a colorless oil. This material was taken up in DCM (10 ml) and TFA (2 ml, 26 mmol) was added at ambient temperature. After 3 h, the solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was taken up in MeOH and passed through an ion exchange cartridge, washed with MeOH/DCM mixtures. The product was eluted with 2 M NH ₃ in MeOH/DCM. The solvent was removed in vacuo to give cis-N-[(6-methylmorpholin-2-yl)methyl]methanesulfonamide A2 (173 mg, 85%) as a white solid, which was used in the next reaction without further purification; ¹ H NMR (500 MHz, chloroform-d) δ 4.66 (br s, 1H), 3.59-3.49 (m, 2H), 3.17 (dd, 1H), 2.99 (dd, 1H), 2.90 (s, 3H), 2.78 (dd, 2H), 2.47 (dd, 1H), 2.35 (dd, 1H), 1.05 (d, 3H); MS m/z: 209 (M+H) ⁺ .

[00475] Synthesis 3: N-((4,4-Difluoropiperidin-3-yl)methyl)methanesulfonamide A3.

[00476] Methanesulfonyl chloride (200 μl, 2.6 mmol) was added to a solution of tert-butyl-3-(aminomethyl)-4,4-difluoropiperidine-1-carboxylate (500 mg, 1.8 mmol) and Et ₃ N (400 µl, 2.9 mmol) in THF (11 ml) under N ₂ atmosphere. The reaction mixture was stirred at ambient temperature for 3 hours, then diluted with DCM and saturated aqueous NaHCO ₃ solution. The mixture was stirred for 10 min, then passed through a phase separation cartridge. The organic phase was concentrated and the residue was taken up in DCM/TFA (2 ml/2 ml), stirred for 2 hours, then concentrated. The residue was taken up in MeOH and passed through an ion exchange cartridge, washed with methanol and the product eluted with 2 M methanol ammonia. The solution was concentrated in vacuo to give a white solid, N-((4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide A3 (450 mg), which was used in the next reaction without further purification; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.10 (t, 1H), 3.27 (ddd, 2H), 3.11-3.01 (m, 1H), 2.91-2, 85 (m, 5H), 2.69-2.56 (m, 1H), 2.40 (dd, 1H), 2.08-1.86 (m, 2H), 1.84-1.66 ( m, 1H).

[00477] Synthesis 4: (S)-N-((6-Oxopiperazin-2-yl)methyl)methanesulfonamide A4.

[00478] Benzyl chloroformate (1.2 mL, 8.5 mmol) was added to an ice-cold solution of (6S)-6-(hydroxymethyl)piperazin-2-one (800 mg, 6.15 mmol) and K ₂ CO ₃ (5 .95 g, 43 mmol) in EtOAc (20 ml)/H ₂ O (20 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography to give benzyl (3S)-3-(hydroxymethyl)-5-oxopiperazine-1-carboxylate as a colorless oil (700 mg, 43%); MS m/z: 265 (M+H) ⁺ .

[00479] DIAD (1.5 mL, 7.6 mmol) was added to an ice-cold solution of phthalimide (1.11 g, 7.6 mmol) and PPh ₃ (1.75 mL, 7.6 mmol) in DCM (10 ml) in an atmosphere of N ₂ . The solution was stirred for 10 min, then benzyl (3S)-3-(hydroxymethyl)-5-oxopiperazine-1-carboxylate (500 mg, 1.9 mmol) was added. The solution was stirred for 18 hours, gradually warming to ambient temperature. The solution was diluted with saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the layers were separated using a phase separation cartridge. The organic phase was concentrated in vacuo and the residue was purified by column chromatography (silica, PE/EtOAc eluting gradient to give benzyl-(3R)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-5 -oxopiperazine-1-carboxylate as an oil (700 mg, ~60% purity), which was immediately used in the next step; MS m/z: 394 (M+H) ⁺ .

[00480] A mixture of benzyl (3R)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-oxopiperazine-1-carboxylate (700 mg, 1.068 mmol) and hydrazine hydrate (100 μl, 2.04 mmol) in ethanol (5 ml) was refluxed for 5 hours. The resulting suspension was filtered and the white solid was washed thoroughly with ethanol. The ethanol solution was loaded into an ion exchange cartridge, washed with methanol, and then the product was eluted with a 2 M methanol solution of NH ₃ . The filtrate was concentrated to give (R)-benzyl-3-(aminomethyl)-5-oxopiperazine-1-carboxylate as a colorless oil, which was immediately used in the next step (240 mg, 85%); MS m/z: 264 (M+H) ⁺ .

[00481] Methanesulfonyl chloride (100 μl, 1.3 mmol) was added to an ice-cold solution of benzyl (3R)-3-(aminomethyl)-5-oxopiperazine-1-carboxylate (240 mg, 1 mmol) and Et ₃ N (200 µl, 1.4 mmol) in DCM (5 ml) under N ₂ atmosphere. The solution was stirred for 3 hours, gradually warming to ambient temperature. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ solution. After 5 min, the organic phase was isolated using a phase separation cartridge and then concentrated in vacuo. The residue was purified by column chromatography (silica, PE/EtOAc gradient elution) to give benzyl (3S)-3-(methanesulfonamidomethyl)-5-oxopiperazine-1-carboxylate as a white foam (233 mg, 75 %), which was immediately used at the next stage; MS m/z: 342 (M+H) ⁺ .

[00482] Mixture of benzyl (3S)-3-(methanesulfonamidomethyl)-5-oxopiperazine-1-carboxylate (230 mg, 0.7 mmol), Pd(OAc) ₂ (60 mg, 0.3 mmol), Et ₃ SiH (500 μl, 3 mmol) and Et ₃ N (300 μl, 2 mmol) in DCM (5 ml) were stirred at ambient temperature for 2 h under N ₂ atmosphere. The residue was passed through an ion exchange cartridge, washed with MeOH/DCM mixtures and the product was eluted with 2 M NH ₃ in MeOH/DCM mixtures. The solvent was removed in vacuo to give (S)-N-((6-oxopiperazin-2-yl)methyl)methanesulfonamide, A4 as a white solid (130 mg, 93%), which was used in the next reaction without further purification; MS m/z: 208 (M+H) ⁺ .

[00483] Synthesis 5: (S)-Dimethyl((morpholin-2-ylmethyl)imino)-λ6-sulfanone A5.

[00484] Sodium triacetoxyborohydride (1.26 g, 5.95 mmol) was added to a mixture of tert-butyl (2S)-2-formylmorpholine-4-carboxylate (320 mg, 1.5 mmol) and (methylsulfonimidoyl)methane (165 mg, 1.8 mmol) in DCE (20 ml) and the reaction mixture was stirred at ambient temperature for 60 hours. The mixture was diluted with DCM and saturated aqueous NaHCO ₃ and stirred for 30 minutes. The layers were separated and the organic layer was washed with saturated aqueous NaHCO ₃ (×2), brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give tert-butyl-(S)-2-(((dimethyl(oxo)-λ6 -sulfanilidene)amino)methyl)morpholine-4-carboxylate (343 mg); MS m/z: 293 (M+H) ⁺ .

[00485] The residue was transferred to DCM (10 ml) and TFA (5 ml) was added at ambient temperature. The mixture was stirred at ambient temperature for 17 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was passed through an ion exchange cartridge, washed with MeOH/DCM mixtures and the product was eluted with 2 M NH ₃ in MeOH/DCM mixtures. The solvent was removed in vacuo to give (S)-dimethyl((morpholin-2-ylmethyl)imino)-λ6-sulfanone A5 as a pale yellow oil (140 mg, 63%), which was used in the next reaction without further purification; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.54 (s, 1H), 3.69 (ddd, 2H), 3.40 (td, 1H), 3.33-3.26 (m, 2H), 3.25 -3.23 (m, 1H), 2.96 (s, 3H), 2.81 -2.77 (m, 1H), 2.66-2.57 (m, 3H) , 2.32 (dd, 1H); MS m/z: 193 (M+H) ⁺ .

[00486] Synthesis 6: N-((5-Ethyl-4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide A6.

[00487] LiHMDS (5 mL of 1M solution, 5.0 mmol) was added dropwise to a cooled solution of benzyl 3-ethyl-4-oxopiperidine-1-carboxylate (1 g, 3.8 mmol) in THF (14 mL). to -78°C, in N ₂ atmosphere. After 90 min, a solution of 2-(chloromethyl)isoindoline-1,3-dione (1.0 g, 5.1 mmol) in THF (2 ml) was added. The solution was stirred at -78°C for 1 hour, then at 0°C for 1 hour, then the reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl (~2 ml). The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, PE/EtOAc gradient elution) to give benzyl-3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-ethyl-4-oxopiperidin-1- carboxylate as a colorless resinous substance (1.1 g), which was immediately used in the next step; MS m/z: 421 (M+H) ⁺ .

[00488] A mixture of benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-ethyl-4-oxopiperidine-1-carboxylate (1.1 g, 2.6 mmol) and DAST (6 ml , 45 mmol) was stirred at 0°C for 3 hours, then at ambient temperature for 16 hours. The reaction mixture was diluted with DCM and the reaction was carefully stopped with saturated aqueous NaHCO ₃ solution. The layers were separated and the organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The crude mixture was purified by column chromatography to obtain benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-5-ethyl-4,4-difluoropiperidine-1-carboxylate as an off-white solid (200 mg , 17%); MS m/z: 423 (M+H) ⁺ .

[00489] This material was dissolved in EtOH (3 mL) and hydrazine hydrate (60 μL, 1.2 mmol) was added. The mixture was stirred at reflux for 24 hours, then kept at ambient temperature for 36 hours. The resulting suspension was diluted with methanol and passed through an ion exchange cartridge. The cartridge was washed with MeOH and the product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated to give benzyl 3-(aminomethyl)-5-ethyl-4,4-difluoropiperidine-1-carboxylate as a gum (115 mg); MS m/z: 313 (M+H) ⁺ .

[00490] This material was dissolved in DCM (3 ml) under N ₂ atmosphere. Et ₃ N (100 μl, 0.7 mmol) was added and the solution was cooled in an ice bath. Methanesulfonyl chloride (50 μL, 0.6 mmol) was added dropwise and the mixture was stirred for 10 min. The cooling bath was removed and the mixture was stirred at ambient temperature for 10 minutes. The reaction was stopped with a few drops of saturated NaHCO ₃ solution and stirred for 5 minutes, then filtered through a phase separation cartridge and concentrated under reduced pressure to give benzyl-3-ethyl-4,4-difluoro-5-(methylsulfonamidomethyl)piperidine- 1-carboxylate as a colorless oil (140 mg); MS m/z: 391 (M+H) ⁺ .

[00491] This substance was dissolved in DCM (3 ml) and Pd(OAc) ₂ (35.23 mg, 0.2 mmol), Et ₃ N (176.0 μl, 1.3 mmol) and Et ₃ SiH (381.5 µl, 2.4 mmol). The solution was stirred at ambient temperature for 1 hour. The solution was poured into an ion exchange cartridge, washed with methanol, and the product was eluted with 2 M NH ₃ methanol solution. The filtrate was concentrated to give N-((5-ethyl-4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide, A6 as a colorless gum (70 mg), which was used in the next reaction without further purification; MS m/z: 257 (M+H) ⁺ .

[00492] Synthesis 7: N-((1,4-Oxazepan-6-yl)methyl)methanesulfonamide A7.

[00493] Methanesulfonyl chloride (150 μl, 1.9 mmol) was added to a solution of tert-butyl-6-(aminomethyl)-1,4-oxazepane-4-carboxylate (300 mg, 1.3 mmol) and Et ₃ N (300 µl, 2.2 mmol) in DCM (5 ml) under N ₂ while cooling in an ice bath. The solution was stirred at ambient temperature for 2 hours, then diluted with DCM. Saturated aqueous NaHCO ₃ solution was added, the mixture was stirred for 10 minutes and the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo and the residue was taken up in DCM/TFA (1:1, 1 ml total) and stirred at ambient temperature for 2 hours. The solution was concentrated in vacuo to give N-((1,4-oxazepan-6-yl )methyl)methanesulfonamide, A7 as a yellow oil (300 mg), which was used in the following reaction without purification, assuming that the mono-salt was isolated with TFA; MS m/z: 209 (M+H) ⁺ .

[00494] Synthesis 8: 2-Methyl-6-(1H-pyrazol-4-yl)morpholine A8.

[00495] 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 column chromatography (silica, PE/EtOAc eluting gradient) to give 1-(1 -benzylpyrazol-4-yl)-2-nitroethanol as a colorless oil (1 g, 37%), which was immediately used in the next reaction; MS m/z: 248 (M+H) ⁺

[00496] 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 with H ₂ supplied from a cylinder. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give 2-amino-1-(1-benzylpyrazol-4-yl)ethanol as a colorless gum (90 mg), which was immediately used in the next reaction; MS m/z: 218 (M+H) ⁺ .

[00497] 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 2 M aqueous HCl, saturated aqueous NaHCO ₃ and brine. The organic phase was dried (Na ₂ SO ₄ ), 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 MeOH, then diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (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.

[00498] A mixture of 6-(1-benzylpyrazol-4-yl)-2-methylmorpholin-3-one (100 mg, 0.4 mmol) and LiAlH ₄ (184 μl 2 M, 0.4 mmol) in THF (3 ml) was stirred at 60°C for 1 hour. The resulting suspension was quickly cooled 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 MeOH (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 with a supply of H ₂ from a balloon for 18 hours. The reaction mixture was poured into an ion exchange cartridge, washed with methanol and the product was eluted 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 A8 (23 mg), which was immediately used in the next reaction; MS m/z: 168 (M+H) ⁺ .

[00499] Synthesis 9: N-((5,5-Difluoropiperidin-3-yl)methyl)methanesulfonamide A9.

[00500] Methanesulfonyl chloride (151 μl, 2 mmol) was added to an ice-cold solution of tert-butyl-3,3-difluoro-5-(hydroxymethyl)piperidine-1-carboxylate (378 mg, 1.5 mmol) and Et ₃ N ( 314 µl, 2.3 mmol) in DCM (7 ml) under N ₂ atmosphere. The solution was stirred for 18 hours, gradually warming to ambient temperature. The reaction mixture was diluted with DCM and the reaction was stopped with saturated aqueous NaHCO ₃ solution. After stirring for 15 min, the mixture was poured into a phase separation cartridge. The organic phase was concentrated in vacuo to give tert-butyl 3,3-difluoro-5-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate as a colorless oil (400 mg).

[00501 A portion of this substance (100 mg, 0.3 mmol) was transferred to DMF (3 ml) under N ₂ and methanesulfonamide (100 mg, 1.1 mmol) and K ₂ CO ₃ (150 mg, 1.1 mmol) was added . The reaction mixture was stirred at ambient temperature for 18 hours. The resulting suspension was stirred at 80°C for 24 hours, then diluted with water and extracted with EtOAc. The organic phase was washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give tert-butyl 3,3-difluoro-5-(methylsulfonamidomethyl)piperidine-1-carboxylate as a colorless oil (150 mg).

[00502] This material was transferred to TFA (1.5 ml)/DCM (2 ml) and stirred for 2 hours at ambient temperature. The solution was concentrated in vacuo. The residue was taken up in MeOH and poured into an ion exchange cartridge, washed with methanol and the product eluted with 2 M methanol NH ₃ solution. The filtrate was concentrated in vacuo to give N-((5,5-difluoropiperidin-3-yl)methyl)methanesulfonamide A9 as a colorless oil (20 mg), which was used in the next reaction without further purification; MS m/z: 229 (M+H) ⁺ .

[00503] Synthesis 10: (R)-N-((6,6-Dimethylmorpholin-2-yl)methyl)methanesulfonamide A10.

[00504] Methanesulfonyl chloride (80 μl, 1 mmol) was added to a suspension of tert-butyl (6S)-6-(aminomethyl)-2,2-dimethylmorpholine-4-carboxylate (200 mg, 0.8 mmol) and Et with stirring ₃ N (175 µl, 1.3 mmol) in THF (10 ml) under N ₂ and the reaction mixture was stirred at ambient temperature for 15 hours. DMF (2 ml) was added to promote dissolution and the reaction mixture was stirred at ambient temperature medium for another 3 hours. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ 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 washed with brine (×2), dried (MgSO ₄ ), filtered and concentrated in vacuo to give a pale yellow oil (1 g); MS m/z: 323 (M+H) ⁺ .

[00505] This material was dissolved in DCM (5 ml) and TFA (0.5 ml) was added. The reaction mixture was stirred at ambient temperature for 4 hours, then concentrated in vacuo. The residue was azeotroped with DCM (×2) and diethyl ether (×2), then taken up in MeOH and passed through an ion exchange cartridge. The cartridge was washed with MeOH/DCM mixtures and the product was eluted by washing the cartridge with 2 M NH ₃ in MeOH/DCM. The filtrate was concentrated in vacuo to give N-[[(2R)-6,6-dimethylmorpholin-2-yl]methyl]methanesulfonamide A10 (122 mg, 67%) as a colorless oil, which was used in the next reaction without further purification; ¹ H NMR (500 MHz, chloroform-d) δ 4.65 (s, 1H), 3.87-3.82 (m, 1H), 3.22 (ddd, 1H), 3.03-2.99 (m, 1H), 2.99 (s, 3H), 2.87 (ddd, 1H), 2.67 (d, 1H), 2.59 (d, 1H), 2.51 (dd, 1H) , 1.32 (s, 3H), 1.16 (s, 3H); MS m/z: 223 (M+H) ⁺ .

[00506] Synthesis 11: N-((4-Fluoropiperidin-3-yl)methyl)methanesulfonamide A11.

[00507] Methanesulfonyl chloride (100 μl, 1.3 mmol) was added to a solution of tert-butyl-3-(aminomethyl)-4-fluoropiperidine-1-carboxylate (250 mg, 1.1 mmol) and Et ₃ N (200 μl, 1.4 mmol) in DCM (3 ml) while cooling in an ice bath. The solution was stirred at ambient temperature for 2 hours, then diluted with DCM. The mixture was washed with 2 M aqueous HCl, saturated aqueous NaHCO ₃ and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo.

[00508] The residue was taken up in DCM (2 ml) and TFA (2 ml, 26 mmol), stirred at ambient temperature for 1 hour, then concentrated in vacuo. The residue was diluted in MeOH and poured into an ion exchange cartridge, washed with methanol and the product eluted with 2 M methanol NH ₃ solution. The filtrate was concentrated in vacuo to give N-((4-fluoropiperidin-3-yl)methyl)methanesulfonamide A11, which was used without further purification.

[00509] Synthesis 12: 2-(Methylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine A12.

[00510] NaH (79 mg 60% dispersion in mineral oil, 2 mmol) was added in one portion to a solution of tert-butyl 1,4,5,7-tetrahydropyrazolo[3,4-c]pyridine-6-carboxylate (400 mg , 1.8 mmol) in THF (7 ml) under N ₂ with cooling in an ice bath. After 15 min, methanesulfonyl chloride (166 μL, 2.2 mmol) was added to the solution. The reaction mixture was stirred for 18 hours at ambient temperature, then diluted with EtOAc and washed with 2 M aqueous NaOH and brine. The organic phase was dried (Na ₂ SO ₄ ) and concentrated in vacuo.

[00511] The residue was taken up in DCM (3 ml) and TFA (2 ml) and the solution was stirred for 2 hours at ambient temperature, then concentrated in vacuo. The residue was diluted in MeOH and poured into an ion exchange cartridge, washed with methanol and the product eluted with 2 M methanol NH ₃ solution. The filtrate was concentrated in vacuo to give 2-(methylsulfonyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine A12 as a colorless oil (240 mg, 67%), which was used in the following reactions without additional purification; MS m/z: 202 (M+H) ⁺ .

[00512] Synthesis 13: Imino(methyl)(piperidin-3-ylmethyl)-λ6-sulfanone A13.

[00513] tert-Butyl-3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (600 mg, 2.2 mmol) [see synthesis 35] was dissolved in DCM (3 ml) and TFA (1.7 ml, 22 mmol) was added. The mixture was stirred overnight at ambient temperature, then concentrated in vacuo. The residue was taken up in MeOH and loaded into an ion exchange cartridge, the product was eluted with 2 M methanolic ammonia solution. The filtrate was concentrated in vacuo to give imino(methyl)(piperidin-3-ylmethyl)-λ6-sulfanone A13 (250 mg, 65%); ¹ H NMR (500 MHz, methanol-d ₄ ) 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).

[00514] Synthesis 14: 2-(1H-Pyrazol-4-yl)piperazine A14.

[00515] A mixture of 2-(1H-pyrazol-4-yl)pyrazine (400 mg, 2.7 mmol) and PtO ₂ (100 mg, 0.4 mmol) in MeOH (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 A14 as a colorless oil, which was immediately used in the following reactions without purification; MS m/z: 153 (M+H) ⁺ .

[00516] Synthesis 15: N-((4,4-Difluoro-5,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide A15.

[00517] (Bis(trimethylsilyl)amino)lithium (2.4 ml of 1 M solution in THF, 2.4 mmol) was added dropwise to a solution of benzyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (500 mg , 2 mmol) in THF (7 ml) at -78°C in an atmosphere of N ₂ . After 90 min, a solution of 2-(chloromethyl)isoindoline-1,3-dione (560 mg, 3 mmol) in THF (2 ml) was added. The reaction mixture was stirred for 1 hour, then the reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl (~2 ml). The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, PE/EtOAc gradient elution) and then reverse phase chromatography (C18, MeCN/water - 0.1% ammonium hydroxide eluent) to give benzyl-5- [(1,3-dioxoisoindolin-2-yl)methyl]-3,3-dimethyl-4-oxopiperidine-1-carboxylate as a colorless oil (180 mg, 21%); MS m/z: 421 (M+H) ⁺ .

[00518] DAST (450 μL, 3.4 mmol) was added dropwise to the benzyl 5-[(1,3-dioxoisoindolin-2-yl)methyl]-3,3-dimethyl-4-oxopiperidine-1-carboxylate solution (150 mg, 0.4 mmol) in DCM (3 ml) under N ₂ with cooling in an ice bath. After 5 minutes, the ice bath was removed and the solution was stirred at ambient temperature for 22 hours. An additional 0.45 ml of DAST was added to the reaction mixture. After 16 h, the reaction was stopped by careful addition of MeOH. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica, PE/EtOAc gradient elution) to give benzyl-5-((1,3-dioxoisoindolin-2-yl)methyl)-4,4- difluoro-3,3-dimethylpiperidine-1-carboxylate (60 mg, 34%); MS m/z: 443 (M+H) ⁺ .

[00519] The residue was taken up in EtOH (2.8 mL) and hydrazine hydrate (30 μL, 0.6 mmol) was added. The mixture was stirred at reflux for 16 hours. The resulting suspension was diluted with methanol and loaded into an ion exchange cartridge, washed with MeOH and the product eluted with 2 M methanol NH ₃ solution. The filtrate was concentrated in vacuo to give the product as a pale yellow gum; MS m/z: 313 (M+H) ⁺ .

[00520] This material was dissolved in DCM (5 ml) under N ₂ atmosphere. Methanesulfonyl chloride (18 µl, 0.2 mmol) and Et ₃ N (40 µl, 0.3 mmol) were added while cooling in an ice bath. After stirring for 5 minutes, the ice bath was removed and the solution was stirred at ambient temperature for 2 hours. The solution was diluted with DCM and washed with saturated aqueous NaHCO ₃ solution. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was transferred to DCM (3 ml). Pd(OAc) ₂ (20 mg, 0.1 mmol), Et ₃ N (100 μl, 0.7 mmol) and triethylsilane (250 μl, 1.6 mmol) were added and the reaction mixture was stirred at ambient temperature for 1 h. The solution was poured into an ion exchange cartridge, washed with MeOH, then the product was eluted with a 2 M methanol solution of NH ₃ . The filtrate was concentrated in vacuo to give N-((4,4-difluoro-5,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide A15 as a colorless gum (50 mg), which was used in the next reaction without further purification; MS m/z: 257 (M+H) ⁺ .

[00521] Synthesis 16: (S)-N-((1-Methyl-6-oxopiperazin-2-yl)methyl)methanesulfonamide A16.

[00522] NaH (30 mg of 60% dispersion in mineral oil, 0.75 mmol) was added to a solution of benzyl-(3R)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-oxopiperazine-1 -carboxylate (200 mg, 0.5 mmol) in DMF (2 ml) under N ₂ with cooling in an ice bath. After 20 min, MeI (45 μl, 0.7 mmol) was added and the reaction mixture was stirred for 18 h while raising the temperature to ambient temperature. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with DCM/EtOAc) to give benzyl-(R)-3-((1,3-dioxoisoindolin-2-yl)methyl)-4-methyl-5-oxopiperazine- 1-carboxylate as a colorless oil (13 mg, 6%); MS m/z: 408 (M+H) ⁺ .

[00523] This material was taken into EtOH (3 ml) and hydrazine hydrate (1 drop) was added. The reaction mixture was refluxed for 2 hours and then cooled to ambient temperature. The solution was loaded into an ion exchange cartridge, washed with methanol, and the product was eluted with a 2 M methanol solution of NH ₃ . The filtrate was concentrated in vacuo to give a yellow gum which was taken up in DCM (2 ml). Et ₃ N (45 µl, 0.3 mmol) was added followed by methanesulfonyl chloride (15 µl, 0.2 mmol) and the reaction mixture was stirred at ambient temperature for 2 hours. The residue was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 minutes, the organic phase was isolated using a phase separation cartridge and then concentrated in vacuo; MS m/z: 356 (M+H) ⁺ .

[00524] The residue was transferred to DCM (2 ml) and Et ₃ SiH (50 μl, 0.3 mmol), Et ₃ N (45 μl, 0.3 mmol) and Pd(OAc) ₂ (4 mg, 0.3 mmol) were added. 02 mmol). The resulting suspension was stirred at ambient temperature for 3 hours, then diluted with methanol (3 ml) and loaded into an ion exchange cartridge. The cartridge was washed with methanol and the product was eluted with 2 M methanol NH ₃ solution. The filtrate was concentrated in vacuo to give a brown gum (~10 mg) containing (S)-N-((1-methyl-6-oxopiperazin-2-yl)methyl)methanesulfonamide A16; MS m/z: 222 (M+H) ⁺ . This substance was immediately used in the next reaction without further purification.

[00525] Synthesis 17: N-((S)-Morpholin-2-ylmethyl)methanesulfonimidamide A17.

[00526] N-Tosylmethanesulfonimidoyl chloride (297 mg, 3.7 mmol) was added to a solution of tert-butyl-(2R)-2-(aminomethyl)morpholine-4-carboxylate (637 mg, 3 mmol) and Et ₃ N (868 μl , 6 mmol) in DCM (15 ml) under N ₂ with cooling in an ice bath. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with PE/EtOAc) to give tert-butyl-(2S)-2-[[[S-methyl-N-(p-tolylsulfonyl)sulfonimidoyl]amino]methyl]morpholine -4-carboxylate as a colorless oil (400 mg, 30%); MS m/z: 446 (MH) ^- .

[00527] This material was dissolved in THF (10 ml) under argon. A fresh solution of sodium anthracene complex was prepared by adding sodium granules (270 mg, 12 mmol) to a suspension of anthracene (2.14 g, 12 mmol) in THF (30 ml) under argon. The suspension was stirred at ambient temperature for 3 hours to give a dark blue/green solution. This solution was added dropwise to a solution of tert-butyl-(2S)-2-[[[S-methyl-N-(p-tolylsulfonyl)sulfonimidoyl]amino]methyl]morpholine-4-carboxylate until the blue color remained. After 15 min, the reaction was stopped with saturated aqueous NH ₄ Cl and extracted with EtOAc (×2). The combined organics were washed with brine and dried (Na ₂ SO ₄ ), then filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, (EtOAc+10% MeOH)/PE, 5% to 100% gradient elution). Fractions containing product were combined and concentrated in vacuo. The residue was transferred to DCM (1 ml) and treated with TFA (0.5 ml). After stirring at ambient temperature for 3 hours, the reaction mixture was concentrated in vacuo to give N-((S)-morpholin-2-ylmethyl)methanesulfonidamide A17 as a yellow oil (150 mg), which was used in the next reaction without further purification; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.03 (m, 1H), 3.82 (m, 1H), 3.72 (m, 1H), 3.42 (s, 3H), 3 .33-3.17 (m, 4H), 2.99 (m, 1H), 2.83 (m, 1H).

[00528] Synthesis 18: N-(2-(Piperidin-3-yl)propan-2-yl)methanesulfonamide A18.

[00529] Methanesulfonyl chloride (200 µl, 2.6 mmol) was added to a solution of 2-(3-pyridyl)propan-2-amine (250 mg, 1.8 mmol) and Et ₃ N (400 µl, 2.9 mmol) in DCM (4 ml) while cooling in an ice bath. After 5 minutes, the ice bath was removed and the solution was stirred at ambient temperature for 2 hours. The solution was diluted with DCM and saturated aqueous NaHCO ₃ solution was added. The mixture was stirred at ambient temperature for 5 minutes. The organic phase was isolated using a phase separation cartridge and concentrated in vacuo to give a pale yellow gum (350 mg, 90%) which was immediately used in the next reaction; MS m/z: 215 (M+H) ⁺ .

[00530] A mixture of N-[1-methyl-1-(3-pyridyl)ethyl]methanesulfonamide (350 mg, 1.6 mmol), PtO ₂ (100 mg, 0.4 mmol) and HCl (5 ml of 3 M solution in MeOH, 15 mmol) was shaken for 18 hours at a H ₂ pressure of 60 lbf/in ² . The reaction mixture was filtered and the filtrate concentrated in vacuo to give N-(2-(piperidin-3-yl)propan-2-yl)methanesulfonamide A18 as a colorless oil (400 mg, 98%), which was used in the next reaction without purification ( assuming a mono-salt with HCl); MS m/z: 221 (M+H) ⁺ .

[00531] Synthesis 19: N-((5-Methoxypiperidin-3-yl)methyl)methanesulfonamide A19.

[00532] Methanesulfonyl chloride (400 μl, 5.2 mmol) was added dropwise to a solution of (5-methoxy-3-pyridyl)methanamine (500 mg, 3.6 mmol) in DCM (10 ml) under N ₂ while cooling in ice bath. The reaction mixture was stirred at ambient temperature for 2 hours. The resulting suspension was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 minutes, the organic phase was isolated using a phase separation cartridge and concentrated in vacuo to give N-[(5-methoxy-3-pyridyl)methyl]methanesulfonamide as a brown oil (770 mg); MS m/z: 217 (M+H) ⁺ , which was immediately used in the next reaction.

[00533] A mixture of N-[(5-methoxy-3-pyridyl)methyl]methanesulfonamide (300 mg, 1.4 mmol), PtO ₂ (150 mg, 0.6 mmol) and HCl (15 ml of 3 M solution in MeOH , 45 mmol) was shaken for 18 hours at a H ₂ pressure of 60 lbf/in ² . The reaction mixture was filtered and the filtrate concentrated in vacuo to give N-((5-methoxypiperidin-3-yl)methyl)methanesulfonamide A19 as a yellow oil, which was immediately used in the next reaction without purification (assuming mono-salt with HCl); MS m/z: 223 (M+H) ⁺ .

[00534] Synthesis 20: N-((2-Methylpiperidin-3-yl)methyl)methanesulfonamide A20.

[00535] Et ₃ N (400 μl, 2.9 mmol), then methanesulfonyl chloride (200 μl, 2.6 mmol) was added to a solution of benzyl 3-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (500 mg, 1 .9 mmol) in DCM (10 ml) and the mixture was stirred at ambient temperature for 18 hours. The solution was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 minutes, the organic phase was isolated using a phase separation cartridge and concentrated in vacuo; MS m/z: 342 (M+H) ⁺ . The residue was transferred to DMF (5 ml). Methanesulfonamide (600 mg, 6.3 mmol) and K ₂ CO ₃ (1.0 g, 7.2 mmol) were added to the solution, which was stirred at 80°C for 20 hours. The resulting suspension was diluted with DCM and water. After stirring for 5 minutes, the organic phase was isolated using a phase separation cartridge and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with PE/EtOAc) to give benzyl 3-(methanesulfonamidomethyl)-2-methylpiperidine-1-carboxylate as a pale yellow oil (210 mg, 33% in two steps) ; MS m/z: 341 (M+H) ⁺ .

[00536] Suspension of benzyl 3-(methanesulfonamidomethyl)-2-methylpiperidine-1-carboxylate (210 mg, 0.6 mmol), Et ₃ SiH (300 μl, 1.9 mmol), Pd(OAc) ₂ (80 mg , 0.36 mmol) and Et ₃ N (200 μl, 1.4 mmol) in DCM (4 ml) were stirred at ambient temperature for 2 hours. The resulting solution was diluted with MeOH and loaded into an ion exchange cartridge, washed with MeOH and the product were eluted with 2 M methanol NH ₃ solution. The filtrate was concentrated in vacuo to give N-((2-methylpiperidin-3-yl)methyl)methanesulfonamide A20 as a brown oil (120 mg, 97%), which was used in the next reaction without further purification; MS m/z: 207 (M+H) ⁺ .

[00537] Synthesis 21: N-(2-Azaspiro[4.4]nonan-7-yl)methanesulfonamide A21.

[00538] tert-Butyl-8-oxo-2-azaspiro[4.4]nonane-2-carboxylate (100 mg, 0.4 mmol) and ammonium acetate (300 mg, 3.9 mmol) were stirred in methanol (2 ml) at ambient temperature for 3 hours. Sodium cyanoborohydride (26 mg, 0.4 mmol) was added and the mixture was stirred at ambient temperature for 18 hours. The solution was loaded into an ion exchange cartridge, washed with methanol and the product was eluted with methanol ammonia solution. The filtrate was concentrated in vacuo to give a colorless oil (60 mg). This material was taken up in DCM (3 ml) and Et ₃ N (70 µl, 0.5 mmol), then methanesulfonyl chloride (30 µl, 0.4 mmol) was added. After 1 hour, the solution was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 2 minutes, the organic phase was isolated using a phase separation cartridge and concentrated in vacuo. The residue was taken up in TFA (500 µl, 6.5 mmol) and DCM (3 ml) and stirred at ambient temperature for 18 h, then concentrated in vacuo to give N-(2-azaspiro[4.4]nonan-7-yl )methanesulfonamide A21 as a colorless oil, which was immediately used in the next reaction (assuming a mono-salt with TFA); MS m/z: 219 (M+H) ⁺ .

[00539] Synthesis 22: N-((3-Fluoropiperidin-3-yl)methyl)methanesulfonamide A22.

[00540] Methanesulfonyl chloride (82 μl, 1.1 mmol) was added to a solution of tert-butyl-3-(aminomethyl)-3-fluoropiperidine-1-carboxylate (206 mg, 0.9 mmol) and Et ₃ N (185 μl, 1.3 mmol) in DCM (7 ml) under N ₂ atmosphere. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ solution. After 10 min, the mixture was passed through a phase separation cartridge. The organic phase was concentrated in vacuo and the residue was taken up in DCM (2 ml)/TFA (2 ml). After stirring for 2 hours at ambient temperature, the mixture was concentrated in vacuo to give N-((3-fluoropiperidin-3-yl)methyl)methanesulfonamide A22, which was immediately used in the next reaction without purification (assuming a mono-salt with TFA ); ¹ H NMR (500 MHz, CDCl ₃ ) δ 3.31-3.27 (m, 2H), 2.96 (m, 1H), 2.92 (s, 3H), 2.86 (m, 1H) , 2.78-2.71 (m, 1H), 2.62 (m, 1H), 1.95 (m, 1H), 1.75-1.45 (masked, 3H).

[00541] Synthesis 23: N-((5-(Trifluoromethyl)piperidin-3-yl)methyl)methanesulfonamide A23.

[00542] [5-(Trifluoromethyl)-3-pyridyl]methanamine (358 mg, 2 mmol), Et ₃ N (566 μl, 4 mmol) in DCM (7 ml) under N ₂ atmosphere was placed in a round bottom flask. The mixture was then cooled to 0°C and methanesulfonyl chloride (315 μL, 4 mmol) was added dropwise. The mixture was stirred at this temperature for 10 minutes, then the reaction was stopped with a few drops of saturated NaHCO ₃ solution and stirred for 5 minutes. The mixture was passed through a phase separation cartridge and the organic phase was concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). The product fractions were concentrated in vacuo to give N-[[5-(trifluoromethyl)-3-pyridyl]methyl]methanesulfonamide as a white solid (32 mg, 6%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.94-8.88 (m, 1H), 8.88-8.83 (m, 1H), 8.21-8.08 (m, 1H ), 7.71 (t, 1H), 4.34 (d, 2H), 2.96 (s, 3H).

[00543] A suspension of N-[[5-(trifluoromethyl)-3-pyridyl]methyl]methanesulfonamide (32 mg, 0.14 mmol) and PtO ₂ (50 mg, 0.2 mmol) in HCl (1 ml 3 M, 3 mmol) and MeOH (761 μl) were stirred at ambient temperature for 18 hours under 60 psi ^{H 2} _pressure . The catalyst was filtered off and the solvent was removed in vacuo. The residue was taken up in MeOH and passed through an ion exchange cartridge, the product was eluted with methanolic ammonia solution. The filtrate was concentrated in vacuo to give N-((5-(trifluoromethyl)piperidin-3-yl)methyl)methanesulfonamide A23 as a white solid (23 mg, 64%); MS m/z: 261 (M+H) ⁺ .

[00544] Synthesis 24: N-[Ethyl(oxo)[(3S)-piperidin-3-ylmethyl]-λ6-sulfanylidene]-2,2,2-trifluoroacetamide A24.

[00545] Tert-Butyl-(3S)-3-(hydroxymethyl)piperidine-1-carboxylate (1.1 g, 5 mmol) and Et ₃ N (1.4 mL, 10 mmol) in DCM were placed in a round bottom flask. 11 ml) in an atmosphere of N ₂ . The mixture was then cooled to 0°C and methanesulfonyl chloride (791 μL, 10 mmol) was added dropwise. The mixture was stirred for 10 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution and stirred for 5 minutes, then passed through a phase separation cartridge. The organic layer was concentrated in vacuo to give tert-Butyl (3S)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (1.4 g), which was immediately used in the next reaction.

[00546] tert-Butyl-(3S)-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (500 mg, 1.7 mmol) was transferred to DMF (5 ml) and ethylsulfonyl sodium (538 mg, 5 mmol) was added. The reaction mixture was stirred at 130°C in a sealed tube overnight. The reaction mixture was cooled to ambient temperature, then filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, EtOAc/PE 0-50% gradient elution) to give tert-butyl (3S)-3-(ethylsulfanylmethyl)piperidine-1-carboxylate (150 mg, 35%).

[00547] mCPBA (130 mg, 0.6 mmol) was added portionwise to a cold ice/brine (-15°C) solution of tert-butyl (3S)-3-(ethylsulfanylmethyl)piperidine-1-carboxylate (150 mg , 0.6 mmol) in DCM (3 ml). After addition was complete, the reaction was stopped by adding saturated aqueous Na ₂ S ₂ O ₃ solution. After stirring for 1 hour, the mixture was passed through a phase separation cartridge and the organic phase was concentrated in vacuo to give tert-butyl (3S)-3-(ethylsulfinylmethyl)piperidine-1-carboxylate (150 mg, 91%) which was used immediately in the next reaction; MS m/z: 276 (M+H) ⁺ ).

[00548] Rhodium(II) acetate (12 mg, 0.03 mmol) was added to a solution of tert-butyl (3S)-3-(ethylsulfinylmethyl)piperidine-1-carboxylate (150 mg, 0.5 mmol), 2. 2,2-trifluoroacetamide (123 mg, 1 mmol), diacetoxyiodobenzene (263 mg, 0.8 mmol) and MgO (88 mg, 2 mmol) in DCM (6 ml) and the mixture was stirred at ambient temperature overnight. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give a colorless oil (200 mg). This material was transferred to DCM (2.2 ml) and TFA (0.8 ml) was added. The mixture was stirred for 16 hours at ambient temperature, then concentrated in vacuo. The residue, N-[ethyl(oxo)[(3S)-piperidin-3-ylmethyl]-λ6-sulfanylidene]-2,2,2-trifluoroacetamide A24 (120 mg), was used in the next reaction without purification (assuming mono -salts with TFA); MS m/z: 287 (M+H) ⁺ .

[00549] Synthesis 25: N-((4-Fluoro-4-methylpiperidin-3-yl)methyl)methanesulfonamide A25.

[00550] Benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4-oxopiperidine-1-carboxylate (2.58 g, 6 mmol) in THF (58 mL) was placed in a round bottom flask. The reaction mixture was cooled to 0°C and MeMgBr (2.4 ml 3 M, 7 mmol) was added dropwise. After 2 hours, additional MeMgBr (1 mL 3 M, 2.9 mmol) was added and the mixture was stirred for 16 hours. The reaction was stopped by adding saturated aqueous NH ₄ Cl (3 mL) and the mixture was concentrated in vacuo. The residue was extracted with DCM (×3). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 100% EtOAc/PE gradient elution) to give benzyl-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4-hydroxy-4 -methylpiperidine-1-carboxylate as a colorless foam (1.28 g, 52%), which was immediately used in the next reaction; MS m/z: 409 (M+H) ⁺ .

[00551] Benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4-hydroxy-4-methylpiperidine-1-carboxylate (1.28 g, 3 mmol) was dissolved in DCM (25 ml) in atmosphere N ₂ . The solution was cooled to 0°C and DAST (414 μL, 3 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 2 hours, then the reaction was stopped by adding MeOH (2 ml) and concentrated in vacuo. The residue was diluted with DCM and the organics were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 100% EtOAc/PE gradient elution) to obtain 340 mg of a mixture of the desired product and by-product with fluorine removed. This mixture was immediately used in the next reaction.

[00552] A mixture of crude benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoro-4-methylpiperidin-1-carboxylate (340 mg, 0.8 mmol) and hydrazine hydrate (314 μl, 3 mmol) in EtOH (15 ml) was stirred at reflux for 16 hours. The resulting suspension was diluted with MeOH and loaded into an ion exchange cartridge, washed with MeOH, then the product was eluted with 2 M methanol NH ₃ solution. The filtrate was concentrated in vacuo to give benzyl 3-(aminomethyl)-4-fluoro-4-methylpiperidine-1-carboxylate as a pale yellow gum (100 mg), which was immediately used in the next reaction; MS m/z: 281 (M+H) ⁺ .

[00553] Benzyl 3-(aminomethyl)-4-fluoro-4-methylpiperidine-1-carboxylate (100 mg, 0.35 mmol), Et ₃ N (96 μL, 0.7 mmol) in DCM was placed in a round bottom flask (2 ml) under N ₂ atmosphere. The mixture was cooled to 0°C and methanesulfonyl chloride (54 μL, 0.7 mmol) was added dropwise. The mixture was stirred for 10 minutes, then allowed to warm to ambient temperature and stirred for a further 10 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution with stirring for 5 minutes, then passing through a phase separation cartridge. The filtrate was concentrated in vacuo to give a brown oil, which was immediately used in the next reaction (120 mg); MS m/z: 359 (M+H) ⁺ .

[00554] Benzyl 4-fluoro-3-(methanesulfonamidomethyl)-4-methylpiperidine-1-carboxylate (120 mg, 0.3 mmol) was transferred to DCM (2 ml). Pd(OAc) ₂ (34 mg, 0.15 mmol), Et ₃ N (170 µl, 1 mmol) and Et ₃ SiH (390 µl, 2 mmol) were added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was loaded into an ion exchange cartridge, washed with MeOH, then the product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated in vacuo to give N-((4-fluoro-4-methylpiperidin-3-yl)methyl)methanesulfonamide A25 as a brown gum (60 mg), which was used in the next reaction without further purification; MS m/z: 225 (M+H) ⁺ .

[00555] Synthesis 26: 3-(3,3-Difluoroazetidin-1-yl)piperidine A26.

[00556] 1-Benzylpiperidin-3-one salt hydrate with HCl (100 mg, 0.4 mmol), 3,3-difluoroazetidin hydrochloride (80 mg, 0.6 mmol) and AcOH (47 μl, 0.8 mmol) in THF (1 ml). The resulting suspension was stirred at 50°C until a clear solution was formed, then NaBH(OAc) ₃ (261 mg, 1.2 mmol) was added. The reaction mixture was stirred at 50°C for 30 minutes, then it was allowed to cool to ambient temperature and the reaction was stopped by adding saturated aqueous NaHCO ₃ solution. The mixture was stirred for 10 min, then extracted with DCM (×3). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give 1-benzyl-3-(3,3-difluoroazetidin-1-yl)piperidine, which was immediately used in the next step.

[00557] The residue was dissolved in methanol (2 ml) and 2 two drops of concentrated HCl (~15 mg, ~0.4 mmol) was added. The flask was degassed and filled with N ₂ (×3 cycles vacuum - N ₂ ) and Pd at C, wet, Degussa 10% w/w was added in one portion. (44 mg, 0.1 mmol). The flask was supplied with a hydrogen cylinder and filled (×3 vacuum - hydrogen cycles). The reaction mixture was stirred vigorously overnight at ambient temperature. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give 3-(3,3-difluoroazetidin-1-yl)piperidine A26, which was immediately used in the next reaction (assuming quantitative conversion to the salt with HCl); MS m/z: 177 (M+H) ⁺ .

[00558] Synthesis 27: 8a-Methyltetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one A27.

[00559] LiHMDS (9.9 mL 1 M, 9.9 mmol) was added to a solution of 1,4-di-tert-butyl-2-methylpiperazine-1,2,4-tricarboxylate (2.0 g, 5.8 mmol) in THF (30 ml) at -78°C in an N ₂ atmosphere. After 45 min, iodomethane (615 µl, 9.9 mmol) in THF (5 ml) was slowly added. The mixture was allowed to warm slowly to ambient temperature and stirred overnight. The reaction mixture was partitioned between DCM and saturated aqueous NH ₄ Cl. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with DCM/MeOH) to give 1,4-di-tert-butyl-2-methyl-2-methylpiperazine-1,2,4-tricarboxylate as a colorless oil (1 .5 g, 72%); MS m/z: 359 (M+H) ⁺ .

[00560] Lithium triethylborohydride (10.5 ml of 1M, 10.5 mmol) was slowly added to a solution of 1,4-di-tert-butyl-2-methyl-2-methylpiperazine-1,2,4-tricarboxylate (1 .5 g, 4.2 mmol) in THF (37.5 ml) at 0°C. After 10 minutes, the reaction was stopped by adding saturated aqueous NaHCO ₃ solution and extracted with EtOAc. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, DCM/MeOH gradient elution). The product was immediately used in the next reaction; MS m/z: 330 (M+H) ⁺ .

[00561] TFA (1 ml, 13 mmol) was added to a solution of tert-butyl-8a-methyl-3-oxo-1,5,6,8-tetrahydrooxazolo[3,4-a]pyrazine-7-carboxylate (50 mg , 0.2 mmol) in DCM (3 ml). After 20 min, the reaction mixture was concentrated in vacuo to obtain 8a-methyltetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one A27, which was used without further purification in the next step (assuming a quantitative yield of mono-salts with TFA); MS m/z: 157 (M+H) ⁺ .

[00562] Synthesis 28: N-(1-(Morpholin-2-yl)ethyl)methanesulfonamide A28.

[00563] Place 1-(4-benzylmorpholin-2-yl)ethanamine (520 mg, 2.4 mmol) and Et ₃ N (658 μL, 4.7 mmol) in DCM (11 mL) under N atmosphere into a round bottom flask ₂ . The mixture was cooled to -78°C and methanesulfonyl chloride (164 μl, 2 mmol) was added dropwise. The mixture was stirred for 10 minutes, then allowed to warm to ambient temperature and stirred for a further 10 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution. After 5 min, the reaction mixture was passed through a phase separation cartridge and concentrated in vacuo. The resulting brown oil (700 mg) was immediately used in the next reaction; MS m/z: 299 (M+H) ⁺ .

[00564] N-[1-(4-Benzylmorpholin-2-yl)ethyl]methanesulfonamide (700 mg, 2 mmol) in MeOH (10 mL) was placed in a round bottom flask and concentrated HCl (196 μL, 2 mmol) was added. The flask was degassed and filled with N ₂ (×3 cycles vacuum - N ₂ ) and Pd at C, wet, Degussa 10% w/w was added in one portion. (249 mg, 0.2 mmol). The flask was connected to a hydrogen cylinder and filled (×3 vacuum - hydrogen cycles). The reaction mixture was stirred vigorously at ambient temperature for 16 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was dissolved in methanol and loaded into an ion exchange cartridge, washed with MeOH, then the product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated in vacuo to give N-(1-(morpholin-2-yl)ethyl)methanesulfonamide A28 (450 mg), which was immediately used in the next reaction without further purification; MS m/z: 209 (M+H) ⁺ .

[00565] Synthesis 29: Dimethyl[(piperidin-3-ylmethyl)imino]-λ6-sulfanone A29.

[00566] NaBH(OAc) ₃ (455 mg, 2 mmol) was added to a mixture of tert-butyl-3-formylpiperidine-1-carboxylate (230 mg, 1 mmol) and (methylsulfonimidoyl)methane (50 mg, 0.5 mmol) in DCE (7 ml) and the reaction mixture was stirred at 35°C for 15 hours. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water, the pH was adjusted to ~1 with 2 M HCl aqueous solution and the mixture was extracted with DCM (×3). The pH was adjusted to ~9 with 2 M NaOH and extracted with DCM (×3). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give a colorless oil (83 mg, 53%), which was used in the next reaction without further purification; ¹ H NMR (500 MHz, chloroform-d) δ 4.05-3.90 (m, 2H), 3.02 (2×s, 6H), 2.95 (dd, 2H), 2.82 (br s, 1H), 2.61 (dd, 1H), 1.91-1.86 (m, 1H), 1.69-1.64 (m, 1H), 1.60 (br s, 1H), 1.50-1.46 (m, 1H), 1.48 (s, 9H), 1.24-1.16 (m, 1H); MS m/z: 291 (M+H) ⁺ .

[00567] TFA (500 μl, 6.5 mmol) was added with stirring to a solution of tert-butyl 3-({[dimethyl(oxo)-λ6-sulfanylidene]amino}methyl)piperidine-1-carboxylate (82 mg, 0 .3 mmol) in DCM (5 ml) and the reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was loaded into an ion exchange cartridge, washed with MeOH/DCM, then the product was eluted with 2 M NH ₃ in MeOH/DCM. The filtrate was concentrated in vacuo to give dimethyl[(piperidin-3-ylmethyl)imino]-λ6-sulfanone A29 as a colorless oil (51 mg, 96%); ¹ H NMR (500 MHz, chloroform-d) δ 3.19 (dd, 1H), 3.03-3.00 (m, 2H), 3.02 (s, 6H), 2.92 (dd, 2H ), 2.57 (td, 1H), 2.32 (dd, 1H), 1.93-1.88 (m, 1H), 1.71-1.60 (m, 1H), 1.51- 1.42 (m, 1H), 1.16-1.08 (m, 1H); MS m/z: 191 (M+H).

[00568] Synthesis 30: N-((3-Hydroxypiperidin-3-yl)methyl)methanesulfonamide A30.

[00569] A solution of tert-butyl-3-(aminomethyl)-3-hydroxypiperidine-1-carboxylate (333 mg, 1.4 mmol) and Et ₃ N (605 μl, 4.3 mmol) in DCM (10 ml) was treated methanesulfonyl chloride (123 µl, 1.6 mmol) at ambient temperature. The mixture was stirred for 10 minutes, then washed with saturated aqueous sodium bicarbonate. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give an oil. This material was dissolved in DCM (3 ml) and treated with TFA (1.67 ml, 22 mmol) at ambient temperature. After 1 hour, the reaction mixture was concentrated in vacuo. The residue was taken up in MeOH and loaded into an ion exchange cartridge. The cartridge was washed with MeOH/DCM, then the product was eluted with 2 M NH ₃ in MeOH. The filtrate was concentrated in vacuo to give N-((3-hydroxypiperidin-3-yl)methyl)methanesulfonamide A30 as an oil (289 mg), which was immediately used in the next reaction without further purification; MS m/z 209 (M+H) ⁺ .

[00570] Synthesis 31: N-((4-Hydroxypiperidin-3-yl)methyl)methanesulfonamide A31.

[00571] Methanesulfonamide (846 mg, 9 mmol), tert-butyl 4-[tert-butyl(dimethyl)silyl]oxy-3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (1.08 g, 2.5 mmol) and K ₂ CO ₃ (1.23 g, 9 mmol) were combined in DMF (12 ml) and heated at 120°C under N ₂ for 16 hours. The mixture was allowed to cool to ambient temperature, diluted with EtOAc, then washed with saturated aqueous sodium bicarbonate and brine (×2). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was treated with DCM (3 ml) and TFA (3 ml, 39 mmol) and the mixture was stirred at 40°C under N ₂ for 18 hours. The reaction mixture was concentrated in vacuo and the residue was treated with TBAF (12.7 ml 1 M solution in THF, 12.7 mmol) and stirred at 65°C for 16 hours. The reaction mixture was concentrated in vacuo to give N-((4-hydroxypiperidin-3-yl)methyl)methanesulfonamide A31, which was used in the following reactions without purification under the assumption of quantitative transformation; MS m/z 209 (M+H) ⁺ .

[00572] Synthesis 32: N-((5-Hydroxypiperidin-3-yl)methyl)methanesulfonamide A32.

[00573] tert-Butyl-N-methylsulfonylcarbamate (1.11 g, 5.7 mmol), benzyl 3-[tert-butyl(dimethyl)silyl]oxy-5-(hydroxymethyl)piperidine-1-carboxylate (1, 43 g, 3.8 mmol) and Ph ₃ P (2.97 g, 11.33 mmol) were dissolved in THF (15 ml). DEAD (1.25 mL, 7.9 mmol) was added dropwise to the mixture at ambient temperature. After 3 hours the mixture was diluted with EtOAc and saturated aqueous sodium bicarbonate. The organic phase was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluent PE). The product fractions were combined and concentrated in vacuo. The residue was taken up in DCM (5 ml) and TFA (5 ml, 65 mmol) and stirred at ambient temperature for 3 hours, then heated to 40°C and stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc/PE gradient elution) to give benzyl 3-hydroxy-5-(methanesulfonamidomethyl)piperidine-1-carboxylate (313 mg, 24%); MS m/z 343 (M+H) ⁺ .

[00574] This substance was dissolved in DCM (10 ml). The resulting solution was sequentially treated with N,N-diethylenamine (127 μl, 0.9 mmol), with Pd(OAc) ₂ (103 mg, 0.46 mmol) and Et ₃ SiH (950 μl, 6 mmol). The mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuo. The residue was taken up in MeOH and loaded into an ion exchange cartridge, washed with MeOH/DCM, then the product was eluted with 2 M NH ₃ in MeOH. The filtrate was concentrated in vacuo to give N-((5-hydroxypiperidin-3-yl)methyl)methanesulfonamide A32, which was immediately used in the next reaction without further purification, assuming quantitative conversion; MS m/z: 209 (M+H) ⁺ .

[00575] Synthesis 33: N-((5-Hydroxy-5-methylpiperidin-3-yl)methyl)methanesulfonamide, A33.

[00576] Benzyl 3-hydroxy-5-(methanesulfonamidomethyl)piperidine-1-carboxylate (200 mg, 0.58 mmol) was dissolved with DCM (20 ml) under N ₂ atmosphere. Dess-Martin periodinane (396 mg, 0.9 mmol) was added at ambient temperature. The reaction mixture was stirred for 16 hours, then additional Dess-Martin periodinane (200 mg) was added and the reaction mixture was stirred for another 16 hours. The reaction was stopped by adding a 1:1 mixture of saturated aqueous sodium bicarbonate: saturated aqueous sodium thiosulfate (15 ml). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo; MS m/z: 341 (M+H) ⁺ .

[00577] The residue was dissolved in THF (10 ml) under N ₂ atmosphere. The solution was cooled to -78°C and MeMgBr (388 µl 3 M, 1.2 mmol) was added dropwise. The cooling bath was removed and the mixture was allowed to warm to ambient temperature. After 2 hours, additional MeMgBr (388 µl 3 M, 1.2 mmol) was added and the mixture was stirred for 16 hours. Additional MeMgBr (1.9 ml 3 M) was added and after a further 5 hours the reaction was stopped by adding water (3 ml) . Saturated aqueous ammonium chloride was added and the mixture was extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue (200 mg) was dissolved in DCM (10 ml) and treated with Pd(OAc) ₂ (42 mg, 0.19 mmol), Et ₃ N (235 μl, 1.7 mmol) and Et ₃ SiH (421 μl , 2.6 mmol). The mixture was stirred at ambient temperature under N ₂ atmosphere and after 7 hours further Et ₃ SiH (421 μl, 2.6 mmol) and Pd(OAc) ₂ (42 mg, 0.19 mmol) were added. After 90 min, the reaction mixture was diluted with MeOH and loaded into an ion exchange cartridge. The product was eluted with 2 M methanolic ammonia and the filtrate was concentrated in vacuo. The residue, which contained the desired product N-((5-hydroxy-5-methylpiperidin-3-yl)methyl)methanesulfonamide A33, was immediately used in the next reaction without further purification; MS m/z: 223 (M+H) ⁺ .

[00578] Synthesis 34: N-(Piperidin-3-yloxy)methanesulfonamide A34.

[00579] A solution of tert-butyl-3-aminooxypiperidine-1-carboxylate (2.1 g, 9.7 mmol) and Et ₃ N (2.71 mL, 19.4 mmol) in DCM (10 mL) was treated with methanesulfonyl chloride ( 751 µl, 9.7 mmol). The mixture was stirred at ambient temperature for 16 hours. The resulting suspension was filtered, washed with DCM. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, PE/EtOAc gradient elution). The product fractions were concentrated in vacuo and the residue was taken up in DCM (10 ml). TFA (7.48 mL, 97.10 mmol) was added and after stirring for 30 min at ambient temperature, the mixture was concentrated in vacuo. The residue was loaded into an ion exchange cartridge, washed with MeOH, then the product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated in vacuo to give N-(piperidin-3-yloxy)methanesulfonamide A34 (876 mg, 46%), which was used in the next reaction without further purification; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.73 (tt, 1H), 3.46 (s, 1H), 3.03-2.99 (m, 1H), 2.97 (s, 3H), 2.68 (dt, 1H), 2.45 (dt, 2H), 1.94-1.86 (m, 1H), 1.61 (dtt, 1H), 1.46-1.36 (m, 1H), 1.36-1.27 (m, 1H).

[00580] Synthesis 35: Methyl(methylimino)(piperidin-3-ylmethyl)-λ6-sulfanone, A35.

[00581] NaSMe (4.06 g, 58 mmol) was added to a solution of tert-butyl 3-(methylsulfonyloxymethyl)piperidine-1-carboxylate (8.5 g, 29 mmol) in EtOH (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 and the organic phase was separated, dried and concentrated in vacuo. The residue was purified by column chromatography (silica, MeOH/DCM gradient elution) to give a pale yellow oil (6.9 g). This material was dissolved in DCM (100 ml), the solution was cooled in an ice bath and mCPBA (6.93 g purity 70% w/w, 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 column chromatography (silica, DCM/MeOH gradient elution) to give tert-butyl 3-((methylsulfinyl)methyl)piperidine-1-carboxylate (5.5 g, 72% in two steps) in the form of a colorless oil.

[00582] 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 rhodium(II) acetate dimer (0.9 g) was added , 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 ₂ CO ₃ (17.44 g, 126.2 mmol) was added. 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 NaHCO ₃ solution. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give tert-butyl 3-((S-methylsulfonimidoyl)methyl)piperidine-1-carboxylate (5.96 g) as an amber oil, which was used without additional cleaning.

[00583] tert-Butyl-3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (2 g, 7.2 mmol) was dissolved in THF (12 ml) under N ₂ atmosphere. The solution was cooled in an ice bath and NaH (868 mg of a 60% dispersion in mineral oil, 22 mmol) was added with stirring, followed by MeI (5.4 mL of a 2 M solution in TBME, 10.85 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. Additional NaH (289 mg of 60% dispersion in mineral oil, 1 eq.) and MeI (5.4 ml of 2 M solution in TBME, 10.85 mmol) were added. . After 5 h, the reaction was stopped by adding water drop by drop. The mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, MeOH/DCM gradient elution) to give an oil (1.59 g). This material was dissolved in DCM (3 ml), treated with TFA (3 ml) and stirred at ambient temperature for 45 minutes, then concentrated in vacuo. The residue was loaded into an ion exchange cartridge, washed with MeOH, then the product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated in vacuo to give methyl(methylimino)(piperidin-3-ylmethyl)-λ6-sulfanone A35 (612 mg, 44%), which was used in the next reaction without further purification; ¹ H NMR (500 MHz, methanol-d ₄ ) δ 3.39 (s, 1H), 3.32-3.25 (m, 1H), 3.21-3.08 (m, 2H), 3, 05 (d, 2H), 3.04-2.96 (m, 1H), 2.79 (s, 3H), 2.66-2.56 (m, 1H), 2.51-2.42 ( m, 1H), 2.27-2.15 (m, 1H), 2.07 (m, 1H), 1.79 -1.70 (m, 1H), 1.61 (m, 1H), 1 .36 (m, 1H).

[00584] Synthesis 36: 2-(3-Methyl-1H-pyrazol-4-yl)morpholine A36 and 2-((1H-pyrazol-4-yl)methyl)morpholine A37.

[00585] Benzyl chloroformate (5.9 mL, 41 mmol) was added dropwise to an ice-cold solution of 2-morpholin-2-ylethanol (4.5 g, 34 mmol) and DIPEA (9 mL, 52 mmol) in DCM (50 mL ) in an N ₂ atmosphere. The solution was allowed to warm to ambient temperature over 18 hours. The solution was diluted with 2 M aqueous HCl, stirred for 10 minutes and the layers were separated. The aqueous layer was extracted with DCM (×3) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 100% EtOAc/PE gradient elution) to give benzyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (7.18 g, 79%) in in the form of a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.41-7.33 (m, 5H), 5.17 (d, 2H), 4.04-3.91 (m, 3H), 3.81 (t, 2H), 3.66-3.55 (m, 2H), 3.04 (s, 1H), 2.77 (s, 1H), 2.28 (s, 1H), 1.73 ( s, 2H); MS m/z: 266 (M+H) ⁺ .

[00586] Dess-Martin periodinane (11.5 g, 27 mmol) was added to a solution of benzyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (7.18 g, 27 mmol) in DCM (100 ml) with stirring. at 0°C and the reaction mixture was allowed to warm to ambient temperature over 16 hours. The reaction was stopped by adding a 1:1 mixture of saturated aqueous NaHCO ₃ /sodium thiosulfate solution, stirred for 10 minutes and the layers were separated. The aqueous layer was extracted with DCM (×2) and the combined organic extracts were washed with 1:1 saturated aqueous NaHCO ₃ /sodium thiosulfate solution (×2) and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give benzyl- 2-(2-oxoethyl)morpholine-4-carboxylate (6.91 g, 97%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 9.79 (dd, 1H), 7.41-7.33 (m, 5H), 5.17 (d, 2H), 4.09-3.88 (m, 4H), 3.59 (br t, 1H), 3.04 (s, 1H), 2.78 (s, 1H), 2.63 (ddd, 1H), 2.51 (dd, 1H ).

[00587] MeMgBr (1.8 mL 3 M, 5.4 mmol) was added with stirring to a solution of benzyl 2-(2-oxoethyl)morpholine-4-carboxylate (720 mg, 2.7 mmol) in THF (20 mL ) at 0°C and the reaction mixture was allowed to warm to ambient temperature over 20 hours. The reaction was stopped by adding 2 M HCl and the mixture was extracted with DCM (×3). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc/PE gradient elution) to give benzyl 2-(2-hydroxypropyl)morpholine-4-carboxylate (563 mg, 74%) as a colorless oil ; ¹ H NMR (500 MHz, chloroform-d) δ 7.43-7.32 (m, 5H), 5.19-5.14 (m, 2H), 4.13-3.93 (m, 4H) , 3.70-3.54 (m, 2H), 3.21-3.04 (m, 2H), 2.75 (br s, 1H), 1.65-1.57 (m, 2H), 1.22(dd,3H); MS m/z: 280 (M+1) ⁺ .

[00588] Dess-Martin periodinane (855 mg, 2 mmol) was added with stirring to a solution of benzyl 2-(2-hydroxypropyl)morpholine-4-carboxylate (563 mg, 2 mmol) in DCM (10 ml) at 0°C and the reaction mixture was allowed to warm to ambient temperature over 24 hours. The reaction was stopped by adding a 1:1 mixture of saturated aqueous NaHCO ₃ solution/sodium thiosulfate solution, stirred for 10 minutes and the layers were separated. The aqueous layer was extracted with DCM (×2) and the combined organic extracts were washed with 1:1 saturated aqueous NaHCO ₃ /sodium thiosulfate solution (×2) and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give benzyl- 2-acetonylmorpholine-4-carboxylate (558 mg, 100%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.41-7.33 (m, 5H), 5.20-5.14 (m, 2H), 3.96 (br d, 4H), 3, 57 (t, 1H), 3.02 (s, 1H), 2.72 (s, 1H), 2.68 (dd, 1H), 2.47 (dd, 1H), 2.21 (s, 3H ); MS m/z: 278.2 (M+H) ⁺ .

[00589] A mixture of benzyl 2-acetonylmorpholine-4-carboxylate (557 mg, 2 mmol) and DMF-DMA (270 μl, 2 mmol) in DMF (10 ml) was stirred at 80°C for 21 hours. Another portion was added DMF-DMA (140 µl, 1.1 mmol) and the reaction mixture was stirred at 80°C for another 6 hours. Another portion of DMF-DMA (100 µl, 0.75 mmol) was added and the reaction mixture was stirred at 80°C in for another 18 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was used immediately, assuming 100% yield and purity.

[00590] Hydrazine hydrate (100 μl, 2 mmol) was added to a solution of benzyl 2-(4-(dimethylamino)-2-oxobut-3-en-1-yl)morpholine-4-carboxylate (668 mg, 2 mmol) with stirring ) in EtOH (10 ml) and the reaction mixture was stirred at 80°C for 4 hours. Another portion of hydrazine hydrate (100 μl, 2 mmol) was added and the reaction mixture was stirred at 80°C for 1.5 hours. The solvent was removed in vacuum and the residue was purified by column chromatography (silica, 0-100% EtOAc/PE gradient elution) to give benzyl 2-(1H-pyrazol-3-ylmethyl)morpholine-4-carboxylate (215 mg, 36% ) in the form of a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 10.19 (s, 1H), 7.51 (d, 1H), 7.40-7.33 (m, 5H), 6.14 (weak d, 1H), 5.16 (s, 2H), 4.05-3.95 (m, 3H), 3.68 (s, 1H), 3.59-3.56 (m, 1H), 3.06 (s, 1H), 2.88 (s, 2H), 2.75 (s, 1H); MS m/z: 302 (M+H) ⁺ ; and benzyl 2-(3-methyl-1H-pyrazol-4-yl)morpholine-4-carboxylate (76 mg, 13%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.42 (s, 1H), 7.32-7.24 (m, 5H), 5.10 (s, 2H), 4.41-4.34 (m, 1H), 4.03-3.89 (m, 2H), 3.61-3.55 (m, 2H), 3.08-3.01 (m, 2H), 2.24 (s , 3H); MS m/z: 302 (M+H) ⁺ .

[00591] Pd on C, wet, Degussa 10% w/w. (7 mg, 0.007 mmol) was added with stirring to a solution of benzyl 2-(3-methyl-1H-pyrazol-4-yl)morpholine-4-carboxylate (76 mg, 0.25 mmol) in MeOH (1 ml) and EtOAc (1 ml) and the reaction mixture was placed under a hydrogen atmosphere. The reaction mixture was stirred at ambient temperature for 15 h, then additional Pd at C, wet, Degussa 10% w/w was added. (7 mg, 0.07 mmol) and the reaction mixture was placed under a hydrogen atmosphere. The reaction mixture was stirred at ambient temperature for 6 hours, then the catalyst was removed by filtration and the solvent was removed in vacuo to give 2-(3-methyl-1H-pyrazol-4-yl)morpholine A36 (41 mg, 98%); MS m/z: 168 (M+H) ⁺ .

[00592] Pd on C, wet, Degussa 10% w/w, (20 mg, 0.02 mmol) was added to the benzyl 2-(1H-pyrazol-3-ylmethyl)morpholine-4-carboxylate solution with stirring (215 mg, 0.7 mmol) in MeOH (1.5 ml)/EtOAc (1.5 ml) and the reaction mixture was placed under a hydrogen atmosphere. The reaction mixture was stirred at ambient temperature for 15 hours, then the catalyst was removed by filtration and the solvent was removed in vacuo to give 2-(1H-pyrazol-4-ylmethyl)morpholine A37 (113 mg, 94%) as a colorless oil; MS m/z: 168 (M+H) ⁺ .

[00593] Synthesis 37: N-((4,4-Dimethylpyrrolidin-3-yl)methyl)methanesulfonamide A38.

[00594] Benzyl chloroformate (1.4 mL, 9.807 mmol) was added dropwise with stirring to a solution of methyl 4,4-dimethylpyrrolidine-3-carboxylate (1 g, 6.36 mmol) and DIPEA (2.4 mL, 13. 78 mmol) in DCM (20 ml) at 0°C and the reaction mixture was allowed to warm to ambient temperature over 48 hours. The reaction mixture was diluted with saturated aqueous NH ₄ Cl and the layers were separated. The organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 30% EtOAc/petroleum ether gradient elution) to give O1-Benzyl-O3-methyl-4,4-dimethylpyrrolidine-1,3-dicarboxylate (1.49 g, 81%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.32-7.22 (m, 5H), 5.11-5.04 (m, 2H), 3.74-3.59 (m, 2H) , 3.64 (s, 3H), 3.31 (dd, J=28.1, 10.5 Hz, 1H), 3.14 (t, J=10.6 Hz, 1H), 2.69 ( dt, J=17.6, 8.1 Hz, 1H), 1.15 (d, J=12.7 Hz, 3H), 0.94 (s, 3H); MS m/z: 292.0 (M+H) ⁺ .

[00595] O1-Benzyl-O3-methyl-4,4-dimethylpyrrolidine-1,3-dicarboxylate (1.49 g, 5 mmol) in THF (10 ml) was cooled to 0°C, then NaBH ₄ (580 mg) was added , 15 mmol) and MeOH (1 ml). The mixture was allowed to warm to ambient temperature for 24 hours. Another portion of NaBH ₄ (580 mg, 15 mmol) was added and the reaction mixture was stirred at ambient temperature for another 4 hours. The mixture was diluted with H ₂ O and EtOAc and the layers were separated . The organic layer was washed with saturated aqueous NaHCO ₃ (×2), brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 30% EtOAc/PE gradient elution) to give benzyl 4-(hydroxymethyl)-3,3-dimethylpyrrolidine-1-carboxylate (898 mg, 67%) in the form of a colorless oil; MS m/z: 264 (M+H) ⁺ .

[00596] To a solution of benzyl 4-(hydroxymethyl)-3,3-dimethylpyrrolidine-1-carboxylate (300 mg, 1.14 mmol), tert-butyl-N-methylsulfonylcarbamate (330 mg, 1.7 mmol) and PPh ₃ (890 mg, 3.4 mmol) in THF (20 ml), DEAD (390 μl, 2.5 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature under N ₂ for 16 h. The reaction mixture was concentrated in vacuum and the residue was purified by column chromatography (silica, 0 to 50% EtOAc/PE gradient elution) to give benzyl-4-[[tert-butoxycarbonyl(methylsulfonyl)amino]methyl]-3,3-dimethylpyrrolidine -1-carboxylate as a colorless oil, which was immediately used in the next step; MS m/z: 441 (M+H) ⁺ .

[00597] TFA (2 mL, 26 mmol) was added to a solution of benzyl 4-[[tert-butoxycarbonyl(methylsulfonyl)amino]methyl]-3,3-dimethylpyrrolidine-1-carboxylate (502 mg, 1.1 mmol) with stirring ) in DCM (15 ml) and the reaction 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 diluted with EtOAc and washed with saturated aqueous NaHCO ₃ (×2) and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The remainder was immediately used in the next step.

[00598] Pd on C, wet, Degussa 10% w/w. (60 mg, 0.06 mmol) was added with stirring to a solution of benzyl 4-(methanesulfonamidomethyl)-3,3-dimethylpyrrolidine-1-carboxylate (388 mg, 1.1 mmol) in MeOH (10 ml) and EtOAc (10 ml) and the reaction mixture was placed under a hydrogen atmosphere. The reaction mixture was stirred at ambient temperature for 4 hours, then the catalyst was removed by filtration and the solvent was removed in vacuo. The residue was loaded into an ion exchange cartridge, washed with MeOH, then the product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated in vacuo to give N-[(4,4-dimethylpyrrolidin-3-yl)methyl]methanesulfonamide A38 (188 mg, 80%) as a pale yellow oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.88 (s, 1H), 3.17 (s, 2H), 3.05-3.01 (m, 2H), 2.88 (s, 3H), 2.73 (t, 1H), 2.55-2.51 (m, 1H), 1.74-1.67 (m, 1H), 1.01 (s, 3H), 0.85 (s, 3H); MS m/z: 207 (M+H) ⁺ .

[00599] Synthesis 38: N-((4-Hydroxypyrrolidin-3-yl)methyl)methanesulfonamide A39.

[00600] Methanesulfonyl chloride (115 μl, 1.5 mmol) was added to a solution of tert-butyl 3-(aminomethyl)-4-hydroxypyrrolidine-1-carboxylate (250 mg, 1.2 mmol) and Et ₃ N (250) with stirring µl, 1.6 mmol) in THF (10 ml) under N ₂ and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ 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 (MgSO ₄ ), filtered and concentrated in vacuo to give tert-butyl 3-hydroxy-4-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate as a pale yellow oil.

[00601] TFA (0.5 ml) was added with stirring to a solution of crude tert-butyl 3-hydroxy-4-(methanesulfonamidomethyl)pyrrolidine-1-carboxylate (340 mg, 1.2 mmol) in DCM (5 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was loaded into an ion exchange cartridge, washed with MeOH and the product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated in vacuo to give N-((4-hydroxypyrrolidin-3-yl)methyl)methanesulfonamide A39 as a pale orange oil, which was immediately used in the next reaction without further purification; MS m/z: 195 (M+H) ⁺ .

[00602] Synthesis 39: N-((2-Methylpyrrolidin-3-yl)methyl)methanesulfonamide A40.

[00603] 1-tert-Butoxycarbonyl-2-methylpyrrolidine-3-carboxylic acid (1 g, 4.4 mmol) was suspended in THF (20 ml) and cooled to -20°C. Et ₃ N (910 μl, 6.5 mmol) was added, then isobutyl chloroformate (850 μl, 6.6 mmol). The reaction mixture was allowed to warm to ambient temperature over 60 minutes, then NaBH ₄ (250 mg, 6.6 mmol) was added, followed by methanol (7.5 ml). The reaction mixture was stirred for 2.5 hours at ambient temperature, then the reaction was stopped by adding saturated aqueous NaHCO ₃ solution and stirred for 10 minutes. Water was added to dissolve the salts and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 50% EtOAc/PE gradient elution) to give tert-butyl 3-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (395 mg, 42%) as a mixture of diastereoisomers (~1:1) as a colorless oil, which was immediately used in the next reaction.

[00604] To a solution of tert-butyl-3-(hydroxymethyl)-2-methylpyrrolidine-1-carboxylate (394 mg, 1.8 mmol), tert-butyl-N-methylsulfonylcarbamate (530 mg, 2.7 mmol) and PPh ₃ (1.4 g, 5.3 mmol) in THF (25 ml), DEAD (625 µl, 4 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature under N ₂ for 16 hours. The reaction mixture was then concentrated in vacuum and the residue was used immediately without further purification; MS m/z: 393 (M+H) ⁺ .

[00605] TFA (2 mL, 26 mmol) was added to the solution of tert-butyl 3-[[tert-butoxycarbonyl(methylsulfonyl)amino]methyl]-2-methylpyrrolidine-1-carboxylate (718 mg, 1.83 mmol) with stirring ) in DCM (10 ml) and the reaction mixture was stirred at ambient temperature for 22 hours. Another portion of TFA (5 ml, 65 mmol) was added and the reaction mixture was stirred at ambient temperature for another 4 hours. The solvent was removed in vacuum and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was loaded into an ion exchange cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2 M NH ₃ in MeOH/DCM mixtures. The solvent was removed in vacuo to give N-[(2-methylpyrrolidin-3-yl)methyl]methanesulfonamide A40, which was immediately used in the next reaction; MS m/z: 193 (M+H) ⁺ .

[00606] Synthesis 40: 4-((3-Fluoroazetidin-1-yl)methyl)piperidine A41.

[00607] A mixture of 3-fluoroazetidine hydrochloride (1.0 g, 9 mmol), tert-butyl-4-formylpiperidine-1-carboxylate (2.3 g, 11 mmol), DIPEA (1.7 mL, 10 mmol) and ground 4 Å molecular sieves (1 g) in DCE (30 ml) were stirred at ambient temperature for 5 hours. NaBH(OAc) ₃ (3.8 g, 18 mmol) was added and the reaction mixture was stirred at ambient temperature for another 16 hours. The mixture was filtered through celite (wash with DCM) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica, 0-10% MeOH/DCM eluting gradient) to give tert-butyl 4-[(3-fluoroazetidin-1-yl)methyl]piperidine-1-carboxylate as colorless oil (2.44 g); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 5.20-5.04 (m, 1H), 3.90 (d, 2H), 3.61-3.47 (m, 2H), 3, 07-3.00 (m, 2H), 2.65 (s, 1H), 2.31 (d, 2H), 1.62 (dd, 2H), 1.44-1.39 (m, 2H) , 1.39 (s, 9H), 1.08-0.82 (m, 2H).

[00608] TFA (5 mL, 65 mmol) was added to a solution of tert-butyl 4-[(3-fluoroazetidin-1-yl)methyl]piperidine-1-carboxylate (2.44 g, 9 mmol) in DCM (15 ml) and the reaction mixture was stirred at ambient temperature for 15 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and ether (×2). The residue was loaded into an ion exchange cartridge, washed with MeOH/DCM mixtures and then the product was eluted with 2 M NH ₃ in MeOH/DCM mixtures. The filtrate was concentrated in vacuo to give 4-((3-fluoroazetidin-1-yl)methyl)piperidine A41 as a pale yellow oil (1.11 g, 72% in two steps); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 5.11 (dtt, 1H), 3.59-3.48 (m, 2H), 3.04-2.97 (m, 2H), 2, 87 (dt, 2H), 2.38 (td, 2H), 2.27 (d, 2H), 1.97 (s, 1H), 1.62-1.48 (m, 2H), 1.31 (ttt, 1H), 1.04-0.83 (m, 2H).

[00609] Synthesis 41: N-(Indolin-3-ylmethyl)methanesulfonamide A42.

[00610] tert-Butyl-3-(aminomethyl)indoline-1-carboxylate (172 mg, 0.7 mmol) was dissolved in DCM (5 ml) and DIPEA (241 μl, 1.4 mmol) was added. The solution was cooled in an ice bath and methanesulfonyl chloride (59 μL, 0.8 mmol) was added slowly while stirring. After 5 min, water (~0.2 ml) was added and the reaction mixture was concentrated to dryness in vacuo. DCM (5 ml) and TFA (2 ml, 26 mmol) were added to the residue and the resulting solution was stirred for 16 hours. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM (×2), then taken up in EtOAc and washed with saturated aqueous solution of NaHCO ₃ . The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-10% MeOH/DCM gradient elution) to give N-(indolin-3-ylmethyl)methanesulfonamide A42 as a pale yellow glassy solid (115 mg, 73% per two stages); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.16 (t, 1H), 7.09 (dt, 1H), 7.01-6.90 (m, 1H), 6.61-6, 45 (m, 2H), 5.47 (s, 1H), 3.51 (dd, 1H), 3.30-3.24 (m, 2H), 3.20 (dt, J=12.6, 5.6 Hz, 1H), 2.98 (ddd, 1H), 2.89 (s, 3H); MS m/z: 227 (M+H) ⁺ .

[00611] Synthesis 42: 4-(Methylsulfonyl)octahydropyrrolo[3,4-b][1,4]oxazine A43.

[00612] tert-Butyl-3,4,4a,5,7,7a-hexahydro-2H-pyrrolo[3,4-b][1,4]oxazine-6-carboxylate (107 mg, 0.5 mmol) dissolved in DCM (2 ml) under N ₂ atmosphere. DIPEA (163 μl, 1 mmol) was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (54 μL, 0.7 mmol) was added with stirring. After 1 hour, water (~0.1 ml) was added and the mixture was diluted with DCM (10 ml). Saturated aqueous NaHCO ₃ solution was added and the layers were separated. The aqueous phase was extracted with DCM. The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was taken up in DCM and purified by column chromatography (silica, 0-10% MeOH/DCM gradient elution) to give a brown glass (116 mg). This substance was dissolved in DCM (3 ml) and TFA (2 ml) was added. After 30 minutes, the mixture was concentrated in vacuo and the residue was azeotroped with DCM. The residue was taken up in MeOH and passed through an SPE cartridge with bicarbonate. The filtrate was concentrated to give 4-(methylsulfonyl)octahydropyrrolo[3,4-b][1,4]oxazine A43 as a light brown oil (69 mg, 71% in two steps), which was used in the next reaction without further purification; MS m/z: 207 (M+H) ⁺ .

[00613] Synthesis 43: N-((1SR,6RS,8RS)-3-Azabicyclo[4.2.0]octan-8-yl)methanesulfonamide A44.

[00614] (1SR,6RS,7RS)-4-tert-Butoxycarbonyl-4-azabicyclo[4.2.0]octane-7-carboxylic acid (590 mg, 2.3 mmol), DIPEA (886 μl, 5 mmol) and 2-trimethylsilylethanol (2.65 ml, 18.5 mmol) was dissolved in toluene (20 ml) and refluxed. DPPA (1.1 mL, 5 mmol) was added slowly and the reaction mixture was refluxed for 16 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was transferred to DCM and purified by column chromatography (silica, 0-5% MeOH/DCM gradient elution) to give tert-butyl-(1S,6R,8R)-8-(((2-(trimethylsilyl )ethoxy)carbonyl)amino)-3-azabicyclo[4.2.0]octane-3-carboxylate as a sticky brown solid (800 mg, 94%); MS m/z: 371 (M+H) ⁺ .

[00615] This material was dissolved in THF (5 ml) under N ₂ atmosphere and TBAF (3.3 ml of 1 M, 3.2 mmol) was added. The reaction mixture was stirred overnight at ambient temperature. Additionally, TBAF (3 ml 1 M, 3 mmol) was added. After 2 hours, the reaction mixture was concentrated in vacuo. The residue was taken up in DCM and immediately purified by column chromatography (silica, 0-10% MeOH/DCM gradient elution) to give a colorless oil. This substance was dissolved in DCM (5 ml) and the solution was cooled to -5°C. DIPEA (565 μL, 3.2 mmol) was added, then methanesulfonyl chloride (84 μL, 1.1 mmol) was added dropwise. The reaction mixture was stirred for 2 hours with the temperature raised to 5°C. The reaction was stopped by adding a small amount of water, then concentrated to dryness in vacuo. The residue was transferred to DCM and purified by column chromatography (silica, 0-10% MeOH/DCM gradient elution) to give tert-butyl-(1S,6R,8R)-8-(methylsulfonamido)-3-azabicyclo [4.2.0]octane-3-carboxylate as a glassy substance (70 mg, 21% in two steps); MS m/z: 305 (M+H) ⁺ .

[00616] This substance was dissolved in DCM (5 ml) and TFA (500 μl) was added. The reaction mixture was stirred for 3 hours at ambient temperature, then concentrated in vacuo. The residue was azeotroped with DCM (×3), then transferred to MeOH and filtered through an SPE cartridge with bicarbonate. The filtrate was concentrated in vacuo to give N-((1SR,6RS,8RS)-3-azabicyclo[4.2.0]octan-8-yl)methanesulfonamide A44 as a pale yellow glassy solid (39 mg, 83%), which was used in the next reaction without further purification; MS m/z: 205 (M+H) ⁺ .

[00617] Synthesis 44: 3-(Piperidin-3-yl)oxetan-3-amine A45.

[00618] 3-(3-Pyridyl)oxetane-3-amine hydrochloride (100 mg, 0.5 mmol) was dissolved in MeOH (10 ml). The solution was recirculated for 8 hours through the PtO ₂ catalyst cartridge at 2.5 ml min ^-1 with an H ₂ pressure of 60 bar at 60°C in an H-cube. The solution was then concentrated in vacuo to give 3-(piperidin-3-yl)oxetan-3-amine A45 as a pale yellow solid (84 mg, 80%), which was immediately used in the next reaction; MS m/z: 157 (M+H) ⁺ .

[00619] Synthesis 45: N-(((3S,5S)-4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide A46.

[00620] 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 (1 M 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 column chromatography (silica, eluting with EtOAc/PE). The product fractions were combined and concentrated in vacuo and the residue was recrystallized from EtOAc to give benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4-oxopiperidine-1-carboxylate as a white solid ( 7.56 g, 23%).

[00621] 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 was kept 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 organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with EtOAc/PE) to give benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate in the form of a glassy substance (32.5 g, 51%); ¹ H 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.

[00622] 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-dioxoisoindoline -2-yl)methyl]-4,4-difluoro-5-methylpiperidin-1-carboxylate, (98.7% ee).

[00623] 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, then the product was eluted with 2 M methanol ammonia. The filtrates were combined and concentrated in vacuo. The residue was taken up in MeOH and concentrated in vacuo (×2), then treated with heptane and concentrated in vacuo. The resulting yellow oil was dried in vacuo overnight to give benzyl (3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate as a solid (6.77 g), which used immediately 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) ⁺ .

[00624] 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 a bath with ice. 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 (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 100% EtOAc/PE gradient elution). The product fractions were combined and concentrated in vacuo and the residue was dried overnight in vacuo to give benzyl (3S,5S)-4,4-difluoro-3-(methanesulfonamidomethyl)-5-methylpiperidine-1-carboxylate as 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) ⁺ .

[00625] 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) was added Et ₃ N (8.38 ml, 60 mmol), then Pd(OAc) ₂ (1.80 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×6). The cartridges were washed with DCM, 1:1 MeOH:DCM and MeOH and the product was eluted with 2 M methanolic ammonia. The filtrates were combined and concentrated in vacuo. The residue was azeotroped with DCM, then taken up in MeOH (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, 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 A46 as a white solid (4.40 g, 91% ); ¹ H NMR (400 MHz, DMSO-d6) 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 (M+H) ⁺ .

[00626] Synthesis 46: N-[[(2S)-Morpholin-2-yl]methyl]methanesulfonamide A47.

[00627] Tert-Butyl-(2R)-2-(aminomethyl)morpholine-4-carboxylate (5 g, 23 mmol) and Et ₃ N (16.1 mL, 115 mmol) were added to the round bottom flask, followed by THF (100 ml). DCM (50 ml) was added 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 30 minutes, then kept at ambient temperature for 16 hours under N ₂ atmosphere. The reaction was stopped with saturated aqueous NaHCO ₃ solution (100 ml) and concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (3×50 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 70 to 100% EtOAc/PE gradient elution). The product fractions were combined and concentrated in vacuo. The residue was dried overnight in vacuo to give tert-butyl (2S)-2-(methanesulfonamidomethyl)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).

[00628] TFA (9 mL, 115 mmol) was added with stirring to a solution of tert-butyl (2S)-2-(methanesulfonamidomethyl)morpholine-4-carboxylate (3.6 g, 12 mmol) in DCM (60 mL) 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 taken up in MeOH and passed through an ion exchange cartridge, washed with methanol, then the product was eluted with 2 M methanol ammonia. The filtrate was concentrated in vacuo to give N-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide A47 (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) ⁺ .

[00629] Synthesis 47: N-[(4-Hydroxy-4-methyl-3-piperidyl)methyl]methanesulfonamide A48.

[00630] A solution of 1-benzyl-3-[[tert-butyl(dimethyl)silyl]oxymethyl]piperidin-4-one (2.5 g, 7.5 mmol) in diethyl ether (22 ml) under N ₂ was cooled to 0°C, then MeMgBr (3 ml of 3 M solution in ether, 9 mmol) was added dropwise. The mixture was stirred and then allowed to warm to ambient temperature for 20 minutes. The mixture was diluted with a saturated aqueous solution of NH ₄ Cl and EtOAc. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in THF (3 ml) and treated with TBAF (2.5 ml of a 75% w/v solution in water, 7.2 mmol) and stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo and dissolved in DCM (8 ml). Et ₃ N (2.7 mL, 19 mmol) was added under N ₂ and the solution was cooled in an ice bath. Methanesulfonyl chloride (789 μL, 10.2 mmol) was added and the mixture was stirred for 3 hours while raising the temperature to ambient temperature. Methanesulfonyl chloride (789 μL, 10.2 mmol) was added and the reaction mixture was stirred for 90 minutes. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO ₃ solution and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give (1-benzyl-4-hydroxy-4-methyl-3-piperidyl)methylmethanesulfonate (2.0 g, 100%) as an oil; MS m/z: 314 (M+H) ⁺ .

[00631] Methanesulfonamide (607 mg, 6.38 mmol), (1-benzyl-4-hydroxy-4-methyl-3-piperidyl)methylmethanesulfonate (2.00 g, 6.38 mmol) and K ₂ CO ₃ (3 .09 g, 22.3 mmol) were combined in dry DMF (24 ml) and stirred at 100°C under nitrogen for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and washed with saturated aqueous sodium bicarbonate (×2). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-10% [10% NH ₄ OH in MeOH]-DCM gradient elution) to give N-[(1-benzyl-4-hydroxy-4-methyl-3 -piperidyl)methyl]methanesulfonamide (550 mg, 28%) as a yellow oil, which was immediately used in the next reaction; MS m/z: 313 (M+H) ⁺ .

[00632] Place N-[(1-benzyl-4-hydroxy-4-methyl-3-piperidyl)methyl]methanesulfonamide (550 mg, 1.76 mmol) in MeOH (8 mL) into a round bottom flask and add concentrated HCl ( 147 µl 37% w/v, 1.760 mmol). The flask was degassed and filled with nitrogen (×3 vacuum-nitrogen cycles) and Pd/C (Degussa) (187 mg 10% w/w, 0.18 mmol) was added in one portion. N ₂ was replaced with H ₂ (×3 cycles of vacuum - hydrogen) and the reaction mixture was stirred at ambient temperature. After 3 h, additional concentrated HCl (147 μL 37% w/v, 1.760 mmol) and Pd/C (Degussa) (187 mg 10% w/w, 0.18 mmol) were added and the mixture was degassed and refilled using H ₂ as above. The mixture was stirred for 20 hours, then filtered through celite. The filtrate was concentrated in vacuo to give N-[(4-hydroxy-4-methyl-3-piperidyl)methyl]methanesulfonamide A48 (321 mg, 70%), which was used in the next reaction without further purification; MS m/z: 223 (M+H) ⁺ .

[00633] Synthesis 48: N-[(6-Methyl-3-piperidyl)methyl]methanesulfonamide A49.

[00634] To a solution of (6-methyl-3-pyridyl)methanol (250 mg, 2.03 mmol), tert-butyl-N-methylsulfonylcarbamate (590 mg, 3.02 mmol) and PPh ₃ (1.6 g, 6.10 mmol) in THF (10 ml), DEAD (690 µl, 4.38 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 2 hours. The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica, 0-50% EtOAc/PE gradient elution) to give tert-butyl ((6-methylpyridin-3-yl)methyl)(methylsulfonyl)carbamate (567 mg, 93 %) as a white solid, which was immediately used in the next reaction; MS m/z: 301 (M+H) ⁺ .

[00635] tert-Butyl-((6-methylpyridin-3-yl)methyl)(methylsulfonyl)carbamate (566 mg, 1.88 mmol) was dissolved in MeOH (30 ml). Rh on alumina (56 mg 5% w/w, Degussa) was added and the reaction mixture was placed under a hydrogen atmosphere and stirred at ambient temperature for 54 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (10 ml) and TFA (2 ml) was added. The mixture was stirred at ambient temperature for 17 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was passed through an ion exchange cartridge, washed with MeOH/DCM mixtures, then the product was eluted with 2 M NH ₃ in MeOH/DCM mixtures. The filtrates were concentrated in vacuo to give N-[(6-methyl-3-piperidyl)methyl]methanesulfonamide A49 (98 mg, 25%) as a brown solid, which was used in the next reaction without further purification; MS m/z: 207 (M+H) ⁺ .

[00636] Synthesis 49: 2-Methylsulfonyl-2,6-diazaspiro[4.5]decane A50.

[00637] To a solution of tert-butyl-2,6-diazaspiro[4.5]decane-6-carboxylate (250 mg, 1.04 mmol) and Et ₃ N (200 μl, 1.44 mmol) in DCM (4 ml) methanesulfonyl chloride (100 μl, 1.3 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 hours, then diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo to give a colorless oil, MS m/z: 319 (M+H) ⁺ .

[00638] The residue was taken into DCM (3 ml)/TFA (1 ml) and the reaction mixture was stirred at ambient temperature for 2 hours. The mixture was concentrated in vacuo to give 2-methylsulfonyl-2,6-diazaspiro[4.5]decane A50 (250 mg, 72%) as a yellow oil, which was immediately used in the next reaction.

[00639] Synthesis 50: N-[[5-(Dimethylamino)-4,4-difluoro-3-piperidyl]methyl]methanesulfonamide A51.

[00640] tert-Butyl-3-bromo-4-oxopiperidine-1-carboxylate (2 g, 7.2 mmol) was suspended in THF (2 ml) and cooled in an ice bath, then dimethylamine (16 ml 2 M, 32 mmol). After addition was complete, the ice bath was removed and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in THF (28 ml) under N ₂ atmosphere. The solution was cooled to -78°C and LiHMDS (10 ml 1 M, 10 mmol) was added dropwise. After 40 minutes, 2-(chloromethyl)isoindoline-1,3-dione (2.32 g, 11.8 mmol) was added in portions over 5 minutes. The solution was stirred for 1 hour, then left to warm to 0°C, then the reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl. The mixture was partitioned between saturated aqueous sodium bicarbonate and EtOAc. The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-10% MeOH/DCM gradient elution) to give tert-butyl-3-(dimethylamino)-5-[(1,3-dioxoisoindolin-2-yl)methyl ]-4-oxopiperidine-1-carboxylate (1.58 g, 50%); MS m/z: 402 (M+H) ⁺ .

[00641] tert-Butyl-3-(dimethylamino)-5-[(1,3-dioxoisoindolin-2-yl)methyl]-4-oxopiperidine-1-carboxylate (1.4 g, 3.5 mmol) in DCM (5 mL) was cooled in an ice bath, then DAST (3.7 mL, 28 mmol) was added slowly. The mixture was stirred under N ₂ for 3.5 hours. The ice bath was removed and DAST (2 mL, 15 mmol) was added and the mixture was stirred for 18 hours. Additional DAST (3.7 mL, 28 mmol) was added and the mixture was stirred. for another 18 hours. The reaction was stopped by slowly adding ice/DCM to the mixture with vigorous stirring. The aqueous phase was carefully made alkaline by adding NaHCO ₃ , the layers were separated and the organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-15% MeOH/DCM gradient elution) to give tert-butyl-3-(dimethylamino)-5-[(1,3-dioxoisoindolin-2-yl)methyl ]-4,4-difluoropiperidine-1-carboxylate (500 mg, 34%); MS m/z: 424 (M+H) ⁺ .

[00642] tert-Butyl-3-(dimethylamino)-5-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoropiperidine-1-carboxylate (500 mg, 1.181 mmol) and hydrazine hydrate (240 µl of 50% w/v, 2.4 mmol) was combined in EtOH (5 ml) and the mixture was refluxed for 1 h. The mixture was allowed to cool to ambient temperature, then loaded into an ion exchange cartridge. The product was eluted with methanolic ammonia and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (5 ml), the solution was cooled in an ice bath and Et ₃ N (494 µl, 3.5 mmol) was added, then methanesulfonyl chloride (114 µl, 1.5 mmol) was added. After 5 minutes, the ice bath was removed and the mixture was stirred at ambient temperature overnight. Methanesulfonyl chloride (25 µl, 0.3 mmol) was added. After 30 minutes, a saturated aqueous sodium bicarbonate solution was added. The mixture was stirred vigorously for 5 min, then passed through a phase separation cartridge. The filtrate was concentrated in vacuo. The residue was dissolved in DCM (3 ml) and TFA (1.5 ml) was added. The mixture was stirred at ambient temperature for 45 minutes, then concentrated in vacuo. The residue was loaded into an ion exchange cartridge, washed with DCM/MeOH mixtures, and then the product was eluted with a methanolic ammonia solution. The filtrate was concentrated in vacuo to give N-[[5-(dimethylamino)-4,4-difluoro-3-piperidyl]methyl]methanesulfonamide A51 (219 mg, 68%) as an oil, which was immediately used in the next reaction without further purification ; MS m/z: 272 (M+H) ⁺ .

[00643] Synthesis 51: N-[(2,6-Dimethyl-3-piperidyl)methyl]methanesulfonamide A52.

[00644] Et ₃ N (600 μL, 4.3 mmol), then methanesulfonyl chloride (300 μL, 4 mmol) was added to an ice-cold solution of (2,6-dimethyl-3-pyridyl)methanamine (400 mg, 3 mmol) in DCM (10 ml) under N ₂ atmosphere. After 5 minutes, the ice bath was removed and the solution was stirred at ambient temperature for 1 hour. The solution was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo to give N-[(2,6-dimethyl-3-pyridyl)methyl]methanesulfonamide (700 mg), which was used in the next step without further purification; MS m/z: 215 (M+H) ⁺ .

[00645] A suspension of N-[(2,6-dimethyl-3-pyridyl)methyl]methanesulfonamide (700 mg, 3.3 mmol), PtO ₂ (200 mg, 0.9 mmol) and HCl (5 ml of 3 M solution in MeOH, 15 mmol) in MeOH (2 ml) was shaken in a Parr hydrogenator at 60 psi H ₂ pressure for 72 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give N ^- [(2 ,6-dimethyl-3-piperidyl)methyl] methanesulfonamide A52 (500 mg, 69%) as a colorless oil, which was used in the following reaction without further purification; MS m/z: 221 (M+H) ⁺ .

[00646] Synthesis 52: ((2S,6S)-6-(Trifluoromethyl)morpholin-2-yl)methanol A53 and ((2R,6S)-6-(trifluoromethyl)morpholin-2-yl)methanol A54.

[00647] Mixture of (2S)-3-amino-1,1,1-trifluoropropan-2-ol hydrochloride (1.0 g, 6.0 mmol), benzaldehyde (740 μl, 7.3 mmol), DIPEA (1, 2 ml, 6.889 mmol) and crushed 4 Å MS (1 g) in DCE (30 ml) were stirred at ambient temperature for 1.5 h. NaBH(OAc) ₃ (2.56 g, 12.1 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 18.5 hours. The mixture was filtered through celite (DCM wash) and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica, 0-10% (10% NH ₄ OH in MeOH)/DCM gradient elution) to give an off-white solid, which was dissolved in DCM and passed through an ion exchange cartridge. The cartridge was washed with MeOH/DCM mixtures and the product was eluted by washing the cartridge with 2 M NH ₃ in MeOH/DCM mixtures. The solvent was removed in vacuo to give (2S)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol (515 mg, 39%) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.35-7.30 (m, 4H), 7.25-7.22 (m, 1H), 6.22 (d, 1H), 4, 10-4.02 (m, 1H), 3.74 (d, 2H), 2.70 (dd, 1H), 2.65-2.61 (m, 1H), 2.18 (br s, 1H ); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -76.87; MS m/z: 220 (M+H) ⁺ .

[00648] A solution of (2S)-3-(benzylamino)-1,1,1-trifluoropropan-2-ol (515 mg, 2.35 mmol) in toluene (10 ml) was treated with 2-(chloromethyl)oxirane (240 μl , 3.1 mmol) and lithium perchlorate (325 mg, 3.06 mmol) and the mixture was stirred at ambient temperature for 18 hours. MeOH (2.6 ml) and sodium methoxide (320 mg, 5.9 mmol) were added. and the reaction mixture was stirred at ambient temperature for another 25 hours. The reaction was stopped by adding saturated aqueous NH ₄ Cl and the aqueous layer was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) and the appropriate fractions were concentrated in vacuo. The residue was dissolved in MeOH (5 ml). Sodium methoxide (320 mg, 5.9 mmol) was added and the reaction mixture was refluxed for 21 hours. The reaction mixture was cooled to ambient temperature and the reaction was stopped by adding saturated aqueous NH ₄ Cl. The aqueous layer was diluted with water to dissolve the salts and extracted with EtOAc (×3). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-30% EtOAc-PE gradient elution) to give [(2S,6S)-4-benzyl-6-(trifluoromethyl)morpholin-2-yl]methanol (221 .9 mg, 34%) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.47-7.11 (m, 5H), 4.70 (t, 1H), 4.34 (ddt, 1H), 3.87 (d, 1H), 3.59-3.45 (m, 4H), 2.56-2.49 (m, 3H), 2.30 (dd, 1H); and [(2R,6S)-4-benzyl-6-(trifluoromethyl)morpholin-2-yl]methanol (86.1 mg, 13%) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.37-7.26 (m, 5H), 4.78 (t, 1H), 4.26-4.19 (m, 1H), 3, 65-3.60 (m, 1H), 3.61 (d, 1H), 3.54 (d, 1H), 3.45 (dt, 1H), 3.35 (dt, 1H), 2.89 (dt, 1H), 2.81 (dt, 1H), 2.03 (t, 1H), 1.87-1.83 (m, 1H).

[00649] Mixture of [(2S,6S)-4-benzyl-6-(trifluoromethyl)morpholin-2-yl]methanol (220 mg, 0.8 mmol), Pd at C, wet, Degussa (30 mg, 0. 3 mmol) and HCl in MeOH (5 ml 3 M, 15.0 mmol) were placed under a hydrogen atmosphere and stirred at ambient temperature for 24 hours. The catalyst was removed by filtration through celite, washed with MeOH and the filtrate was concentrated in vacuo to give [(2S,6S)-6-(trifluoromethyl)morpholin-2-yl]methanol A53 (183 mg, 103%) as a yellow oil, which was used in the next step without further purification (assuming mono-salt with HCl) ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.40 (s, 2H), 4.78-4.71 (m, 1H), 4.07 (p, 1H), 3.70 (dd, 1H), 3.64 (dd, 1H), 3.40 (dd, 1H), 3.30-3.23 (m, 2H), 3.17 (dd, 1H); MS m/z: 186 (M+H) ⁺ .

[00650] A mixture of [(2R,6S)-4-benzyl-6-(trifluoromethyl)morpholin-2-yl]methanol (86 mg, 0.312 mmol), Pd at C, wet, Degussa 10% w/w. (15 mg, 0.14 mmol) and HCl in MeOH (3 ml 3 M, 9.0 mmol) were placed under a hydrogen atmosphere and stirred at ambient temperature for 24 hours. The catalyst was removed by filtration through celite, washed with MeOH and the filtrate was concentrated in vacuo to obtain [(2R,6S)-6-(trifluoromethyl)morpholin-2-yl]methanol A54 (76.2 mg, quantitative yield), which was used in the next step without further purification (assuming mono- salts with HCl); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.79 (s, 2H), 4.66-4.60 (m, 1H), 4.02-3.98 (m, 1H), 3, 54-3.48 (m, 3H), 3.32-3.29 (m, 1H), 3.00 (t, 1H), 2.90 (t, 1H); MS m/z: 186.0 (M+H) ⁺ .

[00651] Synthesis 53: ((2R,6R)-6-(Trifluoromethyl)morpholin-2-yl)methanol A55 and ((2S,6R)-6-(trifluoromethyl)morpholin-2-yl)methanol A56

[00652] Following the procedure described in Synthesis 52 for A53 and A54, A55 and A56 were prepared using (2R)-3-amino-1,1,1-trifluoropropan-2-ol hydrochloride instead of (2S)-3-amino-1 ,1,1-trifluoropropan-2-ol hydrochloride.

[00653]((2R,6R)-6-(Trifluoromethyl)morpholin-2-yl)methanol A55 was obtained as the free base; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.68 (br s, 1H), 4.19-4.12 (m, 1H), 3.72-3.67 (m, 1H), 3 .56-3.54 (m, 2H), 2.91 (dd, 1H), 2.80 (dd, 1H), 2.74 (dd, 1H), 2.65 (dd, 1H), 2, 39 (br s, 1H); MS m/z: 186 (M+H) ⁺ .

[00654]((2S,6R)-6-(Trifluoromethyl)morpholin-2-yl)methanol A56 was obtained as the free base; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.72 (t, 1H), 4.06-4.00 (m, 1H), 3.53-3.48 (m, 1H), 3, 41 (dt, 1H), 3.35-3.31 (m, 2H), 2.93-2.90 (m, 1H), 2.85-2.81 (m, 1H), 2.59 ( br s, 1H), 2.33 (dd, 1H); MS m/z: 186 (M+H) ⁺ .

[00655] Synthesis 54: (S)-N-(Piperidin-3-ylmethyl)methanesulfonamide A57.

[00656] Methanesulfonyl chloride (465 μl, 6.0 mmol) was added to a solution of tert-butyl (3R)-3-(aminomethyl)piperidine-1-carboxylate (1.0 g, 4.7 mmol) and Et ₃ with stirring N (1 ml, 7.2 mmol) in THF (20 ml) under nitrogen and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with DCM (×2). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give a pale yellow oil, which was transferred to DCM (30 ml). TFA (7.5 mL, 97.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 20 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was passed through an ion exchange cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2 M NH ₃ in MeOH/DCM mixtures. The solvent was removed in vacuo to give (S)-N-(piperidin-3-ylmethyl)methanesulfonamide A57 (846 mg, 94%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 3.13 (dd, 1H), 3.06 (d, 2H), 3.02-2.98 (m, 1H), 2.97 (s, 3H ), 2.64-2.58 (m, 1H), 2.41 (dd, 1H), 1.89-1.83 (m, 1H), 1.75-1.67 (m, 1H), 1.59 (br s, 1H), 1.54-1.45 (m, 1H), 1.22-1.14 (m, 1H); MS m/z: 193 (M+H) ⁺ .

[00657] Synthesis 55: Mixture of N-((4,4-Difluoro-2-methylpiperidin-3-yl)methyl)methanesulfonamide A58 and N-((4,4-difluoro-6-methylpiperidin-3-yl)methyl) methanesulfonamide, A59.

[00658] LiHMDS (37 mL of a 1 M solution in THF, 37.0 mmol) was added dropwise to a solution of benzyl 2-methyl-4-oxopiperidine-1-carboxylate (7.5 g, 30.3 mmol) in THF (150 ml) at -78°C under N ₂ atmosphere. After 50 min, a solution of 2-(chloromethyl)isoindoline-1,3-dione (8.0 g, 40.9 mmol) in THF (30 ml) was added to the reaction mixture over 5 min. The solution was stirred for 2 hours, then the reaction was stopped with a saturated aqueous solution of NH ₄ Cl. After warming to ambient temperature, the reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtAOc/PE gradient elution) to give benzyl-5-((1,3-dioxoisoindolin-2-yl)methyl)-2-methyl-4 -oxopiperidin-1-carboxylate and benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-2-methyl-4-oxopiperidine-1-carboxylate (2.4 g). This material was treated with DAST (8 mL, 61 mmol) while cooling in an ice bath. The resulting solution was stirred at 0°C for 15 minutes, then allowed to warm to ambient temperature and stirred for 5 hours. The solution was carefully poured dropwise into the ice/water/NaHCO ₃ /DCM mixture while stirring. After 30 min, the organic phase was isolated and washed with brine. Organic matter was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give a colorless oil (1.5 g), of which 540 mg was dissolved in ethanol (15 ml) and hydrazine hydrate was added ( 100 µl, 2.0 mmol). The mixture was refluxed for 3 hours and then cooled to ambient temperature. The resulting suspension was filtered and the filtrate was poured directly into a pre-wetted ion exchange cartridge. The cartridge was washed with methanol and the product was eluted with 2 M methanol ammonia. The filtrate was concentrated under reduced pressure to give a pale yellow oil (300 mg). This material was dissolved in DCM (3 ml) and Et ₃ N (200 μl, 1.4 mmol) was added under N ₂ atmosphere. The solution was cooled in an ice bath and methanesulfonyl chloride (100 μL, 1.3 mmol) was added. After 5 minutes, the cooling bath was removed and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. After concentration in vacuo, the residue was purified by column chromatography (silica, 0-100% [10% MeOH in EtOAc]-PE gradient elution) to give a pale yellow oil (150 mg). This substance was transferred into DCM (3 ml) and Pd(OAc) ₂ (40 mg, 0.18 mmol), Et ₃ SiH (150 μl, 0.94 mmol) and Et ₃ N (100 μl, 0.72 mmol) added. The reaction mixture was stirred at ambient temperature for 1 hour, then diluted with MeOH. It was loaded into a pre-humidified ion exchange cartridge. The cartridge was washed with MeOH, then the product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated under reduced pressure to give a brown oil (70 mg) containing a mixture of N-((4,4-difluoro-2-methylpiperidin-3-yl)methyl)methanesulfonamide A58 and N-((4,4-difluoro-6 -methylpiperidin-3-yl)methyl)methanesulfonamide A59, which was immediately used in the next reaction; MS m/z: 234 (M+H) ⁺ .

[00659] Synthesis 56: tert-Butyl-((3-methylpiperazin-2-yl)methyl)(methylsulfonyl)carbamate A60.

[00660] DEAD (810 μL, 5.1 mmol) was added dropwise to a solution of PPh ₃ (2.0 g, 7.7 mmol), (3-methylpyrazin-2-yl)methanol (300 mg, 2.42 mmol ) and tert-butyl-N-methylsulfonylcarbamate (1.1 g, 5.6 mmol) in DCM (15 ml). The solution was stirred at ambient temperature for 36 hours. The resulting suspension was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge and then concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give tert-butyl ((3-methylpyrazin-2-yl)methyl)(methylsulfonyl)carbamate as a white solid (1.0 g).

[00661] tert-Butyl-((3-methylpyrazin-2-yl)methyl)(methylsulfonyl)carbamate (500 mg, 1.66 mmol) was dissolved in 3 M methanolic HCl solution (20 ml) and PtO ₂ (200 mg) was added , 0.9 mmol). The reaction mixture was shaken in ^{a Parr hydrogenator for 18 hours at 60 psi H 2} _pressure . The mixture was filtered and the catalyst was washed with methanol. The filtrate was concentrated under reduced pressure to give tert-butyl ((3-methylpiperazin-2-yl)methyl)(methylsulfonyl)carbamate A60 as an off-white solid (500 mg, 79%), which was immediately used in the next reaction without purification (assuming the formation of bis-salt with HCl); MS m/z: 308 (M+H) ⁺ .

[00662] Synthesis 57: (3S,5S)-4,4-Difluoro-3-methyl-5-[(sulfamoylamino)methyl]piperidine A61.

[00663] Benzyl-(3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (100 mg, 0.34 mmol) (see A46) and sulfonamide (81 mg, 0.84 mmol) was dissolved in 1,4-dioxane (1 ml) under N ₂ atmosphere. The reaction mixture was heated at 100°C and stirred for 16 hours. The reaction mixture was cooled and partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (×2). The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a yellow oil (147 mg); MS m/z: 378 (M+H) ⁺ .

[00664] This material was dissolved in DCM (2 mL) and DIPEA (190 μL, 1.1 mmol), then Et ₃ SiH (340 μL, 2.13 mmol) was added. The mixture was degassed with N ₂ and Pd(OAc) ₂ (32 mg, 0.14 mmol) was added under N ₂ atmosphere. After 15 min the mixture was diluted with DCM and filtered through GF/C paper. The filtrate was loaded into an ion exchange cartridge, washed with DCM, then DCM-MeOH (1:1) and the product was eluted with 2 M methanol ammonia. The filtrate was concentrated in vacuo to give (3S,5S)-4,4-difluoro-3-methyl-5-[(sulfamoylamino)methyl]piperidine A61 as a colorless glass (43 mg, 49%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 6.57 (d, 3H), 3.23 (d, 1H), 2.93-2.85 (m, 1H), 2.74-2, 66 (m, 1H), 2.25 (q, 2H), 2.08-1.80 (m, 2H), 0.89 (d, 3H); MS m/z: 244 (M+H) ⁺ .

[00665] Synthesis 58: 2-(Piperidin-3-yl)ethane-1-sulfonamide A62.

[00666] tert-Butyl-3-(2-bromoethyl)piperidine-1-carboxylate (270 mg, 0.92 mmol) was suspended in EtOH (2 ml) and water (2 ml) and Na ₂ SO ₃ (233 mg) was added , 1.85 mmol). The mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated to dryness in vacuo. The residue was taken into MeCN/water and freeze-dried to give a white powder (406 mg). This material was suspended in SOCl ₂ (2.0 ml, 27.4 mmol) in a reaction tube under N ₂ atmosphere. The reaction mixture was heated at 80°C and stirred for 16 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was treated with aqueous NH ₄ OH solution (3 ml of 30% w/v solution) at ambient temperature and NMP (2 ml) was added to solubilize the mixture. After 1 hour, the mixture was concentrated in vacuo and the resulting suspension was filtered to remove inorganic salts. The resulting clear solution in NMP of 2-(piperidin-3-yl)ethane-1-sulfonamide A62 was immediately used in the next reaction; MS m/z: 193 (M+H) ⁺ .

[00667] Synthesis 59: 2-(Morpholin-2-yl)ethane-1-sulfonamide A63.

[00668] CBr ₄ (3.05 g, 9.2 mmol) was added to a solution of tert-butyl 2-(2-hydroxyethyl)morpholine-4-carboxylate (1.42 g, 6.14 mmol), PPh, with stirring ₃ (1.53 g, 5.83 mmol) and imidazole (835 mg, 12.3 mmol) in DCM (30 ml) at 0°C under nitrogen and the reaction mixture was allowed to warm to ambient temperature over 17 h. The reaction mixture was diluted with DCM, washed with water (×2) and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-30% EtOAc-PE) to give tert-butyl 2-(2-bromoethyl)morpholine-4-carboxylate (951 mg, 55%) as a white solid; ¹ H NMR (500 MHz, chloroform-d) δ 3.88 (d, 2H), 3.88 (br s, 1H), 3.60-3.50 (m, 4H), 2.94 (s, 1H), 2.64 (s, 1H), 2.09-2.02 (m, 1H), 1.98-1.92 (m, 1H), 1.49 (s, 9H); MS m/z: 194 (M-Boc) ⁺ .

[00669] tert-Butyl-2-(2-bromoethyl)morpholine-4-carboxylate (250 mg, 0.85 mmol) was suspended in EtOH (2 ml) and water (2 ml) and Na ₂ SO ₃ (214 mg) was added , 1.70 mmol). The mixture was stirred at reflux for 16 hours. The reaction mixture was concentrated to dryness and the residue was taken up in MeCN/water and freeze-dried to give a white powder (330 mg) which was used in the next reaction without further purification. The material was suspended in SOCl ₂ (2 ml, 27.4 mmol) under N ₂ atmosphere. The mixture was heated at 80°C and stirred for 16 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was treated with aqueous NH ₄ OH (3 ml 30% w/v) at ambient temperature. NMP (2 ml) was added to solubilize the mixture. After 1 hour, the mixture was concentrated in vacuo to remove the aqueous ammonia solution and the resulting suspension was filtered to remove inorganic salts. The resulting clear solution in NMP 2-(morpholin-2-yl)ethane-1-sulfonamide A63 was immediately used in the next reaction; MS m/z: 195 (M+H) ⁺ .

[00670] Synthesis 60: tert-Butyl-((5,5-difluoro-2-methylpiperidin-3-yl)methyl)(methylsulfonyl)carbamate A64.

[00671] A mixture of ethyl 5-hydroxy-2-methylpyridine-3-carboxylate (500 mg, 2.8 mmol) and PtO ₂ (300 mg, 1.3 mmol) in 3 M methanolic HCl solution (30 ml, 90 mmol ) was shaken in ^a Parr hydrogenator for 18 hours at 60 psi H ₂ pressure. The reaction mixture was filtered and the filtrate concentrated in vacuo to give ethyl 5-hydroxy-2-methylpiperidine-3-carboxylate hydrochloride as a yellow oil (800 mg), which was immediately used in the next step.

[00672] Benzyl chloroformate (1.9 mL, 13.1 mmol) was added to a suspension of ethyl 5-hydroxy-2-methylpiperidine-3-carboxylate hydrochloride (2.5 g, 11.2 mmol) and potassium carbonate (15 g, 109 mmol) in EtOAc (50 ml) and water (25 ml). The reaction mixture was stirred vigorously for 18 hours at ambient temperature. The organic phase was separated and collected, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with water, dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give 1-benzyl-3-ethyl-5-hydroxy-2-methylpiperidine-1,3-dicarboxylate as a colorless oil (270 mg), which was immediately used in the next step without further purification; MS m/z: 322 (M+H)⁺.

[00673] Dess-Martin periodinane (360 mg, 0.85 mmol) was added to an ice-cold solution of 1-benzyl-3-ethyl-5-hydroxy-2-methylpiperidine-1,3-dicarboxylate (270 mg, 0.84 mmol ) in DCM (5 ml) under N ₂ atmosphere. After 5 minutes, the cooling bath was removed and the mixture was stirred at ambient temperature for 24 hours. The resulting suspension was diluted with DCM, saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ S ₂ O ₃ . After stirring for 30 minutes, the organic phase was isolated using a phase separation cartridge and the filtrate was concentrated under reduced pressure to give a yellow oil. This material was treated with DAST (1.2 ml, 9.1 mmol) and the resulting solution was stirred at ambient temperature for 4 hours. The solution was carefully poured into a mixture of DCM, ice, water and NaHCO ₃ while stirring. After stirring for 10 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, 0-60% EtOAc-PE gradient elution) to give a colorless oil (110 mg), which was used in the next step without further purification; MS m/z: 342 (M+H) ⁺ .

[00674] Lithium borohydride (200 μl of 2 M, 0.40 mmol) was added to an ice-cold solution of 1-benzyl-3-ethyl-5,5-difluoro-2-methylpiperidine-1,3-dicarboxylate (110 mg, 0. 32 mmol) in THF (4 ml) under N ₂ atmosphere. The solution was stirred for 18 hours with the temperature raised to ambient temperature. The reaction was stopped with a saturated aqueous solution of NaHCO ₃ . DCM was added to the mixture and the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated under reduced pressure to give a brown oil (100 mg), which was immediately used in the next reaction without further purification; MS m/z: 300 (M+H) ⁺ .

[00675] DEAD (100 μL, 0.6351 mmol) was added to an ice-cold solution of benzyl 5,5-difluoro-3-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (100 mg, 0.33 mmol), PPh ₃ (250 mg, 0.95 mmol) and tert-butyl-N-methylsulfonylcarbamate (130 mg, 0.67 mmol) in DCM (4 ml) under N ₂ atmosphere. The reaction mixture was stirred at ambient temperature for 20 hours. The resulting suspension was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give a colorless oil (120 mg). This substance was transferred into DCM (5 ml) and Pd(OAc) ₂ (25 mg, 0.11 mmol), Et ₃ SiH (100 μl, 0.63 mmol) and Et ₃ N (70 μl, 0.50 mmol) added. The mixture was stirred at ambient temperature for 1 hour, then diluted with MeOH. The solution was poured into a pre-wetted ion exchange cartridge, washed with methanol, then the product was eluted with a 2 M methanol solution of NH ₃ . The filtrate was concentrated to give tert-butyl-((5,5-difluoro-2-methylpiperidin-3-yl)methyl)(methylsulfonyl)carbamate A64 as a brown oil (70 mg), which was used in the next reaction without further purification; MS m/z: 343 (M+H) ⁺ .

[00676] Synthesis 61: ((2S)-3-Methylmorpholin-2-yl)methanol A65 and C-3 epimer A66.

[00677] 1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]ethanone (2.4 g, 16.7 mmol) was dissolved in DCE (132 ml). Acetic acid (5.2 mL, 91.6 mmol) and benzylamine (10.0 mL, 91.6 mmol) were added and the reaction mixture was stirred for 30 min at ambient temperature, then cooled to 0°C. Sodium triacetoxyborohydride (14.1 g, 66.6 mmol) was added portionwise over 25 minutes. The reaction mixture was stirred for 16 hours with the temperature raised to ambient temperature. Saturated aqueous NaHCO ₃ solution was added and the mixture was extracted with DCM (×2). The combined organics were washed with NaHCO ₃ solution, dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography (silica, 20-80% EtOAc-PE gradient elution). Two diastereoisomers were isolated in a ratio of ~2:1: (minor) diastereoisomer 1 (800 mg); ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.41-7.21 (m, 5H), 4.85 (s, 2H), 4.05 (dd, 1H), 3.98-3, 88 (m, 2H), 3.72 (d, 1H), 3.66 (dd, 1H), 2.71 (dq, 1H), 1.33 (d, 6H), 1.03 (d, 3H ); (major) diastereoisomer 2 (2.9 g, containing 1 eq. BnNH ₂ ); ¹ H NMR (400 MHz, methanol- _d4 ) δ 7.44-7.20 (m, 10H, 5H from _BnNH2 ), 4.09-4.01 (m, 2H), 3.88 (d, 1H), 3.82-3.77 (m, 1H), 3.76-3.70 (m, 3H, 2H from BnNH ₂ ), 2.89-2.70 (m, 1H), 1.38 (s, 3H), 1.33 (d, 3H), 1.12 (d, 3H).

[00678] Diastereoisomer 1 (100 mg, 0.42 mmol) was dissolved in DCM (4 ml) under N ₂ atmosphere. Et ₃ N (150 μl, 1.1 mmol) was added and the mixture was cooled in an ice bath. 2-bromoacetyl bromide (75 μl, 0.85 mmol) was added and the reaction mixture was allowed to warm to ambient temperature. After 45 min, the reaction mixture was diluted with DCM and washed with water (×2). The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo to give a brown oil (110 mg), which was used in the next step without further purification; MS m/z: 357 (M+H) ⁺ .

[00679] 4-Methylbenzenesulfonic acid hydrate (150 μL, 0.84 mmol) was added to a solution of N-benzyl-2-bromo-N-[1-[(4S)-2,2-dimethyl-1,3-dioxolane- 4-yl]ethyl]acetamide (600 mg, 1.68 mmol) in MeOH (6 ml) and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed with saturated aqueous solution NaHCO ₃ (×2). The aqueous phase was extracted with EtOAc (×3). The combined organic phases were dried (MgSO ₄ ), filtered and concentrated in vacuo to give an oil (530 mg), which was immediately used in the next step; MS m/z: 317 (M+H) ⁺ .

[00680] NaH (100 mg, 4.2 mmol) was added to a solution of N-benzyl-2-bromo-N-[(2S)-2,3-dihydroxy-1-methylpropyl]acetamide (530 mg, 1.68 mmol ) in THF (11 ml) and the reaction mixture was stirred at ambient temperature for 100 min. The reaction was stopped by slowly adding water and the mixture was extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo. The residue (200 mg) was immediately used in the next reaction; MS m/z: 236 (M+H) ⁺ .

[00681] BH ₃ .THF (4.25 ml of 1 M, 4.25 mmol) was added to a solution of (6S)-4-benzyl-6-(hydroxymethyl)-5-methylmorpholin-3-one (200 mg, 0. 85 mmol) in THF (3 ml) with stirring at 0°C under N ₂ atmosphere. After addition was complete, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 40 minutes. The reaction mixture was cooled in an ice bath and MeOH was added until gas evolution ceased. The reaction mixture was concentrated and the residue was taken up in MeOH and passed through an ion exchange cartridge, washed with MeOH and the product eluted with methanolic ammonia. The filtrate was concentrated in vacuo to give an oil (140 mg), which was immediately used in the next step; ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 7.45-7.17 (m, 5H), 4.15 (d, 1H), 3.80 (ddd, 1H), 3.74 (dd, 1H), 3.67 (dd, 1H), 3.65-3.57 (m, 1H), 3.33 (p, 1H), 3.25 (ddd, 1H), 3.20 (d, 1H ), 2.61 (dt, 1H), 2.39 (dq, 1H), 2.25 (td, 1H), 1.24 (d, 3H).

[00682] A mixture of [(2S)-4-benzyl-3-methylmorpholin-2-yl]methanol (140 mg, 0.63 mmol), Pd at C, wet, Degussa 10% w/w. (30 mg, 0.29 mmol) and 3 M methanolic HCl solution (6 ml) were placed under a hydrogen atmosphere and stirred at ambient temperature for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness in vacuo. The residue, ((2S)-3-methylmorpholin-2-yl)methanol A65 (103 mg) was used in the following reaction without purification or investigation, assuming that the salt was isolated with HCl in quantitative yield.

[00683] Epimer A66 was prepared from the main product of the reductive amination reaction (diastereoisomer 2) in the same manner as described above and used in the following reaction without purification, assuming the salt was isolated with HCl in quantitative yield; ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 4.14 (ddd, 1H), 3.91-3.77 (m, 2H), 3.70-3.61 (m, 2H), 3, 53 (dd, 1H), 3.37 (s, 1H), 3.12 (dt, 1H), 1.39 (d, 3H).

[00684] Synthesis 62: (2,5-Dioxa-8-azaspiro[3.5]nonan-6-yl)methanol A67.

[00685] A mixture of 3-(aminomethyl)oxetan-3-ol (1.0 g, 9.7 mmol), benzaldehyde (1.2 mL, 11.8 mmol) and ground 4 Å MS (1 g) in DCE ( 30 ml) was stirred at ambient temperature for 1.5 hours. NaBH(OAc) ₃ (4.1 g, 19.4 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 19 hours. The mixture was filtered through celite (wash with DCM) and the filtrate was concentrated in vacuo. The residue was passed through an ion exchange cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2 M NH ₃ in MeOH/DCM mixtures. The filtrates were concentrated in vacuo and the residue was purified by column chromatography (silica, 0-5% (10% NH ₄ OH in MeOH)/DCM gradient elution) to give 3-[(benzylamino)methyl]oxetane-3- ol (1.02 g, 55%) as a pale yellow oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.30-7.20 (m, 5H), 4.59-4.58 (m, 2H), 4.36-4.34 (m, 2H) , 3.77 (s, 2H), 2.99 (s, 2H); MS m/z: 194 (M+H) ⁺ .

[00686] A solution of 3-[(benzylamino)methyl]oxetan-3-ol (1.02 g, 5.28 mmol) in toluene (15 ml) was treated with 2-(chloromethyl)oxirane (540 μl, 6.90 mmol) and lithium perchlorate (730 mg, 6.86 mmol) and the mixture was stirred at ambient temperature for 17 hours. The mixture was diluted with EtOAc and washed with water (×2). The combined aqueous layers were extracted with EtOAc (×2) and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in MeOH (5 ml), sodium methoxide (715 mg, 13.2 mmol) was added and the reaction mixture was refluxed for 23 hours. The reaction mixture was cooled to ambient temperature and the reaction was stopped by adding saturated aqueous NH ₄ solution Cl. The aqueous layer was diluted with water to dissolve the salts and extracted with EtOAc (×3) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give (8-benzyl-2,5-dioxa-8-azaspiro[3.5]nonan-6-yl)methanol ( 381 mg, 29%) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.37-7.31 (m, 4H), 7.29-7.26 (m, 1H), 4.68 (t, 1H), 4, 50 (dd, 1H), 4.37 (d, 1H), 4.33 (d, 1H), 4.23 (d, 1H), 3.53 (q, 1H), 3.48-3.41 (m, 1H), 3.35-3.28 (m, 2H), 3.05 (dd, 1H), 2.73 (dt, 1H), 2.02 (dd, 1H), 1.81 ( dd, 1H); MS m/z: 251 (M+H) ⁺ .

[00687] Mixture of (8-benzyl-2,5-dioxa-8-azaspiro[3.5]nonan-6-yl)methanol (380 mg, 1.52 mmol), Pd at C, wet, Degussa 10% wt./ wt. (60 mg, 0.56 mmol) and 3 M methanolic HCl solution (15 ml, 45 mmol) were placed under a hydrogen atmosphere and stirred at ambient temperature for 3 hours. The catalyst was removed by filtration through celite, washed with MeOH and the filtrate was concentrated. in a vacuum. The residue was passed through an ion exchange cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2 M NH ₃ in MeOH/DCM mixtures and the solvent was removed in vacuo to give 2,5-dioxa-8-azaspiro[3.5]nonan-6-ylmethanol A67 (243 mg, 100%) as colorless oil; MS m/z: 160 (M+H) ⁺ .

[00688] Synthesis 63: (4-Oxa-7-azaspiro[2.5]octan-5-yl)methanol A68.

[00689] Using the same procedure as used above for A67, (4-oxa-7-azaspiro[2.5]octan-5-yl)methanol A68 was prepared using 1-(aminomethyl)cyclopropanol instead of 3-(aminomethyl)oxetane- 3-ola; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.53-4.51 (m, 1H), 3.48-3.43 (m, 1H), 3.32-3.23 (m, 2H ), 3.03 (dd, 1H), 2.86 (ddd, 1H), 2.39 (dd, 1H), 2.16 (d, 1H), 0.69-0.65 (m, 1H) , 0.54-0.39 (m, 3H); MS m/z: 144 (M+H) ⁺ .

[00690] Synthesis 64: Mixture of N-((4-hydroxy-4,6-dimethylpiperidin-3-yl)methyl)methanesulfonamide A69 and N-((4-hydroxy-2,4-dimethylpiperidin-3-yl)methyl) methanesulfonamide A70.

[00691] LiHMDS (10 mL of 1 M solution, 10 mmol) was added dropwise to a solution of benzyl 2-methyl-4-oxopiperidine-1-carboxylate (2.0 g, 8.1 mmol) in THF (40 mL), cooled to -78°C in N atmosphere₂. After 50 min, a solution of 2-(chloromethyl)isoindoline-1,3-dione (2.1 g, 10.7 mmol) in THF (~30 ml) was added to the reaction mixture over 5 min. The solution was stirred for 2 hours, then the reaction was stopped with a saturated aqueous solution of NH₄Cl. The reaction mixture was warmed to ambient temperature, diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give a mixture of regioisomers (above) (1.7 g); MS m/z: 407 (M+H)⁺. This substance was dissolved in toluene (15 ml) and ethylene glycol (330 μl, 5.92 mmol) and 4-methylbenzenesulfonic acid hydrate (20 mg, 0.11 mmol) were added. The mixture was refluxed for 18 hours and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give a colorless oil (480 mg); MS m/z: 451 (M+H)⁺. This substance was dissolved in ethanol (7 ml) and hydrazine hydrate (250 µl 50% w/v, 2.5 mmol) was added. The mixture was refluxed for 2 hours and then cooled to ambient temperature. The resulting suspension was filtered and the filtrate was concentrated in vacuo to give a white solid. The residue was dissolved in DCM (5 ml) and Et was added₃N (200 µl, 1.44 mmol) under N atmosphere₂. The solution was cooled in an ice bath and methanesulfonyl chloride (100 μL, 1.29 mmol) was added. After 5 minutes, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 18 hours. The resulting suspension was diluted with DCM and saturated aqueous NaHCO₃. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give a gum (240 mg); MS m/z: 399 (M+H)⁺. This substance was dissolved in THF (4 ml) and treated with aqueous HCl solution (1.5 ml of 2 M solution, 3.0 mmol). The mixture was refluxed for 18 hours and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc, then washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give a colorless gum (120 mg); MS m/z: 355 (M+H)⁺. This substance was dissolved in THF (3 ml) under N atmosphere₂ and the solution was cooled in an ice bath. MeMgBr was added (300 µl of 3 M solution in Et₂O, 0.90 mmol) and the reaction mixture was stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride, then diluted with EtOAc. The organic phase was washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo to give a colorless oil. The residue was transferred to DCM (3 ml). Et was sequentially added to the reaction mixture₃N (100 µl, 0.72 mmol), Et₃SiH (100 µl, 0.63 mmol) and Pd(OAc)₂ (76 mg, 0.34 mmol). After stirring at ambient temperature for 90 min, the solution was loaded into the SCX-2 cartridge. The cartridge was washed with MeOH/DCM mixtures, then the product was eluted with 2 M methanolic ammonia solution. The filtrate was concentrated in vacuo to obtain a mixture of N-((4-hydroxy-4,6-dimethylpiperidin-3-yl)methyl)methanesulfonamide A69 and N-((4-hydroxy-2,4-dimethylpiperidin-3-yl)methyl) methanesulfonamide A70 (70 mg); MS m/z: 237 (M+H)⁺; which was used in the following reaction without further purification or testing.

[00692] Synthesis 65: Imino(methyl)(piperidin-3-ylmethyl)-λ6-sulfanone A71.

[00693] A mixture of tert-butyl-3-(chloromethyl)piperidine-1-carboxylate (500 mg, 2.14 mmol), NaSMe (3 mL 20% w/v, 8.56 mmol) and 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.

[00694] mCPBA (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 N ₂ . The reaction mixture was stirred for 20 hours with the temperature raised to ambient temperature. The reaction mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo to give a pale brown oil (460 mg), which was used in the next step without further purification or testing; MS m/z: 262 (M+H) ⁺ .

[00695] 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 N ₂ atmosphere. Rh ₂ (OAc) ₄ (0.9 g, 2.0 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was filtered through celite, washed with MeOH and DCM. The filtrate was concentrated in vacuo and the residue was taken up in MeOH (5 ml) and MeCN/water (3:1) (5 ml) was added. K ₂ CO ₃ (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 (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give tert-butyl 3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (5.96 g, 103%) as an amber oil, which used immediately in the next reaction; MS m/z: 277 (M+H) ⁺ .

[00696] 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 ambient temperature for 16 hours. The reaction mixture was concentrated in vacuo, then dissolved in MeOH and loaded into an ion exchange cartridge. The cartridge was washed with a MeOH/DCM mixture, then the product was washed with a methanolic ammonia solution. The filtrate was concentrated in vacuo to give imino(methyl)(piperidin-3-ylmethyl)-λ6-sulfanone A71, (250 mg, 65%); ¹ H NMR (500 MHz, MeOH-d ₄ ) 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).

[00697] Synthesis 66: 1,1,1-Trifluoro-N-(piperidin-3-ylmethyl)methanesulfonamide A72.

[00698] Trifluoromethylsulfonyltrifluoromethanesulfonate (1.1 ml of 1 M in DCM, 1.1 mmol) was added to a solution of tert-butyl-3-(aminomethyl)piperidine-1-carboxylate (200 mg, 0.93 mmol) and DIPEA (490 μl , 2.80 mmol) in DCM (5 ml) while cooling in an ice bath. The reaction mixture was stirred for 16 hours at ambient temperature, then concentrated in vacuo and the residue partitioned between DCM and saturated aqueous sodium bicarbonate. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in DCM (5 ml) and TFA (1.4 ml, 18.7 mmol) was added. After stirring at ambient temperature for 1 hour, the reaction mixture was concentrated in vacuo to give a yellow oil. The residue was taken up in MeOH and loaded into an ion exchange cartridge. The cartridge was washed with MeOH/DCM mixtures, then the product was eluted with 2 M methanolic ammonia solution. The filtrate was concentrated in vacuo to give 1,1,1-trifluoro-N-(piperidin-3-ylmethyl)methanesulfonamide A72 as a yellow oil that solidified on standing (230 mg, quantitative yield); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 3.48-3.37 (m, 1H), 3.33 (p, 2H), 3.30 (d, 1H), 3.15 (dd, 1H), 3.04 (dd, 1H), 2.86 (td, 1H), 2.64 (t, 1H), 2.00-1.82 (m, 3H), 1.79-1.62 (m, 1H), 1.38-1.21 (m, 1H).

[00699] Synthesis 67: N-((5,5-Difluoro-4-methylpiperidin-3-yl)methyl)methanesulfonamide A73.

[00700] Add tert-butylchlorodimethylsilane:imidazole (3.95 g, 18.1 mmol) in DMF (40 ml). The mixture was stirred at ambient temperature. After 2 hours, TBSCl (2.72 g, 18.1 mmol) was added and the mixture was stirred for another 2 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give O1-benzyl-O3-methyl-5-[tert-butyl(dimethyl)silyl]oxypiperidine-1,3-dicarboxylate (7.36 g , quantitative yield) as an amber oil, which was immediately used in the next reaction; MS m/z: 408 (M+H) ⁺ .

[00701] A solution of O1-Benzyl-O3-methyl-5-[tert-butyl(dimethyl)silyl]oxypiperidine-1,3-dicarboxylate (7.36 g, 18.1 mmol) in THF (50 ml) and MeOH ( 5 ml) was treated with NaBH ₄ (2.05 g, 54.2 mmol) under N ₂ atmosphere. After 2 hours NaBH ₄ (680 mg, 18.1 mmol) was added and after a further 2 hours the reaction was stopped by adding water (2 ml) and diluted with EtOAc. The mixture was washed with saturated aqueous sodium bicarbonate (×2), then with brine. The organic phase was separated, dried (Na ₂ SO ₄ ), filtered and concentrated to give benzyl 3-[tert-butyl(dimethyl)silyl]oxy-5-(hydroxymethyl)piperidine-1-carboxylate (6.86 g) which used immediately in the next reaction without further purification, assuming quantitative yield; MS m/z: 380 (M+H) ⁺ .

[00702] A solution of benzyl 3-[tert-butyl(dimethyl)silyl]oxy-5-(hydroxymethyl)piperidine-1-carboxylate (6.86 g, 18.1 mmol) and Et ₃ N (7.6 ml, 54.4 mmol) in DCM (15 ml) under N ₂ and cooled to 0°C in an ice bath. Methanesulfonyl chloride (1.5 mL, 20.0 mmol) was added dropwise. After 20 minutes, the mixture was diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give an oil (9 g), which was immediately used in the next reaction, assuming quantitative yield; MS m/z: 458 (M+H) ⁺ .

[00703] A mixture of potassium phthalimide (2.86 g, 15.5 mmol) and benzyl 3-[tert-butyl(dimethyl)silyl]oxy-5-(methylsulfonyloxymethyl)piperidine-1-carboxylate (7.86 g, 17 .2 mmol) in DMF (63 ml) was heated at 110°C. After stirring for 3 hours, the reaction mixture was allowed to cool to ambient temperature and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was separated and washed with brine (×2), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a light yellow solid, which was dissolved in MeOH (20 ml) and treated with concentrated HCl (2.5 ml 37% w/v, 25.8 mmol). The mixture was stirred for 2 hours, then concentrated in vacuo. The residue was suspended in DCM and filtered. The filtrate was purified by column chromatography (silica, 15-90% EtOAc-PE gradient elution) to give benzyl-3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-hydroxypiperidin-1- carboxylate (1.86 g, 27%); MS m/z: 395 (M+H) ⁺ .

[00704] A solution of benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-hydroxypiperidine-1-carboxylate (1.86 g, 4.71 mmol) in DCM (20 ml) under N atmosphere ₂ was treated with Dess-Martin periodinane (7.0 g, 16.5 mmol). The mixture was stirred at ambient temperature under a nitrogen atmosphere. After 2 hours, additional Dess-Martin periodinane (2.0 g, 4.71 mmol) was added and the mixture was stirred for 5 hours. The reaction was stopped by adding a 1:1 mixture of saturated aqueous sodium bicarbonate/saturated aqueous sodium thiosulfate (20 ml ). The organic layer was separated, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was taken up in THF (20 ml) under N ₂ atmosphere. The solution was cooled to -78°C and LiHMDS (6.6 ml of 1 M solution in THF, 6.6 mmol) was added. After 15 min, MeI (290 μl, 4.7 mmol) was added. After addition was complete, the cooling bath was removed and the reaction mixture was stirred for 3 hours at ambient temperature. The reaction mixture was partitioned between EtOAc and saturated aqueous ammonium chloride. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-50% EtOAc-PE gradient elution) to give benzyl-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4-methyl-5- oxopiperidine-1-carboxylate (300 mg, 16%); MS m/z: 407 (M+H) ⁺ .

[00705] Benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4-methyl-5-oxopiperidine-1-carboxylate (300 mg, 0.74 mmol) was dissolved in DCM (10 ml) in atmosphere N ₂ . The solution was cooled to -78°C and DAST (195 μl, 1.48 mmol) was added. The mixture was allowed to warm to ambient temperature. After stirring for 1 hour, DAST (195 μL, 1.476 mmol) was added and after another 2 hours, another portion of DAST (195 μL, 1.48 mmol) was added. After another 2 hours, additional DAST (293 μL, 2.22 mmol) was added and another portion of DAST (586 μL, 4.44 mmol) was added after another 3 hours. The mixture was stirred for 16 hours, then slowly added to the ice mixture and saturated aqueous sodium bicarbonate solution. The mixture was extracted with EtOAc. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-50% EtOAc-petroleum ether gradient elution) to give benzyl 5-[(1,3-dioxoisoindolin-2-yl)methyl]-3,3-difluoro -4-methylpiperidine-1-carboxylate (259 mg); MS m/z: 429 (M+H) ⁺ .

[00706] Benzyl 5-[(1,3-dioxoisoindolin-2-yl)methyl]-3,3-difluoro-4-methylpiperidine-1-carboxylate (259 mg, 0.60 mmol) in EtOH (10 ml) treated with hydrazine hydrate (60 μl, 1.2 mmol) and the mixture was refluxed for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with EtOAc and the combined organic extracts were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in DCM (15 ml) and Et ₃ N (253 μl, 1.81 mmol), then methanesulfonyl chloride (70 μl, 0.91 mmol) was added. The solution was stirred at ambient temperature for 1 hour, then the reaction was stopped by adding saturated aqueous sodium bicarbonate. The mixture was extracted with DCM (×2). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the desired product (206 mg); MS m/z: 377 (M+H) ⁺ . The residue was dissolved in MeOH (1.6 ml) and EtOAc (2.4 ml). Pd(OH) ₂ (38 mg 20% w/w, 0.05 mmol) was added and the mixture was degassed (×3 cycles vacuum - N ₂ ). N ₂ was replaced with H ₂ (×3 cycles) and the mixture was stirred at ambient temperature. After 72 h, the reaction mixture was filtered through Celite, eluting with MeOH. The filtrate was concentrated in vacuo to give N-((5,5-difluoro-4-methylpiperidin-3-yl)methyl)methanesulfonamide A73 (127 mg), which was used in the next step without further purification; MS m/z: 243 (M+H) ⁺ .

[00707] Synthesis 68: N-((2-Ethylpiperidin-3-yl)methyl)methanesulfonamide A74.

[00708] LiAlH₄ (9.0 ml of 1 M solution in THF, 9.0 mmol) was added dropwise to a suspension of 2-ethylpyridine-3-carboxylic acid (500 mg, 3.31 mmol) in THF (5 ml) under N atmosphere₂when cooling in an ice bath. The resulting solution was stirred for 1 hour, then the reaction was stopped by carefully adding water (0.35 ml), then NaOH aqueous solution (0.25 ml of a 15% w/v solution), then water (1 ml). After stirring for 10 minutes, the mixture was filtered and the filtrate was concentrated in vacuo to give a colorless oil (250 mg); MS m/z: 138 (M+H)⁺. This material was dissolved in DCM (10 ml) and tert-butyl-N-methylsulfonylcarbamate (630 mg, 3.23 mmol) and PPh were added₃ (950 mg, 3.62 mmol), then DEAD (500 μl, 3.04 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, then partitioned between EtOAc and saturated aqueous sodium bicarbonate. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The solvent was removed in vacuo and the residue was purified by column chromatography (silica, eluting with DCM-EtOAc) to give an oil, which was taken up in HCl (10 ml of 3 M in MeOH). PtO₂ (150 mg, 0.66 mmol) was added and the mixture was shaken in a Parr hydrogenator for 18 hours at pressure H₂60 lbf/in². The reaction mixture was poured into a pre-wetted ion exchange cartridge, washed with MeOH, then the product was eluted with 2 M methanolic NH solution₃. The filtrate was concentrated in vacuo to give N-((2-ethylpiperidin-3-yl)methyl)methanesulfonamide A74 as a colorless oil (70 mg), which was immediately used in the next reaction without further purification; MS m/z: 221 (M+H)⁺.

[00709] Synthesis 69: N-((5-Methylpiperidin-3-yl)methyl)methanesulfonamide A75.

[00710] Methanesulfonyl chloride (700 μL, 9.00 mmol) was added to a solution of (5-methyl-3-pyridyl)methanamine (1.0 g, 8.2 mmol) and triethylamine (1.25 mL, 9.0 mmol) in DCM (33 ml) at ambient temperature. After stirring for 1 hour, the reaction mixture was diluted in DCM (30 volumes) and washed with saturated aqueous NaHCO ₃ solution (2 x 50 volumes). The organic layer was dried (MgSO ₄ ), filtered and evaporated in vacuo to give N-((5-methylpyridin-3-yl)methyl)methanesulfonamide as a white solid, (1.5 g, 92%); ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.41-8.35 (m, 1H), 8.34-8.28 (m, 1H), 7.72 (d, 1H), 4, 29 (s, 2H), 2.95 (s, 3H), 2.39 (s, 3H).

[00711] N-((5-Methylpyridin-3-yl)methyl)methanesulfonamide (1.5 g, 7.49 mmol) was dissolved in MeOH (74 ml). HCl (37.5 mL of 3 M solution in MeOH, 112 mmol) and PtO ₂ (225 mg, 0.99 mmol) were added and the reaction mixture was shaken in a Parr hydrogenator at ⁶⁰ psi hydrogen pressure for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was taken up in MeOH and loaded into an ion exchange cartridge, washed with DCM/MeOH mixtures, then the product was eluted with 2 M methanol ammonia. The filtrate was concentrated to give N-((5-methylpiperidin-3-yl)methyl)methanesulfonamide A75 as a white solid (200 mg, 13%) as a mixture of diastereoisomers, which was used in the next reaction without further purification; MS m/z: 207 (M+H) ⁺ .

[00712] Synthesis 70: tert-Butyl-((6-methylpiperazin-2-yl)methyl)(methylsulfonyl)carbamate A76.

[00713] DEAD (1.7 mL, 10.8 mmol) was added dropwise to a solution of PPh ₃ (4.0 g, 15.3 mmol), (6-methylpyrazin-2-yl)methanol (630 mg, 5. 08 mmol) and tert-butyl-N-methylsulfonylcarbamate (2.3 g, 11.8 mmol) in DCM (30 ml). The solution was stirred at ambient temperature for 18 hours. The resulting suspension was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give a white solid (2.2 g). This substance was dissolved in methanolic HCl solution (40 ml of 3 M solution, 120 mmol) and PtO ₂ (200 mg, 0.88 mmol) was added. The reaction mixture was stirred under H ₂ for 18 hours. The reaction mixture was directly loaded into a pre-wetted ion exchange cartridge, washed with methanol, then the product was eluted with 2 M methanol ammonia. The filtrate was concentrated in vacuo to give tert-butyl ((6-methylpiperazin-2-yl)methyl)(methylsulfonyl)carbamate A76 as a white solid (1.0 g, 45%), which was used in the next reaction without further purification ; MS m/z: 308 (M+H) ⁺ .

[00714] Synthesis 71: (2-Methylpiperidin-3-yl)methanesulfonamide A77.

[00715] Benzyl 3-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (537 mg, 2.04 mmol) was dissolved in DCM (10 ml) under N ₂ and CBr ₄ (1.15 g, 3. 47 mmol). The solution was cooled in an ice bath and PPh ₃ (910 mg, 3.47 mmol) was added in two portions. The reaction mixture was stirred overnight at ambient temperature, then concentrated in vacuo. The residue was treated with EtOAc (~100 ml) and the resulting white solid was filtered. The filtrate was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was taken up in DCM and purified by column chromatography (silica, 0-5% MeOH-DCM gradient elution) to give the product as a colorless oil (412 mg, 62%); MS m/z: 326 (M+H) ⁺ . The substance was used without additional research.

[00716] Benzyl 3-(bromomethyl)-2-methylpiperidine-1-carboxylate (412 mg, 1.26 mmol) was suspended in EtOH (5 ml) and water (5 ml) and Na ₂ SO ₃ (478 mg, 3.79 mmol). The reaction mixture was heated at 80°C for 16 hours. Additional Na ₂ SO ₃ (500 mg) was added and the temperature was raised to 100°C. After 2 hours, a final portion of Na ₂ SO ₃ (500 mg) was added along with EtOH (5 ml) and water (5 ml). The reaction mixture was stirred overnight, then cooled to ambient temperature and concentrated in vacuo. The resulting cloudy solution was acidified to ~pH 1 by adding a 2 M aqueous HCl solution, then concentrated to dryness in vacuo. The resulting white solid was triturated with MeOH, the fine precipitate was filtered through GF/C paper and the clear filtrate was concentrated to dryness in vacuo. The resulting white solid was triturated with EtOH. The ethanol suspension was filtered and concentrated as above to give a white solid (585 mg) which was immediately used in the next reaction assuming quantitative yield; MS m/z: 328 (M+H) ⁺ .

[00717](1-Benzyloxycarbonyl-2-methyl-3-piperidyl)methanesulfonic acid (413 mg, 1.26 mmol) was dissolved in SOCl ₂ (5 ml) and the mixture was heated at 80°C for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was cooled in an ice bath and an aqueous solution of NH ₄ OH (10 ml 30% w/v) was added. The cooling bath was removed and the resulting cloudy solution was stirred vigorously at ambient temperature for 3 hours. The reaction mixture was partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc (×2). The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The product was obtained as a waxy solid (137 mg, 33% in two steps), which was immediately used in the next reaction without further purification; MS m/z: 327 (M+H) ⁺ .

[00718] Benzyl 2-methyl-3-(sulfamoylmethyl)piperidine-1-carboxylate (137 mg, 0.42 mmol) was dissolved in DCM (5 ml) and DIPEA (220 μl, 1.26 mmol) was added. The mixture was degassed (×2 cycles of vacuum - N ₂ ) and Pd(OAc) ₂ (38 mg, 0.17 mmol) was added. The mixture was degassed (×2 cycles) and Et ₃ SiH (400 μl, 2.52 mmol) was added at ambient temperature. After stirring for 20 min, the reaction mixture was diluted with DCM and filtered through GF/C paper. The filtrate was concentrated in vacuo and the residue was taken up in MeOH and loaded into an ion exchange cartridge. The cartridge was washed sequentially with DCM, 1:1 DCM-MeOH and MeOH. The filtrates were discarded and the product was eluted with 2 M methanol ammonia. The filtrate was concentrated in vacuo to give (2-methylpiperidin-3-yl)methanesulfonamide A77 as a gummy (52 mg, 64%), which was used in the next step without further purification; MS m/z: 193 (M+H) ⁺ .

[00719] Synthesis 72: N-((3,6-Dimethylpiperazin-2-yl)methyl)methanesulfonamide A78.

[00720] NaBH ₄ (1.2 g, 31.5 mmol) was added to a solution of methyl 3,6-dimethylpyrazine-2-carboxylate (1.0 g, 6.0 mmol) in water (10 ml) while cooling in ice bath. After 5 min, the ice bath was removed and the solution was stirred at ambient temperature for 1 h. Saturated aqueous K ₂ CO ₃ solution (20 mL) was added and ethanol (10 mL) was added and the mixture was stirred for another 2 h, then extracted with using EtOAc (×2). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give an orange oil (470 mg, 56%), which was immediately used in the next reaction; MS m/z: 139 (M+H) ⁺ .

[00721] Methanesulfonyl chloride (350 μL, 4.52 mmol) was added to an ice-cold solution of (3,6-dimethylpyrazin-2-yl)methanol (470 mg, 3.40 mmol) and Et ₃ N (700 μL, 5.02 mmol) in DCM (7 ml) under N ₂ atmosphere. After 5 minutes, the ice bath was removed and the solution was stirred at ambient temperature for 2 hours. The resulting suspension was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated under reduced pressure to give a yellow oil, which was taken up in DMF (7 ml). Potassium carbonate (1.5 g, 10.9 mmol) and methanesulfonamide (800 mg, 8.41 mmol) were added and the reaction mixture was stirred at 80°C for 18 hours under N ₂ atmosphere. The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 5-100% (EtOAc/MeOH/Et ₃ N 90-10-1)-petroleum ether gradient elution) to give a yellow oil, which was taken up in methanolic HCl (10 ml 3 M solution, 30 mmol). PtO ₂ (150 mg, 0.66 mmol) was added and the reaction mixture was stirred under H ₂ for 18 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give N-((3,6-dimethylpiperazin-2-yl )methyl)methanesulfonamide A78 as a yellow resinous substance (460 mg), which was used in the following reaction without further purification, assuming that the bis-salt was isolated with HCl in quantitative yield; MS m/z: 222 (M+H) ⁺ .

[00722] Synthesis 73: N-((5-(3-Fluoroazetidin-1-yl)piperidin-3-yl)methyl)methanesulfonamide A79.

[00723] 3-Fluoroazetidin hydrochloride (739 mg, 6.63 mmol) was dissolved in MeOH (10 ml) and DIPEA (1.21 ml, 6.96 mmol) was added under N ₂ atmosphere. The solution was stirred for 10 min, then a solution of O1-tert-butyl-O3-ethyl-5-oxopiperidine-1,3-dicarboxylate (899 mg, 3.31 mmol) in MeOH (10 ml) was added. The reaction mixture was cooled in an ice bath and NaBH(OAc) ₃ (2.11 g, 9.94 mmol) was added in portions. The reaction mixture was stirred for 16 hours with the temperature raised to ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and brine. The layers were separated and the aqueous phase was extracted with EtOAc (×2). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was transferred to DCM and purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give the product as a pale yellow oil (654 mg, 60%); MS m/z: 331 (M+H) ⁺ . The substance was used at the next stage without additional research.

[00724] O1-tert-Butyl-O3-ethyl-5-(3-fluoroazetidin-1-yl)piperidine-1,3-dicarboxylate (654 mg, 1.98 mmol) was dissolved in THF (10 ml) under N atmosphere ₂ and the solution was cooled in an ice bath. LiAlH ₄ (2.2 ml of 1 M solution in THF, 2.2 mmol) was added slowly. After 1 hour, the reaction was stopped by adding water (~5 ml) dropwise. The reaction mixture was concentrated and the residue was partitioned between EtOAc and water, then filtered through GF/C paper. The filtrate was separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as a colorless oil (552 mg, 97%); MS m/z: 289 (M+H) ⁺ . The product was immediately used in the next reaction.

[00725] tert-Butyl-3-(3-fluoroazetidin-1-yl)-5-(hydroxymethyl)piperidine-1-carboxylate (552 mg, 1.91 mmol) was dissolved in DCM (6 ml) under N ₂ atmosphere. The solution was cooled in an ice bath and DIPEA (500 μL, 2.87 mmol) was added, followed by methanesulfonyl chloride (180 μL, 2.326 mmol). The reaction mixture was stirred for 16 hours with the temperature raised to ambient temperature. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ solution. The layers were separated and the aqueous phase was extracted with DCM. The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue (pale brown oil, 660 mg) was dissolved in DMF (8 ml) under N ₂ atmosphere. Methanesulfonamide (550 mg, 5.78 mmol) and K ₂ CO ₃ (794 mg, 5.75 mmol) were added and the mixture was heated at 80°C for 24 hours. The reaction mixture was partitioned between EtOAc and water and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give a yellow oil. The residue (817 mg) was transferred to DCM (2 ml) and TFA (2 ml) was added at ambient temperature. After 30 min, the reaction mixture was concentrated and the residue was azeotroped with DCM (×2). The residue was taken up in MeOH and passed through SPE cartridges with bicarbonate. The filtrate was concentrated in vacuo and the residue, N-((5-(3-fluoroazetidin-1-yl)piperidin-3-yl)methyl)methanesulfonamide A79, was obtained as a pale brown viscous oil (903 mg); MS m/z: 266 (M+H) ⁺ . This substance was immediately used in the next reaction without further purification.

[00726] Synthesis 74: N-(Piperazin-2-ylmethyl)methanesulfonamide A80.

[00727] Methanesulfonyl chloride (1.0 mL, 12.9 mmol) was added to a solution of pyrazin-2-ylmethanamine (1.0 g, 9.2 mmol) and Et ₃ N (2.0 mL, 14.4 mmol) in DCM (15 ml) under N ₂ while cooling in an ice bath. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with DCM and washed with saturated aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was taken up in MeOH (20 ml) and PtO ₂ (300 mg, 1.32 mmol) was added. The reaction mixture was shaken in ^{a Parr hydrogenator for 20 hours at 60 psi H 2} _pressure . The reaction mixture was filtered and the filtrate concentrated in vacuo to give N-(piperazin-2-ylmethyl)methanesulfonamide A80 (1.0 g, 56%), which was used in the next reaction without further purification or assay; MS m/z: 194 (M+H) ⁺ .

[00728] Synthesis 75: N-((5,5-Dimethylmorpholin-2-yl)methyl)methanesulfonamide A81.

[00729] Chloroacetyl chloride (490 μL, 6.14 mmol) was added dropwise to a solution of 2-(benzylamino)-2-methylpropan-1-ol (1.0 g, 5.58 mmol) and DIPEA (1.3 mL, 7.3 mmol) in DCM (56 ml) at 0°C. The reaction mixture was warmed to ambient temperature for 30 minutes, then stirred at ambient temperature for 2 hours. Saturated aqueous NaHCO ₃ solution was added and the aqueous layer was extracted with DCM. The organics were washed successively with saturated aqueous NH ₄ Cl and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a brown oil (1.59 g), which was immediately used in the next reaction without further purification; MS m/z: 256 (M+H) ⁺ .

[00730] N-Benzyl-2-chloro-N-(2-hydroxy-1,1-dimethylethyl)acetamide (1.43 g, 5.58 mmol) and KO ^t Bu (751, 6.70 mmol) were stirred in THF (38 ml) at 0°C. After 15 minutes, the reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. Saturated aqueous NH ₄ Cl was added and the organics were extracted with EtOAc, dried (MgSO ₄ ), filtered and concentrated in vacuo to give an orange oil. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give the product as a white solid (879 mg, 72% in 2 steps); MS m/z: 220 (M+H) ⁺ .

[00731] Butyllithium (3.0 mL of 1.6 M solution in hexanes, 4.81 mmol) was added dropwise to a solution of diisopropylamine (674 μL, 4.81 mmol) in THF (6 mL) at -78°C. The reaction mixture was stirred at this temperature for 15 minutes and then at 0°C for 15 minutes. The LDA solution was added dropwise with stirring to a solution of 4-benzyl-5,5-dimethylmorpholin-3-one (879 mg, 4.01 mmol) in THF (2 ml) at -78°C and stirred at this temperature for 1 h. Paraformaldehyde (151 mg, 5.01 mmol) was added and the mixture was heated to ambient temperature for 3 hours. After stirring at ambient temperature for an additional 2 hours, water was added to the reaction mixture. The aqueous layer was separated and extracted with EtOAc and the combined organics were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a pale yellow oil. The residue was purified by column chromatography (silica, 0 to 100% EtOAc-PE gradient elution) to give 4-benzyl-2-(hydroxymethyl)-5,5-dimethylmorpholin-3-one as a colorless oil ( 494 mg, 49%); MS m/z: 250 (M+H) ⁺ .

[00732] BH ₃ .THF (9.9 ml of 1 M solution in THF, 9.9 mmol) was carefully added to a solution of 4-benzyl-2-(hydroxymethyl)-5,5-dimethylmorpholin-3-one (494 mg, 1.98 mmol) in THF (3 ml) at 0°C. After 10 minutes, the reaction mixture was warmed to ambient temperature and stirred for 2 hours. The reaction mixture was cooled to 0°C and the reaction was stopped (very carefully) with MeOH until gas evolution ceased. The reaction mixture was passed through an ion exchange cartridge and washed with MeCN/MeOH. The product was eluted with 2 M methanolic NH ₃ solution. The filtrate was concentrated in vacuo to give a colorless oil (227 mg, 49%), which was immediately used in the next reaction; MS m/z: 236 (M+H) ⁺ .

[00733] Methanesulfonyl chloride (112 μl, 1.45 mmol) was added to a solution of (4-benzyl-5,5-dimethylmorpholin-2-yl)methanol (227 mg, 0.96 mmol) and Et ₃ N (270 μl, 1 .93 mmol) in DCM (4 ml) at 0°C. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. Saturated aqueous NaHCO ₃ was added and the organics were extracted with DCM, dried (MgSO ₄ ), filtered and concentrated in vacuo to give an orange oil (320 mg), which used immediately in the next reaction; MS m/z: 314 (M+H) ⁺ .

[00734] (4-Benzyl-5,5-dimethylmorpholin-2-yl)methylmethanesulfonate (302 mg, 0.96 mmol), methanesulfonamide (275 mg, 2.90 mmol) and potassium carbonate (467 mg, 3.38 mmol ) were mixed in DMF (5 ml) and heated at 120°C for 16 hours. The mixture was cooled to ambient temperature and diluted with water. Organics were extracted with EtOAc and washed with brine (×3), dried (MgSO ₄ ), filtered and concentrated in vacuo to give an orange oil, which was purified by column chromatography (silica, 0-100% EtOAc-PE eluting in gradient mode). The product was obtained as a colorless oil (143 mg, in 2 steps); MS m/z: 313 (M+H) ⁺ .

[00735] HCl (4 ml of 3 M solution in MeOH, 12 mmol) was added to N-[(4-benzyl-5,5-dimethylmorpholin-2-yl)methyl]methanesulfonamide (143 mg, 0.46 mmol) and palladium on coal (30 mg, 0.28 mmol). The solution was stirred with hydrogen supplied from a cylinder for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was passed through an ion exchange cartridge and washed with MeCN/MeOH. The product was eluted with 2 M methanol NH ₃ and the filtrate was concentrated in vacuo to give N-((5,5-dimethylmorpholin-2-yl)methyl)methanesulfonamide A81 as a colorless oil (87 mg), which was used in the next reaction without further purification ; MS m/z: 223 (M+H) ⁺ .

[00736] Synthesis 76: (1-Methylpiperazin-2-yl)methanesulfonamide A82.

[00737] (1-Methylpiperazin-2-yl)methanol dihydrochloride (993 mg, 4.89 mmol) was suspended in DCM (50 ml) under N ₂ and DIPEA (3.0 ml, 17.2 mmol) was added. The mixture was cooled in an ice bath and Cbz-Cl (730 μL, 5.11 mmol) was added slowly. The reaction mixture was stirred for 16 hours with the temperature raised to ambient temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was transferred to DCM and purified by column chromatography (silica, 5-10% MeOH-DCM gradient elution) to give benzyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate as a colorless oil, ( 537 mg, 42%); MS m/z: 265 (M+H) ⁺ .

[00738] Benzyl 3-(hydroxymethyl)-4-methylpiperazine-1-carboxylate (537 mg, 2.03 mmol) was dissolved in DCM (10 ml) under N ₂ atmosphere. DIPEA (1 mL, 5.74 mmol) was added and the solution was cooled in an ice bath. Methanesulfonyl chloride (170 μL, 2.20 mmol) was added slowly and the mixture was stirred for 16 hours while raising the temperature to ambient temperature. The reaction mixture was concentrated in vacuo and the residue was taken up in EtOH (10 ml). The solution was transferred to a 35 ml microwavable vessel and water (10 ml) and Na ₂ SO ₃ (770 mg, 6.11 mmol) were added. The mixture was heated in a microwave oven at 130°C for 20 minutes. The reaction mixture was concentrated to dryness in vacuo and the residue was triturated with EtOH. The fine white precipitate was filtered off and the filtrate was concentrated in vacuo to give a sticky white solid which was immediately used in the next reaction without further purification or testing, assuming the sodium salt was isolated in quantitative yield (892 mg); MS m/z: 329 (M+H) ⁺ .

[00739] SOCl ₂ (5.0 mL, 68.6 mmol) was slowly added to (4-benzyloxycarbonyl-1-methylpiperazin-2-yl)methanesulfonic acid sodium salt (713 mg, 2.03 mmol) under N ₂ at ambient temperature. The mixture was heated at 80°C. After 2 hours, the reaction mixture was cooled to ambient temperature and concentrated to dryness in vacuo. The residue was cooled in an ice bath and NH ₄ OH (5 mL 28% w/w, 36.0 mmol) was added carefully. The ice bath was removed and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was extracted with EtOAc (×3). The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as a yellow oil (107 mg, 16% in 4 steps); MS m/z: 328 (M+H) ⁺ . This substance was used in the next step without further purification or testing.

[00740] Benzyl 4-methyl-3-(sulfamoylmethyl)piperazine-1-carboxylate (107 mg, 0.33 mmol) was dissolved in DCM (5 ml) under N ₂ atmosphere. DIPEA (170 μl, 0.98 mmol) was added and the mixture was degassed (×2 cycles of vacuum - N ₂ ). Pd(OAc) ₂ (30 mg, 0.13 mmol) was added and the mixture was degassed (×3 cycles), then Et ₃ SiH (320 μl, 2.0 mmol) was added and the mixture was degassed (×3 cycles). After stirring for 3 hours, the reaction mixture was loaded into an ion exchange cartridge. The cartridge was washed sequentially with DCM, 1:1 DCM-MeOH and MeOH. These filtrates were discarded and the product was eluted with 2 M methanol ammonia. The filtrate was concentrated in vacuo to give (1-methylpiperazin-2-yl)methanesulfonamide A82 as a pale brown oil (65 mg), which was immediately used in the next reaction without further purification or testing; MS m/z: 194 (M+H) ⁺ .

[00741] Synthesis 77: N-(1-(Piperazin-2-yl)ethyl)methanesulfonamide A83.

[00742] 1-Pyrazin-2-ylethanamine (252 mg, 2.05 mmol) was dissolved in DCM (3 ml) under N ₂ atmosphere. DIPEA (700 μL, 4.02 mmol) was added and the solution was cooled in an ice bath. Methanesulfonyl chloride (160 μL, 2.07 mmol) was added slowly. After 20 min, the reaction mixture was diluted with DCM and washed with water. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-5% MeOH-DCM gradient eluting) to give N-(1-pyrazin-2-ylethyl)methanesulfonamide as a colorless oil (236 mg, 57%); MS m/z: 202 (M+H) ⁺ .

[00743] N-(1-Pyrazin-2-ylethyl)methanesulfonamide (236 mg, 1.17 mmol) was dissolved in MeOH (5 ml) and the solution was degassed (×3 vacuum cycles - N ₂ ). Pd at C, wet, Degussa (126 mg 10% w/w, 0.12 mmol) was added and the mixture was degassed (×3 cycles). The N ₂ atmosphere was replaced with H ₂ (×5 cycles) and the reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was diluted with MeOH and filtered through GF/C paper. The filtrate was concentrated in vacuo to give N-(1-(piperazin-2-yl)ethyl)methanesulfonamide A83 as a colorless oil (241 mg, 99%), which was immediately used in the next reaction without further purification; MS m/z: 208 (M+H) ⁺ .

[00744] Synthesis 78: 3-Methylpiperazine-2-carboxamide A84.

[00745] 3-Methylpyrazine-2-carboxylic acid (500 mg, 3.62 mmol) was suspended in SOCl ₂ (2 ml, 27.4 mmol) and the mixture was heated under N ₂ at 80°C for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was cooled in an ice bath. NH ₄ OH (10 mL 28% w/w, 71.9 mmol) was added carefully and the mixture was stirred for 16 hours. The reaction mixture was concentrated to dryness and the resulting dark brown solid (730 mg) was immediately used in the next reaction without cleaning; MS m/z: 138 (M+H) ⁺ .

[00746] 3-Methylpyrazine-2-carboxamide (730 mg, 2.66 mmol) was suspended in MeOH (60 ml). 2 M aqueous HCl solution (~10 ml) was added and the mixture was degassed (×3 cycles of vacuum - N ₂ ) and Pd on C, wet, Degussa (567 mg 5% w/w, 0.27 mmol) was added. The mixture was degassed (×3 cycles), then the N ₂ atmosphere was replaced with H ₂ (×5 cycles). The reaction mixture was stirred for 16 hours at ambient temperature, then filtered through GF/C paper. The filtrate was concentrated in vacuo to give a light yellow solid containing 3-methylpiperazine-2-carboxamide A84 (698 mg), which was immediately used in the next reaction without further purification; MS m/z: 144 (M+H) ⁺ .

[00747] Synthesis 79: 2-(Piperazin-2-yl)acetamide A85.

[00748] 2-[1,4-Bis(tert-butoxycarbonyl)piperazin-2-yl]acetic acid (500 mg, 1.45 mmol) was dissolved in THF (10 ml) under N ₂ and DIPEA (1, 0 ml, 5.74 mmol). The solution was cooled in an ice bath and isobutyl chloroformate (210 μL, 1.62 mmol) was added slowly. After stirring for 1 hour, NH ₄ OH (1.5 ml 28% w/w, 22.20 mmol) was added to the cloudy solution. The resulting clear solution was stirred for an additional 1 hour. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and brine. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to yield a sticky foam (570 mg) which was immediately used in the next reaction; MS m/z: 344 (M+H) ⁺ .

[00749] Di-tert-butyl-2-(2-amino-2-oxoethyl)piperazine-1,4-dicarboxylate (570 mg, 1.50 mmol) was dissolved in DCM (10 ml) at ambient temperature and TFA was added (5 ml). After 15 min, the reaction mixture was concentrated in vacuo and the residue was subjected to azeotropic distillation with DCM (×2). The residue was taken up in MeOH and passed through SPE cartridges with bicarbonate. The filtrate was concentrated to give 2-(piperazin-2-yl)acetamide A85 as a colorless oil (250 mg), which was immediately used in the next reaction assuming quantitative yield in two steps; MS m/z: 144 (M+H) ⁺ .

[00750] Synthesis 80: N-((3,6,6-Trimethylmorpholin-2-yl)methyl)methanesulfonamide A86.

[00751] LiBr (275 mg, 3.17 mmol) was added with stirring to a mixture of 2,2-dimethyloxirane (1.7 mL, 19.1 mmol) and N-benzylbut-3-en-2-amine (2.56 g, 15.9 mmol) and the mixture was stirred at ambient temperature for 15 hours. The mixture was diluted with DCM (50 ml) and washed with water (2×15 ml). The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-30% EtOAc-PE gradient elution) to give 1-[benzyl(1-methylallyl)amino]-2-methylpropan-2-ol (2.46 g, 66%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.39-7.33 (m, 4H), 7.28-7.25 (m, 1H), 5.90 (ddd, 1H), 5.20 (dt, 1H), 5.07 (dt, 1H), 3.81 (d, 1H), 3.76 (d, 1H), 3.30 (pt, 1H), 2.87 (s, 1H) , 2.57 (d, 1H), 2.46 (d, 1H), 1.18-1.16 (m, 9H); MS m/z 234 (M+H) ⁺ .

[00752] I ₂ (2.94 g, 11.6 mmol) was added with stirring to a biphasic mixture of 1-[benzyl(1-methylallyl)amino]-2-methylpropan-2-ol (2.46 g, 10.5 mmol ) with MTBE (35 ml) and 1 M NaHCO ₃ (15 ml) and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was diluted with MTBE (35 ml) and another portion of I ₂ (2.94 g, 11.6 mmol). The reaction mixture was stirred at ambient temperature for an additional 24 hours. The reaction was stopped by adding saturated aqueous Na ₂ S ₂ O ₃ (30 ml), diluted with MTBE (30 ml) and the layers were separated. The organic phase was washed with a 1:1 mixture of saturated aqueous Na ₂ S ₂ O ₃ /saturated aqueous NaHCO ₃ (60 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-10% EtOAc-PE gradient elution) to give 4-benzyl-6-(iodomethyl)-2,2,5-trimethylmorpholine (646 mg, 17%) in in the form of purple oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.39-7.25 (m, 5H), 4.18 (td, 1H), 3.72 (d, 1H), 3.52 (d, 1H ), 3.10 (d, 2H), 2.97 (dd, 1H), 2.37 (d, 1H), 2.07 (d, 1H), 1.33 (s, 3H), 1.16 (s, 3H), 0.90 (d, 3H); MS m/z: 360 (M+H) ⁺ .

[00753] 4-Benzyl-6-(iodomethyl)-2,2,5-trimethylmorpholine (645 mg, 1.80 mmol), methanesulfonamide (510 mg, 5.36 mmol) and potassium carbonate (870 mg, 6.30 mmol) was heated at 120°C in DMF (10 ml) for 20 hours. The mixture was cooled to ambient temperature and diluted with water. The mixture was extracted with EtOAc (x2) and the combined organic extracts were washed with water (x3), brine (x2), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-50% EtOAc-PE gradient elution) to give N-[(4-benzyl-3,6,6-trimethylmorpholin-2-yl)methyl]methanesulfonamide (249 mg, 43%) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.37-7.29 (m, 5H), 7.23 (tt, 1H), 6.98 (t, 1H), 3.94 (td, 1H), 3.66 (d, 1H), 3.47 (d, 1H), 2.89 (s, 3H), 2.87-2.83 (m, 2H), 2.82-2.77 (m, 1H), 2.32 (d, 1H), 2.09 (d, 1H), 1.27 (s, 3H), 1.07 (s, 3H), 0.84 (d, 3H) ; MS m/z: 327 (M+1) ⁺ .

[00754] A mixture of N-[(4-benzyl-3,6,6-trimethylmorpholin-2-yl)methyl]methanesulfonamide (249 mg, 0.76 mmol), Pd at C, wet, Degussa (30 mg 10% wt ./wt., 0.03 mmol) and HCl (3 M in methanol) (10 ml, 30 mmol) were placed under an H ₂ atmosphere and stirred at ambient temperature for 15 hours. The catalyst was removed by filtration through celite, washed with MeOH and the filtrate were concentrated in vacuo. The residue was redissolved in HCl (3 M in methanol) (10 ml, 30 mmol) and re-added Pd on C, wet, Degussa (60 mg 10% w/w, 0.06 mmol), placed under H ₂ and stirred at ambient temperature for 24 hours. The catalyst was removed by filtration through Celite, washed with MeOH and the filtrate was concentrated in vacuo. The residue was passed through an ion exchange cartridge and washed with MeOH/DCM mixtures. The product was eluted with 2 M NH ₃ in MeOH/DCM mixtures and the solvent was removed in vacuo to give N-[(3,6,6-trimethylmorpholin-2-yl)methyl]methanesulfonamide A86 (73 mg, 41%) as colorless oils; MS m/z: 237 (M+H) ⁺ .

[00755] Synthesis 81: 3-(2-(Methylsulfonyl)ethyl)piperidine A87.

[00756] tert-Butyl-3-(2-bromoethyl)piperidine-1-carboxylate (338 mg, 1.16 mmol) and sodium methanesulfinate (209 mg, 1.74 mmol) were combined in EtOH under N ₂ in a sealed tube and heated for 16 h at 80°C. The reaction mixture was partitioned between EtOAc and water, the layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a colorless oil, which was transferred to DCM (10 ml). TFA (3 ml) was added and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM (×2). The residue was taken up in MeOH and passed through SPE cartridges with bicarbonate. The filtrates were combined and concentrated in vacuo to give 3-(2-(methylsulfonyl)ethyl)piperidine A87 as a colorless oil (301 mg, 87% in two steps), which was immediately used in the next reaction without further purification or testing; MS m/z: 192 (M+H) ⁺ .

[00757] Synthesis 82: tert-Butyl-((2,5-dimethylpiperidin-3-yl)methyl)(methylsulfonyl)carbamate A88.

[00758] DIAD (1.6 g, 7.91 mmol) in DCM (0.5 mL) was slowly added to a solution of (2,5-dimethyl-3-pyridyl)methanol (690 mg, 5.03 mmol), tert. -butyl-N-methylsulfonylcarbamate (1.8 g, 9.2 mmol) and PPh ₃ (1.9 g, 7.2 mmol) in DCM (40 ml) and the mixture was stirred at ambient temperature for 1 hour. Reaction the mixture was partitioned between DCM and saturated aqueous NaHCO ₃ solution. The combined organics were dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0-50% EtOAc-PE) to give the product as an oil (500 mg, 32%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.18 (dd, 1H), 7.40-7.17 (m, 1H), 4.76 (s, 2H), 3.45 (s, 3H), 2.42 (s, 3H), 2.26 (dd, 3H), 1.42 (s, 9H); MS m/z: 315 (M+H) ⁺ .

[00759] A mixture of PtO ₂ (45 mg, 0.20 mmol) and tert-butyl-((2,5-dimethylpyridin-3-yl)methyl)(methylsulfonyl)carbamate (500 mg, 1.59 mmol) in AcOH ( 15 ml) was shaken in ^a Parr hydrogenator at 60 psi H ₂ pressure for 4 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl-((2,5-dimethylpiperidin-3- yl)methyl)(methylsulfonyl)carbamate A88, which was immediately used in the next step without further purification; MS m/z: 321 (M+H) ⁺ .

[00760] Synthesis 83: 2,2,2-Trifluoro-N-(methyl(oxo)(piperidin-3-yl)-λ6-sulfanylidene)acetamide A89.

[00761] Di-tert-butyl dicarbonate (282 mg, 1.29 mmol) was added to a solution of 3-methylsulfanylpiperidine hydrochloride (199 mg, 1.19 mmol) and Et ₃ N (330 μl, 2.37 mmol) in DCM (10 ml ) and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated and the residue was transferred to DCM (5 ml). mCPBA (288 mg, 1.17 mmol) was added and the mixture was stirred at ambient temperature for 30 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ S ₂ O ₃ . After 30 min, the phases were separated and the aqueous phase was extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was taken up in DCE (12 ml) and Rh ₂ (OAc) ₆ (47 mg, 0.11 mmol), 2,2,2-trifluoroacetamide (272 mg, 2.40 mmol) and MgO (176 mg, 4, 37 mmol). Iodobenzene diacetate (528 mg, 1.64 mmol) was then added and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM (5 ml) and TFA (1 ml) was added. The mixture was stirred for 1 hour at ambient temperature, then concentrated in vacuo. The residue was azeotroped with toluene (×2) to give 2,2,2-trifluoro-N-(methyl(oxo)(piperidin-3-yl)-λ6-sulfanylidene)acetamide A89 (260 mg); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.97 (s, 2H), 4.04 (qt, 1H), 3.74 (d, 1H), 3.69 (d, 3H), 3 .31 (m, 1H), 3.19 (dt, 1H), 2.93 (tt, 1H), 2.24 (d, 1H), 2.02 (dq, 1H), 1.88-1, 62 (m, 2H). This substance was immediately used in the next reaction.

[00762] Synthesis 84: (S)-N-(Piperidin-3-ylmethyl-d ₂ )methanesulfonamide A90.

[00763](3S)-1-tert-Butoxycarbonylpiperidine-3-carboxylic acid (500 mg, 2.18 mmol) was suspended in THF (10 ml) and cooled to -20°C. Et ₃ N (455 μl, 3.26 mmol) was added, then isobutyl chloroformate (425 μl, 3.28 mmol). The reaction mixture was allowed to warm to ambient temperature for 1 hour, then sodium tetradeuterioboranide (140 mg, 3.35 mmol) was added, followed by trideuterio(deuteriooxy)methane (3.5 ml). The reaction mixture was stirred for 2.5 hours at ambient temperature, then the reaction was stopped by adding saturated aqueous NaHCO ₃ solution and stirred for 10 minutes. Water was added to dissolve the salts and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-50% EtOAc-PE gradient elution) to give tert-butyl (3S)-3-[dideuterio(hydroxy)methyl]piperidine-1-carboxylate (281 mg , 59%) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.44 (s, 1H), 3.93 (br s, 1H), 3.82-3.77 (m, 1H), 2.71 (t , 1H), 2.53-2.47 (m, 1H), 1.69-1.64 (m, 1H), 1.61-1.56 (m, 1H), 1.48-1.42 (m, 1H), 1.39 (s, 9H), 1.34-1.24 (m, 1H), 1.08 (qd, 1H); MS m/z: 218 (M+H) ⁺ .

[00764] To a solution of tert-butyl-(3S)-3-[dideuterio(hydroxy)methyl]piperidine-1-carboxylate (280 mg, 1.29 mmol), tert-butyl-N-methylsulfonylcarbamate (375 mg, 1. 92 mmol) and PPh ₃ (990 mg, 3.78 mmol) in THF (15 ml), DEAD (440 µl, 2.79 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (10 ml) and TFA (2.5 ml, 32.5 mmol) was added. After stirring for 22 h, TFA (1 mL, 13.0 mmol) was added and the reaction mixture was stirred at ambient temperature for a further 5 h. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether ( ×2). The residue was passed through an ion exchange cartridge, washed with MeOH/DCM and the product eluted with 2 M methanol NH ₃ /DCM mixtures. The combined filtrates were concentrated in vacuo to give (S)-N-(piperidin-3-ylmethyl-d ₂ )methanesulfonamide A90, (508 mg) as a solid, which was used in the next step without further purification; MS m/z: 195 (M+H) ⁺ .

[00765] Synthesis 85: N-((5-Methyl-4-oxopiperidin-3-yl)methyl)methanesulfonamide A91.

[00766] Mixture of benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-methyl-4-oxopiperidine-1-carboxylate (550 mg, 1.35 mmol) (see A46), ethylene glycol (250 µl, 4.48 mmol) and 4-methylbenzenesulfonic acid hydrate (15 mg, 0.08 mmol) in toluene (10 ml) were refluxed for 24 hours. The reaction mixture was diluted with EtOAc and washed with saturated aqueous solution sodium bicarbonate and brine. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtAOc-PE gradient elution) to give a colorless oil (370 mg), which was immediately used in the next reaction; MS m/z: 451 (M+H) ⁺ .

[00767] A mixture of benzyl 6-[(1,3-dioxoisoindolin-2-yl)methyl]-10-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (370 mg, 0. 82 mmol) and hydrazine hydrate (180 μl 50% w/v, 1.80 mmol) in ethanol (7 ml) were refluxed for 2 h, then cooled to ambient temperature. The resulting suspension was filtered and washed with EtOH. The filtrate was concentrated under reduced pressure to give a white solid, which was taken up in DCM (4 ml). Et ₃ N (160 μl, 1.15 mmol) was added under N ₂ and the solution was cooled in an ice bath. Methanesulfonyl chloride (80 µl, 1.034 mmol) was added. After 5 minutes, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 18 hours. The resulting suspension was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give benzyl-6-(methanesulfonamidomethyl)-10-methyl-1,4-dioxa-8- azaspiro[4.5]decane-8-carboxylate as a white resinous substance (250 mg), which was immediately used in the next reaction; MS m/z: 399 (M+H) ⁺ .

[00768] A mixture of HCl (1.8 ml of 2 M aqueous solution, 3.6 mmol) and benzyl 6-(methanesulfonamidomethyl)-10-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-carboxylate (250 mg, 0.63 mmol) in THF (4 ml) was refluxed for 18 h, then cooled to ambient temperature. The solution was diluted with EtOAc and water. After stirring for 5 minutes, the organic phase was isolated and washed with saturated aqueous NaHCO ₃ solution and brine. The organic phase was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was transferred to DCM (5 ml). Et ₃ SiH (150 µl, 0.94 mmol), Et ₃ N (150 µl, 1.08 mmol) and Pd(OAc) ₂ (30 mg, 0.13 mmol) were successively added to the solution, which was then stirred in for 2 hours at ambient temperature. The resulting suspension was diluted with methanol (~5 ml) and loaded directly into the ion exchange cartridge. The cartridge was washed with methanol, then the product was eluted with 2 M methanol NH ₃ solution. The filtrate was concentrated in vacuo to give N-((5-methyl-4-oxopiperidin-3-yl)methyl)methanesulfonamide A91 as a brown oil (100 mg, 72%), which was used in the next reaction without further purification; MS m/z: 221 (M+H) ⁺ .

[00769] Synthesis 86: N-((8,8-Difluoro-5-azaspiro[2.5]octan-7-yl)methyl)methanesulfonamide A92.

[00770] LiHMDS (2.33 mL of 1 M, 2.33 mmol) was slowly added to a solution of tert-butyl-8-oxo-5-azaspiro[2.5]octane-5-carboxylate (500 mg, 2.22 mmol) in THF (10 ml) and stirred at -78°C under N ₂ atmosphere. After 10 minutes, a solution of 2-(chloromethyl)isoindoline-1,3-dione (478 mg, 2.44 mmol) in THF (2 ml) was slowly added and the mixture was stirred at -78°C for 10 minutes. A saturated aqueous NH ₄ Cl solution was added and the mixture was allowed to warm to ambient temperature, then partitioned between water and DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-30% EtOAc-PE gradient eluting) to give tert-butyl 7-[(1,3-dioxoisoindolin-2-yl)methyl]-8-oxo-5 -azaspiro[2.5]octane-5-carboxylate as an oil that solidified on standing (285 mg, 33%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.94-7.82 (m, 4H), 4.12-4.02 (m, 1H), 3.89-3.78 (m, 1H ), 3.60 (td, 2H), 3.46 (d, 2H), 3.07 (ddt, 1H), 1.37 (s, 9H), 1.16-1.04 (m, 2H) , 0.91-0.83 (m, 2H).

[00771] tert-Butyl 7-[(1,3-dioxoisoindolin-2-yl)methyl]-8-oxo-5-azaspiro[2.5]octane-5-carboxylate (263 mg, 0.68 mmol) was treated with DAST (904 μl, 6.84 mmol) and the mixture was stirred for 96 h at ambient temperature. Additional DAST (904 µl, 6.84 mmol) was added and the mixture was stirred for 24 hours, then carefully poured into a mixture of ice and saturated aqueous NaHCO ₃ solution. The mixture was stirred for 30 minutes, then extracted with DCM. The combined organics were dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-50% EtOAc-PE gradient elution) to give tert-butyl 7-[(1,3-dioxoisoindolin-2-yl)methyl]-8,8-difluoro -5-azaspiro[2.5]octane-5-carboxylate (280 mg), which was immediately used in the next reaction.

[00772] tert-Butyl 7-[(1,3-dioxoisoindolin-2-yl)methyl]-8,8-difluoro-5-azaspiro[2.5]octane-5-carboxylate (280 mg, 0.69 mmol), hydrazine (54 μl, 1.72 mmol) in EtOH (2.8 ml) was heated at 80°C for 2 hours. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The residue was loaded into an ion exchange cartridge. The cartridge was washed with DCM-MeOH mixtures, then the product was eluted with 2 M methanolic NH ₃ solution. The bulk eluate was concentrated in vacuo and the residue azeotroped with toluene, then dissolved in DCM (2 ml). Et ₃ N (96 µl, 0.69 mmol) was added followed by methanesulfonyl chloride (69 µl, 0.90 mmol) and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was treated with TFA/DCM . After 1 hour at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-((8,8-difluoro-5- azaspiro[2.5]octan-7-yl)methyl)methanesulfonamide A92, (90 mg, 99%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.22 (s, 2H), 7.32 (t, 1H), 3.66-3.28 (m, 3H), 3.14-2, 90 (m, 6H), 2.63-2.52 (m, 1H), 1.02 (ddd, 1H), 0.90-0.77 (m, 2H), 0.74 (ddd, 1H) .

[00773] Synthesis 87: N-((5,6-Dimethylpiperidin-3-yl)methyl)methanesulfonamide A93.

[00774] Methanesulfonyl chloride (200 μl, 2.58 mmol) was added to a solution of (5,6-dimethyl-3-pyridyl)methanamine dihydrochloride (400 mg, 1.91 mmol) and Et ₃ N (1.0 ml, 7. 18 mmol) in DCM (6 ml). The solution was stirred at ambient temperature for 19 hours. The resulting suspension was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo to give a brown oil (370 mg), which was used in the next step without further purification; MS m/z: 215 (M+H) ⁺ .

[00775] A mixture of N-[(5,6-dimethyl-3-pyridyl)methyl]methanesulfonamide (370 mg, 1.73 mmol), PtO ₂ (70 mg, 0.31 mmol) and HCl (10 ml 3 M solution in MeOH, 30 mmol) was shaken in a Parr hydrogenator for 3 hours at 60 psi ^{H 2} _pressure . The reaction mixture was filtered and washed with methanol. The filtrate was concentrated in vacuo to give N-((5,6-dimethylpiperidin-3-yl)methyl)methanesulfonamide A93 as a brown oil (350 mg, 79%), which was used in the next reaction without further purification; MS m/z: 221 (M+H) ⁺ .

[00776] Synthesis 88: 8-Methylhexahydro-3H-oxazolo[3,4-a]pyrazin-3-one A94.

[00777] (3-Methylpyrazin-2-yl)methanol (4.92 g, 39.6 mmol) was dissolved in MeOH (200 ml) and HCl (20 ml of 2 M aqueous solution, 40 mmol) was added. The solution was degassed (×3 vacuum cycles - N ₂ ) and Pd at C, wet, Degussa (2.5 g 10% w/w, 2.35 mmol) was added. The mixture was degassed (×3 cycles) and N ₂ was replaced with H ₂ (×5 cycles). The mixture was stirred for 48 hours. The reaction mixture was degassed with N ₂ then filtered through GF/F paper. The filtrate was concentrated in vacuo to give the product as a brown oil (6.7 g), which was immediately used in the next reaction without purification, assuming that the salt had liberated with HCl; MS m/z: 131 (M+H) ⁺ .

[00778] (3-Methylpiperazin-2-yl)methanol hydrochloride (6.7 g, 36.2 mmol) was dissolved in MeOH (50 ml) and DIPEA (19.0 ml, 109.1 mmol) was added under N ₂ atmosphere. The solution was cooled in an ice bath and a solution of di-tert-butyl dicarbonate (19.0 g, 87.06 mmol) in MeOH (50 mL) was added slowly over 10 min. The reaction mixture was stirred while cooling for 1 hour, then at ambient temperature for 1 hour. The reaction mixture was then heated to 50°C and stirred for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water, the aqueous phase was extracted with EtOAc and the combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give the product as a colorless oil (3.72 g, 31%) which was immediately used in the next reaction; MS m/z: 331 (M+H) ⁺ .

[00779] Di-tert-butyl-2-(hydroxymethyl)-3-methylpiperazine-1,4-dicarboxylate (3.72 g, 11.3 mmol) was dissolved in THF (80 ml) under N ₂ atmosphere. The solution was cooled in an ice bath and NaH (550 mg 60% w/w dispersion in mineral oil, 13.8 mmol) was added in one portion. The cooling bath was removed and the mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was cooled in an ice bath and the reaction was stopped by carefully adding water. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as a colorless oil (2.40 g, 83%) which was immediately used in the next reaction without further purification; MS m/z: 201 (M-tBu) ⁺ .

[00780] tert-Butyl-8-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxylate (156 mg, 0.61 mmol) was dissolved in DCM (2 ml) and TFA (0.5 ml) was added. The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was azeotroped with DCM (×2). The residue was taken up in MeOH and passed through SPE cartridges with bicarbonate. The combined filtrates were concentrated in vacuo to give 8-methylhexahydro-3H-oxazolo[3,4-a]pyrazin-3-one A94 as a pale yellow glass (95 mg, quantitative yield), which was immediately used in the next reaction; MS m/z: 157 (M+H) ⁺ .

[00781] Synthesis 89: N-((5-Cyanopiperidin-3-yl)methyl)methanesulfonamide A95.

[00782] Platinum oxide (2.72 g, 12.0 mmol), acetic acid (20 ml) and methyl 5-(hydroxymethyl)pyridine-3-carboxylate (2.0 g, 12.0 mmol) were combined and shaken in ^{a Parr hydrogenator for 3 days at 60 psi H 2} _pressure . The catalyst was filtered off and washed with acetic acid. The filtrate was concentrated under reduced pressure to give a pale yellow gum (2.8 g). This material was treated with EtOAc (100 ml) and water (50 ml) and benzyl chloroformate (1.7 ml, 11.9 mmol) and K ₂ CO ₃ (10 g, 72.4 mmol) were added. The mixture was stirred at ambient temperature for 18 hours. The phases were separated and the aqueous phase was diluted with water and extracted with EtOAc. The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give a pale yellow oil (1 g) which was dissolved in DCM (10 ml). Imidazole (440 mg, 6.46 mmol) and TBDMS chloride (600 mg, 3.98 mmol) were added and the resulting suspension was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0-50% EtOAc-PE gradient eluting) to give a colorless oil (800 mg, 58%); MS m/z: 422 (M+H) ⁺ . This material was dissolved in THF (8 ml) under N ₂ and the solution was cooled in an ice bath. LiBH ₄ (1.2 ml of 2 M solution in THF, 2.4 mmol) was added and the reaction mixture was stirred for 18 hours while raising the temperature to ambient temperature. Additional LiBH ₄ (0.4 ml of 2 M solution in THF, 0.8 mmol) was added and the solution was stirred for 2 hours at ambient temperature. The reaction was stopped with 2 M aqueous NaOH and diluted with EtOAc. The organic phase was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtain benzyl 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(hydroxymethyl)piperidine-1-carboxylate as a colorless oils (710 mg, 95%); MS m/z: 394 (M+H) ⁺ .

[00783] DMSO (200 μl, 2.82 mmol) was added dropwise to a solution of oxalyl chloride (160 μl, 1.83 mmol) in DCM (10 ml) cooled to -78°C under N ₂ atmosphere. After 10 min, a solution of benzyl 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-(hydroxymethyl)piperidine-1-carboxylate (700 mg, 1.78 mmol) in DCM (5 ml). After 50 minutes at -78°C, Et ₃ N (750 μl, 5.38 mmol) was added. After 10 min, the reaction mixture was allowed to warm to ambient temperature, then the reaction was stopped with a 10% aqueous solution of citric acid. The mixture was extracted with DCM and the organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as a light yellow oil (660 mg, 95%); MS m/z: 392 (M+H) ⁺ .

[00784] A mixture of benzyl 3-[[tert-butyl(dimethyl)silyl]oxymethyl]-5-formylpiperidine-1-carboxylate (660 mg, 1.69 mmol), hydroxylamine hydrochloride (140 mg, 2.02 mmol) and NaOAc (110 mg, 1.34 mmol) in ethanol (10 ml) and water (5 ml) was stirred at ambient temperature for 3 days. The solution was diluted with water and EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a yellow gum (590 mg), which was immediately used in the next reaction; MS m/z: 293 (M+H) ⁺ .

[00785] 2-Chloro-1-methylpyridin-1-iodide (470 mg, 1.84 mmol) was added to a solution of benzyl 3-[(E)-hydroxyiminomethyl]-5-(hydroxymethyl)piperidine-1-carboxylate (490 mg, 1.68 mmol) in DCM (5 ml) at ambient temperature. After 10 minutes, Et ₃ N (350 μl, 2.51 mmol) was added and the suspension was stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between EtOAc and 10% aqueous citric acid. The organic phase was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give a colorless oil (80 mg, 17%); MS m/z: 275 (M+H) ⁺ .

[00786] Methanesulfonyl chloride (15 μl, 0.19 mmol) was added to a solution of benzyl 3-cyano-5-(hydroxymethyl)piperidine-1-carboxylate (40 mg, 0.15 mmol) and Et ₃ N (30 μl, 0 .22 mmol) in DCM (2 ml). The solution was stirred at ambient temperature for 1 hour. The resulting suspension was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo to give a yellow oil which was taken up in DMF (2 ml). K ₂ CO ₃ (60 mg, 0.43 mmol) and methanesulfonamide (40 mg, 0.42 mmol) were added to the solution, which was stirred at 80°C for 18 hours, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc. The organic phase was washed with saturated aqueous sodium bicarbonate and brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo to give a pale yellow oil, which was transferred to DCM (2 ml). Et ₃ N (30 μl, 0.22 mmol), Et ₃ SiH (30 μl, 0.188 mmol), then Pd(OAc) ₂ (10 mg, 0.04 mmol) was added to the reaction mixture. After stirring for 2 hours at ambient temperature, the reaction mixture was diluted with methanol and poured into an ion exchange cartridge. The cartridge was washed with methanol, and the product was eluted with a 2 M methanol solution of NH ₃ . The filtrate was concentrated under reduced pressure to give N-((5-cyanopiperidin-3-yl)methyl)methanesulfonamide A95 as a pale yellow film-like substance (17 mg, 54%), which was immediately used in the next reaction; MS m/z: 218 (M+H) ⁺ .

[00787] Synthesis 90: (1-(tert-Butyl)-3-methylpiperazin-2-yl)methanol A96.

[00788] (3-Methylpyrazin-2-yl)methanol (4.92 g, 39.6 mmol) was dissolved in MeOH (200 ml) and HCl (20 ml of 2 M aqueous solution, 40 mmol) was added. The solution was degassed (×3 vacuum cycles - N ₂ ) and Pd at C, wet, Degussa (2.5 g 10% w/w, 2.35 mmol) was added. The mixture was degassed (×3 cycles) and N ₂ was replaced with H ₂ (×5 cycles). The mixture was stirred for 2 days. The reaction mixture was degassed with N ₂ then filtered through GF/F paper. The filtrate was concentrated in vacuo to give the product as a brown oil (6.7 g), which was immediately used in the next reaction without purification, assuming that the salt had liberated with HCl; MS m/z: 131 (M+H) ⁺ .

[00789] (3-Methylpiperazin-2-yl)methanol hydrochloride (6.7 g, 36.2 mmol) was dissolved in MeOH (50 ml) and DIPEA (19.0 ml, 109 mmol) was added under N ₂ atmosphere. The solution was cooled in an ice bath and a solution of di-tert-butyl dicarbonate (19.0 g, 87.1 mmol) in MeOH (50 ml) was added slowly over 10 min. The reaction mixture was stirred while cooling for 1 hour, then at ambient temperature for 1 hour. The reaction mixture was heated at 50°C overnight, then cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc and the combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give the product as a colorless oil (3.72 g, 31%) which was immediately used in the next reaction; MS m/z: 331 (M+H) ⁺ .

[00790] Di-tert-butyl-2-(hydroxymethyl)-3-methylpiperazine-1,4-dicarboxylate (3.72 g, 11.26 mmol) was dissolved in THF (80 ml) under N ₂ atmosphere. The solution was cooled in an ice bath and NaH (550 mg 60% w/w dispersion in mineral oil, 13.8 mmol) was added in one portion. The cooling bath was removed and the mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was cooled in an ice bath and the reaction was stopped by carefully adding water. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc. The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the product as a colorless oil (2.40 g, 83%), which was immediately used in the next reaction without further purification; MS m/z: 201 (M-tBu) ⁺ .

[00791] tert-Butyl-8-methyl-3-oxo-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxylate (2.24 g, 8.76 mmol ) was suspended in EtOH (30 ml) and a solution of NaOH (1.75 g, 43.8 mmol) in water (30 ml) was added. The reaction mixture was stirred overnight at 100°C. The reaction mixture was cooled to ambient temperature and the pH of the solution was adjusted to ~pH 10 by adding 2 M aqueous HCl. The mixture was extracted with CHCl ₃ (×2). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was taken up in MeOH and concentrated in vacuo to give the product as a yellow oil (1.91 g, 95%) which was immediately used in the next reaction; MS m/z: 231 (M+H) ⁺ .

[00792] tert-Butyl-3-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (1.9 g, 8.25 mmol) was dissolved in dry acetone (3.0 ml, 40.9 mmol) under N ₂ atmosphere and BF ₃ .OEt ₂ (100 μl, 0.79 mmol) was added. The mixture was heated at 100°C for 20 min in a microwave reactor. The reaction mixture was concentrated in vacuo to give a yellow oil, which was transferred to EtOAc and purified by column chromatography (neutral alumina, 0-100% EtOAc-PE gradient elution). The product fractions were combined and concentrated in vacuo to give the product as a colorless oil (540 mg, 24%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.25 (vbrs, 1H), 3.90-3.71 (m, 2H), 3.37 (dd, 1H), 3.07-2, 69 (m, 3H), 2.14 (ddd, 1H), 1.41 (s, 9H), 1.22 (s, 3H), 1.04 (d, 3H), 1.00 (s, 3H ); MS m/z: 271 (M+H) ⁺ .

[00793] tert-Butyl-3,3,8-trimethyl-5,6,8,8a-tetrahydro-1H-oxazolo[3,4-a]pyrazine-7-carboxylate (540 mg, 2.0 mmol) was dissolved in THF (10 ml) under N ₂ atmosphere. The solution was cooled to -10°C and MeMgCl (1.5 ml of 3 M solution in THF, 4.5 mmol) was added. The reaction mixture was stirred for 16 hours with the temperature raised to ambient temperature. MeMgCl (1.5 ml of 3 M solution in THF, 4.5 mmol) was added and the reaction mixture was heated at 40°C. After 3 hours, the reaction mixture was cooled to ambient temperature and the reaction was stopped by carefully adding water. The reaction mixture was extracted with EtOAc (×2). The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give a yellow oil. The residue was taken up in EtOAc and purified by column chromatography (neutral alumina, 0-100% EtOAc-PE gradient elution). The product was obtained as a colorless oil (122 mg, 21%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.46 (t, 1H), 4.21 (p, 1H), 3.65-3.52 (m, 1H), 3.45 (ddd, 1H), 3.02-2.81 (m, 3H), 2.71 (ddd, 1H), 1.39 (s, 10H), 1.15 (d, J=6.9 Hz, 3H), 1.04(s,9H); MS m/z: 287 (M+H) ⁺ . This substance was immediately used in the next reaction.

[00794] tert-Butyl-4-tert-butyl-3-(hydroxymethyl)-2-methylpiperazine-1-carboxylate (122 mg, 0.426 mmol) was dissolved in DCM (5 ml) and TFA (1 ml) was added under N ₂ . After 2 h, the reaction mixture was concentrated in vacuo and the residue was subjected to azeotropic distillation with DCM (×2). The residue was taken up in MeOH and passed through an SPE cartridge with bicarbonate. The filtrate was concentrated in vacuo to give (1-(tert-butyl)-3-methylpiperazin-2-yl)methanol A96 (TFA salt) as a pale yellow glassy solid (125 mg, 88%), which was immediately used in the following reactions; MS m/z: 187 (M+H) ⁺ .

[00795] Synthesis 91: N-(((8aS)-Octahydropyrrolo[1,2-a]pyrazin-4-yl)methyl)methanesulfonamide A97.

[00796] 2-(3-Bromo-2-oxopropyl)isoindoline-1,3-dione (550 mg, 1.95 mmol) was dissolved in DCM (20 ml), then tert-butyl-(2S)-2- was added (aminomethyl)pyrrolidine-1-carboxylate (391 mg, 1.95 mmol) and triethylamine (300 μl, 2.15 mmol). The colorless solution was stirred at ambient temperature for 1 hour. Cbz-Cl (334 μL, 2.34 mmol) then triethylamine (815 μL, 5.85 mmol) was added to the yellow solution and stirring was continued at ambient temperature. After 5 min, the reaction mixture was diluted with water (20 ml), the layers were separated and the aqueous layer was extracted with DCM (2×30 ml). The combined organics were washed with 1 M aqueous HCl (20 ml), brine (20 ml), dried and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, 30-80% EtOAc-PE gradient elution) to give tert-butyl-(2S)-2-[[benzyloxycarbonyl-[3-(1, 3-dioxoisoindolin-2-yl)-2-oxopropyl]amino]methyl]pyrrolidine-1-carboxylate (550 mg, 53%) as a colorless resinous substance; MS m/z: 536 (M+H) ⁺ .

[00797] tert-Butyl-(2S)-2-[[benzyloxycarbonyl-[3-(1,3-dioxoisoindolin-2-yl)-2-oxopropyl]amino]methyl]pyrrolidine-1-carboxylate (550 mg, 1 .03 mmol) was dissolved in DCM (6 ml), then cooled to 0°C. TFA (4 ml) was then added slowly and stirring was continued at 0°C. After 45 minutes, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in methanol (13 ml), then NaCNBH ₃ (226 mg, 3.60 mmol) was added. The solution was stirred at ambient temperature. After 1 hour, the reaction was stopped with saturated aqueous NaHCO ₃ solution, then extracted with EtOAc (3x40 ml). The combined organics were washed with water (30 ml) and brine (20 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give benzyl-(8aS)-4-[(1,3-dioxoisoindoline-2- yl)methyl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylate (390 mg, 80%) as a colorless resinous substance; MS m/z: 420 (M+H) ⁺ .

[00798] Benzyl-(8aS)-4-[(1,3-dioxoisoindolin-2-yl)methyl]-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a] pyrazine-2-carboxylate (140 mg, 0.31 mmol) was dissolved in ethanol (3 ml), then hydrazine hydrate (46 μl, 0.94 mmol) was added. The colorless solution was then heated at 80°C. After 3 hours, the reaction mixture was cooled to ambient temperature, then filtered through celite. The filtrate was concentrated in vacuo to obtain a colorless resinous substance. This material was transferred to DCM (3 ml), then cooled to 0°C. Triethylamine (66 µl, 0.47 mmol) was added followed by methanesulfonyl chloride (29 µl, 0.38 mmol) and stirring was continued for 45 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ (10 ml), then the layers were separated and the aqueous layer was extracted with DCM (2 x 30 ml). The combined organics were washed with water and passed through a hydrophobic frit. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica, 20-80% EtOAc-PE gradient elution) to give the product (35 mg, 27%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.43-7.30 (m, 5H), 5.15 (d, 2H), 4.88 (s, 1H), 4.18 (dd, 3H ), 3.37-3.28 (m, 1H), 3.26-3.13 (m, 2H), 2.98 (s, 3H), 2.63-2.56 (m, 1H), 2.38 (s, 1H), 2.11 (q, 4H), 1.88-1.68 (m, 4H); MS m/z: 368 (M+H) ⁺ .

[00799] Benzyl-(8aS)-4-(methanesulfonamidomethyl)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylate (35 mg, 0. 09 mmol) was dissolved in EtOAc (724 µl) and MeOH (181 µl) and stirred with H ₂ supplied from a cylinder. Pd(OH) ₂ (6.4 mg 20% w/w, 0.009 mmol) was added and the black suspension was stirred at ambient temperature for 45 minutes. The reaction mixture was filtered through celite and then concentrated in vacuo to give N-(((8aS)-octahydropyrrolo[1,2-a]pyrazin-4-yl)methyl)methanesulfonamide A97 (20 mg, 95%) as a colorless resin. , which was immediately used in the next reaction; MS m/z: 234 (M+H) ⁺ .

[00800] Synthesis 92: N-(((7S,8aS)-7-Fluorooctahydropyrrolo[1,2-a]pyrazin-4-yl)methyl)methanesulfonamide A98.

[00801] Using tert-butyl-(2S,4S)-2-(aminomethyl)-4-fluoropyrrolidine-1-carboxylate instead of tert-butyl-(2S)-2-(aminomethyl)pyrrolidine-1-carboxylate in the above following the procedure for A97, N-(((7S,8aS)-7-fluoroctahydropyrrolo[1,2-a]pyrazin-4-yl)methyl)methanesulfonamide A98 was obtained as a colorless resinous substance, which was immediately used in the next reaction; MS m/z: 252 (M+H) ⁺ .

[00802] Synthesis 93: tert-Butyl-((6-azaspiro[2.5]octan-4-yl)methyl)(methylsulfonyl)carbamate A99.

[00803] A mixture of K ₂ CO ₃ (2.0 g, 14.4 mmol), BnBr (855 μl, 7.19 mmol) and 6-azaspiro[2.5]octane-5,7-dione (1 g, 7. 19 mmol) in DMF (10 ml) was stirred at ambient temperature for 72 hours. The solvent was removed in vacuo and the residue was triturated with water. The solid was washed with water and dried in vacuo at 60°C for 3 hours to give 6-benzyl-6-azaspiro[2.5]octane-5,7-dione (1.42 g, 84%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.31 (dd, 2H), 7.28-7.16 (m, 3H), 4.88 (s, 2H), 2.64 (s, 4H), 0.49 (s, 4H); MS m/z: 230 (M+H) ⁺ .

[00804] LiHMDS (9.16 mL of 1 M, 9.16 mmol) was slowly added to a solution of 6-benzyl-6-azaspiro[2.5]octane-5,7-dione (1 g, 4.36 mmol) in THF ( 20 ml) at -78°C in an N ₂ atmosphere. The mixture was stirred at this temperature for 30 minutes, then ethyl cyanoformate (610 μl, 6.54 mmol) was added. After 30 minutes, a saturated aqueous NH ₄ Cl solution was added and the mixture was warmed to ambient temperature, then concentrated in vacuo. The residue was partitioned between DCM and water. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 5-50% EtOAc-PE gradient elution) to give ethyl 6-benzyl-5,7-dioxo-6-azaspiro[2.5]octane-8-carboxylate as colorless oil (950 mg, 68%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.34-7.28 (m, 2H), 7.27-7.20 (m, 3H), 5.00-4.84 (m, 2H ), 4.18 (qd, 2H), 3.43 (d, 1H), 3.05 (dd, 1H), 2.30 (dd, 1H), 1.19 (t, 3H), 0.85 -0.78 (m, 1H), 0.74-0.67 (m, 1H), 0.67-0.57 (m, 2H); MS m/z: 302 (M+H) ⁺ .

[00805] LiAlH ₄ (95 mg, 2.5 mmol) was added to a solution of ethyl 6-benzyl-5,7-dioxo-6-azaspiro[2.5]octane-8-carboxylate (203 mg, 0.67 mmol) in THF (10 ml) under N ₂ atmosphere. After stirring at ambient temperature for 2 h, the reaction was stopped by sequentially adding H ₂ O (100 μl), 15% aqueous NaOH (100 μl) and H ₂ O (300 μl). The mixture was stirred at ambient temperature overnight, filtered through celite and the filtrate was concentrated in vacuo. The residue was taken up in DCM (5 ml) and tert-butyl-N-methylsulfonylcarbamate (262 mg, 1.34 mmol) and PS-PPh ₃ (476 mg 2.11 mmol/g, 1.00 mmol) were added. With stirring at ambient temperature, DIAD (182 μL, 0.94 mmol) in DCM (1 mL) was slowly added. After 4 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was loaded into an ion exchange column. The column was washed with MeOH and the product was eluted with 2 M methanol ammonia. The filtrate was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water - 0.1% ammonium hydroxide as eluent). Product fractions were lyophilized to give tert-butyl-N-[(6-benzyl-6-azaspiro[2.5]octan-8-yl)methyl]-N-methylsulfonylcarbamate (19 mg, 7%), which was immediately used in the next reaction; MS m/z: 409 (M+H) ⁺ .

[00806] Pd on C, wet, Degussa (5 mg 10% w/w, 0.047 mmol) was transferred to a nitrogen-filled vessel and the vessel was evacuated and refilled with nitrogen. A solution of tert-butyl-N-[(6-benzyl-6-azaspiro[2.5]octan-8-yl)methyl]-N-methylsulfonylcarbamate (19 mg, 0.047 mmol) in MeOH (5 ml) was added and the resulting solution was degassed with using vacuum/nitrogen cycles (×3). The atmosphere was replaced using vacuum/hydrogen cycles (×3) and the reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated in vacuo to give tert-butyl((6-azaspiro[2.5]octan-4-yl)methyl)(methylsulfonyl)carbamate A99 (15 mg), which was immediately used in the next step without any purification; MS m/z: 319 (M+H) ⁺ .

[00807] Synthesis 94: N-((6,6-Dimethylpiperazin-2-yl)methyl)methanesulfonamide A100.

[00808] 2-(3-Bromo-2-oxopropyl)isoindoline-1,3-dione (250 mg, 0.89 mmol) was dissolved in DCM (9 ml), then tert-butyl-N-(2-amino) was added -1,1-dimethylethyl)carbamate (167 mg, 0.89 mmol) and triethylamine (136 μl, 0.97 mmol). The colorless solution was stirred at ambient temperature for 1 hour. Cbz-Cl (152 µl, 1.06 mmol) and triethylamine (370 µl, 2.66 mmol) were added and stirring was continued. After 50 min, the reaction mixture was diluted with water (20 ml). The layers were separated and the aqueous phase was extracted with DCM (2×30 ml). The combined organics were washed with 1 M aqueous HCl (20 ml) and brine (20 ml) and filtered through a hydrophobic frit. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, 30-80% EtOAc-PE gradient elution) to give benzyl N-[2-(tert-butoxycarbonylamino)-2-methylpropyl]-N-[ 3-(1,3-dioxoisoindolin-2-yl)-2-oxopropyl]carbamate (260 mg, 54%) as a colorless resinous substance; MS m/z: 524 (M+H) ⁺ .

[00809] Benzyl N-[2-(tert-butoxycarbonylamino)-2-methylpropyl]-N-[3-(1,3-dioxoisoindolin-2-yl)-2-oxopropyl]carbamate (260 mg, 0.48 mmol ) was dissolved in DCM (3 ml) and the solution was cooled to 0°C. TFA (1.8 ml) was added slowly. After 15 minutes, the reaction mixture was concentrated in vacuo. The orange residue was dissolved in methanol, then sodium cyanoborohydride (75 mg, 1.19 mmol) was added. The solution was stirred at ambient temperature for 1 hour. The reaction was stopped with saturated aqueous NaHCO ₃ solution, then extracted with EtOAc (3×40 ml). The combined organics were washed with water (30 ml) and brine (20 ml), then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give benzyl-5-[(1,3-dioxoisoindolin-2-yl)methyl] -3,3-dimethylpiperazine-1-carboxylate (190 mg, 95%) as a colorless resinous substance; MS m/z: 408 (M+H) ⁺ .

[00810] Benzyl 5-[(1,3-dioxoisoindolin-2-yl)methyl]-3,3-dimethylpiperazine-1-carboxylate (190 mg, 0.44 mmol) was dissolved in ethanol (4 ml), then added hydrazine hydrate (64 µl, 1.32 mmol). The colorless solution was then heated at 80°C for 90 minutes. The resulting white suspension was allowed to cool to ambient temperature, then filtered through celite. The filtrate was concentrated, the residue was dissolved in DCM and filtered again. The filtrate was concentrated to give a colorless gum, which was dissolved in DCM (4.5 ml), then cooled to 0°C. Triethylamine (90 µl, 0.66 mmol) was added followed by methanesulfonyl chloride (41 µl, 0.53 mmol) and stirring was continued for 15 min. The reaction was stopped by adding saturated aqueous NaHCO ₃ (10 ml), then the layers were separated and the aqueous layer was extracted with DCM (2 x 30 ml). The combined organics were washed with water and passed through a hydrophobic frit. The organic phase was concentrated and the residue was purified by column chromatography (silica, 20-80% EtOAc-PE gradient elution) to give benzyl 5-(methanesulfonamidomethyl)-3,3-dimethylpiperazine-1-carboxylate (119 mg, 76%) as a colorless oil; MS m/z: 356 (M+H) ⁺ .

[00811] Benzyl 5-(methanesulfonamidomethyl)-3,3-dimethylpiperazine-1-carboxylate (119 mg, 0.33 mmol) was dissolved in ethyl acetate (2.5 ml) and MeOH (600 μl) and placed under H ₂ atmosphere . Pd(OH) ₂ (24 mg 20% w/w, 0.03 mmol) was added and the black suspension was stirred at ambient temperature for 30 minutes. The reaction mixture was filtered through celite and then concentrated to give N-((6,6-dimethylpiperazin-2-yl)methyl)methanesulfonamide A100 as a colorless resin, (71 mg, 96%); MS m/z: 222 (M+H) ⁺ . This substance was used in the next reaction without further purification.

[00812] Synthesis 95: N-(1-(Morpholin-2-yl)propyl)methanesulfonamide A101.

[00813] 1-(4-Benzylmorpholin-2-yl)propan-1-amine (594 mg, 2.54 mmol) and Et ₃ N (707 μl, 5.07 mmol) in DCM (12 ml) cooled to 0 °C in an ice bath, then methanesulfonyl chloride (220 μL, 2.84 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 4 hours. The reaction was stopped with saturated aqueous NaHCO ₃ solution. The layers were separated and the aqueous phase was extracted once with DCM. The combined organics were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give the product as a pale yellow solid (652 mg, 82%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.39-7.17 (m, 5H), 3.86-3.73 (m, 1H), 3.55-3.34 (m, 4H ), 3.31 (m, 2H), 3.23-3.04 (m, 1H), 2.87 (d, J=2.5 Hz, 3H), 2.08-1.97 (m, 1H), 1.97-1.83 (m, 1H), 1.64-1.47 (m, 1H), 1.42-1.23 (m, 1H), 0.87 (td, J= 7.4, 1.3 Hz, 3H); MS m/z: 313 (M+H) ⁺ .

[00814] Pd on C, wet, Degussa (88 mg 10% w/w, 0.08 mmol) was transferred to a nitrogen-filled vessel and the vessel was evacuated and refilled with nitrogen. A solution of N-[1-(4-benzylmorpholin-2-yl)propyl]methanesulfonamide (350 mg, 1.12 mmol) in HCl (14.7 mL of 3 M MeOH, 44.1 mmol) was added and the resulting solution was degassed using vacuum/nitrogen cycles (×3). The atmosphere was changed using vacuum/hydrogen cycles (×3) and the reaction mixture was stirred at ambient temperature for 6 hours. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated in vacuo to give N-(1-(morpholin-2-yl)propyl)methanesulfonamide A101 as a yellow oil (246 mg, 85%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.42 (s, NH), 3.99 (dt, J=12.5, 3.8 Hz, 1H), 3.74 (td, J= 12.4, 2.3 Hz, 1H), 3.63 (ddd, J=11.3, 6.1, 2.1 Hz, 1H), 3.23 (ddt, J=14.9, 9, 2, 3.1 Hz, 2H), 3.17 (m, 2H), 2.96 (s, 3H), 2.87-2.73 (m, 1H), 1.59 (dtd, J=15 ,0, 7.4, 4.7 Hz, 1H), 1.39 (dddd, J=16.7, 14.0, 9.0, 7.2 Hz, 1H), 0.91 (td, J =7.4, 4.6 Hz, 3H); MS m/z: 223 (M+H) ⁺ . This substance was used in the next step without further purification.

[00815] Synthesis 96: Dimethyl((piperidin-3-ylmethyl)imino)-λ6-sulfanone A102.

[00816] Benzyl 3-formylpiperidine-1-carboxylate (100 mg, 0.40 mmol) was dissolved in DCE (2 ml). Dimethylsulfoximine (57 mg, 0.61 mmol) was added followed by NaBH(OAc) ₃ (341 mg, 1.62 mmol) and the mixture was stirred at ambient temperature for 30 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution. The mixture was stirred until gas evolution stopped. The layers were separated and the aqueous phase was extracted with DCM (2×20 ml). The combined organics were washed with brine, filtered through a hydrophobic frit and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica, 30-100% EtOAc-PE, then 0-20% MeOH-DCM gradient elution) to give benzyl-3-[[[dimethyl(oxo)-λ6-sulfanylidene] amino]methyl]piperidine-1-carboxylate as a colorless oil (55 mg, 42%); ¹ H NMR (500 MHz, chloroform-d) δ 7.42-7.28 (m, 5H), 5.15 (d, J =2.8 Hz, 2H), 4.18-4.08 (m , 1H), 3.98 (s, 1H), 2.97 (d, J=8.4 Hz, 9H), 2.76-2.67 (m, 1H), 1.89 (dd, J= 13.3, 4.3 Hz, 1H), 1.70 (s, 2H), 1.50 (s, 1H), 1.31-1.18 (m, 1H); MS m/z: 325 (M+H) ⁺ .

[00817] Benzyl 3-[[[dimethyl(oxo)-λ6-sulfanylidene]amino]methyl]piperidine-1-carboxylate (55 mg, 0.17 mmol) was dissolved in EtOAc (1.2 ml) and MeOH (310 µl) and placed in an _H2 atmosphere. Pd(OH) ₂ (12 mg 20% w/w, 0.02 mmol) was added and the black suspension was stirred at ambient temperature overnight. Pd(OH) ₂ (12 mg 20% w/w, 0.02 mmol) was added. After stirring for 30 minutes, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to give dimethyl((piperidin-3-ylmethyl)imino)-λ6-sulfanone A102, (28 mg, 87%) as a colorless gum, which was used in the next reaction without further purification; MS m/z: 191 (M+H) ⁺ .

[00818] Synthesis 97: (2,5-Dimethylpiperidin-3-yl)methanol A103.

[00819] 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 3 M solution in MeOH, 171 .1 mmol) was stirred with H ₂ supplied from a cylinder for 16 hours at ambient temperature. The reaction mixture was 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 1 M solution in THF) were added successively , 17.4 mmol). The reaction mixture was stirred overnight, then partitioned between EtOAc and water. The organic layer was separated and washed with NH ₄ Cl solution, water, brine, then dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-10% EtOAc-PE gradient elution). The product fractions were combined and concentrated in vacuo to give the product as a colorless oil containing a mixture of diastereoisomers (1.4 g, 33%); ¹ H NMR (400 MHz, MeOH-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) .

[00820] O1-tert-Butyl-O3-methyl-2,5-dimethylpiperidine-1,3-dicarboxylate (1.4 g, 5.16 mmol) was dissolved in THF (42 ml) and cooled to 0°C. Lithium borohydride (10.3 mL of 2 M 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, 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, MeOH-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).

[00821] tert-Butyl 3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate (1.25 g, 5.14 mmol) was dissolved in DCM (62.5 ml) and stirred at 0°C. TFA (6.0 mL, 77.1 mmol) was added and the reaction mixture was allowed to warm slowly to ambient temperature. After stirring for 16 hours, the reaction mixture was concentrated in vacuo. The residue was taken up in MeOH and passed through an ion exchange cartridge, the product was eluted with 2 M methanolic ammonia solution. The filtrate was concentrated in vacuo to give (2,5-dimethylpiperidin-3-yl)methanol A103 as a colorless oil (510 mg, 69%); ¹ H NMR (400 MHz, MeOH-d ₄ ) δ 3.76 (d, 1H), 3.38 (d, 2H), 2.72 (ddd, 1H), 2.45 (dd, 1H), 1 .99 (dtdd, 1H), 1.61 (dddd, 2H), 1.10 (d, 3H), 1.02 -0.95 (m, 1H), 0.92 (d, 3H).

[00822] Synthesis 98: Dimethyl((2-methylpiperidin-3-yl)imino)-λ6-sulfanone A104.

[00823] 3-Bromo-2-methylpyridine (5.17 g, 30.1 mmol), iminodimethyl-λ6-sulfane (2.94 g, 31.6 mmol), Xantphos (1.74 g, 3.0 mmol ) and cesium carbonate (14.7 g, 45.0 mmol) were dissolved in 1,4-dioxane (52 ml). The reaction mixture was degassed (vacuum/N ₂ cycles) and Pd ₂ (dba) ₃ (1.38 g, 1.50 mmol) was added. The reaction flask was purged under N ₂ and the mixture was refluxed for 7 hours, then allowed to cool to ambient temperature. The reaction mixture was filtered, washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, 0-10% MeOH-DCM gradient elution) to give the product as an orange oil (5.46 g, 97%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.96 (dd, 1H), 7.32 (ddd 1H), 7.03 (ddd, 1H), 3.24 (s, 6H), 2, 35 (s, 3H); MS m/z: 185 (M+H) ⁺ .

[00824] To a solution of dimethyl((2-methylpyridin-3-yl)imino)-λ6-sulfanone (5.38 g, 28.6 mmol) in MeCN (53 mL) was added BnBr (3.44 mL, 28.9 mmol). The mixture was refluxed 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 (8.56 g, 84%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.58 (dd, J=6.1, 1.2 Hz, 1H), 8.11 (dd, J=8.5, 1.2 Hz, 1H), 7.81 (dd, J=8.4, 6.1 Hz, 1H), 7.51-7.36 (m, 3H), 7.28-7.14 (m, 2H), 5 .87 (s, 2H), 3.37 (d, J=61.8 Hz, 6H), 2.57 (s, 3H).

[00825] NaBH ₄ (1.28 g, 33.8 mmol) was added in portions to a solution of 1-benzyl-3-((dimethyl(oxo)-λ6-sulfanylidene)amino)-2-methylpyridin-1-ium bromide (4, 0 g, 11.3 mmol) in MeOH (25 ml) at 0°C under N ₂ atmosphere. After 30 minutes, NaBH ₄ (1.28 g, 33.8 mmol) was added and the reaction mixture was stirred for 16 hours while raising the temperature to ambient temperature. The mixture was partitioned between DCM and water. The layers were separated and the aqueous phase was extracted with DCM (×2). The combined organics were dried (MgSO ₄ ), filtered and concentrated in vacuo to give the title product (2.61 g, 83%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.39-7.15 (m, 5H), 3.77-3.51 (m, 2H), 3.11-2.98 (m, 6H ), 2.83-2.68 (m, 2H), 2.42 (ddd, J=12.3, 5.6, 3.4 Hz, 2H), 2.27-2.05 (m, 1H ), 1.95-1.77 (m, 1H), 1.12 (d, J=6.6 Hz, 3H); MS m/z: 279 (H+H) ⁺ .

[00826] Pd(OH) ₂ (1.36 g, 20% w/w, Degussa, 9.68 mmol) was transferred to a nitrogen-filled vessel and the vessel was evacuated and refilled with nitrogen. A solution of ((1-benzyl-2-methyl-1,2,5,6-tetrahydropyridin-3-yl)imino)dimethyl-λ6-sulfanone (2.45 g, 8.80 mmol) in MeOH (120 ml) was then added ) 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 4 days at 60 psi H 2} _pressure . The reaction mixture was filtered through celite, washed with MeOH. The combined filtrates were concentrated in vacuo. ^{The residue was subjected to the reaction conditions again and shaken at 60 psi H 2} _pressure for 1 day. The reaction mixture was filtered through celite, washed with MeOH. The filtrate was concentrated in vacuo to give dimethyl((2-methylpiperidin-3-yl)imino)-λ6-sulfanone A104 as an oil which solidified to a white solid on standing (1.46 g, 83%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.34-3.22 (m, 1H), 3.06-2.97 (m, 6H), 2.88 (d, J=13.0 Hz, 1H), 2.85-2.72 (m, 2H), 2.65-2.54 (m, 2H), 2.41 (td, J=12.0, 2.8 Hz, 1H) , 2.23 (dq, J=8.8, 6.2 Hz, 1H), 1.82-1.70 (m, 2H), 1.69-1.61 (m, 1H), 1.63 -1.47 (m, 2H), 1.40 (qt, J=12.7, 3.9 Hz, 1H), 1.31-1.14 (m, 2H), 0.99 (d, J =6.2 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), a mixture of approximately 1:1 rotamers was observed, therefore doubling all aliphatic peaks; MS m/z: 191 (M+H) ⁺ .

[00827] Synthesis 99: Dimethyl((4-methylpiperidin-3-yl)imino)-λ6-sulfanone A105.

[00828] Using the same procedure as used above for A104, ((1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)imino)dimethyl-λ6-sulfanone was prepared using 3- bromo-4-methylpyridine instead of 3-bromo-2-methylpyridine.

[00829] ((1-Benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)imino)dimethyl-λ6-sulfanone (860 mg, 3.03 mmol), Pd(OH) ₂ ( 425 mg, 3.03 mmol), AcOH (258 μl, 4.54 mmol) in MeOH was shaken in a Parr hydrogenator at ambient temperature with an H ₂ pressure of 60 lbf/in ² for 48 hours. The reaction mixture The residue containing

[00830] Dimethyl((4-methylpiperidin-3-yl)imino)-λ6-sulfanone A105 was used immediately in the next reaction without purification; MS m/z: 191 (M+H) ⁺ .

[00831] Synthesis 100: Dimethyl(((2-methylpiperidin-3-yl)methyl)imino)-λ6-sulfanone A106.

[00832] Benzyl 3-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (500 mg, 1.90 mmol) was dissolved in DCM (19 ml), then Dess-Martin periodinane (967 mg, 2.28 mmol) was added. . The resulting suspension was stirred at ambient temperature for 50 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution and stirring for 20 minutes. The layers were separated and the aqueous layer was extracted with DCM (2×20 ml). The combined organics were dried (Na ₂ SO ₄ ), filtered through a hydrophobic frit and purified by column chromatography (silica, 0-40% EtOAc-PE gradient elution) to give benzyl-3-formyl-2-methylpiperidin- 1-carboxylate (360 mg, 47%); MS m/z: 262 (M+H) ⁺ .

[00833] Benzyl 3-formyl-2-methylpiperidine-1-carboxylate (360 mg, 1.38 mmol) was dissolved in DCE (14 ml), then dimethylsulfoximine (193 mg, 2.07 mmol) was added, then NaBH(OAc ) ₃ (1.13 g, 5.51 mmol). After 80 minutes, the reaction was stopped by adding a saturated aqueous solution of NaHCO ₃ and stirring until gas evolution ceased. The layers were separated and the aqueous phase was extracted with DCM (2×20 ml). The combined organics were washed with brine, filtered through a hydrophobic frit and purified by column chromatography (silica, 0-20% MeOH-DCM gradient elution) to give benzyl-3-(((dimethyl(oxo)-λ6-sulfanylidene )amino)methyl)-2-methylpiperidine-1-carboxylate (260 mg, 56%) as a colorless oil; MS m/z: 261 (M-SOMe ₂ ) ⁺ .

[00834] Benzyl 3-(((dimethyl(oxo)-λ6-sulfanylidene)amino)methyl)-2-methylpiperidine-1-carboxylate (260 mg, 0.768 mmol) was dissolved in EtOAc (6 ml) and MeOH (1, 5 ml) and placed in an H ₂ atmosphere. Pd(OH) ₂ (54 mg 20% w/w, 0.08 mmol) was added and the black suspension was stirred at ambient temperature for 15 minutes. The reaction mixture was filtered through celite and then concentrated in vacuo to give dimethyl-[(2-methyl-3-piperidyl)methylimino]-oxo-λ6-sulfane A106 (145 mg, 92%) as a colorless gum; MS m/z: 205 (M+H) ⁺ .

[00835] Synthesis 101: N-((4-Hydroxy-2,4,5-trimethylpiperidin-3-yl)methyl)methanesulfonamide, A107.

[00836] A mixture of ethyl 3-amino-2-methylpropanoate (6.0 g, 45.7 mmol) and (E)-but-2-enenitrile (4.0 ml, 49.1 mmol) in ethanol (60 ml ) was refluxed for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to give a colorless oil. The residue was purified by column chromatography (silica, 5-100% [EtOAc+1% Et ₃ N]-PE gradient elution) to give the product as an oil (2.5 g, 28%); MS m/z: 199 (M+H) ⁺ .

[00837] Ethyl 3-[(2-cyano-1-methylethyl)amino]-2-methylpropanoate (1.46 g, 7.36 mmol) and K ₂ CO ₃ (3.6 ml 4 M aqueous solution, 14 .5 mmol) were combined in 1,4-dioxane (3.4 ml) and water (6.7 ml) and di-tert-butyl dicarbonate (2.67 g, 12.2 mmol) was added. The mixture was stirred at ambient temperature for 16 hours, then diluted with saturated aqueous sodium bicarbonate and extracted with EtOAc. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-65% EtOAc-PE gradient elution) to give ethyl 3-[tert-butoxycarbonyl-(2-cyano-1-methylethyl)amino]-2-methylpropanoate ( 2.3 g, quantitative yield) as a colorless oil, which was used in the next step without further purification; ¹ H NMR (500 MHz, chloroform-d) δ 4.17 (qtd, 2H), 3.87 (dt, 1H), 3.48-3.27 (m, 2H), 2.87 (d, 2H ), 2.71-2.51 (m, 1H), 1.49 (d, 9H), 1.37 (dd, 3H), 1.28 (td, 3H), 1.22-1.12 ( m, 3H).

[00838] Potassium tert-butoxide (958 mg, 8.54 mmol) in toluene (50 ml) was heated at 75°C, then ethyl 3-[tert-butoxycarbonyl-(2-cyano-1-methylethyl)amino] was added -2-methylpropanoate (2.39 g, 8.00 mmol). The mixture was refluxed. After 2 hours, potassium tert-butoxide (200 mg, 1.78 mmol) was added. After 4 hours, the reaction mixture was allowed to cool to ambient temperature and then concentrated in vacuo. The residue was partitioned between DCM and water and the layers were separated. The aqueous phase was acidified to pH 4 and extracted with EtOAc (×2). The combined extracts were dried (MgSO ₄ ), filtered and concentrated to give tert-butyl-3-cyano-2,5-dimethyl-4-oxopiperidine-1-carboxylate (1.14 g, 56%) as an orange oil, which was immediately used in the next reaction; ¹ H NMR (500 MHz, chloroform-d) δ 5.11 (d, J=30.5 Hz, 1H), 4.13 (d, J=7.1 Hz, 1H), 4.00 (d, J=5.8 Hz, 1H), 3.53-3.47 (m, 1H), 2.70 (qdd, J=7.1, 3.9, 3.0 Hz, 1H), 1.53 (d, J=1.4 Hz, 9H), 1.34-1.28 (m, 3H), 1.25 (s, 3H).

[00839] tert-Butyl-3-cyano-2,5-dimethyl-4-oxopiperidine-1-carboxylate (1.14 g, 4.52 mmol) in EtOH (23 ml) and CHCl ₃ (500 μl) was purged ( ×3 cycles of N ₂ /vacuum), then PtO ₂ (180 mg, 0.79 mmol) was added. N ₂ was replaced with H ₂ (×3 purge vacuum/H ₂ ) and the reaction mixture was stirred at ambient temperature for 16 hours. PtO ₂ (56 mg, 0.25 mmol) was added and the reaction mixture was stirred for 24 hours. The mixture filtered through celite, washed with MeOH. The filtrate was concentrated to give tert-butyl 3-(aminomethyl)-4-hydroxy-2,5-dimethylpiperidine-1-carboxylate (1.18 g, 100%), which was immediately used in the next reaction; MS m/z: 259 (M+H) ⁺ .

[00840] tert-Butyl-3-(aminomethyl)-4-hydroxy-2,5-dimethylpiperidine-1-carboxylate (1.18 g, 4.57 mmol) in DCM (20 ml) was cooled to 0°C, then treated with Et ₃ N (1.9 ml, 13.7 mmol), then methanesulfonyl chloride (354 μl, 4.57 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature. After stirring for 3 hours, the reaction mixture was partitioned between saturated aqueous sodium bicarbonate and DCM. The layers were separated and the organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was partially purified by column chromatography (silica, 0-10% MeOH-DCM gradient elution) to give a mixture of O- and N-mesylated products (575 mg) as an orange oil. This material was dissolved in DCM (5 ml) under N ₂ atmosphere and the solution was cooled in an ice bath. Dess-Martin periodinane (750 mg, 1.77 mmol) was added and the reaction mixture was stirred for 18 hours while raising the temperature to ambient temperature. The resulting solution was diluted with DCM, saturated aqueous sodium thiosulfate and saturated aqueous NaHCO ₃ . After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. The organic phase was concentrated in vacuo and the residue was taken up in THF (10 ml) under N ₂ atmosphere. The solution was cooled to 0°C and MeMgBr (3 ml of 3 M solution in ether, 9 mmol) was added dropwise. The reaction mixture was stirred for 18 hours with the temperature raised to ambient temperature. The reaction mixture was diluted with EtOAc. The organic phase was washed with 10% aqueous citric acid, saturated aqueous sodium bicarbonate and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was taken up in DCM (2 ml), TFA (2 ml) was added and the resulting mixture was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo to give a brown oil containing N-((4-hydroxy-2,4,5-trimethylpiperidin-3-yl)methyl)methanesulfonamide A107 (400 mg), which was used in the next reaction without further purification; MS m/z: 251 (M+H) ⁺ .

[00841] Synthesis 102: Diethyl((5-methylpiperidin-3-yl)imino)-λ6-sulfanone A108.

[00842] 3-Bromo-5-methylpyridine (676 mg, 3.93 mmol), diethyl(imino)-λ6-sulfanone (500 mg, 4.13 mmol), Xantphos (227 mg, 0.39 mmol) and carbonate cesium (1.92 g, 5.89 mmol) was dissolved in 1,4-dioxane (7 ml). The reaction mixture was degassed (vacuum/nitrogen cycles) and Pd ₂ (dba) ₃ (180 mg, 0.20 mmol) was added. The reaction flask was purged under N ₂ and the mixture was refluxed for 4 hours. The reaction mixture was cooled to ambient temperature and filtered, washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (40 g silica, 0-10% MeOH-DCM gradient elution) to give the product as a yellow solid (741 mg, 89%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.00 (d, J=2.6 Hz, 1H), 7.90 (dd, J=1.9, 0.9 Hz, 1H), 7 .15 (ddd, J=2.7, 1.9, 0.8 Hz, 1H), 3.37-3.26 (m, 4H), 2.21 (d, J=0.7 Hz, 3H ), 1.26 (t, J=7.4 Hz, 6H); MS m/z: 213 (M+H) ⁺ .

[00843] To a solution of diethyl-[(5-methyl-3-pyridyl)imino]-oxo-λ6-sulfane (741 mg, 3.49 mmol) in MeCN (11 mL) was added BnBr (420 μL, 3.53 mmol ). The mixture was refluxed for 3 hours and then cooled to ambient temperature. The resulting precipitate was collected by filtration and washed with MeCN. The filtrate was concentrated and the residue was triturated with MeCN. This was combined with the first portion to give (1-benzyl-5-methyl-3-pyridyl)iminodiethyloxo-λ6-sulfane bromide as a white solid (855 mg, 64%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.64-8.38 (m, 2H), 7.88 (ddd, 1H), 7.66-7.23 (m, 5H), 5, 67 (s, 2H), 3.53 (q, 4H), 2.40 (d, 3H), 1.28 (t, 6H).

[00844] To a solution of (1-benzyl-5-methyl-3-pyridyl)iminodiethyloxo-λ6-sulfan bromide (855 mg, 2.23 mmol) in MeOH (11 ml) was added NaBH ₄ (169 mg, 4.46 mmol) at 0°C. The reaction mixture was stirred for 30 minutes, then NaBH ₄ (84 mg, 2.23 mmol) was added. Two additional additions of NaBH ₄ (84 mg, 2.23 mmol) were made at 60 and 90 minutes. After 2 hours, the reaction mixture was diluted with water and concentrated in vacuo. The residue was partitioned between DCM and water. The organic layer was separated, dried (MgSO ₄ ), filtered and concentrated in vacuo to give the product as a yellow oil (585 mg), which was immediately used in the next reaction; MS m/z: 307 (M+H) ⁺ .

[00845] Pd(OH) ₂ (206 mg, 1.47 mmol) was added to a solution of ((1-benzyl-5-methyl-1,2,5,6-tetrahydropyridin-3-yl)imino)diethyl-λ6- sulfanone (585 mg, 1.34 mmol) and AcOH (150 μl, 2.64 mmol) in MeOH (15 ml). The mixture was shaken in ^{a Parr hydrogenator at 60 psi H 2} _pressure for 24 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue containing diethyl((5-methylpiperidin-3-yl)imino)-λ6-sulfanone A108 was immediately used in the next reaction; MS m/z: 219 (M+H) ⁺ .

[00846] Synthesis 103: Cyclopropyl(methyl)((5-methylpiperidin-3-yl)imino)-λ6-sulfanone, A109.

[00847] Following the procedure used above for A108, cyclopropyl(methyl)((5-methylpiperidin-3-yl)imino)-λ6-sulfanone, A109, [MS m/z: 217 (M+H) ⁺ ] was prepared from using cyclopropyl(imino)(methyl)-λ6-sulfanone instead of diethyl(imino)-λ6-sulfanone.

[00848] Synthesis 104: Ethyl(methyl)((5-methylpiperidin-3-yl)imino)-λ6-sulfanone A110.

[00849] Similarly, ethyl(methyl)((5-methylpiperidin-3-yl)imino)-λ6-sulfanone A110 was prepared using ethyl(imino)(methyl)-λ6-sulfanone instead of diethyl(imino)-λ6-sulfanone ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.88-2.79 (m, 3H), 2.71-2.57 (m, 2H), 2.14-2.03 (m, 1H ), 1.83-1.73 (m, 1H), 1.27-1.12 (m, 5H), 0.98-0.88 (m, 4H), 0.76 (d, J=6 ,6 Hz, 3H).

[00850] Synthesis 105: ((2,5-Dimethylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone A111.

[00851] Xantphos (622 mg, 1.08 mmol), cesium carbonate (5.25 g, 16.1 mmol) and Pd ₂ (dba) ₃ (492 mg, 0.54 mmol) were combined under N ₂ atmosphere. The mixture was dissolved in 1,4-dioxane (22 ml), then 3-bromo-2,5-dimethylpyridine (2.0 g, 10.8 mmol) and iminodimethyl-λ6-sulfanone (1.05 g, 11.3 mmol). The reaction mixture was heated at 105°C for 4 hours, then cooled to ambient temperature. The reaction mixture was filtered, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica, 0-20% MeOH-DCM gradient eluting) to give the product as a pale yellow solid (1.85 g, 87%); ¹ H NMR (500 MHz, chloroform-d) δ 7.99 (dd, 1H), 7.31-7.27 (m, 1H), 3.17 (s, 6H), 2.44 (s, 3H ), 2.26 (q, 3H); MS m/z: 199 (M+H) ⁺ .

[00852] BnBr (420 μL, 3.46 mmol) was added to a solution of (2,5-dimethyl-3-pyridyl)iminodimethyl-λ6-sulfane (680 mg, 3.43 mmol) in MeCN (17 mL). The resulting white suspension was heated at 85°C. After stirring for 3 hours, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was triturated with TBME (20 ml) and MeCN. The resulting solid was collected by filtration and dried overnight under vacuum to give 1-benzyl-3-((dimethyl(oxo)-λ6-sulfanylidene)amino)-2,5-dimethylpyridinium-1-ium bromide as a white solid (1 .1 g, 87%); MS m/z: 289 (M ⁺ ).

[00853] Platinum oxide (25 mg, 0.11 mmol) was added to the flask under a nitrogen atmosphere, then 1-benzyl-3-((dimethyl(oxo)-λ6-sulfanylidene)amino)-2,5-dimethylpyridine-1 was added -ium bromide (200 mg, 0.54 mmol), methanol (2.7 ml) and triethylamine (151 μl, 1.08 mmol). The flask was purged with air (evacuate/refill with N ₂ x 3), then placed under H ₂ and stirred at ambient temperature. After 90 minutes, platinum oxide (25 mg, 0.11 mmol) was added and stirring was continued for 90 minutes. Platinum oxide (25 mg, 0.11 mmol) was added and stirring was continued for 2 hours. Pd(OH) ₂ (8 mg, 0.05 mmol) was added and stirring was continued for 16 hours.

[00854] The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue, which contained ((2,5-dimethylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone, A111 (190 mg, 17%) was immediately used in the next reaction without further purification; MS m/z: 201 (M+H) ⁺ .

[00855] Synthesis 106: ((5-Ethylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone A112.

[00856] Following the procedure used above for A111, ((5-ethylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone A112 [MS m/z: 205 (M+H) ⁺ ] was prepared using 3-bromo- 5-ethylpyridine instead of 3-bromo-2,5-dimethylpyridine.

[00857] Synthesis 107: 1-((5-Methylpiperidin-3-yl)imino)tetrahydro-1H-1 ^λ6 -thiophene-1-oxide A113.

[00858] Using the same procedure as used for A108, 1-((5-methylpiperidin-3-yl)imino)tetrahydro-1H-1 ^λ6 -thiophene-1-oxide A113 [MS m/z: 217 (M+ H) ⁺ ] was prepared using 1-iminotetrahydro-1H-1 ^λ6 -thiophene-1-oxide instead of diethyl(imino)-λ6-sulfanone.

[00859] Synthesis 108: Dimethyl((5-(trifluoromethyl)piperidin-3-yl)imino)-λ6-sulfanone A114.

[00860] Following the same procedure as used for A111, dimethyl((5-(trifluoromethyl)piperidin-3-yl)imino)-λ6-sulfanone A114 was prepared using 3-bromo-5-(trifluoromethyl)pyridine instead of 3- bromo-2,5-dimethylpyridine. The crude reaction mixture after the hydrogenation reaction was immediately used in the next reaction.

[00861] Synthesis 109: 2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazine A115.

[00862] 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) and 1,4-dioxane (100 ml) was added. Pd(PPh ₃ ) ₄ (2 g, 2 mmol) and Na ₂ CO ₃ (60 ml 2 M, 100 mmol) and the solution was evacuated and refilled with N ₂ (×2). The solution was heated at 100°C and stirred for 16 hours. 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 column chromatography (silica, 0-100% [EtOAc+2% 2 M methanol ammonia]-PE gradient elution) 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) ⁺ .

[00863] 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 3 M 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 A115 as an off-white solid (4.0 g, 61%) which was used in the following reactions assuming the release of dihydrochloride; MS m/z: 181 (M+H) ⁺ .

[00864] Synthesis 110: Dimethyl((5-methylpiperidin-3-yl)imino)-λ6-sulfanone A116.

[00865] Following the same procedure as used for A104, dimethyl((5-methylpiperidin-3-yl)imino)-λ6-sulfanone A116 [MS m/z: 191 (M+H) ⁺ ] was prepared using 3- bromo-5-methylpyridine instead of 3-bromo-2-methylpyridine.

[00866] Synthesis 111: N-((4-Methoxypiperidin-2-yl)methyl)methanesulfonamide A117.

[00867] Methanesulfonyl chloride (1.4 mL, 18.09 mmol) was added with stirring to a solution of (4-methoxy-3-pyridyl)methanamine (2 g, 14.5 mmol) and Et ₃ N (3.0 mL, 21 .5 mmol) in THF (50 ml) under nitrogen and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ 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 (MgSO ₄ ), filtered and concentrated in vacuo. The residue was triturated with DCM and the precipitate was isolated by filtration to give N-[(4-methoxy-3-pyridyl)methyl]methanesulfonamide as a beige solid (1.82 g, 58%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.41 (d, 1H), 8.36 (s, 1H), 7.38 (t, 1H), 7.05 (d, 1H), 4 .14 (d, 2H), 3.88 (s, 3H), 2.90 (s, 3H).

[00868] Mixture of N-[(4-methoxy-3-pyridyl)methyl]methanesulfonamide (50 mg, 0.23 mmol), 10% Pd at C, wet, Degussa (100 mg 10% w/w, 0 .09 mmol) in acetic acid (2 ml)/methanol (5 ml) was stirred at ambient temperature for 18 h under H ₂ atmosphere. The reaction mixture was filtered through a Celite cartridge and washed with MeOH. The filtrate was concentrated under reduced pressure to give a colorless oil containing N-((4-methoxypiperidin-2-yl)methyl)methanesulfonamide A117, which was immediately used in the next reaction without further purification; MS m/z: 223 (M+H) ⁺ .

[00869] Synthesis 112: (R)-Dimethyl((morpholin-2-ylmethyl)imino)-λ6-sulfanone A118.

[00870] In the preparation procedure of A5, (R)-dimethyl((morpholin-2-ylmethyl)imino)-λ6-sulfanone A118 [MS m/z: 193 (M+H) ⁺ ] was prepared using tert-butyl-( R)-2-formylmorpholine-4-carboxylate instead of tert-butyl-(S)-2-formylmorpholine-4-carboxylate.

[00871] Synthesis 113: N-((4-Fluoro-5-methyl-1,2,5,6-tetrahydropyridin-3-yl)methyl)methanesulfonamide A119.

[00872] Mixture of benzyl 5-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoro-3-methyl-3,6-dihydro-2H-pyridine-1-carboxylate (600 mg, 1. 47 mmol) (formed as a by-product of the fluorination reaction described in preparation of A46) and hydrazine hydrate (290 µl, 2.9 mmol) in ethanol (15 ml) were refluxed for 2 hours. The reaction mixture was cooled to ambient temperature medium and filtered, washed with EtOH. The filtrate was concentrated under reduced pressure and the residue was taken up in DCM (10 ml). Et ₃ N (300 μl, 2.2 mmol) and methanesulfonyl chloride (140 μl, 1.8 mmol) were added and the mixture was stirred at ambient temperature for 2 hours. The solution was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 min, the organic phase was isolated using a phase separation cartridge. To this solution was added Et ₃ SiH (300 μl, 1.9 mmol) and Et ₃ N (300 μl, 2.2 mmol), then Pd(OAc) ₂ (30 mg, 0.13 mmol). The solution was stirred at ambient temperature for 90 min, then diluted with methanol. The solution was loaded into an ion exchange cartridge, washed with methanol, and then the product was eluted with a 2 M methanol ammonia solution. The filtrate was concentrated under reduced pressure to give a yellow resinous substance containing N-((4-Fluoro-5-methyl-1,2,5,6-tetrahydropyridin-3-yl)methyl)methanesulfonamide A119, which was used in the next reaction without further cleaning; MS m/z: 223 (M+H) ⁺ .

[00873] Synthesis 114: (4,4-Difluoro-5-methylpiperidin-3-yl)methanol A120.

[00874] Ethyl 1-benzyl-5-methyl-4-oxopiperidine-3-carboxylate (10.0 g, 1 eq.) was placed in a 250 ml stainless steel autoclave. The vessel was cooled to -60°C and anhydrous HF (7 eq.) was added under reduced pressure. The vessel was cooled to -90°C with liquid N ₂ and SF ₄ (3 eq.) was added. An ectotherm from -90°C to -48°C was observed. The vessel was cooled below -70°C and then allowed to warm to ambient temperature for 21 hours (4 bar pressure). The pressure from the vessel was released through a gas scrubber containing KOH. DCM (10 vol) was added and the reaction mixture was poured onto ice (5 wt/v). The mixture was made alkaline to pH 8 with KHCO ₃ solution and the mixture was stirred for 20 minutes. The layers were separated and the aqueous phase was extracted with DCM (2×20 volumes). The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue contained a mixture of two diastereoisomers and was purified by column chromatography (silica, 0-1% EtOAc-PE to elute one isomer, then 1-100% EtOAc-PE to elute the second). The product fractions were combined and concentrated in vacuo. The first eluting isomer was obtained as a solid (3.0 g) and the second eluting isomer as a yellow oil (5.8 g) (81% overall yield); MS m/z: 298 (M+H) ⁺ . The main isomer was used in the next step.

[00875] LiBH ₄ (618 μL 2 M, 1.24 mmol) at ambient temperature. MeOH (50 μL, 1.2 mmol) was added to the clear yellow solution and the reaction mixture was heated at 50°C. After 45 minutes, the reaction mixture was cooled to ambient temperature, then further cooled in an ice bath. A saturated aqueous solution of NH ₄ Cl was added and the mixture was stirred until gas evolution ceased. The mixture was diluted with water and EtOAc. The organic layer was separated, washed with brine (1×), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was taken up in MeOH (1.5 ml) and Pd/C (7 mg 10% w/w, 0.06 mmol) was added. The mixture was degassed (×3 vacuum cycles - N ₂ ) and filled with H ₂ (×3 vacuum cycles - H ₂ ). The reaction mixture was stirred at ambient temperature. After 3 hours, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and the residue containing (4,4-difluoro-5-methylpiperidin-3-yl)methanol A120 (100 mg) was used immediately in the next reaction without further purification; MS m/z: 166 (M+H) ⁺ .

[00876] Synthesis 115: N-((4,4-difluoro-2,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide diastereoisomers A121, A122 and A123.

[00877] Cbz-Cl (10 mL, 70 mmol) was added to 2,5-dimethylpiperidin-4-one (10 g, 78.6 mmol) and K ₂ CO ₃ (25 g, 180.9 mmol) in EtOAc ( 200 ml) and water (100 ml). The reaction mixture was stirred vigorously at ambient temperature. After 18 h, the organic phase was isolated. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with water and brine, then dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient eluting) to give the product as a colorless oil (6.5 g, 32%); MS m/z: 262 (M+H) ⁺ .

[00878] LiHMDS (16 mL 1 M, 16 mmol) was added dropwise to a solution of benzyl 2,5-dimethyl-4-oxopiperidine-1-carboxylate (3.8 g, 14.5 mmol) in THF (70 mL) , cooled to -78°C in an N ₂ atmosphere. After 90 min, a solution of 2-(chloromethyl)isoindoline-1,3-dione (3.4 g, 17.4 mmol) in THF (2 ml) was added dropwise. After 1 hour, the reaction mixture was allowed to warm to 0°C, then the reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl (~10 ml). The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. Organic matter was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution). Two diastereoisomers were isolated as colorless oils: diastereoisomer 1 (700 mg) and diastereoisomer 2 (2.0 g).

[00879] Diastereoisomer 1 (600 mg, 1.43 mmol) and DAST (5 mL, 38 mmol) were stirred at ambient temperature for 3 days, then poured dropwise into DCM/ice/water/NaHCO ₃ while stirring. This mixture was stirred for 30 minutes. The organic phase was isolated using a phase separation cartridge. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica, 0-50% EtOAc-PE gradient elution) to give a colorless oil (450 mg), which was immediately used in the next reaction; MS m/z: 443 (M+H) ⁺ .

[00880] A mixture of benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-2,5-dimethylpiperidine-1-carboxylate (450 mg, 1.02 mmol) and hydrazine hydrate ( 150 μl, 3.06 mmol) in ethanol (4 ml) was refluxed for 2 h, then allowed to cool to ambient temperature. The reaction mixture was filtered, washed with MeOH and the filtrate was poured into a pre-wetted ion exchange cartridge. The cartridge was washed with methanol, then the product was eluted with 2 M methanol ammonia solution. The filtrate was concentrated under reduced pressure to give a colorless oil. The residue was dissolved in DCM (3 ml). Et ₃ N (200 μl, 1.44 mmol) and methanesulfonyl chloride (70 μl, 0.9 mmol) were added under N ₂ and the solution was stirred at ambient temperature. After 2 hours, the reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 minutes, the organic layer was isolated using a phase separation cartridge. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give a colorless oil (180 mg), which was immediately used in the next reaction; MS m/z: 391 (M+H) ⁺ .

[00881] Mixture of benzyl 4,4-difluoro-3-(methanesulfonamidomethyl)-2,5-dimethylpiperidine-1-carboxylate (180 mg, 0.46 mmol), Et ₃ SiH (150 μl, 0.939 mmol), Et ₃ N (180 µl, 1.3 mmol) and Pd(OAc) ₂ (50 mg, 0.2 mmol) in DCM (4 ml) were stirred at ambient temperature for 2 h, then diluted with methanol (~ 5 ml). The mixture was poured into a pre-moistened ion exchange cartridge. The cartridge was washed with methanol, then the product was eluted with 2 M methanol ammonia solution. The filtrate was concentrated under reduced pressure to give a brown oil containing A121 (120 mg), which was immediately used in the next reaction without further purification; MS m/z: 257 (M+H) ⁺ .

[00882] A122 [MS m/z: 257 (M+H) ⁺ ] was prepared similarly using diastereoisomer 2 as the starting material and was immediately used in the next reaction.

[00883] Diastereoisomer 3 was prepared by mixing diastereoisomer 2 (600 mg, 1.43 mmol) in THF (7 ml) with DBU (150 μl, 1.00 mmol) in THF (7 ml) at ambient temperature for 20 hours The reaction mixture was diluted with EtOAc, washed with 2 M aqueous HCl, saturated aqueous sodium bicarbonate and brine. Organic matter was dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. Diastereoisomer 3 was obtained as a white foam (600 mg), which was processed as above to give A123 [MS m/z: 257 (M+H) ⁺ ], which was immediately used in the next reaction.

[00884] Synthesis 116: N-(((2S,3R,5S)-4,4-Difluoro-2,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide A124.

[00885] Ethyl (S)-3-(((S)-1-phenylethyl)amino)butanoate (40 g, 170 mmol) was dissolved in MeCN (400 ml). Ethyl 2-(bromomethyl)acrylate was dissolved in MeCN (100 ml) and added to the amine solution. K ₂ CO ₃ (47 g, 340 mmol) was added and the mixture was stirred overnight at ambient temperature. The reaction mixture was filtered, washed with MeCN. The filtrate was evaporated in vacuo to give an oily solid. The residue was taken up in DCM (~400 ml) and purified by column chromatography (silica, eluting with DCM). Fractions containing product were combined and concentrated in vacuo to give ethyl (3S)-3-[2-ethoxycarbonylallyl-[(1S)-1-phenylethyl]amino]butanoate as a colorless oil (38.8 g, 65%); MS m/z: 348 (M+H) ⁺ .

[00886] Ethyl (3S)-3-[2-ethoxycarbonylallyl-[(1S)-1-phenylethyl]amino]butanoate (33.4 g, 96.0 mmol) was dissolved in anhydrous THF (500 ml) in a flame dried three-neck round-bottomed flask with a volume of 1000 ml, equipped with a thermocouple, in an atmosphere of N ₂ . The flask was cooled to 0°C in an ice bath. KO ^t Bu (210 ml of 1 M solution, 210 mmol) was added using a syringe. After 30 minutes, the reaction mixture was poured into saturated aqueous NH ₄ Cl and extracted with Et ₂ O. The extract was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was transferred to DCM and passed through a pad of silica gel, eluting with DCM. The filtrate was concentrated in vacuo to give the product as a light yellow oil (27.9 g, 96%); MS m/z: 302 (M+H) ⁺ .

[00887] Acetyl chloride (200 ml, 2.8 mol) was dissolved in EtOH (2.6 L). The solution was stirred for 30 min and then added to ethyl (2S)-2-methyl-5-methylene-4-oxo-1-[(1S)-1-phenylethyl]piperidine-3-carboxylate (223 g, 740 mmol ). Pd/C (50 g 10% w/w, 47 mmol) was added. The atmosphere was evacuated in a vacuum and replaced with hydrogen from a cylinder. The reaction mixture was stirred at ambient temperature for 9 days, then filtered through a pad of celite, washed with EtOH. The filtrate was concentrated in vacuo. The residue was dissolved in THF (1 L). NaOH (1 L of 1 M aqueous solution) was added to this solution. The mixture was cooled in an ice bath and CbzCl (110 mL, 771 mmol) was added dropwise. The mixture was stirred overnight at ambient temperature. MTBE was added and the layers were separated. The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo. This material was combined with the product of a separate reaction using ethyl (2S)-2-methyl-5-methylene-4-oxo-1-[(1S)-1-phenylethyl]piperidine-3-carboxylate (303 g, 1.0 praying). The combined material was purified by column chromatography (silica, 10-40% DCM-heptane gradient elution). Two isomers were isolated (total yield 32%): the main anti-isomer benzyl (2S,5R)-2,5-dimethyl-4-oxopiperidine-1-carboxylate (105 g); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.43-7.27 (m, 5H), 5.11 (q, 2H), 4.36 (pd, 1H), 3.71 (dd, 1H), 3.62 (dd, 1H), 2.84 (dd, 1H), 2.51 (m, 1H), 2.28 (dd, 1H), 1.16 (d, 3H), 1, 00 (d, 3H); and the minor syn isomer benzyl (2S,5S)-2,5-dimethyl-4-oxopiperidine-1-carboxylate (43 g); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.46-7.27 (m, 5H), 5.21-5.05 (m, 2H), 4.72 (q, 1H), 4, 22 (d, 1H), 2.89 (d, 1H), 2.80-2.70 (m, 1H), 2.67-2.53 (m, 1H), 2.13 (dd, 1H) , 1.06 (d, 3H), 0.90 (d, 3H).

[00888] A solution of benzyl (2S,5S)-2,5-dimethyl-4-oxopiperidine-1-carboxylate (46.3 g, 177.2 mmol) in THF (280 ml) was cooled to -78°C, then LiHMDS (1 M in THF) (212 ml of 1 M, 212 mmol) was added at a rate such that the temperature remained below -65°C. After addition was complete, the mixture was stirred at -78°C for an additional 10 min, then a solution of 2-(chloromethyl)isoindoline-1,3-dione (41.6 g, 213 mmol) in THF (230 ml) was added at a rate so that the temperature remains below -65°C. After the addition of the cooling bath was completed, the solid carbon dioxide/acetone was removed and the reaction flask was placed in an ice/water bath. The reaction mixture was allowed to warm to 0°C for 30 min. The mixture was re-cooled to -78°C, then the reaction was carefully stopped with saturated aqueous NH ₄ Cl (93 ml) at such a rate that the internal temperature remained below -65°C. After addition was complete, the cooling bath was removed and the mixture was allowed to warm to ambient temperature. EtOAc (500 ml) was added and the organic phase was separated. The organic phase was washed with water (×2), brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. IPA (500 ml) was added to the residue and the resulting solution was kept over the weekend. The resulting crystallized solid was collected by filtration, washed with a minimal amount of IPA and dried in vacuo to give benzyl-(2S,3S,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-2,5-dimethyl- 4-oxopiperidine-1-carboxylate (31 g, 42%) as a colorless solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.95-7.78 (m, 5H), 7.49-7.24 (m, 6H), 5.25-5.07 (m, 2H ), 4.73-4.53 (m, 1H), 4.33 (t, 1H), 3.95-3.75 (m, 2H), 3.01 (s, 2H), 2.70- 2.57 (m, 1H), 1.11 (d, 3H), 0.88 (d, 3H); MS m/z: 421 (M+H) ⁺ .

[00889] Benzyl-(2S,3S,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-2,5-dimethyl-4-oxopiperidine-1-carboxylate (77.1 g, 183 .4 mmol) was suspended in hydrogen chloride (325 ml of 4 M solution in 1,4-dioxane, 1.30 mol). The reaction mixture was stirred at ambient temperature. After 5.5 hours, the resulting yellow solution was diluted with EtOAc (500 ml) and water (200 ml). The organic phase was washed with brine (200 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo to give a yellow oil (102.5 g). IPA (500 ml) was added and the mixture was stirred for 72 hours. The resulting white precipitate was collected by filtration, washed with IPA. The filtrate was concentrated in vacuo and the residue was azeotroped with DCM (×3). The residue was purified by column chromatography (silica, 0-60% EtOAc-heptane gradient elution) to give benzyl-(2S,3R,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl ]-2,5-dimethyl-4-oxopiperidine-1-carboxylate as a pale yellow sticky resinous substance (37.6 g, 49%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.92-7.83 (m, 4H), 7.48-7.08 (m, 5H), 5.22-4.94 (m, 2H ), 4.64 (m, 1H), 4.32 (m, 1H), 3.87 (dd, 1H), 3.61-3.48 (m, 1H), 3.39-3.32 ( m, 1H), 2.90 (m, 1H), 2.77 (br s, 1H), 1.07 (m, 3H), 0.90 (m, 3H); MS m/z: 421 (M+H) ⁺ .

[00890] White solid, benzyl (2S,3S,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-2,5-dimethyl-4-oxopiperidine-1-carboxylate (33, 4 g, 43%) was suspended in hydrogen chloride (160 ml of 4 M solution in 1,4-dioxane, 640 mmol) and the reaction mixture was stirred at ambient temperature. After 5.5 hours, the reaction mixture was diluted with MTBE (220 ml) and water (85 ml). The organic phase was washed with brine (85 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was stirred in IPA (220 ml) overnight. The resulting mixture was processed as above to additionally obtain benzyl-(2S,3R,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-2,5-dimethyl-4-oxopiperidine-1-carboxylate ( 14.7 g, 44%).

[00891] To a solution of benzyl-(2S,3R,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-2,5-dimethyl-4-oxopiperidine-1-carboxylate (51.2 g , 122 mmol) and Deoxofluor ^® (485 ml of a 50% w/v solution in toluene, 1.1 mol) BF ₃ .OEt ₂ (7.4 ml, 60.0 mmol) was added. The mixture was heated at 60°C (internal temperature) for 24 hours. The mixture was then cooled to ambient temperature and the reaction was carefully stopped by slowly adding saturated aqueous NaHCO ₃ (30 ml) with stirring. After addition was complete, the mixture was stirred for 30 minutes. The mixture was then extracted with EtOAc (2×20 ml). The combined organics were washed with water (2×20 ml), brine (20 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-20% EtOAc-PE gradient elution). Fractions containing the product were combined and concentrated in vacuo and the residue was further purified with SFC (15% MeOH @ 5 ml/min on CHIRALPAK IC, 4.6 x 100 mm, 100 bar, 35 C, 220 nm) to give benzyl-( 2S,3R,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-2,5-dimethylpiperidine-1-carboxylate as an orange resinous substance (12.8 g, 24%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97-7.78 (m, 4H), 7.44-7.14 (m, 5H), 5.21-4.95 (m, 2H ), 4.46 (s, 1H), 4.03-3.85 (m, 2H), 3.74-3.53 (m, 1H), 2.96-2.59 (m, 2H), 2.25-1.96 (m, 1H), 1.18 (s, 3H), 1.03-0.85 (m, 3H); MS m/z: 443 (M+H) ⁺ . At this stage, absolute configurations were confirmed using 2D NMR.

[00892] To a solution of benzyl-(2S,3R,5S)-3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-2,5-dimethylpiperidine-1-carboxylate (12, 8 g, 28.8 mmol) in ethanol (190 ml), hydrazine hydrate (3.3 ml, 43 mmol) was added and the resulting solution was refluxed for 2 hours. Additionally, hydrazine hydrate (1.2 ml, 16 mmol) was added and the mixture was refluxed for 16 hours. The mixture was diluted with ethanol (100 ml), cooled to ambient temperature and stirred briefly for 1 hour. The resulting suspension was filtered, washed with a minimum amount of ethanol and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and a minimum amount of water, stirred and the organic phase was separated. The organic substances were washed with water (2×), brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to obtain benzyl-(2S,3R,5S)-3-(aminomethyl)-4,4-difluoro-2, 5-dimethylpiperidine-1-carboxylate (8.3 g, 92%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.45-7.27 (m, 5H), 5.21-5.00 (m, 2H), 4.77-4.57 (m, 1H ), 4.02-3.86 (m, 1H), 3.01 (dd, 1H), 2.77 (dt, 1H), 2.20-1.90 (m, 2H), 1.44 ( s, 2H), 1.09-0.98 (m, 3H), 0.98-0.85 (m, 4H); MS m/z: 313 (M+H) ⁺ .

[00893] A solution of benzyl (2S,3R,5S)-3-(aminomethyl)-4,4-difluoro-2,5-dimethylpiperidine-1-carboxylate (8.27 g, 26.5 mmol) in DCM (100 ml) was cooled to 0°C, then Et ₃ N (4.1 ml, 29 mmol) was added, then methanesulfonyl chloride (2.2 ml, 28 mmol) was added slowly over 2 min. The mixture was stirred in an ice bath for 1 hour. The reaction mixture was washed with water (3×) and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give benzyl-(2S,3R,5S)-4,4-difluoro -3-(methanesulfonamidomethyl)-2,5-dimethylpiperidine-1-carboxylate (10.4 g, quantitative yield) as a yellow foam, which was immediately used in the next reaction without further purification.; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47-7.27 (m, 5H), 7.23 (dd, 1H), 5.24-5.00 (m, 2H), 4, 63 (s, 1H), 4.51 (s, 1H), 4.06-3.86 (m, 1H), 3.39 (dt, 1H), 3.07-2.92 (m, 4H) , 2.92-2.63 (m, 1H), 2.35 (s, 1H), 2.10 (d, 1H), 1.08 (t, 3H), 0.94 (t, 3H); MS m/z: 391 (M+H) ⁺ .

[00894] A mixture of benzyl (2S,3R,5S)-4,4-difluoro-3-(methanesulfonamidomethyl)-2,5-dimethylpiperidine-1-carboxylate (10.6 g, 27.2 mmol) and Pd(OH ) ₂ (1.9 g of 20% w/w, 2.7 mmol) in IPA (100 ml) was heated at 45°C and stirred for 3 days with a supply of hydrogen from a cylinder. The mixture was purged with nitrogen and then filtered through celite, washed with IPA, then EtOAc, then methanol. The filtrate was concentrated in vacuo. Pd(OH) ₂ (1.9 g of 20% w/w, 2.7 mmol) was added to the residue, followed by IPA (160 ml) and the mixture was stirred under hydrogen atmosphere for 16 hours. The mixture was filtered through celite, washed with IPA and EtOAc and concentrated in vacuo. Pd(OH) ₂ (1.9 g of 20% w/w, 2.7 mmol) was added to the residue, followed by IPA (160 ml) and stirred under hydrogen atmosphere for 16 hours. The mixture was filtered through celite, washed with using IPA. The filtrate was concentrated in vacuo, dissolved in methanol (280 ml) and SMP-32 (40.72 g 0.8 mmol/g) was added. The mixture was heated at 50°C and stirred for 3 hours, then cooled to ambient temperature, then filtered through celite, washed with methanol. The filtrate was concentrated in vacuo and dried overnight in vacuo to give N-(((2S,3R,5S)-4,4-difluoro-2,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide A124 (6.06 g , 87%); ¹ H NMR (400 MHz, chloroform-d) δ 3.66 (dh, 1H), 3.50 (dd, 1H), 3.16 (dd, 1H), 3.04-2.89 (m, 4H ), 2.85-2.70 (m, 1H), 2.54-2.34 (m, 1H), 2.20-1.97 (m, 1H), 1.20 (dd, 3H), 1.06-0.93 (m, 3H); MS m/z: 257 (M+H) ⁺ .

[00895] Synthesis 117: Dimethyl((6-methylpiperidin-3-yl)imino)-λ6-sulfanone A125.

[00896] Following the same procedure as used to prepare A104, dimethyl((6-methylpiperidin-3-yl)imino)-λ6-sulfanone A125 [MS m/z: 191 (M+H) ⁺ ] was prepared using 5 -bromo-2-methylpyridine instead of 3-bromo-2-methylpyridine. The crude reaction mixture after the hydrogenation reaction was immediately used in the next reaction.

[00897] Synthesis 118: ((2-(Difluoromethyl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone A126.

[00898] Using the same procedure as used to prepare A111, ((2-(difluoromethyl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone A126 [MS m/z: 227 (M+H) ⁺ ] was prepared using 3-bromo-2-(difluoromethyl)pyridine instead of 3-bromo-2,5-dimethylpyridine. The crude reaction mixture after the hydrogenation reaction was immediately used in the next reaction.

[00899] Synthesis 119: 2-Methyl-3-(1H-pyrazol-4-yl)piperazine A127.

[00900] To a suspension of 2-chloro-3-methylpyrazine (500 mg, 3.89 mmol) in 1,4-dioxane (10 ml) was added tert-butyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazol-1-carboxylate (1.26 g, 4.28 mmol), Pd(Ph ₃ ) ₄ (225 mg, 0.19 mmol) and Na ₂ CO ₃ (5 .8 ml of 2 M aqueous solution, 11.7 mmol). The reaction mixture was stirred in a sealed tube at 130°C for 3 hours, then cooled and filtered through a pad of celite. The filtrate was concentrated in vacuo to give 2-methyl-3-(1H-pyrazol-4-yl)pyrazine (750 mg, 94%) as a white solid; MS m/z: 161 (M+H) ⁺ .

[00901] A mixture of 2-methyl-3-(1H-pyrazol-4-yl)pyrazine (585 mg, 3.65 mmol), PtO ₂ (84 mg, 0.37 mmol) and concentrated HCl (2 ml, 55 mmol ) in methanol (60 ml) was shaken at ambient temperature in ^a Parr hydrogenator at 60 psi H ₂ pressure for 6 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in MeOH and loaded into an ion exchange cartridge. The cartridge was washed with MeOH, then the product was eluted with methanol ammonia. The filtrate was concentrated under reduced pressure to give 2-methyl-3-(1H-pyrazol-4-yl)piperazine A127 (600 mg, 99%) as a brown solid; MS m/z: 167 (M+H) ⁺ . This substance was used in the next reaction without further purification.

[00902] Synthesis 120: Dimethyl(5-methylpiperidin-3-yl)phosphine oxide A128.

[00903] Methylphosphonoylmethane (45 mg, 0.58 mmol), 3-bromo-5-methylpyridine (100 mg, 0.58 mmol), NEt ₃ (324 μl, 2.32 mmol) and Pd(PPh ₃ ) ₄ ( 288 mg, 0.25 mmol) were combined in MeCN (580 µl) and the solution was degassed, then heated to reflux. The reaction mixture was stirred at reflux for 18 hours, then further methylphosphonoylmethane (45 mg, 0.58 mmol) was added. After 1 hour, additional methylphosphonoylmethane (45 mg, 0.58 mmol) was added. After 1 h, the reaction mixture was cooled to ambient temperature, diluted in MeCN and purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 3-dimethylphosphoryl-5-methylpyridine (98 mg , 100%); ¹ H NMR (500 MHz, MeOH-d ₄ ) δ 8.84-8.70 (m, 1H), 8.62 (t, 1H), 8.08 (dt, 1H), 2.46 (s, 3H), 1.88 (s, 3H), 1.85 (s, 3H), MS m/z: 170 (M+H) ⁺ .

[00904] 3-Dimethylphosphoryl-5-methylpyridine (100 mg, 0.59 mmol) and PtO ₂ (27 mg, 0.12 mmol) were combined in methanol (3.3 ml) and HCl (985 μl 3M, 2.96 mmol). The mixture was degassed and stirred with H ₂ from a cylinder for 2 hours, then passed through celite. The filtrate was concentrated in vacuo to give 3-dimethyl(5-methylpiperidin-3-yl)phosphine oxide A128 as a 1:1 mixture of diastereoisomers (189 mg, 100%); MS m/z: 176 (M+H) ⁺ . This substance was used in the next reaction without further purification.

[00905] Synthesis 121: (5,5-Difluoro-2-methylpiperidin-3-yl)methanol A129.

[00906] Mixture of benzyl 5,5-difluoro-3-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (see A64), (110 mg, 0.37 mmol), Pd(OAc) ₂ (35 mg, 0.16 mmol), Et ₃ SiH (140 µl, 0.88 mmol) and Et ₃ N (100 µl, 0.717 mmol) in DCM (4 ml) were stirred at ambient temperature for 1 hour. The reaction mixture was diluted with methanol and the solution was poured into an ion exchange cartridge. The cartridge was washed with methanol, then the product was eluted with 2 M methanol ammonia solution. The filtrate was concentrated in vacuo to give (5,5-difluoro-2-methylpiperidin-3-yl)methanol A129 (55 mg, 91%) as a brown oil; MS m/z: 166 (M+H) ⁺ . This substance was used in the next reaction without further purification.

[00907] Synthesis 122: 2-(3-Methylpiperazin-2-yl)ethan-1-ol A130.

[00908] 2-(3-Methylpyrazin-2-yl)ethanol (930 mg, 6.73 mmol) was dissolved in MeOH (20 ml). HCl (340 μl of 2 M, 0.68 mmol) was added and the mixture was degassed (×3 cycles of vacuum - N ₂ ). Pd on C, wet, Degussa (430 mg 10% w/w, 0.40 mmol) was added and the mixture was degassed (×3 cycles), then the N ₂ atmosphere was replaced with H ₂ (×5 cycles) and the reaction mixture was stirred for 16 hours. Additional Pd was added at C, wet, Degussa (430 mg 10% w/w, 0.404 mmol) was added (degassed as above). After 5 h, Pd at C, wet, Degussa (430 mg 10% w/w, 0.404 mmol) and HCl (340 μl 2 M, 0.680 mmol) were added and the mixture was degassed as above and stirred for a further 16 h. The reaction mixture was degassed with N ₂ then filtered and concentrated in vacuo to give a colorless oil. The residue was taken up in MeOH (~5 ml) and passed through SPE cartridges with bicarbonate. The filtrate was concentrated in vacuo to give 2-(3-methylpiperazin-2-yl)ethan-1-ol A130 as a pale yellow oil (781 mg, 80%), which was immediately used in the next reaction without further purification; MS m/z: 145 (M+H) ⁺ .

[00909] Synthesis 123: N-((5-Methylpiperazin-2-yl)methyl)methanesulfonamide A131.

[00910] Methanesulfonyl chloride (240 μL, 3.10 mmol) was added to an ice-cold solution of (5-methylpyrazin-2-yl)methanamine (300 mg, 2.44 mmol) and Et ₃ N (500 μL, 3.59 mmol) in DCM (4 ml) under N ₂ atmosphere. After addition, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 hours. The solution was diluted with DCM and saturated aqueous NaHCO ₃ solution. The organic phase was isolated using a phase separation cartridge and the filtrate was concentrated under reduced pressure to give a brown oil. This material was combined with PtO ₂ (200 mg, 0.88 mmol) in 3 M methanolic HCl (15 ml, 45 mmol) and stirred vigorously at ambient temperature with H ₂ supplied from a balloon for 18 hours. The reaction mixture was poured directly into the ion exchange cartridge. The cartridge was washed with methanol, then the product was eluted with 2 M methanol ammonia solution. The filtrate was concentrated under reduced pressure to give N-((5-methylpiperazin-2-yl)methyl)methanesulfonamide A131 (271 mg, 56%) as a brown gum, which was used in the next reaction without further purification; MS m/z: 208 (M+H) ⁺ .

[00911] Synthesis 124: trans-(4-Benzyl-6-cyclopropylmorpholin-2-yl)methanol A132 and cis-(4-benzyl-6-cyclopropylmorpholin-2-yl)methanol A133.

[00912] A mixture of 2-amino-1-cyclopropylethanol (1.0 g, 9.9 mmol), benzaldehyde (1.2 mL, 11.8 mmol) and ground 4 Å MS (1 g) in DCE (30 mL) stirred at ambient temperature for 1 hour. NaBH(OAc) ₃ (4.2 g, 19.9 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 15 hours. The mixture was filtered through celite (washed with DCM ) and the filtrate was concentrated in vacuo. The residue was passed through an ion exchange cartridge, washed with MeOH/DCM mixtures and the product was eluted with 2 M NH ₃ in MeOH/DCM mixtures. The solvent was removed in vacuo and the residue was purified by column chromatography (silica, 0-10% [10% NH ₄ OH in MeOH]-DCM gradient elution) to give 2-(benzylamino)-1-cyclopropylethanol (1, 04 g, 55%) as a colorless oil. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.19-7.14 (m, 4H), 7.09-7.06 (m, 1H), 4.33 (d, 1H), 3, 56 (d, 2H), 2.87-2.82 (m, 1H), 2.43 (dd, 1H), 2.39-2.35 (m, 1H), 1.84 (br s, 1H ), 0.68-0.61 (m, 1H), 0.22-0.15 (m, 2H), 0.13-0.07 (m, 1H), 0.02-0.03 (m , 1H); MS m/z: 192 (M+H) ⁺ .

[00913] A solution of 2-(benzylamino)-1-cyclopropylethanol (1.03 g, 5.39 mmol) in toluene (15 mL) was treated with 2-(chloromethyl)oxirane (550 μL, 7.03 mmol) and lithium perchlorate ( 750 mg, 7.05 mmol) and the mixture was stirred at ambient temperature for 22 hours. The mixture was diluted with EtOAc and washed with water (×2). The combined aqueous layers were extracted with EtOAc (×2) and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was dissolved in MeOH (5 ml) and NaOMe (730 mg, 13.5 mmol) was added. The reaction mixture was refluxed for 23 hours, then cooled to ambient temperature and the reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl. The aqueous layer was diluted with water to dissolve the salts, extracted with EtOAc (×3) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc-PE gradient elution) to give trans-(4-benzyl-6-cyclopropylmorpholin-2-yl)methanol (229 mg, 17%) as colorless oil and cis-(4-benzyl-6-cyclopropylmorpholin-2-yl)methanol (293 mg, 22%) as a colorless oil.

[00914] A mixture of trans-(4-benzyl-6-cyclopropylmorpholin-2-yl)methanol (228 mg, 0.92 mmol), Pd at C, wet, Degussa (50 mg, 0.47 mmol) and HCl (10 ml of 3 M in methanol, 30 mmol) was placed under a hydrogen atmosphere and stirred at ambient temperature for 62 hours. The catalyst was removed by filtration through celite, washed with MeOH and the filtrate was concentrated in vacuo. The residue was loaded into an ion exchange cartridge. The cartridge was washed with MeOH/DCM mixtures, then the product was eluted with 2 M NH ₃ in MeOH/DCM mixtures. The filtrates were combined and concentrated in vacuo to give trans-(6-cyclopropylmorpholin-2-yl)methanol A132 (107 mg, 74%) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.52 (br s, 1H), 3.64 (qd, 1H), 3.44 (d, 2H), 2.81-2.75 (m , 3H), 2.57 (ddd, 1H), 1.21-1.14 (m, 1H), 0.46-0.38 (m, 2H), 0.26-0.11 (m, 2H ), MS m/z: 158 (M+H) ⁺ .

[00915] A mixture of cis-(4-benzyl-6-cyclopropylmorpholin-2-yl)methanol (293 mg, 1.19 mmol), Pd on C, wet, Degussa (50 mg, 0.47 mmol) and HCl (3M in methanol) (10 ml, 30 mmol) was placed under a hydrogen atmosphere and stirred at ambient temperature for 62 hours. The catalyst was removed by filtration through celite, washed with MeOH and the filtrate was concentrated in vacuo. The residue was loaded into an ion exchange cartridge. The cartridge was washed with MeOH/DCM mixtures, then the product was eluted with 2 M NH ₃ in MeOH/DCM mixtures. The filtrates were combined and concentrated in vacuo to give cis-(6-cyclopropylmorpholin-2-yl)methanol A133 (93 mg, 50%) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 4.55 (t, 1H), 3.38-3.23 (m, 3H), 2.82-2.78 (m, 2H), 2, 68 (ddd, 1H), 2.38 (dd, 1H), 2.26 (dd, 1H), 0.76-0.69 (m, 1H), 0.43-0.35 (m, 2H) , 0.27-0.15 (m, 2H); MS m/z: 158 (M+H) ⁺ .

[00916] Synthesis 125: 2-[(E)-2-Ethoxyvinyl]-4-methylsulfanylpyrimidine

[00917] A solution of 2-chloro-4-methylsulfanylpyrimidine (1 g, 6.23 mmol), Na ₂ CO ₃ (9.3 ml of 2 M aqueous solution, 18.60 mmol) and 2-[(E)-2- ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.35 g, 6.82 mmol) in 1,2-dimethoxyethane (15 ml) was degassed with nitrogen. Pd(PPh ₃ ) ₄ (600 mg, 0.519 mmol) was added and the mixture was re-degassed with nitrogen. The mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature, partitioned between EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc/petroleum ether gradient) to give 2-[(E)-2-ethoxyvinyl]-4-methylsulfanylpyrimidine (1.10 g, 90%); ¹ H NMR (500 MHz, chloroform-d) δ 8.19 (d, 1H), 7.94 (d, 1H), 6.85 (d, 1H), 5.90 (d, 1H), 4, 02 (q, 2H), 2.56 (s, 3H), 1.40 (t, 3H); MS m/z 197.1 (M+H).

[00918] Synthesis 126: 2-Chloro-4-(2-ethoxyvinyl)pyrimidine

[00919] To a solution of 2,4-dichloropyrimidine (750 mg, 5.03 mmol) and Na ₂ CO ₃ (7.4 mL 2 M, 14.80 mmol) in 1,2-dimethoxyethane (15 mL) was added 2- (2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.05 g, 5.30 mmol). The mixture was then degassed with nitrogen and Pd(PPh ₃ ) ₄ (295 mg, 0.255 mmol) was added and the mixture was degassed again with nitrogen. The mixture was refluxed for 16 hours. The reaction mixture was cooled to ambient temperature, partitioned between EtOAc and water, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc/petroleum ether gradient) to give (2-chloro-4-(2-ethoxyvinyl)pyrimidine (472.4 mg, 51%); MS m/z: 185, 1 (M+H).

[00920] Synthesis 127: 1-[4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazin-1-yl]ethanone

[00921] Acetyl chloride (280 μL, 3.94 mmol) was added to the 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine solution (750 mg, 2.59 mmol) and Et ₃ N (900 μl, 6.46 mmol) in DCM (7.5 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The residue was immediately purified by passing through a cartridge Florisil (petroleum ether/EtOAc gradient elution) to give 1-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl] piperazin-1-yl]ethanone as an off-white solid (693 mg, 81%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.16 (dd, 1H), 6.98 (s, 1H), 6.85 (dd, 1H), 3.55-3.52 (m, 6H), 3.48-3.46 (m, 2H), 2.04 (s, 3H), 1.31 (s, 12H); MS m/z: 332.2 (M+1) ⁺ .

[00922] Synthesis 128: 4-[(E)-2-ethoxyvinyl]-6-methylsulfanylpyrimidine

[00923] To a suspension of 4-chloro-6-methylsulfanylpyrimidine (30 g, 186.8 mmol) and Na ₂ CO ₃ (280.2 ml 2 M, 560.4 mmol) in 1,2-dimethoxyethane (400 ml) was added 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (37.7 g, 190.3 mmol). The mixture was then degassed using vacuum/nitrogen cycles (×3), then Pd(PPh ₃ ) ₄ (12.95 g, 11.21 mmol) was added and the vessel was purged with nitrogen using vacuum/nitrogen cycles (x3) and boiled with reflux for 2 hours. The dark brown reaction mixture was cooled to ambient temperature and the crude mixture was partitioned between EtOAc (600 ml) and water (300 ml). The combined organic extract was washed with water (300 ml), brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 30% EtOAc/petroleum ether gradient elution) to give 4-[(E)-2-ethoxyvinyl]-6-methylsulfanylpyrimidine as an orange oil which crystallized at aging (27.39 g, 74%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.65 (d, J=1.2 Hz, 1H), 7.87 (d, J=12.5 Hz, 1H), 7.18 (d , J=1.3 Hz, 1H), 5.80 (d, J=12.5 Hz, 1H), 4.01 (q, J=7.0 Hz, 2H), 1.28 (t, J =7.0 Hz, 3H); MS m/z: 197.3 (M+H) ⁺

[00924] The following intermediate was prepared according to a procedure similar to that described in Synthesis 128:

(E)-2-(2-Ethoxyvinyl)-5-fluoro-4-(methylthio)pyridine;

[00925] Synthesis 129: 3-Chloro-6-(difluoromethyl)pyridazine

[00926] Deoxofluor ^® (485 μl, 2.631 mmol) was added to a solution of 6-chloropyridazine-3-carbaldehyde (250 mg, 1.754 mmol) in DCM (10 ml) at 0°C and the mixture was warmed to ambient temperature and stirred for 17 hours. Saturated aqueous sodium bicarbonate solution was added dropwise and the reaction mixture was stirred for 30 minutes. The layers were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine and dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 100% EtOAc/petroleum ether gradient elution) to give 3-chloro-6-(difluoromethyl)pyridazine as a white solid (234.2 mg, 81% ); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.29 (t, J=54.0 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 8.16 (d , J=9.0 Hz, 1H); MS m/z: 165.1 (M+H) ⁺ .

[00927] Synthesis 130: 6-(Difluoromethyl)pyridazin-3-amine

[00928] In a sealed 1 L vessel, NH ₄ OH (265.8 g, 295.3 mL, 7.584 mol) was added to the solution of 3-chloro-6-(difluoromethyl)pyridazine (20.8 g, 126.4 mmol) in THF (160 ml) and the biphasic solution was heated at 100°C for 16 hours. The brown reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was triturated with EtOAc (10 volumes) and the insoluble material was filtered off. The filtrate was concentrated in vacuo to give 6-(difluoromethyl)pyridazin-3-amine as a yellow solid (16 g, 87%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.53 (d, J=9.2 Hz, 1H), 7.07-6.85 (m, 4H); MS m/z: 146.1 (M+H) ⁺ .

[00929] Synthesis 131: 6-(Difluoromethyl)-3-(6-methylsulfanylpyrimidin-4-yl)imidazo[1,2-b]pyridazine

[00930] 4-[(E)-2-Ethoxyvinyl]-6-methylsulfanylpyrimidine (19.4 g, 98.82 mmol) was dissolved in a mixture of 1,4-dioxane (390 ml) and water (145 ml) at ambient temperature environment. NBS (17.59 g, 98.82 mmol) was added and the bright yellow solution was stirred at ambient temperature for 15 min, then 6-(difluoromethyl)pyridazin-3-amine (14.34 g, 98.82 mmol) was added ). The orange reaction mixture was heated at 80°C. After 2 hours, the mixture was cooled to ambient temperature and diluted with saturated aqueous NaHCO ₃ (390 ml) and water (485 ml). The brown solid was filtered, washed with plenty of water and dried in vacuo to give 3-(6-methylsulfanylpyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine as a brown solid (16.4 g, 56%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (d, J=1.3 Hz, 1H), 8.74 (s, 1H), 8.56 (d, J=9.4 Hz , 1H), 8.53 (d, J=1.3 Hz, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.39 (t, J=53.7 Hz, 1H ), 2.64 (s, 3H); MS m/z: 294.2 (M+H) ⁺ .

[00931] The following compounds were prepared according to a procedure similar to that described in Synthesis 131:

3-(6-(Methylthio)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine;

6-Ethyl-3-(6-(methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazine;

6-Methyl-3-(6-(methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazine;

6-Cyclopropyl-3-(6-(methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazine;

1-(3-(6-(Methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)ethan-1-one;

3-(6-(Methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazine-6-carbonitrile.

6-(Difluoromethyl)-3-(5-fluoro-4-(methylthio)pyridin-2-yl)imidazo[1,2-b]pyridazine

[00932] Synthesis 132: 3-(6-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine

3-(6-Methylsulfanylpyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine (7.8 g, 25.06 mmol) was suspended in MeCN (133 ml) and concentrated HCl (2 .2 ml 37% w/w, 40.1 mmol). Sulfuryl chloride (13.52 g, 8.11 mL, 100.2 mmol) was slowly added to the pale yellow suspension. 20 minutes after the addition of sulfuryl chloride was completed, the reaction mixture was slowly added to ice water (230 mL) at a rate such that the temperature was maintained below 10°C. The suspension was aged for 1 hour, then the precipitate was filtered off and washed with water. The solid was stirred for 1 hour in saturated aqueous NaHCO ₃ solution (78 ml), then filtered, washed with water and dried in an oven at 45°C under reduced pressure overnight to give 3-(6-chloropyrimidin-4-yl )-6-(difluoromethyl)imidazo[1,2-b]pyridazine as a beige solid (7 g, 93%); 1H NMR (500 MHz, DMSO-d ₆ ) δ 9.12 (d, J=1.1 Hz, 1H), 8.82 (s, 1H), 8.67 (d, J=1.1 Hz, 1H), 8.59 (d, J=9.5 Hz, 1H), 7.79 (d, J=9.5 Hz, 1H), 7.43 (t, J=53.6 Hz, 1H) ; MS m/z: 282.0 (M+H) ⁺ .

[00933] The following compounds were prepared according to a procedure similar to that described in Synthesis 132:

3-(6-Chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine;

3-(6-Chloropyrimidin-4-yl)-6-ethylimidazo[1,2-b]pyridazine;

3-(6-Chloropyrimidin-4-yl)-6-methylimidazo[1,2-b]pyridazine;

3-(6-Chloropyrimidin-4-yl)-6-cyclopropylimidazo[1,2-b]pyridazine;

1-(3-(6-Chloropyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)ethan-1-one;

3-(6-Chloropyrimidin-4-yl)imidazo[1,2-b]pyridazine-6-carbonitrile;

3-(4-Chloro-5-fluoropyridin-2-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine;

3-(6-Chloropyrimidin-4-yl)imidazo[1,2-b]pyridazine-6-carboxamide.

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

[00934] Synthesis 133: Tributyl-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]stannane

[00935] A solution of 6-(difluoromethyl)-3-iodimidazo[1,2-b]pyridazine (2 g, 6.78 mmol) in dry THF (36 ml) was cooled to 0°C, then EtMgBr (6 .78 ml 3 M in Et ₂ O, 20.34 mmol). The mixture was stirred for 10 min at 0°C, then tributylchlorostannane (2.76 g, 2.3 ml, 8.47 mmol) was added. The mixture was allowed to warm to ambient temperature and stirred for 25 minutes. The reaction was then carefully stopped by adding water (10 ml) and the mixture was then partitioned between saturated aqueous NH ₄ Cl (20 ml) and EtOAc (50 ml). The organic layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo to give tributyl-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]stannane (3.45 g). The residue was used in the next step without further purification.

[00936] Synthesis 134: 6-(Difluoromethyl)-3-(6-fluoropyrimidin-4-yl)imidazo[1,2-b]pyridazine

[00937] Tributyl-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]stannane (3.4 g, 7.421 mmol) was added to a degassed solution of 4-bromo-6-fluoropyrimidine (1.313 g, 7.421 mmol) and PdCl ₂ (PPh ₃ ) ₂ (520.9 mg, 0.742 mmol) in DMF (45 ml). The mixture was further degassed, then heated at 70°C for 16 hours. The mixture was concentrated in vacuo and purified by chromatography (silica, 0-45% EtOAc in PE with gradient elution) to give 6-(difluoromethyl)-3 -(6-fluoropyrimidin-4-yl)imidazo[1,2-b]pyridazine (500 mg, 25%); MS m/z: 266.1 (M+H) ⁺ .

[00938] Synthesis 135: 6-(Difluoromethyl)-N-(2,2-dimethoxyethyl)pyridazin-3-amine

[00939] Acetaldehyde aminodimethyl acetate (24.2 mL, 221.83 mmol) was added to 3-difluoromethyl-6-chloropyridazine (7.3 g, 44.3 mmol) at ambient temperature. The mixture was heated at 95°C for 20 hours, then cooled to ambient temperature. The reaction mixture was diluted with dichloromethane (400 ml) and the solution was washed with 5% aqueous NaHCO ₃ solution (3×100 ml) and brine. The aqueous phase was extracted with dichloromethane (3×150 ml). The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and the solvent was removed under reduced pressure, then dried in vacuo. The resulting solid was triturated with heptane (2 x 100 mL), filtered and dried to give 6-(difluoromethyl)-N-(2,2-dimethoxyethyl)pyridazin-3-amine as a beige solid (9.8 g, 94 %); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.32 (s, 6H), 3.52 (t, J=5.7 Hz, 2H), 4.56 (t, J=5.4 Hz , 1H), 6.75-7.16 (m, 2H), 7.41 (t, J=6.0 Hz, 1H), 7.52(d, J=9.0 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -112.8 (d, J=54.9 Hz, 2F); MS m/z: 234.1 (M+H) ⁺ .

[00940] Synthesis 136: 6-(Difluoromethyl)imidazo[1,2-b]pyridazine

[00941] Concentrated sulfuric acid (13.3 mL, 249.5 mmol, 95-98%) was added to a three-neck round bottom flask equipped with a thermometer under a nitrogen atmosphere. The sulfuric acid was cooled to 15°C (internal temperature), then 6-(difluoromethyl)-N-(2,2-dimethoxyethyl)pyridazin-3-amine (9.7 g, 41.6 mmol) was added in portions while maintaining the internal temperature equal to below 20°C. The cooling bath was removed and after 15 minutes at ambient temperature, the reaction mixture was heated at 70°C for 5 hours. After cooling to ambient temperature, the reaction mixture was added dropwise to a cooled (0°C) aqueous sodium hydroxide solution (19.96 g NaOH, 499.1 mmol, in 400 ml water). During the addition of the reaction mixture, the internal temperature was maintained below 10°C. After addition was complete, the pH of the aqueous mixture was adjusted to 8 with NaHCO ₃ and/or 3% HCl. The aqueous phase was extracted with dichloromethane. The combined organic extracts were dried (Na ₂ SO ₄ ), filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica, 0-60% EtOAc in DCM with gradient elution) to give 6-(difluoromethyl)imidazo[1,2-b]pyridazine as a beige solid (6.53 g, 86% (2 stages)); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.07 (t, J=54.0 Hz, 1H), 7.48 (d, J=9.4 Hz, 1H, 7.92-7, 98 (m, 1H), 8.35 (d, J=9.4 Hz, 1H), 8.46 (s, 1H); ¹⁹ F NMR (282 MHz, DMSO-d6) δ -115.0 (d , J=53.4 Hz, 2F); MS m/z: 170.1(M+H) ⁺ .

[00942] Synthesis 137: 3-Iodo-6-(difluoromethyl)imidazo[1,2-b]pyridazine

[00943] To a round bottom flask equipped with a condenser and dropping funnel, add 6-(difluoromethyl)imidazo[1,2-b]pyridazine (15.2 g, 89.87 mmol), followed by dichloroethane (200 mL) and anhydrous pyridine ( 130 ml, 1.617 mol). The solution was cooled to 0°C and iodine monochloride (269.6 ml, 0.269 mol, 1M solution in dichloromethane) was added dropwise. The reaction mixture was stirred for 20 minutes at 0°C, then for 30 hours at 45°C. The reaction mixture was cooled to 0°C, then another 3 eq. was added. ICl (269.6 ml). The reaction mixture was stirred at 0°C for 20 min, then at 45°C overnight. The reaction mixture was diluted with dichloromethane, then the organic phase was washed with saturated aqueous sodium thiosulfate and brine, dried (Na ₂ SO ₄ ), filtered and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica, eluting with 0-50% EtOAc in DCM) to give 3-iodo-6-(difluoromethyl)imidazo[1,2-b]pyridazine as a yellow solid (26.75 g, 83%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.23 (t, J=54.0 Hz, 1H), 7.54 (d, J=9.5 Hz, 1H), 8.07 (s , 1H), 8.34 (d, J=9.4 Hz, 1H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -114.9 (d, J=54.9 Hz, 2F); MS m/z: 295.9 (M+H) ⁺ .

[00944] Synthesis 138: 6-(Difluoromethyl)-3-(2-fluoro-4-pyridyl)imidazo[1,2-b]pyridazine

[00945] 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.966 g, 8.813 mmol), 6-(difluoromethyl)-3-iodimidazo [1,2-b]pyridazine (2 g, 6.779 mmol) and Na ₂ CO ₃ (10.2 ml 2 M, 20.34 mmol) were combined in 1,4-dioxane (80 ml) and degassed several times with cycle N ₂ /vacuum, then dichloropalladium triphenylphosphane (476 mg, 0.678 mmol) was added. The mixture was subjected to additional degassing cycles, then sealed and heated at 90°C for 8 hours. Additional dichloropalladium triphenylphosphane (119 mg, 0.025 eq.) and 2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (453 mg, 0.3 eq.) and the mixture was heated at 95°C for 4 hours. The mixture was partitioned between DCM and water. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 6-(difluoromethyl)-3-(2-fluoro-4-pyridyl)imidazo[1,2-b]pyridazine; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.82 (s, 1H), 8.53 (d, J=9.4 Hz, 1H), 8.39 (d, J=5.4 Hz , 1H), 8.23 (dt, J=5.4, 1.7 Hz, 1H), 8.09 (s, 1H), 7.71 (d, J=9.4 Hz, 1H), 7 .35 (t, J=53.7 Hz, 1H); MS m/z: 265.1 (M+H) ⁺ .

[00946] Synthesis 139: 6-(Difluoromethyl)-3-(2,6-difluoropyridin-4-yl)imidazo[1,2-b]pyridazine

[00947] A mixture of 6-(difluoromethyl)-3-iodimidazo[1,2-b]pyridazine (250 mg, 0.847 mmol), 2,6-difluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine (306 mg, 1.271 mmol), PdCl ₂ (dppf).CH ₂ Cl ₂ (69.2 mg, 0.0847 mmol) and Na ₂ CO ₃ (1.27 ml 2 M, 2.542 mmol) in THF (4.2 ml) was degassed with N ₂ and then heated at 80°C for 16 hours. The reaction mixture was cooled to ambient temperature, partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give 6-(difluoromethyl)-3-(2,6-difluoropyridin-4-yl)imidazo[1,2-b]pyridazine as a light brown solid (350 mg, 89%); MS m/z: 283.1 (M+H) ⁺ .

[00948] The following intermediates were prepared according to a procedure similar to that described in Synthesis 139:

6-Chloro-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)picolinonitrile;

3-(2-Chloro-6-(trifluoromethyl)pyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine;

3-(2,6-Dichloropyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine;

4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-2-fluorobenzonitrile;

5-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-3-fluoropicolinonitrile;

3-(2-Chloro-6-methylpyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine;

6-(Difluoromethyl)-3-(2,5-difluoropyridin-4-yl)imidazo[1,2-b]pyridazine;

3-(5-Chloro-2-fluoropyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine;

3-(2-Chloro-6-methoxypyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine;

6-(Difluoromethyl)-3-(2-fluoro-5-methylpyridin-4-yl)imidazo[1,2-b]pyridazine;

8-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-2-(methylsulfonyl)-5-oxa-2,8-diazaspiro[3.5] nonane II-126.

6-(Difluoromethyl)-3-(2,5-difluoropyridin-4-yl)imidazo[1,2-b]pyridazine;

3-(5-Chloro-2-fluoropyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine

[00949] Synthesis 140: 6-(Difluoromethyl)-3-(4-fluoro-2-pyridyl)imidazo[1,2-b]pyridazine

[00950] A mixture of 6-(difluoromethyl)-3-iodimidazo[1,2-b]pyridazine (480 mg, 1.63 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridine (725 mg, 3.25 mmol), Cs ₂ CO ₃ (1.59 g, 4.88 mmol), Pd(OAc) ₂ (18.3 mg, 0.081 mmol ), dppf (90.2 mg, 0.163 mmol) and CuCl (161.1 mg, 1.627 mmol) in DMF (20 ml) were degassed with N ₂ and then heated at 90°C for 3 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 6-(difluoromethyl)-3-(4-fluoro-2-pyridyl)imidazo[1,2-b]pyridazine as a dark solid (270 mg) , which was used in the next step without further purification; MS m/z: 265.1 (M+H) ⁺ .

[00951] Synthesis 141: 2-(Methylsulfonyl)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-5-oxa -2,8-diazaspiro[3.5]nonane

[00952] Step 1: tert-Butyl 8-(4-bromopyridin-2-yl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate

[00953] A solution of 4-bromo-2-fluoropyridine (50 mg, 0.284 mmol), tert-butyl-5-oxa-2,8-diazaspiro[3.5]nonane-2-carboxylate (97.3 mg, 0.426 mmol) and Et ₃ N (120 μl, 0.861 mmol) in NMP (1 ml) was heated at 110°C in a sealed tube for 21 hours. The reaction mixture was cooled to ambient temperature and partitioned between EtOAc and brine. The layers were separated and the organic phase was washed with brine (×3), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 30% EtOAc/petroleum ether gradient elution) to give tert-butyl-8-(4-bromo-2-pyridyl)-5-oxa-2,8 -diazaspiro[3.5]nonane-2-carboxylate (75.8 mg, 0.197 mmol, 69%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 8.03 (d, J=5.3 Hz, 1H), 6.86 (d, J=5.2 Hz, 1H), 6.83 (s, 1H), 3.90 (d, J=9.3 Hz, 2H), 3.84 (d, J=9.2 Hz, 2H), 3.80 (t, J=5.0 Hz, 2H) , 3.66 (s, 2H), 3.47 (dd, J=5.7, 4.6 Hz, 2H), 1.47 (s, 9H); MS m/z: 384.1 (M+H) ⁺ .

[00954] Step 2: 8-(4-Bromopyridin-2-yl)-5-oxa-2,8-diazaspiro[3.5]nonane

[00955] TFA (1 ml, 12.98 mmol) was added to the solution of tert-butyl-8-(4-bromo-2-pyridyl)-5-oxa-2,8-diazaspiro[3.5]nonane-2- with stirring carboxylate (75 mg, 0.195 mmol) in DCM (5 ml) and the reaction mixture was stirred at ambient temperature for 17 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 2 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2 M NH ₃ in MeOH/DCM mixtures. The solvent was removed in vacuo to give 8-(4-bromo-2-pyridyl)-5-oxa-2,8-diazaspiro[3.5]nonane (55.5 mg, 0.195 mmol, 100%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 8.02 (d, J=5.3 Hz, 1H), 6.89 (d, J=1.4 Hz, 1H), 6.83 (dd, J=5.3, 1.5 Hz, 1H), 3.77-3.75 (m, 2H), 3.71-3.66 (m, 4H), 3.53-3.51 (m, 2H), 3.47-3.45 (m, 2H); MS m/z: 286.1 (M+H) ⁺ .

[00956] Step 3: 8-(4-Bromopyridin-2-yl)-2-(methylsulfonyl)-5-oxa-2,8-diazaspiro[3.5]nonane

[00957] Methanesulfonyl chloride (20 μl, 0.258 mmol) was added to a solution of 8-(4-bromo-2-pyridyl)-5-oxa-2,8-diazaspiro[3.5]nonane (55 mg, 0.194 mmol) and Et with stirring ₃ N (50 µl, 0.359 mmol) in THF (2 ml) under nitrogen. The reaction mixture was stirred at ambient temperature for 16 hours, then diluted with DCM and saturated aqueous NaHCO ₃ 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 (MgSO ₄ ), filtered and concentrated in vacuo to obtain a white solid, which was immediately used in the next step without further purification; ¹ H NMR (500 MHz, chloroform-d) δ 8.04 (d, J=5.3 Hz, 1H), 6.88 (dd, J=5.3, 1.5 Hz, 1H), 6, 86-6.84 (m, 1H), 3.95 (d, J=9.0 Hz, 2H), 3.85 (d, J=9.1 Hz, 2H), 3.81-3.79 (m, 2H), 3.73 (s, 2H), 3.49-3.47 (m, 2H), 2.95 (s, 3H); MS m/z: 364.0 (M+H) ⁺ .

[00958] Step 4: 2-(Methylsulfonyl)-8-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-5-oxa -2,8-diazaspiro[3.5]nonane

[00959] 8-(4-Bromo-2-pyridyl)-2-methylsulfonyl-5-oxa-2,8-diazaspiro[3.5]nonane (67 mg, 0.185 mmol) was dissolved in 1,4-dioxane (2.5 ml) and bis(pinacolate)diboron (70 mg, 0.276 mmol) and KOAc (55 mg, 0.560 mmol) were added. The reaction mixture was degassed five times and filled with nitrogen, then PdCl ₂ (PCy ₃ ) ₂ (15 mg, 0.020 mmol) was added and the reaction mixture was heated at 90°C for 2 hours. The reaction mixture was cooled to ambient temperature and the solution was used for the next stage without additional purification.

[00960] Synthesis 142: 3-(2-Fluoropyridin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine

[00961] Step 1: 6-(Trifluoromethyl)pyridazin-3-amine

[00962] A mixture of 3-chloro-6-(trifluoromethyl)pyridazine (0.5 g, 2.739 mmol) and NH ₄ OH (3 mL, 77.04 mmol) in THF (1 mL) was heated at 100°C in a sealed tube for 2 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was diluted with a minimal amount of water and extracted with DCM (×3). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give the title product as an orange solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.66 (d, J=9.3 Hz, 1H), 7.15 (s, 2H), 6.90 (d, J=9.3 Hz , 1H); 19F NMR (471 MHz, DMSO-d ₆ ) δ -64.58; MS m/z: 164.0 (M+H) ⁺ .

[00963] Step 2: 6-(Trifluoromethyl)imidazo[1,2-b]pyridazine

[00964] To a solution of 6-(trifluoromethyl)pyridazin-3-amine (438 mg, 2.685 mmol) in n-BuOH (5 mL) was added 2-chloroacetaldehyde (562 μL 45% w/v in water, 3.22 mmol) and the reaction mixture was refluxed for 20 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was partitioned between DCM and saturated aqueous NaHCO ₃ and the layers were separated. The aqueous layer was extracted with DCM (×3) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 50% EtOAc/petroleum ether gradient elution) to give 6-(trifluoromethyl)imidazo[1,2-b]pyridazine (368.7 mg, 73%) as a beige solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 8.47 (d, J=9.5 Hz, 1H), 8.06 (d, J=1.2 Hz , 1H), 7.67 (d, J=9.5 Hz, 1H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -65.14; MS m/z: 188.0 (M+H) ⁺ .

[00965] Step 3: 3-Iodo-6-(trifluoromethyl)imidazo[1,2-b]pyridazine

[00966] While stirring, monochloride was added dropwise to a solution of 6-(trifluoromethyl)imidazo[1,2-b]pyridazine (268 mg, 1.432 mmol) in DCM (3 mL) and pyridine (1.5 mL) at 0°C iodine (3.6 ml 1 M, 3.6 mmol). The reaction mixture was heated at 50°C in a sealed tube for 137 hours, then cooled to ambient temperature. Another portion of iodine monochloride (1.5 ml of 1 M, 1.5 mmol) was added and the reaction mixture was heated at 50°C in a sealed tube for 45 hours. The reaction mixture was cooled to ambient temperature and diluted with DCM. The mixture was washed with saturated aqueous sodium thiosulfate (×2) and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was triturated with DCM and the resulting precipitate was filtered and dried to give 3-iodo-6-(trifluoromethyl)imidazo[1,2-b]pyridazine (118 mg, 26%) as a pale yellow solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.45 (d, J=9.4 Hz, 1H), 8.18 (s, 1H), 7.72 (d, J=9.4 Hz , 1H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -65.08; MS m/z: 313.9 (M+H) ⁺ .

[00967] Step 4: 3-(2-Fluoro-4-pyridyl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine

[00968] Mixture of 6-(trifluoromethyl)imidazo[1,2-b]pyridazine (300 mg, 1.603 mmol), 4-bromo-2-fluoropyridine (396.3 mg, 2.252 mmol), K ₂ CO ₃ (433, 8 mg, 3.139 mmol), LiCl (70.5 mg, 1.662 mmol), PPh ₃ (86.8 mg, 0.331 mmol) and Pd(OAc) ₂ (38.0 mg, 0.169 mmol) in toluene (6 ml) heated at 150°C for 17 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (silica, hexane/EtOAc gradient elution) to give 3-(2-fluoro-4-pyridyl)-6- (trifluoromethyl)imidazo[1,2-b]pyridazine (150 mg, 0.531 mmol, 33%); MS m/z: 283.1 (M+H) ⁺ .

[00969] Synthesis 143: 3-Iodo-N-methylimidazo[1,2-b]pyridazin-6-amine

[00970] To a solution of 6-chloro-3-iodimidazo[1,2-b]pyridazine (612 mg, 2.19 mmol) in a mixture of isopropyl alcohol (6 ml) and DMF (3 ml) was added methylamine (1.7 ml 40% w/v in water, 21.9 mmol). The mixture was heated at 80°C for 10 hours, then at 100°C for 8 hours. The mixture was diluted with EtOAc and washed successively with saturated aqueous NH ₄ Cl, saturated aqueous NaHCO ₃ and brine. The organic layer was dried (MgSO ₄ ) and concentrated to give an orange solid, which was purified by column chromatography (silica, PE/EtOAc 9/1 to 6/4 gradient elution) to give 3-iodo-N- methylimidazo[1,2-b]pyridazin-6-amine (325 mg, 40%); MS m/z: 275.0 (M+H) ⁺ .

[00971] Synthesis 144: 6-Methylimidazo[1,2-b]pyridazine

[00972] 6-Chloroimidazo[1,2-b]pyridazine (1 g, 6.51 mmol), methylboronic acid (467.7 mg, 7.81 mmol) and K ₃ PO ₄ (4.15 g, 19, 5 mmol) were combined in toluene (15 ml). The mixture was degassed (×2 cycles vacuum - N ₂ ) and SPhos (267.3 mg, 0.651 mmol), then Pd(OAc) ₂ (73.1 mg, 0.326 mmol) was added, then the mixture was heated at 150°C for 3 h. The reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml). The combined organic layers were dried and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-3% MeOH/DCM gradient elution) to give 6-methylimidazo[1,2-b]pyridazine (323 mg, 37%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.17 (dd, J=1.2, 0.7 Hz, 1H), 8.01 (dd, J=9.3, 0.7 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H), 7.13 (d, J=9.3 Hz, 1H), 2.52 (s, 3H); MS m/z: 134.4 (M+H) ⁺ .

[00973] Synthesis 145: 6-(Difluoromethoxy)imidazo[1,2-b]pyridazine

[00974] A mixture of imidazo[1,2-b]pyridazin-6-ol (250 mg, 1.85 mmol), Cs ₂ CO ₃ (845 mg, 2.593 mmol) and methyl 2-chloro-2,2-difluoroacetate (390 μl, 3.697 mmol) in DMF (2.5 ml) was heated at 95°C for 1 hour. The reaction mixture was cooled to ambient temperature and the reaction was stopped with water. The mixture was extracted with EtOAc (×3) and the combined organic extracts were washed with brine (×3), dried (MgSO ₄ ), filtered and concentrated in vacuo. The material was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 6-(difluoromethoxy)imidazo[1,2-b]pyridazine (23 mg, 4.2%) in as an almost white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.32-8.30 (m, 2H), 7.86 (d, J=1.3 Hz, 1H), 7.69 (t, J= 71.3 Hz, 1H), 7.20 (d, J=9.7 Hz, 1H); MS m/z: 186.1 (M+H) ⁺ .

[00975] Synthesis 146: 3-Bromo-6-(trifluoromethyl)imidazo[1,2-b]pyridazine

[00976] A solution of 3-bromoimidazo[2,1-f]pyridazine (50 mg, 0.252 mmol) and zinc trifluoromethanesulfinate (168 mg, 0.507 mmol) in DCM (1 ml) and water (0.4 ml) was cooled to 0° C, then t-BuOOH (100 μL 70% w/v, 0.777 mmol) was added slowly. The solution was warmed to ambient temperature for 15 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO ₃ and the layers were separated. The aqueous layer was extracted with DCM (×3) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 10% EtOAc/petroleum ether gradient elution) to give a mixture of the two regioisomers (29.5 mg, 0.1109 mmol, 44%), which was immediately used in the following reactions; MS m/z: (M+H) ⁺ .

[00977] Synthesis 147: 1-(4-(4-(7-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone

[00978] Step 1: 1-(4-(4-Bromopyridin-2-yl)piperazin-1-yl)ethanone

[00979] Acetyl chloride (335 μl, 4.71 mmol) was added to a solution of 1-(4-bromo-2-pyridyl)piperazine (750 mg, 3.10 mmol) and Et ₃ N (1 ml, 7.18 mmol) in DCM (7.5 ml) and the reaction mixture was stirred at ambient temperature for 48 hours. The mixture was washed with saturated aqueous NaHCO ₃ (x2) and brine (x1), dried (MgSO ₄ ), filtered and concentrated in vacuo . The residue was purified by column chromatography (silica, 0 to 100% EtOAc/petroleum ether gradient elution) to give 1-(4-(4-bromopyridin-2-yl)piperazin-1-yl)ethanone (715 .7 mg, 81%) as a cream solid; ¹ H NMR (500 MHz, chloroform-d) δ 8.02 (dd, J=5.1, 0.9 Hz, 1H), 6.84-6.82 (m, 2H), 3.77-3 .75 (m, 2H), 3.67-3.65 (m, 2H), 3.61-3.59 (m, 2H), 3.55-3.53 (m, 2H), 1.57 (s, 3H); MS m/z: 286.1 (M+H) ⁺ .

[00980] Step 2: 1-(4-(4-(7-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone

[00981] Mixture of 7-chlorimidazo[1,2-b]pyridazine (30 mg, 0.195 mmol), 1-[4-(4-bromo-2-pyridyl)piperazin-1-yl]ethanone (75 mg, 0.264 mmol ), K ₂ CO ₃ (55 mg, 0.398 mmol), LiCl (9 mg, 0.212 mmol), PPh ₃ (12 mg, 0.046 mmol) and Pd(OAc) ₂ (5 mg, 0.022 mmol) in toluene (1 ml ) was heated at 110°C for 17 hours. The reaction mixture was cooled to ambient temperature, diluted with DCM and the precipitate was removed by filtration. The filtrate was concentrated in vacuo and purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 1-(4-(4-(7-chloroimidazo[1,2-b]pyridazine -3-yl)pyridin-2-yl)piperazin-1-yl)ethanone (24.4 mg, 26%) as an off-white solid.

[00982] The following compounds were prepared using a methodology similar to that described in Synthesis 147:

1-(4-(4-(6-(Difluoromethoxy)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone II-182.

[00983] Synthesis 148: 2,5-Dimethylpiperidine-3-carboxamide A134 and 2,5-dimethylpiperidine-3-carboxylic acid A135

m

[00984] Step 1: 2,5-Dimethylnicotinamide

[00985] 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) ⁺ .

[00986] Step 2: 2,5-Dimethylpiperidine-3-carboxamide

[00987] 2,5-Dimethylnicotinamide (99 mg, 0.66 mmol) and PtO₂ (30.4 mg, 0.13 mmol) was dissolved in methanol (3 ml) and 3 M HCl (1.1 ml, 3.30 mmol). The mixture was degassed and stirred with a supply of H₂ from a cylinder for 90 minutes, then passed through celite and the filtrate was concentrated in vacuo to give 2,5-dimethylpiperidine-3-carboxamide (dihydrochloride) (150 mg, 99%); MS m/z: 157.0 (M+H)⁺. Some 2,5-dimethylpiperidine-3-carboxylic acids have also been isolated but not characterized.

[00988] Synthesis 149: cis-[6-Cyclopropyl-4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]morpholin-2-yl] methyl methanesulfonate

[00989] Methanesulfonyl chloride (30 μl, 0.39 mmol) was added to the suspension of cis-[6-cyclopropyl-4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin- 4-yl]morpholin-2-yl]methanol (106 mg, 0.26 mmol) and triethylamine (55 μl, 0.39 mmol) in DCM (15 ml) under N ₂ and the reaction mixture was stirred at ambient temperature in for 3 hours. The mixture was diluted with DCM and the reaction was stopped by adding saturated aqueous NaHCO ₃ solution. After stirring for 10 minutes, the layers were separated and the organic phase was concentrated to give cis-[6-cyclopropyl-4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4- yl]morpholin-2-yl]methylmethanesulfonate (126.6 mg, 100%); MS m/z: 481.3 (M+H) ⁺ .

[00990] The following compounds were prepared according to a procedure similar to that described in Synthesis 149:

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(2-methoxyethoxy)piperidin-3-yl)methylmethanesulfonate;

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methylmethanesulfonate;

(1-(tert-Butyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methylmethanesulfonate ;

(S)-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-yl)methylmethanesulfonate.

[00991] Synthesis 150: 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)-2-iodopyrazolo[1,5-a]pyrimidine

[00992] Step 1: 5-(Difluoromethyl)-3-(6-methylsulfanylpyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine

[00993] 4-(6-Methylsulfanylpyrimidin-4-yl)-1H-pyrazol-3,5-diamine (described in WO2009/085913) (25 g, 112.5 mmol) and 4-ethoxy-1,1-difluoro -But-3-en-2-one (21.1 g, 140.3 mmol) was suspended in 1,4-dioxane (150 ml). KOH (6.23 g, 111.1 mmol) was added and the reaction mixture was stirred at 90°C for 5 hours. The reaction mixture was cooled to ambient temperature and HCl (55.5 ml 2 M, 111.0 mmol) was added slowly. . The mixture was stirred at ambient temperature for 15 minutes, then water (250 ml) was added and stirred for another 1 hour. The solid was isolated by filtration, washed with water and dried in vacuo at 40°C to give 5-(difluoromethyl)-3 -(6-methylsulfanylpyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine as a brown solid (27.0 g, 78%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20 (d, 1H), 8.86 (d, 1H), 8.33 (d, 1H), 7.27 (br s, 2H), 7.24 (d, 1H), 7.10 (t, 1H), 2.59 (s, 3H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -117.1; MS m/z: 309.0 (M+H) ⁺ .

[00994] Step 2: 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-2-amine

[00995] 5-(Difluoromethyl)-3-(6-methylsulfanylpyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine (27.0 g, 87.58 mmol) was suspended in MeCN (459 ml ) and concentrated HCl (13.8 g, 7.67 mL 37% w/w, 140.1 mmol) was added. Sulfuryl chloride (47.3 g, 28.4 mL, 350.3 mmol) was added and the reaction mixture was stirred at ambient temperature for 25 minutes. The reaction mixture was slowly added to ice and water (810 ml) at such a rate that the temperature was maintained below 10°C. The suspension was aged for 1 hour and the solid was isolated by filtration and washed with water. The solid was added to saturated aqueous NaHCO ₃ solution (270 ml) and stirred for 30 minutes. The solid was isolated by filtration, washed with water and dried in vacuo at 40°C to give 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-2-amine as beige solid (21.4 g, 84% purity, 69%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (d, 1H), 8.92 (d, 1H), 8.42 (d, 1H), 7.32 (br s, 2H), 7.30 (d, 1H), 7.13 (t, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -117.1; MS m/z: 296.9 (M+H) ⁺ , 294.9 (MH) ⁺ .

[00996] Step 3: 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)-2-iodopyrazolo[1,5-a]pyrimidine

[00997] p-Toluenesulfonic acid hydrate (483 mg, 2.54 mmol) was added to the 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-2-amine suspension (250 mg, 0.843 mmol) in MeCN (5 ml) at ambient temperature. A solution of KI (350 mg, 2.11 mmol) and sodium nitrite (117 mg, 1.69 mmol) in H ₂ O (2.5 ml) was added dropwise and the reaction mixture was stirred at ambient temperature for 16 hours. Reaction was stopped by adding a saturated aqueous solution of NaHCO ₃ and a saturated aqueous solution of Na ₂ S ₂ O ₃ and the resulting precipitate was isolated by filtration. The solid was taken up in DCM/MeOH and filtered to remove insoluble residues. The filtrate was concentrated in vacuo to give 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)-2-iodopyrazolo[1,5-a]pyrimidine as a red solid, which was immediately used in the next step; MS m/z: 407.9 (M+H) ⁺ .

[00998] Synthesis 151: 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidine

[00999] MeOH (34 ml) was added to 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)-2-iodopyrazolo[1,5-a]pyrimidine (1.37 g, 3.37 mmol) and palladium on carbon (100 mg) in a nitrogen atmosphere. Then the vessel was purged and the solution was mixed with a supply of H₂ from the can for 16 hours. The catalyst was removed by filtration through celite, washed with MeOH and the filtrate was concentrated. Purification by column chromatography (silica, petroleum ether/EtOAc, then MeOH/DCM gradient mode) gave 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidine as a yellow solid (88 mg, 9%); MS m/z: 282.1 (M+H)⁺.

[001000] Synthesis 152: 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)-6-fluoro-2-iodopyrazolo[1,5-a]pyrimidine

[001001] Step 1: 7-(Difluoromethyl)-6-fluoro-3-(6-methylsulfanylpyrimidin-4-yl)pyrazolo[1,5-a]pyrimidin-2-amine

[001002] A solution of 2,4,4-trifluoro-3,3-dihydroxybutanal (0.907 g, 5.74 mmol), 4-(6-methylsulfanylpyrimidin-4-yl)-1H-pyrazol-3,5-diamine (described in WO2009/085913) (776 mg, 3.49 mmol) and KOH (399 mg, 7.10 mmol) in 1,4-dioxane (45 ml) were stirred at 85°C for 16 hours. The reaction mixture was cooled to environment and concentrated in vacuo. The residue was partitioned between DCM and 0.5 M aqueous HCl and the layers were separated. The organic phase was dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, DCM/MeOH gradient as eluent) to give 7-(difluoromethyl)-6-fluoro-3-(6-methylsulfanylpyrimidin-4-yl)pyrazolo[1,5-a ]pyrimidin-2-amine as a golden solid (500 mg, 44%); MS m/z: 327.1 (M+H) ⁺ .

[001003] Step 2: 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)-6-fluoropyrazolo[1,5-a]pyrimidin-2-amine

[001004] SO ₂ Cl ₂ (608 mg, 365 μl, 4.51 mmol) was added to the suspension of 7-(difluoromethyl)-6-fluoro-3-(6-methylsulfanylpyrimidin-4-yl)pyrazolo[1,5-a ]pyrimidin-2-amine (490 mg, 1.50 mmol) and concentrated HCl (142 µl, 1.65 mmol) in acetonitrile (20 ml) and the mixture was stirred at ambient temperature for 10 min. Another portion of SO ₂ Cl ₂ (608 mg, 365 μl, 4.51 mmol) was added and the mixture was stirred for another 5 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution and the acetonitrile was removed in vacuo. The precipitate was isolated by filtration, washed with water and dried in vacuo to obtain 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)-6-fluoropyrazolo[1,5-a]pyrimidin-2-amine as an almost white solid substances (405 mg, 86%); MS m/z: 315.1 (M+H) ⁺ .

[001005] Step 3: 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)-6-fluoro-2-iodopyrazolo[1,5-a]pyrimidine

[001006] 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)-6-fluoropyrazolo[1,5-a]pyrimidin-2-amine (300 mg, 0.953 mmol) suspended in MeCN (12 ml) and p-toluenesulfonic acid hydrate (546 mg, 2.87 mmol) was added, then a solution of KI (396 mg, 2.39 mmol) and sodium nitrite (132 mg, 1.91 mmol) in H ₂ O (3 ml). The reaction mixture was stirred at ambient temperature for 16 hours. Additional p-toluenesulfonic acid hydrate (546 mg, 2.87 mmol) and KI (396 mg, 2.39 mmol) in water (1 ml) were added and the mixture was stirred at environment for 16 hours. The reaction was stopped by adding saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ S ₂ O ₃ and the resulting precipitate was isolated by filtration to give 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl) -6-fluoro-2-iodopyrazolo[1,5-a]pyrimidine as a red solid (351 mg, 84% purity, 73%); MS m/z: 426.0 (M+H) ⁺ .

[001007] Synthesis 153: 5-(Difluoromethyl)-3-(2-fluoro-4-pyridyl)pyrazolo[1,5-a]pyrimidine

[001008] Step 1: 3-Bromo-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidine

[001009] KOH (7.64 g, 136.2 mmol) was added to a solution of 3-(1,3-dioxolan-2-yl)-1,1-difluoropropan-2-one (described in Tetrahedron, 63(30) , 7246-7255, 2007) (27.4 g, 164.9 mmol) and 4-bromo-1H-pyrazol-5-amine (20.1 g, 123.8 mmol) in 1,4-dioxane (200 ml ) and the mixture was stirred at 70°C for 5.5 hours. The reaction mixture was cooled to ambient temperature and 2 M aqueous HCl solution (68.1 ml, 136.2 mmol) was added. The mixture was poured into water (800 ml) and aged for 30 min. The resulting precipitate was isolated by filtration and dried in vacuum. The solid was dispersed in DCM and filtered through a pad of silica (eluting with 1:1 EtOAc/petroleum ether). The solvent was removed in vacuo to provide 3-bromo-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidine as an orange solid (14.8 g, 48%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.38 (d, 1H), 8.54 (s, 1H), 7.36 (d, 1H), 7.08 (t, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -117.0; MS m/z: 249.8 (M+H) ⁺ .

[001010] Step 2: 5-(Difluoromethyl)-3-(2-fluoro-4-pyridyl)pyrazolo[1,5-a]pyrimidine

[001011] To a solution of 3-bromo-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidine (400 mg, 1.61 mmol) in 1,4-dioxane (10 ml) and water (3.3 ml) added 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (540 mg, 2.42 mmol), 2 M aqueous solution of Na ₂ CO ₃ ( 2.4 ml, 4.84 mmol) and Pd(PPh ₃ ) ₄ (93.2 mg, 0.08 mmol), and the reaction mixture was heated at 80°C overnight. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (×3). The combined organics were dried (MgSO ₄ ), filtered and the solvent was removed under reduced pressure. The crude mixture was purified by column chromatography (silica, petroleum ether/EtOAc gradient elution) to give 5-(difluoromethyl)-3-(2-fluoro-4-pyridyl)pyrazolo[1,5-a]pyrimidine in as a yellow solid (334 mg, 78%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.49 (d, 1H), 9.17 (s, 1H), 8.31 (d, 1H), 8.14 (ddd, 1H), 7 .91 (s, 1H), 7.49 (d, 1H), 7.19 (t, 1H); ¹⁹ F NMR (471 MHz, DMSO-d6) δ - 68.69, -117.04, - 117.16; MS m/z: 265.1 (M+H) ⁺ .

[001012] Synthesis 154: 3-Iodo-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[001013] Step 1: 5-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[001014] To a solution of 3-(1,3-dioxolan-2-yl)-1,1,1-trifluoropropan-2-one (described in WO2014/143242 and Journal of Fluorine Chemistry, 126, (2005), 543- 550) (1.2 g, 6.52 mmol) and 4H-pyrazol-3-amine (500 mg, 6.02 mmol) in 1,4-dioxane (3 ml) was added KOH (35 mg, 0.624 mmol). The reaction mixture was stirred at ambient temperature for 2 hours, then at 90°C for 18 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography (silica, petroleum ether/EtOAc gradient elution) to give 5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine as a white solid (246 mg, 22%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.47 (d, 1H), 8.48 (d, 1H), 7.48 (d, 1H), 7.05 (dd, 1H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -67.09.

[001015] Step 2: 3-Iodo-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine

[001016] While stirring, 1 M iodine monochloride in DCM (3.3 ml, 3.3 mmol). The reaction mixture was heated at 50°C in a sealed tube for 3 days, then cooled to ambient temperature. Another portion of 1 M iodine monochloride in DCM (1.5 ml, 1.5 mmol) was added and the reaction mixture was heated at 50°C in a sealed tube for another 2 days. The reaction mixture was cooled to ambient temperature and diluted with DCM. The mixture was washed with saturated aqueous sodium thiosulfate (×2) and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, petroleum ether/EtOAc gradient elution) to give 3-iodo-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine as a yellow solid (249 mg, 60 %); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.50 (d, 1H), 8.58 (s, 1H), 7.53 (d, 1H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -67.03.

[001017] Synthesis 155: (S)-N-((6,6-dimethylmorpholin-2-yl)methyl)methanesulfonamide

[001018] Using the same procedure as used above for A10, (4-oxa-7-azaspiro[2.5]octan-5-yl)methanol A136 was prepared using tert-butyl-(6R)-6-(aminomethyl)- 2,2-dimethylmorpholine-4-carboxylate instead of tert-butyl-(6S)-6-(aminomethyl)-2,2-dimethylmorpholine-4-carboxylate.

[001019] Synthesis 156: 3-(6-Chloropyrimidin-4-yl)-6-(1,1-difluoroethyl)imidazo[1,2-b]pyridazine

[001020] Step 1: 1-(3-(6-(Methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)ethan-1-one

[001021] 1-(3-(6-(Methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)ethan-1-one was prepared from 1-(6-aminopyridazin-3- yl)ethan-1-one using a procedure similar to that described in synthesis 131.

[001022] Step 2: 6-(1,1-Difluoroethyl)-3-(6-(methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazine

[001023] To a suspension of 1-(3-(6-(methylthio)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)ethan-1-one (50 mg, 0.18 mmol) DAST (282 mg, 1.75 mmol) was added to DCM (2 ml). The reaction mixture was stirred at ambient temperature for 4 hours, then additional DAST (282 mg, 1.75 mmol) was added. DAST (282 mg, 1.75 mmol) was added at 24-hour intervals for 3 days, then again (282 mg, 1.75 mmol) after another 3 days and a final portion (282 mg, 1.75 mmol) was added in 14 days. The reaction mixture was then slowly poured into saturated aqueous NaHCO ₃ solution, the layers were separated and the organic layer was dried (MgSO4) and concentrated in vacuo. The substance was used in the next step without further purification.

[001024] Step 3: 3-(6-Chloropyrimidin-4-yl)-6-(1,1-difluoroethyl)imidazo[1,2-b]pyridazine

[001025] 3-(6-Chloropyrimidin-4-yl)-6-(1,1-difluoroethyl)imidazo[1,2-b]pyridazine was prepared using a procedure similar to that described in synthesis 132.

[001026] Synthesis 157: 2-(1H-Pyrazol-4-yl)morpholine

[001027] 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 with stirring at ambient temperature. After 3 h, the solvent was removed in vacuo and the residue was purified by chromatography (silica, petroleum ether/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) ⁺ .

[001028] 3 M HCl in MeOH (45 ml, 135 mmol) was added to a solution of tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate (2.35 g, 9.3 mmol) with stirring ) 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 2 M 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), 2.93-2.88 (m, 2H); MS m/z: 154.2 [M+H] ⁺ .

[001029] Synthesis 158: 2-Methyl-6-(1H-pyrazol-4-yl)morpholine

[001030] 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, petroleum ether/EtOAc 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) ⁺ , which was immediately used in the next reaction.

[001031] 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 H ₂ atmosphere at a pressure of 1 atm. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a colorless gum (90 mg), MS m/z: 218 (M+H) ⁺ , which was immediately used in the next reaction. 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 2 M 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 MeOH, 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.

[001032] A mixture of 6-(1-benzylpyrazol-4-yl)-2-methylmorpholin-3-one (100 mg, 0.4 mmol) and LiAlH ₄ (184 μl 2 M, 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 MeOH (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), which was immediately used in the next reaction; MS m/z: 168 (M+H) ⁺ .

[001033] Synthesis 159: Imino(methyl)(piperidin-3-ylmethyl)-λ6-sulfanone

[001034] 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.

[001035] m-CPBA (324 mg, 1.88 mmol) was added to an ice-cold solution of tert-butyl 3-(methylsulfanylmethyl)piperidine-1-carboxylaate (460 mg, 1.88 mmol) in DCM (7 mL) in atmosphere N ₂ . The reaction mixture was stirred for 20 hours with the temperature 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 MgSO ₄ , filtered and concentrated in vacuo to give a pale brown oil (460 mg), MS m/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 N ₂ atmosphere. Rh ₂ (OAc) ₆ (0.9 g, 2.0 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through celite, washed with MeOH and DCM. The filtrate was concentrated in vacuo and the residue was taken up in MeOH (5 ml) and MeCN/water (3:1) (5 ml). K ₂ CO ₃ (17.4 g, 126.0 mmol) was added 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 (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give tert-butyl 3-[(methylsulfonimidoyl)methyl]piperidine-1-carboxylate (5.96 g, quantitative yield) as an amber oil, MS m/z: 277 (M+H) ⁺ , which was immediately used in the next reaction.

[001036] 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 overnight. The reaction mixture was concentrated in vacuo. The residue was taken up in MeOH 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)-λ6-sulfanone (250 mg, 65%); ¹ H NMR (500 MHz, methanol-d ₄ ) 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).

[001037] Synthesis 160: 2-(1H-Pyrazol-4-yl)piperazine

[001038] A mixture of 2-(1H-pyrazol-4-yl)pyrazine (400 mg, 2.7 mmol), PtO ₂ (100 mg, 0.4 mmol) in MeOH (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) ⁺ ].

[001039] Synthesis 161: 2-Methyl-3-(1H-pyrazol-4-yl)piperazine

[001040] To a suspension of 2-chloro-3-methylpyrazine (500 mg, 3.89 mmol) in 1,4-dioxane (10 ml) was added tert-butyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (1.26 g, 4.28 mmol), tetrakis(triphenylphosphine)palladium(0) (225 mg, 0.19 mmol) and Na ₂ CO ₃ (5.8 ml of 2 M aqueous solution, 11.7 mmol). The reaction mixture was stirred in a sealed tube at 130°C for 3 hours, then cooled and filtered through a pad of celite. The filtrate was concentrated in vacuo to give 2-methyl-3-(1H-pyrazol-4-yl)pyrazine (750 mg, 94%) as a white solid; MS m/z: 161 (M+H) ⁺ .

[001041] A mixture of 2-methyl-3-(1H-pyrazol-4-yl)pyrazine (585 mg, 3.65 mmol), PtO ₂ (84 mg, 0.37 mmol) and concentrated HCl (2 ml, 55 mmol ) in methanol (60 ml) was shaken at ambient temperature in ^a Parr hydrogenator at 60 psi H ₂ pressure for 6 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in methanol and loaded into an ion exchange cartridge. The cartridge was washed with methanol (the filtrate was discarded), then with a methanol ammonia solution. The filtrate was concentrated under reduced pressure to give 2-methyl-3-(1H-pyrazol-4-yl)piperazine (600 mg, 99%) as a brown solid; MS m/z: 167 (M+H) ⁺ . This substance was used in the next reaction without further purification.

[001042] The following amines were prepared using a methodology similar to that shown in Synthesis 161:

3-(Difluoromethoxy)-5-(1H-pyrazol-4-yl)piperidine;

3-Methoxy-5-(1H-pyrazol-4-yl)piperidine;

3-(2H-1,2,3-Triazol-4-yl)piperidine;

2-Methyl-5-(1H-pyrazol-4-yl)piperazine;

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

5-Isopropyl-2-methyl-3-(1H-pyrazol-4-yl)piperazine;

2,3,5-Trimethyl-6-(1H-pyrazol-4-yl)piperazine;

2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperidine;

2-Methyl-3-(1H-pyrazol-4-yl)piperidine;

3-(1H-Imidazol-4-yl)-2-methylpiperidine;

(5-(1H-Pyrazol-4-yl)piperidin-3-yl)methanol;

3-(1H-Imidazol-4-yl)-2-methylpiperidine;

3-(3-Methyl-1H-pyrazol-4-yl)piperidine;

2-Methyl-6-(3-methyl-1H-pyrazol-4-yl)piperazine;

2-Methyl-6-(3-(trifluoromethyl)-1H-pyrazol-4-yl)piperazine;

2,5-Dimethyl-3-(5-methyl-1H-pyrazol-4-yl)piperazine;

2-(1H-Imidazol-4-yl)piperazine;

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

2-(3,5-Dimethyl-1H-pyrazol-4-yl)-6-methylpiperazine;

3-(3,5-Dimethyl-1H-pyrazol-4-yl)piperidine;

2-(1H-Pyrazol-4-yl)-6-(trifluoromethyl)piperazine;

2,5-Dimethyl-3-(2-(trifluoromethyl)-1H-imidazol-4-yl)piperazine;

2-Methyl-6-(1-methyl-1H-pyrazol-5-yl)piperazine;

2-Methyl-6-(1-methyl-1H-imidazol-5-yl)piperazine;

5-(3,6-Dimethylpiperazin-2-yl)pyridin-2(1H)-one;

3-(Azetidin-1-ylmethyl)-5-(1H-pyrazol-4-yl)piperidine;

2-(5-(1H-Pyrazol-4-yl)piperidin-3-yl)propan-2-ol;

2,5-Dimethyl-3-(1-methyl-1H-pyrazol-4-yl)piperazine;

2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazine.

[001043] Synthesis 162: 6-(1H-Pyrazol-4-yl)piperazin-2-one

[001044] Step 1: 2-Methoxy-6-(1H-pyrazol-4-yl)pyrazine

[001045] To a suspension of 2-chloro-6-methoxypyrazine (500 mg, 3.46 mmol) in 1,4-dioxane (10 ml) was added tetrakis(triphenylphosphine) palladium(0) (220 mg, 0.19 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (1.10 g, 3.70 mmol) and 2 M Na ₂ CO ₃ (6 ml, 12 mmol). The reaction mixture was stirred in a sealed tube at 100°C for 2 hours, then filtered and concentrated in vacuo to give 2-methoxy-6-(1H-pyrazol-4-yl)pyrazine (800 mg, 72%); MS m/z: 177.1 (M+H) ⁺ .

[001046] Step 2: 6-(1H-Pyrazol-4-yl)piperazin-2-one

[0100] Mixture of 2-methoxy-6-(1H-pyrazol-4-yl)pyrazine (610 mg, 3.462 mmol), PtO ₂ (120 mg, 0.528 mmol), HCl (3 M in methanol, 2.20 ml, 6.60 mmol) in methanol (40 ml) was shaken in a Parr hydrogenator at 60 psi ^{H 2} _pressure . The catalyst was filtered off and the filtrate was concentrated to give 6-(1H-pyrazol-4-yl)piperazin-2-one (450 mg, 78%); MS m/z: 167.0 (M+H) ⁺ .

[001047] Synthesis 163: ((5-(1H-Pyrazol-4-yl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone

[001048] Step 1: ((5-Bromopyridin-3-yl)imino)dimethyl-λ6-sulfanone

[001049] 3,5-Dibromopyridine (3.0 g, 12.7 mmol), iminodimethyloxo-λ6-sulfane (800 mg, 8.59 mmol), Xantphos (470 mg, 0.81 mmol) and cesium carbonate (4 .0 g, 10.0 mmol) were mixed in 1,4-dioxane (10 ml). The reaction mixture was degassed and treated with tris(benzylideneacetone)dipalladium(0) (370 mg, 0.40 mmol) and the mixture was stirred at 100°C overnight. The reaction mixture was cooled and filtered, and the solid was washed with EtOAc. The combined wash solutions were concentrated in vacuo and purified by column chromatography (40 g SiO ₂ , eluting with 0 to 100% ethyl acetate in petroleum ether gradient) to give ((5-bromopyridin-3-yl)imino)dimethyl -λ6-sulfanone (1.8 g, 84%) as a brown oil; MS m/z: 251.1 (M+H) ⁺ .

[001050] Step 2: ((5-(1H-Pyrazol-4-yl)pyridin-3-yl)imino)dimethyl-λ6-sulfanone

[001051] Mixture of ((5-bromopyridin-3-yl)imino)dimethyl-λ6-sulfanone (770 mg, 3.09 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol), 2 M Na ₂ CO ₃ (3.50 ml, 7.0 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1- carboxylate (1.6 g, 5.4 mmol) in dioxane (15 ml) was stirred at 130°C for 90 min. The reaction mixture was diluted with EtOAc and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography (40 g SiO ₂ , eluting with 90:10:1 petroleum ether/EtOAc/NH ₃ in MeOH) gave ((5-(1H-pyrazol-4-yl)pyridin-3-yl)imino )dimethyl-λ6-sulfanone (100 mg, 14%) as a white solid; MS m/z: 237.2 (M+H) ⁺ .

[001052] Step 3: ((5-(1H-Pyrazol-4-yl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone

[001053] Mixture of ((5-(1H-pyrazol-4-yl)pyridin-3-yl)imino)dimethyl-λ6-sulfanone (100 mg, 0.42 mmol), PtO ₂ (50 mg, 0.22 mmol ), 3 M HCl in methanol (15.0 mL, 45.0 mmol) was shaken in a Parr hydrogenator at 60 psi ^{H 2} _pressure . After 18 hours, more PtO ₂ (50 mg, 0.22 mmol) was added and the reaction mixture was stirred for an additional 24 hours at 60 psi ^{H 2} _pressure . The reaction mixture was filtered to give ((5-(1H-pyrazol-4-yl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone (100 mg, 97%), which was used without further purification; MS m/z: 243.0 (M+H) ⁺ .

[0100] The following compounds were prepared using a methodology similar to that described in Synthesis 163:

(5-(1H-Pyrazol-4-yl)piperidin-3-yl)dimethylphosphine oxide;

Dimethyl(6-methyl-5-(1H-pyrazol-4-yl)piperidin-3-yl)phosphine oxide.

[001054] Synthesis 164: tert-Butyl-5-(isothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[001055] Step 1: tert-Butyl 5-(isothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[001056] 4-Bromoisothiazole (668 mg, 4.08 mmol) and tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- Dihydro-2H-pyridine-1-carboxylate (1.05 g, 3.40 mmol) was mixed in 1,4-dioxane (20 ml) and tetrakis(triphenylphosphine) palladium(0) (196 mg, 0.17 mmol) was added. and Na ₂ CO ₃ (5 ml 2 M, 10 mmol). The reaction mixture was degassed and purged with nitrogen and heated at 130°C for 2 hours. The reaction mixture was cooled and diluted with EtOAc and water, and the aqueous layer was extracted 3 times with EtOAc. The combined organics were passed through a phase separation cartridge and concentrated in vacuo. Purification by column chromatography (24 g SiO ₂ , eluting with 0-100% EtOAc in petroleum ether gradient) gave tert-butyl-5-(isothiazol-4-yl)-3,6-dihydropyridine-1( 2H)-carboxylate (741 mg, 80%) as a yellow oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.83 (s, 1H), 6.50 (tt, J=4.1, 1.9 Hz, 1H) , 4.20-15 (m, 2H), 3.47 (t, J=5.7 Hz, 2H), 2.29-2.21 (m, 2H), 1.43 (s, 9H); MS m/z: 267.0 (M+H) ⁺ .

[001057] Step 2: 4-(1,2,5,6-Tetrahydropyridin-3-yl)isothiazole

[001058] tert-Butyl-5-(isothiazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (499 mg, 1.87 mmol) was dissolved in DCM (2.8 ml) and TFA was added (1.5 ml, 19.5 mmol) and the reaction mixture was stirred at ambient temperature overnight. The mixture was passed through an SCX-2 cartridge, washed with MeOH and the product eluted with methanolic ammonia. The ammonia extracts were concentrated in vacuo to give 4-(1,2,3,6-tetrahydropyridin-5-yl)isothiazole (288 mg, 92%) as a brown oil, which was used without further purification; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.78 (d, J=13.3 Hz, 2H), 6.40 (tt, J=4.0, 1.8 Hz, 1H), 3 .50 (td, J=2.7, 1.7 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.13 (ddq, J=6.9, 5.6 , 2.8 Hz, 2H); MS m/z: 167.0 (M+H).

[001059] The following compounds were prepared using a methodology similar to that described in Synthesis 164:

4-(1,2,5,6-Tetrahydropyridin-3-yl)-1H-pyrazole-3-carbonitrile;

5-(3-Fluoro-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridine;

5-(2-Isopropyl-1H-imidazol-4-yl)-1,2,3,6-tetrahydropyridine;

5-(3-Methyl-1H-pyrazol-4-yl)-1,2,3,6-tetrahydropyridine;

5-(2-Methyl-1H-imidazol-4-yl)-1,2,3,6-tetrahydropyridine.

[001060] Synthesis 165: 5-(Piperidin-3-yl)thiazole

[001061] Step 1: tert-Butyl 5-(thiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[001062] 5-Bromothiazole (520 mg, 3.17 mmol), tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- Dihydro-2H-pyridine-1-carboxylate (1.08 g, 3.49 mmol), (dppf)PdCl ₂ .DCM (259 mg, 0.31 mmol) and 2 M Na ₂ CO ₃ (3.96 ml, 7.93 mmol) was mixed in 1,4-dioxane (18.3 ml). The mixture was degassed and stirred at 85°C for 3 hours, then diluted in EtOAc. The layers were separated and the organic layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography (40 g, SiO ₂ , eluting with a gradient of 0-80% EtOAc in petroleum ether) gave tert-butyl-5-(thiazol-5-yl)-3,6-dihydropyridine-1 (2H)-carboxylate; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.64 (s, 1H), 7.75 (s, 1H), 6.24 (s, 1H), 4.27 (s, 2H), 3 .56 (s, 2H), 2.32 (s, 2H), 1.50 (s, 9H); MS m/z: 267.2 (M+H).

[001063] Step 2: tert-Butyl-3-(thiazol-5-yl)piperidine-1-carboxylate

[001064] Methanol (8.6 ml) was added to tert-butyl-5-(thiazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (230 mg, 0.86 mmol), then added Pd(OH) ₂ (60.6 mg, 0.086 mmol). The mixture was degassed and stirred with H ₂ from a cylinder for 3 days, then filtered through celite. The filtrate was evaporated in vacuo to give tert-butyl-3-(thiazol-5-yl)piperidine-1-carboxylate (230 mg, 100%), which was used without further purification; MS m/z: 269.2 (M+H).

[001065] Step 3: 5-(Piperidin-3-yl)thiazole

[001066] TFA (4.89 g, 3.30 mL, 42.9 mmol) was added to a solution of tert-butyl-3-(thiazol-5-yl)piperidin-1-carboxylate (230 mg, 0.86 mmol) in DCM (2 ml). After 1 hour the solution was concentrated in vacuo and the residue was passed through an SCX-2 cartridge, washed with MeCN/MeOH and the product eluted with 2 M NH ₃ in MeOH. The solution was concentrated in vacuo to give 5-(piperidin-3-yl)thiazole (106 mg, 74% in two steps) as a yellow oil; MS m/z: 169.1 (M+H).

[001067] The following compounds were prepared using a methodology similar to that described in Synthesis 165:

2-(Piperidin-3-yl)oxazole;

(4-(Pyrrolidin-3-yl)-1H-pyrazol-3-yl)methanol;

4-(Pyrrolidin-3-yl)-1H-pyrazole;

3-Fluoro-4-(pyrrolidin-3-yl)-1H-pyrazole;

3-Methyl-4-(pyrrolidin-3-yl)-1H-pyrazole;

3,5-Dimethyl-4-(pyrrolidin-3-yl)-1H-pyrazole;

3-Cyclopropyl-4-(pyrrolidin-3-yl)-1H-pyrazole;

3-(1-Methylcyclopropyl)-4-(pyrrolidin-3-yl)-1H-pyrazole;

4-(Pyrrolidin-3-yl)-3-(trifluoromethyl)-1H-pyrazole;

3-(3-Fluoro-1H-pyrazol-4-yl)piperidine;

3-(2-Methyl-1H-imidazol-4-yl)piperidine;

3-(2-Isopropyl-1H-imidazol-4-yl)piperidine;

4-(Piperidin-3-yl)oxazole.

[001068] Synthesis 166: 3-Methyl-2-(1-trityl-1H-imidazol-4-yl)morpholine

[001069] Step 1: 2-Nitro-1-(1-trityl-1H-imidazol-4-yl)propan-1-ol

[001070] 1-Tritylimidazole-4-carbaldehyde (5.0 g, 14.8 mmol) was added to a solution of 1-nitroethane (13 mL, 180 mmol) in DCM (6 mL). Et ₃ N (300 µl, 2.15 mmol) was added and the solution was stirred for 18 hours, then concentrated in vacuo to give 2-nitro-1-(1-trityl-1H-imidazol-4-yl)propan-1- ol (6.1 g, 100%), which was used without further purification; MS m/z: 414.3 (M+H) ⁺ .

[001071] Step 2: 4-(1-((tert-Butyldimethylsilyl)oxy)-2-nitropropyl)-1-trityl-1H-imidazole

[001072] [tert-Butyl(dimethyl)silyl]trifluoromethanesulfonate (60 μl, 0.26 mmol) was added to a solution of 2-nitro-1-(1-trityl-1H-imidazol-4-yl)propan-1-ol ( 100 mg, 0.24 mmol) and DIPEA (42 µl, 0.24 mmol) in DMF (1 ml). After stirring at ambient temperature for 1 hour, further [tert-butyl(dimethyl)silyl]trifluoromethanesulfonate (60 μL, 0.26 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and water. The organic layer was concentrated in vacuo to give 4-(1-((tert-butyldimethylsilyl)oxy)-2-nitropropyl)-1-trityl-1H-imidazole (128 mg, 100%), which was used without further purification; MS m/z: 528.5 (M+H) ⁺ .

[001073] Step 3: 1-((tert-Butyldimethylsilyl)oxy)-1-(1-trityl-1H-imidazol-4-yl)propan-2-amine

[001074] A saturated aqueous solution of NH ₄ Cl (1 ml, 30 mmol) was added to a suspension of Zn (50 mg, 0.76 mmol) and 4-(1-((tert-butyldimethylsilyl)oxy)-2-nitropropyl)-1 -trityl-1H-imidazole (128 mg, 0.24 mmol) and stirred at ambient temperature in methanol (5 ml). After 1 hour, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was passed through an SCX-2 cartridge and the product was eluted with 2 M NH ₃ in methanol. Concentration in vacuo gave 1-[tert-butyl(dimethyl)silyl]oxy-1-(1-tritylimidazol-4-yl)propan-2-amine (121 mg, 100%), which was used without further purification; MS m/z: 498.5 (M+H) ⁺ .

[001075] Step 4: N-(1-((tert-Butyldimethylsilyl)oxy)-1-(1-trityl-1H-imidazol-4-yl)propan-2-yl)-2-chloroacetamide

[001076] 2-Chloroacetyl chloride (16 μl, 0.20 mmol) was added to a solution of 1-((tert-butyldimethylsilyl)oxy)-1-(1-trityl-1H-imidazol-4-yl)propan-2-amine ( 90 mg, 0.18 mmol) and DIPEA (65 µl, 0.37 mmol) in DCM (3 ml) and the mixture was stirred at ambient temperature. After 5 min, the reaction mixture was diluted in DCM and washed with saturated aqueous NaHCO ₃ solution. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give N-(1-((tert-butyldimethylsilyl)oxy)-1-(1-trityl-1H-imidazol-4-yl)propan-2-yl)-2 -chloroacetamide (104 mg, 100%), which was used without further purification; MS m/z: 574.6 (M+H) ⁺ .

[001077] Step 5: 5-Methyl-6-(1-trityl-1H-imidazol-4-yl)morpholin-3-one

[001078] TBAF (180 μl 1 M, 0.18 mmol) was added to a solution of N-(1-((tert-butyldimethylsilyl)oxy)-1-(1-trityl-1H-imidazol-4-yl)propan-2 -yl)-2-chloroacetamide (104 mg, 0.18 mmol) in THF (4 ml). The mixture was stirred at ambient temperature for 2 hours, then potassium 2-methylpropan-2-olate (180 μl 1 M, 0.18 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted in DCM and washed with saturated aqueous NH ₄ Cl and the organic layer was dried (MgSO ₄ ) and evaporated in vacuo. Purification by column chromatography (SiO ₂ , eluting with 0-15% methanol in DCM gradient) gave 5-methyl-6-(1-trityl-1H-imidazol-4-yl)morpholin-3-one ( 77 mg, 100%) as a colorless glassy substance; MS m/z: 424.4 (M+H) ⁺ .

[001079] Step 6: 2-(1H-Imidazol-4-yl)-3-methylmorpholine

[001080] Borane-tetrahydrofuran complex (1 ml of 1 M, 1.0 mmol) was slowly added to a solution of 5-methyl-6-(1-trityl-1H-imidazol-4-yl)morpholin-3-one (80 mg, 0.19 mmol) in THF (5 ml), stirred at ambient temperature. After 1 hour, the reaction was stopped by adding methanol and the mixture was stirred for 15 minutes, then concentrated HCl (1 ml) was added. The reaction mixture was stirred at ambient temperature for 2 hours, then concentrated in vacuo. The residue was passed through an SCX-2 cartridge, washed with methanol, and the product was eluted with 2 M NH ₃ in methanol. The stock wash solutions were concentrated in vacuo to give 2-(1H-imidazol-4-yl)-3-methylmorpholine (30 mg, 95%); MS m/z: 168.1 (M+H) ⁺ .

[001081] The following compound was prepared using a methodology similar to that used in synthesis 166:

2-(1H-Imidazol-4-yl)-3,6-dimethylmorpholine.

[001082] Synthesis 167: 3,6-Dimethyl-2-(1H-pyrazol-4-yl)morpholine

[001083] Step 1: 1-(1-Benzyl-1H-pyrazol-4-yl)-2-nitropropan-1-ol

[001084] 1-Benzylpyrazole-4-carbaldehyde (10.5 g, 56.4 mmol) was dissolved in 1-nitroethane (49 ml, 681.8 mmol) and the solution was cooled to 0°C, then Et ₃ N (784 µl, 5.62 mmol). The solution was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with concentrated HCl (705 μl 12 M, 8.46 mmol) and the mixture was stirred for 10 min, then concentrated in vacuo. Purification by flash chromatography (330 g SiO ₂ , eluting with 50% EtOAc in petroleum ether) gave 1-(1-benzyl-1H-pyrazol-4-yl)-2-nitropropan-1-ol (10, 5 g, 71%) as a white crystalline solid; MS m/z: 261.1 (M+H) ⁺ .

[001085] Step 2: 2-Amino-1-(1-benzyl-1H-pyrazol-4-yl)propan-1-ol

[001086] Sodium borohydride (6.82 g, 7.21 mL, 180.2 mmol) was added portionwise to a solution of 1-(1-benzyl-1H-pyrazol-4-yl)-2-nitropropan-1-ol (11 .85 g, 45.35 mmol) and nickel(II) chloride hexahydrate (10.8 g, 45.3 mmol) in methanol (225 ml), stirred at 0°C. After addition, the solution was stirred at 0°C for 20 min, then the reaction was stopped by adding water, then 1 M HCl was added and the reaction mixture was stirred for 30 min. The suspension was filtered through celite and the filtrate was concentrated in vacuo. The residue was redissolved in methanol and acidified with HCl. This mixture was concentrated in vacuo to give 2-amino-1-(1-benzyl-1H-pyrazol-4-yl)propan-1-ol (hydrochloride) (12.1 g), which was used without further purification; MS m/z: 232.1 (M+H) ⁺ .

[001087] Step 3: N-(1-(1-Benzyl-1H-pyrazol-4-yl)-1-hydroxypropan-2-yl)-2-chloropropanamide

[001088] 2-Chloropropanoyl chloride (68.6 mg, 52.5 μl, 0.54 mmol) was added to a solution of 2-amino-1-(1-benzylpyrazol-4-yl)propan-1-ol (500 mg, 2.162 mmol) and Et ₃ N (904 μl, 6.49 mmol) and stirred at 0°C in DCM (27 ml). After 30 min at this temperature, the reaction was stopped by adding methanol (5 ml) and concentrated in vacuo. Purification by column chromatography (12 g SiO ₂ , eluting with 0-100% [90% EtOAc-10% 2 M methanol NH ₃ ] in petroleum ether) gave N-(1-(1-benzyl-1H- pyrazol-4-yl)-1-hydroxypropan-2-yl)-2-chloropropanamide (110 mg, 16% in two steps); MS m/z: 261.1 (M+H) ⁺ .

[001089] Step 4: 6-(1-Benzyl-1H-pyrazol-4-yl)-2,5-dimethylmorpholin-3-one

[001090] Potassium tert-butoxide (400 μl of 1 M, 0.40 mmol) was added to a solution of N-(1-(1-benzyl-1H-pyrazol-4-yl)-1-hydroxypropan-2-yl)-2 -chloropropanamide (110 mg, 0.34 mmol) in THF (2 ml) and stirred at ambient temperature. After 3 days, the reaction mixture was diluted with DCM and washed with saturated aqueous NH ₄ Cl. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give 6-(1-benzyl-1H-pyrazol-4-yl)-2,5-dimethylmorpholin-3-one (49 mg, 100%), which was used without additional cleaning; MS m/z: 286.3 (M+H) ⁺ .

[001091] Step 5: 2-(1-Benzyl-1H-pyrazol-4-yl)-3,6-dimethylmorpholine

[001092] Borane-THF complex (1.7 ml of 1 M, 1.70 mmol) was added to a solution of 6-(1-benzylpyrazol-4-yl)-2,5-dimethylmorpholin-3-one (97 mg, 0. 34 mmol) in THF (5 ml) and stirred at 0°C. After 1 hour, the reaction was stopped by adding methanol and the mixture was concentrated in vacuo. Methanol (5 ml) was added followed by 1 M HCl (5 ml) and the mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuo. The residue was passed through an SCX cartridge, washed with DCM/MeOH mixtures and the product was eluted with 2 M NH ₃ in MeOH. The ammonia extracts were concentrated in vacuo and the residue was further dried by azeotropic distillation with methanol and toluene (1:1 mixture) to give 2-(1-benzyl-1H-pyrazol-4-yl)-3,6-dimethylmorpholine (92 mg , 100%); MS m/z: 272.2 (M+H) ⁺ .

[001093] Step 6: 3,6-Dimethyl-2-(1H-pyrazol-4-yl)morpholine

[001094] Solution of 2-(1-benzyl-1H-pyrazol-4-yl)-3,6-dimethylmorpholine (100 mg, 0.37 mmol), palladium on carbon (10% w/w wet, Degussa, 40 mg, 0.038 mmol) and concentrated HCl (200 µl 12 M, 2.4 mmol) in methanol (5 ml) were stirred at ambient temperature with H ₂ supplied from a cylinder overnight. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was further dried by azeotropic distillation with methanol and toluene (1:1 mixture) to obtain 3,6-dimethyl-2-(1H-pyrazol-4-yl)morpholine (80 mg, 100%); MS m/z: 182.2 (M+H) ⁺ .

[001095] Synthesis 168: 2,2-Dimethyl-6-(1H-pyrazol-4-yl)piperazine

[001096] Step 1: 1-(1-Benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one

[001097] Bromine (390 μl, 7.57 mmol) was added dropwise to a solution of 1-(1-benzylpyrazol-4-yl)ethanone (1.5 g, 7.49 mmol) in chloroform (20 ml) and stirred at 0°C in nitrogen atmosphere. After 5 minutes, the reaction mixture was warmed to ambient temperature and stirred overnight. Additional bromine (200 µl, 3.88 mmol) was added and the reaction mixture was stirred for another 4 hours, then the reaction was stopped by adding saturated aqueous NaHCO ₃ solution (30 ml). The layers were separated and the organic layer was washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography (40 g SiO ₂ , 0-100% ethyl acetate in hexanes) gave 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one as a yellow oil (1. 34 g, 61%); MS m/z: 281.1 (M+H) ⁺ .

[001098] Step 2: tert-Butyl-(1-((2-(1-benzyl-1H-pyrazol-4-yl)-2-oxoethyl)amino)-2-methylpropan-2-yl)carbamate

[001099] A solution of 1-(1-benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one (510 mg, 1.83 mmol), Et ₃ N (280 μl, 2.01 mmol) and tert-butyl-(1-amino-2-methylpropan-2-yl)carbamate (344 mg, 1.83 mmol) in DCM (10.2 ml) was stirred at ambient temperature for 90 min, then diluted in DCM. The layers were separated and the organic layer was washed with water and brine, dried (MgSO ₄ ) and concentrated in vacuo. The substance was used in the next step without further purification.

[001100] Step 3: 6-(1-Benzyl-1H-pyrazol-4-yl)-2,2-dimethylpiperazine

[001101] tert-Butyl-(1-((2-(1-benzyl-1H-pyrazol-4-yl)-2-oxoethyl)amino)-2-methylpropan-2-yl)carbamate (700 mg, 1. 81 mmol) was dissolved in DCM (10 ml) and the mixture was stirred at 0°C. TFA (3 ml) was added and the reaction mixture was stirred for 3 hours, then concentrated in vacuo. The residue was dissolved in methanol (16.8 ml) and sodium triacetoxy boroanhydride (1.54 g, 7.24 mmol) was added. After stirring for 30 minutes at ambient temperature, the reaction was stopped by adding saturated aqueous NaHCO ₃ solution and concentrated in vacuo. The residue was passed through an SCX cartridge and the ammonia extracts were concentrated in vacuo to give 6-(1-benzyl-1H-pyrazol-4-yl)-2,2-dimethylpiperazine (400 mg, 82%); MS m/z: 271.3 (M+H) ⁺ .

[001102] Step 4: 2,2-Dimethyl-6-(1H-pyrazol-4-yl)piperazine

[001103] 12 M HCl (616 μl, 7.40 mmol) was added to a solution of 6-(1-benzyl-1H-pyrazol-4-yl)-2,2-dimethylpiperazine (400 mg, 1.48 mmol) and palladium on charcoal (wet, Degussa 10% w/w, 157 mg, 0.15 mmol) in methanol (6 ml). The reaction mixture was stirred with H ₂ from a bottle overnight, then filtered through celite and concentrated in vacuo. The residue was passed through an SCX cartridge and the ammonia extracts were concentrated in vacuo to give 2,2-dimethyl-6-(1H-pyrazol-4-yl)piperazine (133 mg, 50%); MS m/z: 181.0 (M+H) ⁺ .

[001104] Synthesis 169: 3-(1H-Pyrazol-4-yl)piperidin-3-ol

[001105] Step 1: Benzyl 3-hydroxy-3-(1-trityl-1H-pyrazol-4-yl)piperidine-1-carboxylate

[001106] 4-Bromo-1-tritylpyrazole (3.03 g, 7.77 mmol) in THF (40 ml) was cooled to -78°C, then n-BuLi (3.36 ml 2.5 M) was added dropwise in hexanes, 8.39 mmol). After 20 min, benzyl 3-oxopiperidine-1-carboxylate (1.903 g, 8.160 mmol) was added as a solution in THF (15 ml). After another 20 min, the reaction was stopped with a saturated aqueous NH ₄ Cl solution (15 ml) and allowed to warm to ambient temperature. The mixture was partitioned between water and EtOAc, the organic layer was separated, dried (MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography (120 g SiO ₂ , 10-45% ethyl acetate in petroleum ether) gave benzyl 3-hydroxy-3-(1-trityl-1H-pyrazol-4-yl)piperidin-1-carboxylate (2, 00 g, 47%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.60 (d, J=0.8 Hz, 1H), 7.39-7.27 (m, 16H), 7.07-7.00 ( m, 5H), 5.01 (t, J=13.6 Hz, 3H), 3.56 (s, 2H), 3.37 (d, J=12.9 Hz, 1H), 3.18 ( d, J=54.4 Hz, 1H), 1.84 (s, 1H), 1.73 (s, 2H), 1.34 (s, 1H).

[001107] Step 2: Benzyl 3-hydroxy-3-(1H-pyrazol-4-yl)piperidine-1-carboxylate

[001108] TFA (5 mL, 60 mmol) was added to a solution of benzyl 3-hydroxy-3-(1-trityl-1H-pyrazol-4-yl)piperidin-1-carboxylate (1 g, 1.84 mmol) in DCM (10 ml), stirred at ambient temperature. After 40 minutes, the reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous NaHCO ₃ and DCM. The layers were separated and the aqueous layer was re-extracted with DCM. The combined organics were dried (MgSO ₄ ), concentrated in vacuo and purified by column chromatography (24 g SiO ₂ , 20-100% ethyl acetate in petroleum ether) to give benzyl-3-hydroxy-3-(1H-pyrazol-4- yl)piperidine-1-carboxylate (440 mg, 79%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 7.76-7.18 (m, 7H), 5.08 (s, 2H), 4.90 (s, 1H), 3.64 (d, J=16.0 Hz, 2H), 3.35 (d, J=13.0 Hz, 1H), 3.13 (d, J=61.2 Hz, 1H) , 1.95-1.68 (m, 3H), 1.39 (s, 1H).

[001109] Step 3: 3-(1H-Pyrazol-4-yl)piperidin-3-ol

[001110] Pd(OH) ₂ (164 mg 20% w/w, 0.234 mmol) was added to a solution of benzyl 3-hydroxy-3-(1H-pyrazol-4-yl)piperidin-1-carboxylate (440 mg , 1.46 mmol) in degassed methanol (15 ml). The mixture was degassed and stirred with H ₂ supplied from a cylinder. After 1.5 h, the reaction mixture was filtered through celite and concentrated to give 3-(1H-pyrazol-4-yl)piperidin-3-ol (244 mg, 100%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.50 (s, 2H), 4.68 (s, 1H), 3.31 (s, 3H), 2.81 (dt, J=12, 7, 3.8 Hz, 1H), 2.76-2.63 (m, 2H), 2.48 (dd, J=10.0, 3.2 Hz, 1H), 1.83-1.65 (m, 3H), 1.36 (dq, J=12.1, 4.3, 3.9 Hz, 1H)

[001111] Synthesis 170: 3-(2-Chloro-1H-imidazol-4-yl)piperidine

[001112] Step 1: tert-Butyl-5-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H) -carboxylate

[001113] To a suspension of 2-[(4-bromo-2-chlorimidazol-1-yl)methoxy]ethyltrimethylsilane (400 mg, 1.28 mmol) and tert-butyl-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (400 mg, 1.29 mmol) in 1,4-dioxane (8 ml) was added tetrakis(triphenylphosphine )palladium(0) (140 mg, 0.12 mmol) and Na ₂ CO ₃ (2 ml 2 M, 4.00 mmol). The reaction mixture was stirred in a sealed tube at 130°C for 2 hours, then filtered and concentrated in vacuo to give tert-butyl-5-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (500 mg, 94%) as a yellow solid, which was used without further purification; MS m/z: 414.4 (MH) ^- .

[001114] Step 2: 3-(2-Chloro-1H-imidazol-4-yl)piperidine

[001115] Tert-Butyl 5-(2-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate mixture (530 mg, 1.28 mmol), palladium on carbon (wet, Degussa, 10% w/w, 280 mg, 2.63 mmol) in methanol (50 ml) shaken at ambient temperature in a Parr hydrogenator at pressure H ₂ equal to 60 lbf/in ² overnight. The mixture was filtered through celite and concentrated in vacuo to give 3-(2-chloro-1H-imidazol-4-yl)piperidine. The crude material was redissolved in DCM (3 ml) and TFA (3 ml) and the mixture was stirred for 1 hour, then concentrated in vacuo. The crude material was redissolved in methanol and passed through an SCX-2 cartridge, washed with methanol and the product eluted with methanolic ammonia. The ammonia extracts were concentrated in vacuo to obtain (200 mg, 84% in two steps) as a brown solid; MS m/z: 186.0 (M+H) ⁺ .

[001116] The following compound was prepared using a methodology similar to that used in Synthesis 170:

3-(3-Fluoro-1H-pyrazol-4-yl)piperidine.

[001117] Synthesis 171: N-(Pyrrolidin-3-yl)-1H-pyrazol-4-amine

[001118] Step 1: tert-Butyl-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-1H-pyrazole-1-carboxylate

[001119] tert-Butyl-3-oxopyrrolidine-1-carboxylate (309 mg, 1.67 mmol) and tert-butyl-4-aminopyrazole-1-carboxylate (611 mg, 3.34 mmol) were combined in methanol (5 ml ). After stirring for 10 minutes at ambient temperature, the solution was cooled to 0°C and NaBH(OAc) ₃ (1.03 g, 4.88 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred overnight, then heated at 50°C for 6 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and saturated aqueous NaHCO ₃ solution. The aqueous phase was extracted with EtOAc and the combined organics were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by column chromatography (40 g SiO ₂ , eluting with 0-100% EtOAc in petroleum ether) gave tert-butyl-4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)amino)-1H -pyrazole-1-carboxylate, which was used without further purification.

[001120] Step 2: N-(Pyrrolidin-3-yl)-1H-pyrazol-4-amine

[001121] The material obtained in step 1 was dissolved in DCM (2 ml) and TFA (1 ml) was added. After 3 hours at ambient temperature, the reaction mixture was evaporated in vacuo to give N-(pyrrolidin-3-yl)-1H-pyrazol-4-amine (50 mg, 8%) as the TFA salt; MS m/z: 153.0 (M+H) ⁺ .

[001122] Synthesis 172: N-(1-(Morpholin-2-yl)ethyl)methanesulfonamide

[001123] Place 1-(4-benzylmorpholin-2-yl)ethanamine (520 mg, 2.4 mmol), Et ₃ N (658 μL, 4.7 mmol) in DCM (11 mL) under N atmosphere into a round bottom flask ₂ . The mixture was then cooled to -78°C and MsCl (164 μL, 2 mmol) was added dropwise. The mixture was stirred for 10 minutes, then allowed to warm to ambient temperature and stirred for a further 10 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution. After 5 min, the reaction mixture was filtered through a phase separation cartridge and concentrated in vacuo. The resulting brown oil (700 mg) was immediately used in the next reaction; MS m/z: 299 (M+H) ⁺ .

[001124] N-[1-(4-Benzylmorpholin-2-yl)ethyl]methanesulfonamide (700 mg, 2 mmol) in MeOH (10 mL) was placed in a round bottom flask and concentrated HCl (196 μL, 2 mmol) was added. The flask was degassed and filled with N ₂ (×3 cycles vacuum - N ₂ ) and Pd at C, wet, Degussa 10% w/w was added in one portion. (249 mg, 0.2 mmol). The flask was connected to a hydrogen cylinder and filled (×3 vacuum - hydrogen cycles). The reaction mixture was stirred vigorously at ambient temperature overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was dissolved in methanol and loaded into an ion exchange cartridge. The cartridge was 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 N-(1-(morpholin-2-yl)ethyl)methanesulfonamide (450 mg), which was immediately used in the next reaction without further purification; MS m/z: 209 (M+H) ⁺ .

[001125] Synthesis 173: N-[[(2S)-Morpholin-2-yl]methyl]methanesulfonamide

[001126] Add tert-butyl-(2R)-2-(aminomethyl)morpholine-4-carboxylate (5 g, 23 mmol) and Et3N (16.1 mL, 115 mmol) to a 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 Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 70 to 100% EtOAc/petroleum ether). The product fractions were combined and concentrated in vacuo. The residue was dried overnight in vacuo to give N-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide (3.61 g, 53%) as a white solid; 1H 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).

[001127] TFA (9 mL, 115 mmol) was added with stirring to a solution of tert-butyl (2S)-2-(methanesulfonamidomethyl)morpholine-4-carboxylate (3.6 g, 12 mmol) in DCM (60 mL) 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 taken into methanol and passed through an ion exchange cartridge, eluted with methanol (discarded), then with 2 M methanol ammonia. The filtrate was concentrated in vacuo to give N-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide (2.3 g, 97%); 1H 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)+.

[001128] Synthesis 174: 2-Methylpiperidine-3-carboxamide

[001129] Step 1: Benzyl 3-carbamoyl-2-methylpiperidine-1-carboxylate

[001130] Triethylamine (413 μL, 2.96 mmol) was added to a solution of 1-((benzyloxy)carbonyl)-2-methylpiperidine-3-carboxylic acid (685 mg, 2.47 mmol) in THF (5.5 mL) . The reaction mixture was cooled to 10°C, then isobutyl chloroformate (388 mg, 368 μl, 2.84 mmol) was added dropwise. The mixture was stirred for 30 minutes, then NH ₄ OH (4 ml, 103 mmol) was added. The reaction mixture was stirred for another 1 hour, then water (5 ml) was added and the mixture was extracted with DCM (×3). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give benzyl 3-carbamoyl-2-methylpiperidine-1-carboxylate (680 mg, 99%), which was used without further purification; MS m/z: 277.3 (M+H) ⁺ .

[001131] Step 2: 2-Methylpiperidine-3-carboxamide

[001132] A mixture of benzyl-3-carbamoyl-2-methylpiperidine-1-carboxylate (680 mg, 2.46 mmol), Pd(OAc) ₂ (247 mg, 1.10 mmol), Et ₃ SiH (927 μl, 5 .80 mmol) and Et ₃ N (618 µl, 4.43 mmol) in DCM (13.6 ml) were stirred at ambient temperature for 1 hour, then diluted in methanol. The mixture was passed through an SCX-2 cartridge, washed with methanol, and the product was eluted with 2 M NH ₃ in methanol. The ammonia extracts were concentrated in vacuo to give 2-methylpiperidine-3-carboxamide (200 mg, 57%) as a colorless oil; MS m/z: 141.0 (MH) ^- .

[001133] Synthesis 175: 2,5-Dimethylpiperidine-3-carboxamide

[001134] Step 1: 2,5-Dimethylnicotinamide

[001135] 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) ⁺ .

[001136] Step 2: 2,5-Dimethylpiperidine-3-carboxamide

[001137] 2,5-Dimethylnicotinamide (99 mg, 0.66 mmol) and PtO₂ (30.4 mg, 0.13 mmol) was dissolved in methanol (3 ml) and 3 M HCl (1.1 ml, 3.30 mmol). The mixture was degassed and stirred with a supply of H₂ from a cylinder for 90 minutes, then passed through celite and the filtrate was concentrated in vacuo to give 2,5-dimethylpiperidine-3-carboxamide (dihydrochloride) (150 mg, 99%); MS m/z: 157.0 (M+H)⁺.

[001138] Synthesis 176: (S)-N-(Piperidin-3-ylmethyl)methanesulfonamide

[001139] Methanesulfonyl chloride (465 μl, 6.0 mmol) was added to a solution of tert-butyl (3R)-3-(aminomethyl)piperidine-1-carboxylate (1.0 g, 4.7 mmol) and Et ₃ with stirring N (1 ml, 7.2 mmol) in THF (20 ml) under nitrogen and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with DCM and saturated aqueous NaHCO ₃ and the mixture was stirred for 10 min. The layers were separated and the aqueous layer was extracted with DCM (×2). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo to give a pale yellow oil, which was transferred to DCM (30 ml). TFA (7.5 mL, 97.4 mmol) was added and the reaction mixture was stirred at ambient temperature for 20 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The residue was passed through an ion exchange cartridge and washed with MeOH/DCM mixtures (filtrates were discarded). The product was eluted by washing the cartridge with 2 M NH ₃ in MeOH/DCM mixtures. The solvent was removed in vacuo to give (S)-N-(piperidin-3-ylmethyl)methanesulfonamide (846 mg, 94%) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 3.13 (dd, 1H), 3.06 (d, 2H), 3.02-2.98 (m, 1H), 2.97 (s, 3H ), 2.64-2.58 (m, 1H), 2.41 (dd, 1H), 1.89-1.83 (m, 1H), 1.75-1.67 (m, 1H), 1.59 (br s, 1H), 1.54-1.45 (m, 1H), 1.22-1.14 (m, 1H); MS m/z: 193 (M+H) ⁺ .

[001140] Synthesis 177: N-(((3S,5S)-4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

[001141] 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 (1 M 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%).

[001142] 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 was kept 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 organics were washed with brine, 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. 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%); ¹ H NMR (300 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.

[001143] Preparative chiral supercritical liquid chromatography (conditions: Chiralpak ^® IC 5 μm, CO ₂ /iPrOH 90/10, 230 nm) was used to isolate one enantiomer of benzyl-(3R,5S)-3-[(1,3-dioxoisoindoline -2-yl)methyl]-4,4-difluoro-5-methylpiperidin-1-carboxylate, (98.7% ee).

[001144] 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 up in MeOH 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) ⁺ .

[001145] 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 a bath with ice. 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/PE 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) ⁺ .

[001146] 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) was added 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 MeOH. 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 up in MeOH (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) ⁺ .

[001147] Synthesis 178: 2,5-Dimethyl-3-((methylsulfinyl)methyl)piperidine

[001148] Step 1: 1-(tert-Butyl) 3-methyl-2,5-dimethylpiperidine-1,3-dicarboxylate

[001149] 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 3 M solution in MeOH, 171 .1 mmol) was stirred with H ₂ supplied from a cylinder. The reaction mixture was stirred overnight, 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 1 M solution in THF) were added successively , 17.4 mmol). The reaction mixture was stirred overnight, 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, d ₄ -methanol) 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) .

[001150] Step 2: tert-Butyl 3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate

[001151] O1-tert-Butyl-O3-methyl-2,5-dimethylpiperidine-1,3-dicarboxylate (1400 mg, 5.16 mmol) was dissolved in THF (42 ml) and cooled to 0°C. Lithium borohydride (10.3 mL of 2 M 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 at 50°C and stirred overnight. The reaction mixture was cooled to ambient temperature, 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- _d4 ) 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).

[001152] Step 3: tert-Butyl-2,5-dimethyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

[001153] 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 minutes, the reaction was stopped with saturated aqueous NaHCO ₃ solution, stirred for 5 minutes 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.

[001154] Step 4: tert-Butyl 2,5-dimethyl-3-((methylthio)methyl)piperidine-1-carboxylate

[001155] Sodium thiomethoxide (9.939 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 (99 ml), stirred at 0°C. After addition, cooling was stopped and the reaction mixture was heated at 60°C overnight. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by column chromatography (SiO ₂ , eluting with 0-12.5% MeOH in DCM gradient) to give 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).

[001156] Step 5: tert-Butyl 2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate

[001157] 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 a further 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.

[001158] Step 6: 2,5-Dimethyl-3-((methylsulfinyl)methyl)piperidine

[001159] tert-Butyl-2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate (2.1 g, 7.26 mmol) was dissolved in methanol (36 ml) and 4 M HCl was added in dioxane (9.1 ml, 36.3 mmol). The reaction mixture was stirred overnight 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) ⁺ .

[001160] Synthesis 179: Imino(methyl)(piperidin-3-ylmethyl)-λ6-sulfanone

[001161] 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 EtOH (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).

[001162] This material was dissolved in DCM (100 ml) and the solution was cooled in an ice bath. m-CPBA (6.93 g purity 70% w/w, 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.

[001163] 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 ₂ CO ₃ (17.44 g, 126.2 mmol) was added. 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 NaHCO ₃ solution. The organic layer was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give tert-butyl 3-((S-methylsulfonimidoyl)methyl)piperidine-1-carboxylate (5.96 g) as an amber oil, which was used without additional cleaning.

[001164] 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 overnight, then concentrated in vacuo and the residue passed through an SCX-2 cartridge. The product was eluted with methanolic ammonia to give imino(methyl)(piperidin-3-ylmethyl)-λ6-sulfanone (250 mg, 65%); ¹ H NMR (500 MHz, methanol-d ₄ ) 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).

[001165] Synthesis 180: 2-Chloro-4-methyl-6-(methylthio)pyrimidine

[001166] Sodium thiomethoxide (6.4 mL 21% w/v, 19.2 mmol) was added to a solution of 2,4-dichloro-6-methylpyrimidine (3.0 g, 18.4 mmol) in THF (50 ml), stirred at 0°C. The reaction mixture was stirred for 18 hours, gradually warming to ambient temperature. The reaction mixture was diluted in EtOAc and washed with saturated aqueous NaHCO ₃ solution. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by column chromatography (silica, eluting with 0 to 100% ethyl acetate in petroleum ether) gave 2-chloro-4-methyl-6-(methylthio)pyrimidine (2.40 g, 75%) as yellow solid matter; MS m/z: 175.0 (M+H) ⁺ .

[001167] Synthesis 181: 1-(4-(2-Chloropyrimidin-4-yl)piperazin-1-yl)ethan-1-one and 1-(4-(4-chloropyrimidin-2-yl)piperazin-1- yl)ethan-1-one

[001168] To a solution of 1-piperazin-1-ylethanone (1.72 g, 1.91 ml, 13.4 mmol) and triethylamine (1.43 g, 1.96 ml, 14.1 mmol) in 1.2 -dimethoxyethane (30.0 ml), 2,4-dichloropyrimidine (2.0 g, 13.4 mmol) was added and the resulting suspension was stirred at ambient temperature for 5 minutes. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 5-100% EtOAC in hexanes) to give 2 products:

1-(4-(4-chloropyrimidin-2-yl)piperazin-1-yl)ethan-1-one (0.33 g, 10%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 (d, J=5.1 Hz, 1H), 6.53 (d, J=5.1 Hz, 1H), 3.56-3 .44 (m, 2H), 3.32-3.24 (m, 4H), 3.07 (s, 2H), 1.80 (s, 3H).

1-(4-(2-Chloropyrimidin-4-yl)piperazin-1-yl)ethan-1-one (1.23 g, 38%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (d, J=6.2 Hz, 1H), 6.86 (d, J=6.2 Hz, 1H), 3.72-3 .50 (m, 8H), 2.05 (s, 3H).

[001169] The following compounds were prepared using a methodology similar to that described in Synthesis 181:

1-(4-(2-Chloro-6-methylpyrimidin-4-yl)piperazin-1-yl)ethan-1-one;

1-(4-(4-Chloro-6-methylpyrimidin-2-yl)piperazin-1-yl)ethan-1-one.

[001170] Synthesis 182: 1-(4-(6-Chloropyrazin-2-yl)piperazin-1-yl)ethan-1-one

[001171] 2,6-Dichloropyrazine (500 mg, 3.36 mmol), 1-piperazin-1-ylethanone (860 mg, 953 μl, 6.71 mmol) and DIPEA (1.75 ml, 10.1 mmol) mixed and heated at 130°C overnight in a sealed tube. The reaction mixture was allowed to cool to ambient temperature, then partitioned between EtOAc and water, the layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were dried (MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography (silica, eluting gradient with 0-10% methanol in DCM) gave 1-(4-(6-chloropyrazin-2-yl)piperazin-1-yl)ethan-1-one (790 mg, 98%) as a white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 7.88 (s, 1H), 3.64 (td, J=4.7, 2.9 Hz, 2H) , 3.57 (d, J=6.2 Hz, 2H), 3.35-3.27 (m, 1H), 2.70 (t, J=0.8 Hz, 1H), 2.18 ( t, J=8.1 Hz, 1H), 2.05 (s, 3H), 1.97-1.84 (m, 1H).

[001172] The following compound was prepared using a methodology similar to that used in synthesis 182:

1-(4-(6-Chloropyridin-2-yl)piperazin-1-yl)ethan-1-one.

[001173] Synthesis 183: (E)-2-(2-Ethoxyvinyl)-4-(methylthio)pyrimidine

[001174] To a suspension of 2-chloro-4-(methylthio)pyrimidine (56.1 g, 349.3 mmol) and 2 M aqueous Na ₂ CO ₃ (524 ml, 1.05 mol) in 1,2-dimethoxyethane (730 ml) 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (76.1 g, 384 mmol) was added. Pd(PPh ₃ ) ₄ (20.2 g, 17.5 mmol) was added 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 (MgSO ₄ ), 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 solids (62.4 g, 91%); ¹ H 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.

[001175] The following compounds were prepared using a methodology similar to that described in Synthesis 183:

(E)-2-Chloro-4-(2-ethoxyvinyl)pyrimidine;

(E)-1-(4-(2-(2-Ethoxyvinyl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one;

(E)-1-(4-(4-(2-Ethoxyvinyl)pyrimidin-2-yl)piperazin-1-yl)ethan-1-one;

(E)-2-(2-Ethoxyvinyl)-5-fluoro-4-(methylthio)pyrimidine;

(E)-2-(2-Ethoxyvinyl)-4-methyl-6-(methylthio)pyrimidine;

(E)-1-(4-(6-(2-Ethoxyvinyl)pyrazin-2-yl)piperazin-1-yl)ethan-1-one;

(E)-1-(4-(2-(2-ethoxyvinyl)-6-methylpyrimidin-4-yl)piperazin-1-yl)ethan-1-one;

(E)-1-(4-(4-(2-ethoxyvinyl)-6-methylpyrimidin-2-yl)piperazin-1-yl)ethan-1-one;

(E)-1-(4-(6-(2-Ethoxyvinyl)pyridin-2-yl)piperazin-1-yl)ethan-1-one;

(E)-2-Chloro-6-(2-ethoxyvinyl)pyridine;

(E)-2-(2-ethoxyvinyl)-6-fluoropyridine;

(E)-2-Bromo-6-(2-ethoxyvinyl)pyridine;

(E)-2-(2-Ethoxyvinyl)-4,6-difluoropyridine;

(E)-4,6-Dichloro-2-(2-ethoxyvinyl)pyrimidine;

(E)-2-Bromo-4-(2-ethoxyvinyl)-5-fluoropyrimidine.

[001176] Synthesis 184: 5-(Difluoromethyl)pyrazin-2-amine

[001177] Step 1: 5-(Difluoromethyl)-N-(4-methoxybenzyl)pyrazin-2-amine

[001178] (4-Methoxyphenyl)methanamine (35 ml, 267.9 mmol) was added to a solution of 2-chloro-5-(difluoromethyl)pyrazine (17.4 g, 105.7 mmol) in THF (174 ml) with stirring. and the reaction mixture was refluxed overnight. The resulting yellow suspension was cooled to ambient temperature, then partitioned between EtOAc and water. The aqueous phase was removed and the organics were further washed with water (2×), brine (1×), dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, eluting with 0 to 30% EtOAc/petroleum ether) to give 5-(difluoromethyl)-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine as white solid, (17.7 g, 63%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.20 (q, J=1.3 Hz, 1H), 8.04 (t, J=5.9 Hz, 1H), 8.01 (d , J=1.4 Hz, 1H), 7.28-7.25 (m, 2H), 6.91-6.88 (m, 2H), 6.84 (t, J=54.9 Hz, 1H), 4.46 (d, J=5.8 Hz, 2H), 3.73 (s, 3H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -113.02; ES+ [M+H]= 266.2.

[001179] Step 2: 5-(Difluoromethyl)pyrazin-2-amine

[001180] A solution of 5-(difluoromethyl)-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (17.7 g, 66.7 mmol) in TFA (130 ml) was stirred at 60°C for 2 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was azeotroped with DCM (×2) and further dried. The resulting orange solid was dissolved in DCM and a saturated aqueous NaHCO ₃ solution was slowly added until the pH of the solution was 8. The layers were separated and the aqueous layer was extracted with DCM (×2). The combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0 to 50% EtOAc/petroleum ether) to give 5-(difluoromethyl)pyrazin-2-amine as a pale yellow solid (7.5 g, 77 %); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.14 (q, J=1.4 Hz, 1H), 7.90 (d, J=1.4 Hz, 1H), 6.96 (s , 2H), 6.82 (t, J=55.0 Hz, 1H); ES+ [M+H]= 146.0.

[001181] Synthesis 185: 1-(5-Aminopyrazin-2-yl)ethan-1-one

[001182] A solution of ammonium hydroxide (224 mg, 249 μl, 6.39 mmol) was added to a solution of 1-(5-chloropyrazin-2-yl)ethanone (50 mg, 0.3193 mmol) in THF (1 ml) and the mixture heated in a microwave oven at 110°C for 1 hour. The reaction mixture was concentrated in vacuo, the residue was triturated with a minimal amount of EtOAc and the solid was dried in vacuo to give 1-(5-aminopyrazin-2-yl)ethane-1- he (31 mg, 71%); ES+ [M+H]= 138.1.

[001183] Synthesis 186: 6-(Difluoromethyl)-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine

[001184] N-Bromosuccinimide (570 mg, 3.20 mmol) was added to a solution of (E)-2-(2-ethoxyvinyl)-4-(methylthio)pyrimidine (630 mg, 3.21 mmol) in dioxane ( 10 ml) and water (3.75 ml) and the reaction mixture was stirred at ambient temperature for 20 minutes. 5-(difluoromethyl)pyrazin-2-amine (460 mg, 3.170 mmol) in dioxane (0.5 ml) was added and the reaction mixture was heated at 80°C for 2 hours. The mixture was cooled to ambient temperature, then saturated aqueous solution of NaHCO ₃ (10 ml), then water (40 ml). The reaction mixture was stirred for 10 minutes and the resulting precipitate was separated by filtration and washed with water. The solid was transferred to DCM, passed through a phase separation cartridge to remove water and concentrated in vacuo to give 6-(difluoromethyl)-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine as a brown solid (734 mg, 79%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.05-10.04 (m, 1H), 9.36 (d, J=1.4 Hz, 1H), 8.76 (s, 1H) , 8.64 (d, J=5.5 Hz, 1H), 7.44 (d, J=5.5 Hz, 1H), 7.25 (t, J=54.5 Hz, 1H), 2 .71 (s, 3H); ¹⁹ F NMR (471 MHz, DMSO) δ -116.13.

[001185] The following compounds were prepared using a methodology similar to that described in Synthesis 186:

3-(4-(Methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carbonitrile;

3-(4-(Methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide;

3-(6-Chloropyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide;

6-Methyl-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine;

1-(3-(4-(Methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-yl)ethan-1-one;

3-(4-(Methylthio)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine;

6-Chloro-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine;

6-Bromo-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine;

3-(2-Chloropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine;

3-(2-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine;

3-(5-Fluoro-4-(methylthio)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine;

3-(4-Methyl-6-(methylthio)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine;

3-(6-Chloropyridin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine;

3-(6-Chloropyridin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine;

3-(6-Chloropyridin-2-yl)imidazo[1,2-a]pyrazine-6-carbonitrile;

Methyl 3-(6-chloropyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxylate;

6-Bromo-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine;

6-Cyclopropyl-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine;

6-(Difluoromethyl)-3-(6-fluoropyridin-2-yl)imidazo[1,2-a]pyrazine;

3-(6-Bromopyridin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine;

3-(4,6-Difluoropyridin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine;

3-(4,6-Dichloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine.

[001186] The following final compounds were also prepared using a methodology similar to that described in Synthesis 186:

1-(4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-24;

1-(4-(2-(6-Methoxyimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-25;

1-(4-(2-(6-(Hydroxymethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-26;

3-(4-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxylic acid IV-30;

3-(4-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carbonitrile IV-31;

1-(4-(2-(6-Bromimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-32;

1-(4-(2-(6-Cyclopropylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-33;

3-(2-(4-Acetylpiperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-182;

3-(6-(4-Acetylpiperazin-1-yl)pyrazin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-183;

3-(2-(4-Acetylpiperazin-1-yl)-6-methylpyrimidin-4-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-188;

3-(4-(4-Carbamoylpiperazin-1-yl)-6-methylpyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-196;

1-(4-(6-(6-(1H-Pyrazol-1-yl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethane-1- he is IV-209.

[001187] Synthesis 187: 6-(1,1-Difluoroethyl)-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine

[001188] DAST (297 mg, 243 μl, 1.84 mmol) was added to a solution of 1-(3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-yl) ethan-1-one (35 mg, 0.12 mmol) in DCM (1 ml) and the mixture was stirred at room temperature overnight. An additional 3 portions of DAST (297 mg, 243 μL, 1.84 mmol) were added at 24 hour intervals and the reaction mixture was stirred for an additional 7 days after addition was completed. The reaction was stopped by adding a mixture of saturated aqueous NaHCO ₃ and ice and the product was extracted with DCM. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give 6-(1,1-difluoroethyl)-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine (37 mg, 98%), which was used without any additional purification; ES+ [M+H]= 308.2.

[001189] Synthesis 188: 3-(6-Chloropyridin-2-yl)-N,N-dimethylimidazo[1,2-a]pyrazine-6-carboxamide

[001190] N-Methylmethanamine (138 μl of 2 M, 0.28 mmol) and DABAL (56.5 mg, 0.22 mmol) were added to a solution of methyl-3-(6-chloropyridin-2-yl)imidazo[1, 2-a]pyrazine-6-carboxylate (53 mg, 0.18 mmol) in THF (1 ml) and the reaction mixture was heated at 130°C in a microwave oven for 10 min. The reaction was stopped by dropwise addition of DMSO and water, then immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give 3-(6-chloropyridin-2-yl)-N , N-dimethylimidazo[1,2-a]pyrazine-6-carboxamide (15 mg, 27%) as a white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (d, J=1.4 Hz, 1H), 9.23 (d, J=1.4 Hz, 1H), 8.79 (s , 1H), 8.19 (dd, J=7.8, 0.7 Hz, 1H), 8.05 (t, J=7.9 Hz, 1H), 7.54 (dd, J=7, 9, 0.7 Hz, 1H), 3.10 (d, J=19.8 Hz, 6H).

[001191] The following compound was prepared using a methodology similar to that used in Synthesis 188:

3-(6-Chloropyridin-2-yl)-N-methylimidazo[1,2-a]pyrazine-6-carboxamide;

[001192] Synthesis 189: 3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

[001193] 3-(4-(Methylthio)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (3 g, 9.6 mmol) was suspended in MeCN (51 ml) and concentrated HCl (1.52 g 37% w/w, 844 µl 37% w/w, 15.4 mmol) was added. Sulfuryl chloride (5.2 g, 3.12 ml, 38.6 mmol) was added to the suspension ) and the reaction mixture was stirred at ambient temperature for 15 min. The reaction was stopped by adding ice-cooled water (90 ml) and the resulting precipitate was collected by filtration to give 3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine as a pale yellow powder. substances (2.85 g, 99%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 9.46 (d, J=1.4 Hz, 1H), 9.02 (d, J=5.4 Hz , 1H), 8.82 (s, 1H), 7.74 (d, J=5.4 Hz, 1H).

[001194] The following compounds were prepared using a methodology similar to that described in Synthesis 189:

3-(4-Chloropyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide;

6-Bromo-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyrazine;

3-(4-Chloropyrimidin-2-yl)-6-(1,1-difluoroethyl)imidazo[1,2-a]pyrazine.

[001195] Synthesis 190: 3-(4-Chloropyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine

[001196] 6-(Difluoromethyl)-3-(4-(methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine (5.7 g, 19.4 mmol) suspended in MeCN (100 ml) and concentrated HCl (3.0 g 37% w/w, 1.7 ml 37% w/w, 31.1 mmol) was added. Sulfuryl chloride (6.3 mL, 77.8 mmol) was added slowly and the reaction mixture was stirred at ambient temperature for 10 minutes. The resulting solution was slowly poured into ice water (170 ml) while cooling in an external ice/water bath and the resulting creamy suspension was stirred at ambient temperature for 30 minutes. The solid was collected by filtration, washed with water and dried under vacuum for 30 minutes. The solid (still wet) was stirred as a suspension in saturated aqueous NaHCO ₃ solution (50 ml) for 30 min, then the solid was collected by filtration, washed with large quantities of water and dried in vacuum for 1 h at ambient temperature and then in vacuum oven at 40°C overnight to obtain 3-(4-chloropyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine as a beige solid (4.7 g, 86 %); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.93 (q, J=1.4 Hz, 1H), 9.39 (d, J=1.4 Hz, 1H), 8.98 (d , J=5.4 Hz, 1H), 8.75 (s, 1H), 7.69 (d, J=5.4 Hz, 1H), 7.27 (t, J=54.4 Hz, 1H ); 19F NMR (470MHz, DMSO-d ₆ ) -115.98; ES+ [M+H]= 283.9.

[001197] The following compound was prepared using a methodology similar to that used in Synthesis 190:

3-(4-Chloro-5-fluoropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine.

[001198] Synthesis 191: 3-(4-Chloropyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carbonitrile

[001199] 3-(4-(Methylthio)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carbonitrile (500 mg, 1.86 mmol) was suspended in MeCN (8.5 ml) and added concentrated HCl (293 mg 37% w/w, 163 µl 37% w/w, 2.98 mmol). Sulfuryl chloride (1.76 g, 1.06 mL, 13.1 mmol) was added and the reaction mixture was stirred vigorously at ambient temperature for 30 minutes. Saturated aqueous NaHCO ₃ solution (19 mL) was added followed by water (28 mL) and the resulting brown precipitate was collected by filtration and dried to give 3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyrazin-6- carbonitrile as a brown powder (393 mg, 82%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (d, J=1.4 Hz, 1H), 9.41 (d, J=1.4 Hz, 1H), 9.01 (d , J=5.4 Hz, 1H), 8.82 (s, 1H), 7.74 (d, J=5.4 Hz, 1H).

[001200] The following compounds were prepared using a methodology similar to that described in Synthesis 191:

6-Chloro-3-(4-chloropyrimidin-2-yl)imidazo[1,2-a]pyrazine;

3-(4-Chloropyrimidin-2-yl)-6-methylimidazo[1,2-a]pyrazine;

3-(4-Chloro-6-methylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine;

3-(4-Chloropyrimidin-2-yl)-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyrazine;

3-(4-Chloropyrimidin-2-yl)-6-(pyridin-4-yl)imidazo[1,2-a]pyrazine;

3-(4-Chloropyrimidin-2-yl)-6-cyclopropylimidazo[1,2-a]pyrazine;

[001201] Synthesis 192: 5,5-Difluoropiperidine-3-carboxamide

[001202] 1-(tert-Butyl) 3-methyl-5,5-difluoropiperidine-1,3-dicarboxylate (100 mg, 0.358 mmol) was dissolved in ammonium hydroxide (255.6 mg, 284.0 μl, 7.294 mmol) and the reaction mixture was heated at 70°C in a sealed tube. The reaction mixture was stirred at 70°C for 16 h behind an explosion-proof screen. The reaction mixture was then cooled to ambient temperature and the resulting mixture was concentrated in vacuo and then dissolved in DCM (5 ml) and treated with TFA (200 µl, 2.596 mmol) and stirred for 3 hours. The crude material was then immediately used in the next stage without additional purification.

[001203] Synthesis 193: 4-Methylpiperidine-3-carboxamide

[001204] Step 1: tert-Butyl-3-carbamoyl-4-methylpiperidine-1-carboxylate

[001205] While stirring, Et ₃ N (113.3 mg, 156 μL) was added to a solution of 1-tert-butoxycarbonyl-4-methylpiperidine-3-carboxylic acid (227 mg, 0.9330 mmol) in THF (1.8 mL). , 1.120 mmol) and then the mixture was cooled to 0°C. Isobutyl chloroformate (146.5 mg, 139 μL, 1.073 mmol) was added dropwise and the resulting mixture was stirred for 30 minutes. NH ₄ OH (2.616 g, 2.907 mL, 18.66 mmol) was then added at the same temperature and the resulting mixture was stirred for 1 hour. Water (5 mL) was then added and the mixture was extracted three times with DCM, the combined organic extracts were dried over MgSO ₄ was filtered and concentrated under reduced pressure to obtain tert-butyl-3-carbamoyl-4-methylpiperidine-1-carboxylate, which was immediately used in the next step without further purification, assuming quantitative yield; MS m/z: 243 (M+H) ⁺ .

[001206] Step 2: 4-Methylpiperidine-3-carboxamide

[001207] Tert-Butyl-3-carbamoyl-4-methylpiperidine-1-carboxylate (226 mg, 0.933 mmol) in DCM (1.9 mL) was placed in a round bottom flask. TFA (2.127 g, 1.437 mL, 18.65 mmol) was then added and the resulting mixture was stirred at ambient temperature for 12 hours. The crude mixture was loaded onto a methanol pre-washed SCX column, washed with methanol, and extracted with methanol ammonia. The combined ammonia extracts were then concentrated under reduced pressure to obtain 4-methylpiperidine-3-carboxamide, which was immediately used in the next step without further purification; MS m/z: 143 (M+H) ⁺

[001208] Synthesis 194: 2,5-Dimethylpiperidine-3-carboxamide

[001209] Step 1: 2,5-Dimethylnicotinamide

[001210] Methyl 2,5-dimethylpyridine-3-carboxylate (100 mg, 0.6054 mmol) was dissolved in ammonium hydroxide (480 μl, 12.33 mmol) and the reaction mixture was heated at 70°C in a sealed tube. The reaction mixture was stirred at this temperature for 16 hours behind an explosion-proof screen. After 16 hours, the reaction mixture was cooled to ambient temperature, during which time the orange solution had converted to a thick slurry of pale yellow solid. This precipitate was collected by filtration and washed with water. The filtrate was evaporated to dryness to obtain 2,5-dimethylpyridine-3-carboxamide (99 mg, quantitative yield), which was immediately used in the next step without further purification; MS m/z: 151.0 (M+H) ⁺ .

[001211] Step 2: 2,5-Dimethylpiperidine-3-carboxamide

[001212] 2,5-Dimethylpyridine-3-carboxamide (99 mg, 0.6592 mmol) and PtO ₂ (30.4 mg, 0.134 mmol) were mixed and dissolved in methanol (3 ml) and HCl (1.1 ml) was added 3 M, 3.296 mmol). The mixture was degassed and stirred with H ₂ from a cylinder for 1.5 hours, then passed through celite and the filtrate was evaporated to give 2,5-dimethylpiperidine-3-carboxamide (dihydrochloride) (150 mg, 99%) as a mixture of diastereoisomers ( ratio 3:1); MS m/z 157.0 (M+H) ⁺ .

[001213] Synthesis 195: 2-(Pyrrolidin-3-yl)acetamide

[001214] 2-(1-tert-Butoxycarbonylpyrrolidin-3-yl)acetic acid (100 mg, 0.44 mmol) was dissolved in THF (2 ml) under N ₂ and DIPEA (304 μl, 1.75 mmol) was added. . The solution was cooled in an ice bath and isobutyl chloroformate (62 μL, 0.48 mmol) was added slowly. After stirring for 1 hour, NH ₄ OH (440 μl 28% w/w, 6.51 mmol) was added to the cloudy solution. The resulting clear solution was stirred for an additional 1 hour and concentrated in vacuo to give the crude product as a pale yellow oil (140 mg). This residue was dissolved in DCM (5 ml) and TFA (500 µl, 6.49 mmol) was added. The reaction mixture was stirred at ambient temperature overnight, then evaporated in vacuo to give 2-pyrrolidin-3-ylacetamide (60 mg, 57%) as a colorless oil, which was used without further purification; MS m/z 129.0 (M+1) ⁺ .

[001215] Synthesis 196: 3-(1H-Pyrazol-4-yl)piperidin-4-ol

[001216] Step 1: 3-(1-Benzyl-1H-pyrazol-4-yl)-4-methoxypyridine

[001217] To a solution of 3-bromo-4-methoxypyridine (1.5 g, 7.98 mmol) in 1,4-dioxane (30 ml) was added 1-benzyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)pyrazole (2.50 g, 8.80 mmol), Pd(PPh ₃ ) ₄ (480 mg, 0.42 mmol) and Na ₂ CO ₃ (12 ml 2 M, 24.00 mmol). The mixture was degassed (3× vacuum/nitrogen cycle) and stirred at 120°C for 4 hours. The reaction mixture was cooled to ambient temperature and diluted with EtOAc/brine. The layers were separated and the aqueous layer was extracted with EtOAc (×2). The combined organic extracts were washed with brine (×1), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0-100% EtOAc/petroleum ether in DCM) to give 3-(1-benzylpyrazol-4-yl)-4-methoxypyridine (1.85 g, 87%) in the form of a creamy semi-liquid substance; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.73 (s, 1H), 8.34 (d, J=0.8 Hz, 1H), 8.31 (d, J=5.7 Hz , 1H), 8.03 (d, J=0.8 Hz, 1H), 7.38-7.34 (m, 2H), 7.32-7.25 (m, 3H), 7.10 ( d, J=5.7 Hz, 1H), 5.38 (s, 2H), 3.94 (s, 3H); MS m/z 266.5 (M+H) ⁺ .

[001218] Step 2: Benzyl 3-(1-benzyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate

[001219] To a suspension of 3-(1-benzylpyrazol-4-yl)-4-methoxypyridine (500 mg, 1.89 mmol) in MeOH (7 ml) was added sodium borohydride (80 mg, 2.12 mmol) at - 78 °C. After stirring for 15 minutes, a solution of benzyl chloroformate (300 µl, 2.10 mmol) in Et ₂ O (0.3 ml) was added dropwise. After stirring at -78°C for 1.5 hours, water (3 ml) was added and the reaction mixture was warmed to ambient temperature. After stirring for 2.5 hours, the mixture was diluted with water (with brine added to aid separation) and extracted with EtOAc (×3). The combined organic extracts were washed with brine (×3), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0 to 50% EtOAc/petroleum ether in DCM) to give:

Benzyl 5-(1-benzylpyrazol-4-yl)-4-oxo-2,3-dihydropyridine-1-carboxylate (115.3 mg, 16%) as a pale yellow oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.11 (d, J=4.6 Hz, 2H), 7.71 (s, 1H), 7.48-7.46 (m, 2H) , 7.43-7.27 (m, 6H), 7.24-7.21 (m, 2H), 5.32 (s, 2H), 5.29 (s, 2H), 4.04-4 .01 (m, 2H), 2.65-2.62 (m, 2H); MS m/z 388.3 (M+H) ⁺ .

And

Benzyl 3-(1-benzylpyrazol-4-yl)-4-oxo-2,3-dihydropyridine-1-carboxylate (264.2 mg, 36%) as a pale yellow oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.92 (d, J=8.2 Hz, 1H), 7.65 (s, 1H), 7.44-7.26 (m, 9H) , 7.21-7.18 (m, 2H), 5.32-5.24 (m, 5H), 4.12 (qd, J=13.3, 6.7 Hz, 2H), 3.71 (dd, J=7.9, 5.4 Hz, 1H); MS m/z 388.3 (M+H) ⁺ .

These were combined with the mixed fractions to obtain a total recovered amount of 551.9 mg (74%) as a 65:35 mixture of benzyl-3-(1-benzylpyrazol-4-yl)-4-oxo-2,3-dihydropyridinium- 1-carboxylate:benzyl-5-(1-benzylpyrazol-4-yl)-4-oxo-2,3-dihydropyridine-1-carboxylate.

[001220] Step 3: Benzyl 3-(1-benzyl-1H-pyrazol-4-yl)-4-oxopiperidine-1-carboxylate

[001221] A 35:65 solution of benzyl 5-(1-benzylpyrazol-4-yl)-4-oxo-2,3-dihydropyridin-1-carboxylate and benzyl 3-(1-benzylpyrazol-4-yl)- 4-oxo-2,3-dihydropyridine-1-carboxylate (550 mg, 1.420 mmol) in acetic acid (15 ml) was stirred vigorously and zinc (1.4 g, 21.40 mmol) was added in one portion. The mixture was stirred at ambient temperature for 93 hours, filtered through celite, washed with DCM and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0 to 50% EtOAc/petroleum ether in DCM) to give benzyl-3-(1-benzylpyrazol-4-yl)-4-oxopiperidin-1- carboxylate (230.1 mg, 42%) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.44-7.27 (m, 10H), 7.23-7.18 (m, 2H), 5.28 (s, 2H), 5, 13 (s, 2H), 4.18-4.03 (m, 2H), 3.80 (dd, J=10.1, 5.7 Hz, 1H), 3.59-3.47 (m, 2H), 2.64-2.40 (m, 2H); MS m/z 390.3 (M+H) ⁺ .

[001222] Step 4: Benzyl 3-(1-benzyl-1H-pyrazol-4-yl)-4-hydroxypiperidine-1-carboxylate

[001223] To a solution of benzyl 3-(1-benzylpyrazol-4-yl)-4-oxopiperidin-1-carboxylate (230 mg, 0.59 mmol) in methanol (10 ml) was added sodium borohydride (45 mg, 1. 19 mmol) and the mixture was stirred at ambient temperature for 4 hours. Another portion of sodium borohydride (25 mg, 0.66 mmol) was added and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was stopped by adding saturated aqueous NH ₄ Cl and the mixture was extracted with diethyl ether (×3). The combined organic extracts were washed with water (x1), brine (x1), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0 to 100% EtOAc/petroleum ether in DCM) to give benzyl-3-(1-benzylpyrazol-4-yl)-4-hydroxypiperidin-1- carboxylate (171.5 mg, 74%) as a colorless oil; MS m/z 392.4 (M+H) ⁺ .

[001224] Step 5: 3-(1H-Pyrazol-4-yl)piperidin-4-ol

[001225] Mixture of benzyl 3-(1-benzylpyrazol-4-yl)-4-hydroxypiperidine-1-carboxylate (170 mg, 0.43 mmol), Pd at C, wet, Degussa (70 mg 10% wt./ wt., 0.066 mmol) and concentrated HCl (240 μl of 12 M, 2.88 mmol) in methanol (10 ml) were placed under an H ₂ atmosphere and stirred at ambient temperature for 18 hours. The catalyst was removed by filtration through celite, washed with methanol and the filtrate was concentrated in vacuo. The residue was azeotroped with methanol (×3) and diethyl ether (×3) to give 3-(1H-pyrazol-4-yl)piperidin-4-ol (hydrochloride) (88.45 mg, 100%) as beige solid, which was immediately used under the assumption of 100% yield and purity; MS m/z 168.1 (M+H) ⁺ .

[001226] Synthesis 197: 3-methyl-2-(1H-pyrazol-4-yl)morpholine

[001227] Step 1: 2-Amino-1-(1-benzyl-1H-pyrazol-4-yl)propan-1-ol

[001228] Sodium borohydride (6.82 g, 7.22 mL, 180.2 mmol) was added to a solution of 1-(1-benzylpyrazol-4-yl)-2-nitropropan-1-ol (11, 85 g, 45.35 mmol) and nickel dichloride hexahydrate (10.77 g, 45.33 mmol) in methanol (225 ml) at 0°C. Upon addition of sodium borohydride, the initially green solution became dark green/black. After addition, the solution was stirred at 0°C for 20 minutes. The reaction was stopped by adding water, then 1 M HCl and stirring for 30 min. The suspension was filtered through celite and the filtrate was concentrated in vacuo. The residue was redissolved in methanol to give a green solution and a white solid. The suspension was filtered and the filtrate was passed through an SCX-2 cartridge (3x50 g), washed with MeCN/MeOH and extracted with 2 M NH ₃ /MeOH. The ammonia extracts were concentrated in vacuo to obtain 1.95 g of the substance. The aqueous layer was acidified and concentrated. The concentrated residue was then redissolved in MeCN/H ₂ O and lyophilized. This gave 2-amino-1-(1-benzylpyrazol-4-yl)propan-1-ol (hydrochloride) as an off-white solid (7.26 g). It was immediately used in the next step without further purification.

[001229] Step 2: N-(1-(1-Benzyl-1H-pyrazol-4-yl)-1-hydroxypropan-2-yl)-2-chloroacetamide

[001230] 2-Chloroacetyl chloride (approximately 952.2 mg, 670.6 μl, 8.431 mmol) was added dropwise to a solution of 2-amino-1-(1-benzylpyrazol-4-yl)propan-1-ol (1.95 g, 8.431 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.417 g, 1.910 ml, 10.96 mmol) in DCM (84 ml) at 0°C. After addition, an orange color was formed. The resulting solution was heated to ambient temperature for 10 minutes. After 1 hour, the reaction was stopped with a saturated aqueous solution of NaHCO ₃ . The aqueous layer was extracted with DCM, the combined organic layers were washed successively with saturated aqueous NH ₄ Cl and brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give N-(1-(1-benzyl-1H-pyrazol-4- yl)-1-hydroxypropan-2-yl)-2-chloroacetamide as a brown oil (2.25 g, 86%); MS m/z 308.1 (M+H) ⁺ .

[001231] Step 3: 6-(1-Benzyl-1H-pyrazol-4-yl)-5-methylmorpholin-3-one

[001232] N-[2-(1-Benzylpyrazol-4-yl)-2-hydroxy-1-methylethyl]-2-chloroacetamide (2.25 g, 7.311 mmol) and KOtBu (984.4 mg, 8.773 mmol) stirred at 0°C in THF (48 ml). The reaction mixture was warmed to ambient temperature for 15 minutes and then stirred for 2 hours. Saturated aqueous NH ₄ Cl was added and the organics were extracted with EtOAc, dried (MgSO ₄ ), filtered and concentrated in vacuo to give 6-( 1-Benzyl-1H-pyrazol-4-yl)-5-methylmorpholin-3-one as an orange oil. The material was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether, then 0-10% MeOH/DCM) to give 6-(1-benzylpyrazol-4-yl)-5-methylmorpholin-3-one ( 1.55 g, 78%) as an orange foam; MS m/z 272.2 (M+H) ⁺ .

[001233] Step 4: 2-(1-Benzyl-1H-pyrazol-4-yl)-3-methylmorpholine

[001234] Borane-tetrahydrofuran complex (28.56 mL 1 M, 28.56 mmol) was carefully added to a solution of 6-(1-benzylpyrazol-4-yl)-5-methylmorpholin-3-one (1.55 g, 5.713 mmol) in THF (23 ml) at 0°C. After 10 min, the reaction mixture was heated to ambient temperature. After 2 hours, the reaction mixture was cooled to 0°C and the reaction was carefully stopped with methanol until gas evolution ceased. Concentrated HCl (5 ml) was then added and the resulting mixture was stirred for 1 hour. The reaction mixture was passed through an SCX-2 cartridge (25 g), washed with MeCN/MeOH and the product extracted with 2 M NH ₃ /MeOH. The product fractions were concentrated in vacuo to give 2-(1-benzylpyrazol-4-yl)-3-methylmorpholine (0.98 g, 67%) as a pale yellow oil; MS m/z 258.2 (M+H) ⁺ .

[001235] Step 5: 3-Methyl-2-(1H-pyrazol-4-yl)morpholine

[001236] 2-(1-Benzylpyrazol-4-yl)-3-methylmorpholine (1.1 g, 4.275 mmol), Pd at C, wet, Degussa (439.9 mg 10% w/w, 0.413 mmol ) and concentrated HCl (2 mL 12 M, 24.00 mmol) were transferred to methanol (16.5 mL) and stirred at ambient temperature for 22 h under H ₂ atmosphere. The catalyst was filtered through celite and partially concentrated. The crude mixture was loaded onto a methanol-prewashed SCX column, washed with methanol, and extracted with methanol ammonia. The ammonia extracts were concentrated under reduced pressure to give 3-methyl-2-(1H-pyrazol-4-yl)morpholine (720 mg, 76%), which was immediately used in the next step.

[001237] Synthesis 198: 2-Methylpyrrolidine-3-carboxamide

[001238] Methyl 2-methylpyrrolidine-3-carboxylate (100 mg, 0.698 mmol) was dissolved in ammonium hydroxide (500 μl, 12.84 mmol) and the reaction mixture was heated at 70°C in a sealed tube. The reaction mixture was stirred at this temperature for 16 hours behind an explosion-proof screen. After 16 hours, the reaction mixture was cooled to ambient temperature and then concentrated to dryness to give 2-methylpyrrolidine-3-carboxamide as a yellow residue, which was used immediately without further purification; MS m/z 129.1 (M+H) ⁺ .

[001239] Synthesis 199: (S)-Octahydro-6H-pyrido[1,2-a]pyrazin-6-one

[001240] Step 1: Benzyl-(S)-6-oxooctahydro-2H-pyrido[1,2-a]pyrazine-2-carboxylate and benzyl-(R)-6-oxooctahydro-2H-pyrido[1,2- a]pyrazine-2-carboxylate

[001241] Benzyl chloroformate (2.4 mL, 16.81 mmol) was added dropwise to the solution of 1,2,3,4,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-6- with stirring ona (hydrochloride) (2.1 g, 11.01 mmol) and DIPEA (4.2 mL, 24.11 mmol) in DCM (20 mL) at 0°C and the reaction mixture was allowed to warm to ambient temperature for 16 h. The reaction mixture was diluted with a saturated aqueous solution of NH ₄ Cl, water was added to dissolve the resulting precipitate, and the layers were separated. The aqueous layer was extracted with DCM (×2) and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 50-100% EtOAc/petroleum ether, loaded dry) to give the racemic compound as a white solid (2.69 g, 84%). Resolution by SFC (LuxCel2, 30% MeOH, 0.2% DMIPA) gave separated isomers of benzyl-(9aS)-6-oxo-3,4,7,8,9,9a-hexahydro-1H-pyrido[1,2 -a]pyrazine-2-carboxylate (peak 1, 1.09 g, 34.3% yield, 98% ee) and benzyl-(9aR)-6-oxo-3,4,7,8,9,9a- hexahydro-1H-pyrido[1,2-a]pyrazine-2-carboxylate (peak 2, 1.12 g, 35% yield, 98.4% ee) as colorless oils.

[001242] Step 2: (S)-Octahydro-6H-pyrido[1,2-a]pyrazin-6-one

[001243] Pd on C, wet, Degussa (110 mg 10% w/w, 0.103 mmol) was added to the benzyl-6-oxo-3,4,7,8,9,9a-hexahydro-1H solution with stirring -pyrido[1,2-a]pyrazine-2-carboxylate (1.09 g, 3.780 mmol) in methanol (7.5 ml)/EtOAc (7.5 ml) and the reaction mixture was placed under H ₂ atmosphere. The reaction mixture was stirred at ambient temperature for 15 hours, then the catalyst was removed by filtration and the solvent was removed in vacuo. The residue was dissolved in DCM (15 ml) and hydrogen chloride (1.3 ml 4 M, 5.20 mmol) was added. The solvent was removed in vacuo to give (9aS)-1,2,3,4,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-6-one (hydrochloride) (660.4 mg, 92% ) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.28 (br s, 2H), 4.60-4.54 (m, 1H), 3.70 -3.64 (m, 1H), 3 .29-3.24 (m, 2H), 2.86-2.76 (m, 3H), 2.30-2.19 (m, 2H), 1.98-1.93 (m, 1H) , 1.78-1.75 (m, 1H), 1.67-1.64 (m, 1H), 1.50-1.43 (m, 1H); MS m/z 155.1 (M+H) ⁺ ; α _D (20) = -39.2°.

[001244] Synthesis 200: N-((4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

[001245] Step 1: 1-Benzyl-3-methylpiperidin-4-one

[001246] Benzyl chloroformate (6.841 g, 5.73 mL, 40.10 mmol) was added to 3-methylpiperidin-4-one (hydrochloride) (5 g, 33.42 mmol) and K ₂ CO ₃ (37 g, 267, 7 mmol) in EtOAc (100 ml) and water (50 ml). The resulting mixture was stirred vigorously for 16 hours at ambient temperature. The organic phase was separated and collected, and the aqueous phase was extracted with ethyl acetate (2×). The combined organic extracts were washed with water and dried over MgSO ₄ and concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% EtOAc/hexanes). The pure product fractions were combined and concentrated under reduced pressure to give 1-benzyl-3-methylpiperidin-4-one (6.7 g, 81%), which was immediately used in the next step.

[001247] Step 2: 2-((1-Benzyl-5-methyl-4-oxopiperidin-3-yl)methyl)isoindoline-1,3-dione

[001248] (Bis(trimethylsilyl)amino)lithium (33.48 ml 1 M, 33.48 mmol) was added dropwise to a solution of benzyl 3-methyl-4-oxopiperidine-1-carboxylate (6.7 g, 27. 09 mmol) in tetrahydrofuran (100 ml), cooled to -78°C, in an atmosphere of N ₂ . After 90 minutes, a solution of 2-(chloromethyl)isoindoline-1,3-dione (8.002 g, 40.91 mmol) in THF (30 ml) was added. The resulting solution was stirred at -78°C for 1 hour. The reaction was stopped by adding a saturated aqueous solution of NH ₄ Cl (~20 ml) and warmed to ambient temperature. The reaction mixture was diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over MgSO ₄ and concentrated in vacuo. The crude material was purified by column chromatography (silica; 0-100% EtOAc/petroleum ether). The pure product fractions were combined and concentrated under reduced pressure to give 2-((1-benzyl-5-methyl-4-oxopiperidin-3-yl)methyl)isoindoline-1,3-dione (7.4 g, 67%) in in the form of a white resinous substance; MS m/z 407.2 (M+H) ⁺ .

[001249] Step 3: 2-((1-Benzyl-4,4-difluoro-5-methylpiperidin-3-yl)methyl)isoindoline-1,3-dione

[001250] Benzyl-3-[(1,3-dioxoisoindolin-2-yl)methyl]-5-methyl-4-oxopiperidin-1 was placed in a 250 mL round bottom flask equipped with a thermometer, nitrogen inlet, and air cooler. -carboxylate (19.1 g, 46.99 mmol). The vessel was cooled in an ice/salt/water bath, then DAST (60 mL, 454.1 mmol) was added slowly (no exotherm was detected until all DAST was added) and a thick white suspension formed. The mixture was stirred in the ice bath for an additional 20 minutes, then removed from the ice bath and stirred at room temperature for 3 days. After this, the mixture turned into an orange solution. The reaction mixture was diluted with DCM (200 ml) and then solid sodium bicarbonate was slowly added to the ice/water mixture (ca. 800 ml) while stirring, maintaining the temperature at about 0°C and the pH at 7-8 by further adding solid sodium bicarbonate. Once addition was complete, the mixture was allowed to warm to ambient temperature, then transferred to a separatory funnel and extracted with DCM (3×). The organics were combined, washed with water (1×), brine (1×), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo to give the crude product as a viscous orange oil (23.5 g). The crude product was purified by column chromatography (silica, 0-16% EtOAc/petroleum ether) and the product fractions were combined and concentrated in vacuo to give the product as a colorless oil (14 g). The oil was dissolved in ethanol (50 ml) and concentrated in vacuo and the resulting oil was dried under high vacuum for 1 hour to give 2-((1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)methyl)isoindoline -1,3-dione (9.8 g, 49%) as a colorless foam; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.92-7.85 (m, 4H), 7.25 (br m, 5H), 4.98 (m, 2H), 4.10-4 .06 (m, 1H), 4.03-4.01 (m, 1H), 3.99-3.94 (m, 1H), 3.57 (dd, 1H), 2.64 (br m, 2H), 2.50 (m, 1H), 2.17 (m, 1H) and 0.93 (d, 3H); MS m/z 429.3 (M+H+) ⁺ .

[001251] Step 4: (1-Benzyl-4,4-difluoro-5-methylpiperidin-3-yl)methanamine

[001252] A mixture of benzyl 3-[(1,3-dioxoisoindolin-2-yl)methyl]-4,4-difluoro-5-methylpiperidine-1-carboxylate (600 mg, 1.40 mmol) and hydrazine monohydrate (204, 2 mg, 200 μl, 4.079 mmol) in ethanol (10 ml) was stirred at reflux for 16 hours. The reaction mixture was cooled to ambient temperature and the crude suspension was diluted with methanol. The solution was passed through a pre-wetted 5 g SCX cartridge. The column was eluted with methanol and then the product was eluted with 2 M methanol ammonia and the product fractions were concentrated in vacuo to give (1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)methanamine (370 mg, 89%) as pale -yellow resin, which was immediately used in the next stage without additional purification; MS m/z 299.2 (M+H) ⁺ .

[001253] Step 5: N-((1-Benzyl-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

[001254] Benzyl 3-(aminomethyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (1.4 g, 4.693 mmol) and Et ₃ N (961.6 mg, 1.325 mL) were placed in a round bottom flask. 9.503 mmol) in DCM (19 ml) under nitrogen. The mixture was then cooled to 0°C and then MsCl (1.009 g, 681.8 μL, 8.804 mmol) was added dropwise. The resulting mixture was stirred at 0°C for 10 minutes and then stirred at ambient temperature for another 10 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution and stirring at ambient temperature for 5 minutes. The solution was filtered through a phase separation cartridge and concentrated under reduced pressure. The crude mixture was purified by column chromatography (silica; EtOAc/petroleum ether). The product fractions were combined and concentrated under reduced pressure to give N-((1-benzyl-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide (1.3 g, 74%) as a colorless oil, which immediately used in the next stage; MS m/z 377.1 (M+H) ⁺ .

[001255] Step 6: N-((4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

[001256] Benzyl 4,4-difluoro-3-(methanesulfonamidomethyl)-5-methylpiperidine-1-carboxylate (1.3 g, 3.454 mmol) was dissolved in DCM (26 ml). Pd(OAc) ₂ (340 mg, 1.514 mmol), Et ₃ N (1.7 ml, 12.20 mmol) and Et ₃ SiH (3.6 ml, 22.54 mmol) were added to the reaction mixture under nitrogen atmosphere. Gas evolution was observed so the reaction mixture was cooled in an ice bath for 10 minutes and then stirred at ambient temperature for 1 hour. The reaction mixture was poured onto a 50 g SCX-2 column. The column was eluted with methanol, then with 2 M methanol ammonia. The product fractions were concentrated in vacuo to give N-((4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide (1.5 g, 75%) as a colorless gum; MS m/z 243.1 (M+H) ⁺ .

[001257] Synthesis 201: 2-[(E)-2-Ethoxyvinyl]-4-methylsulfanylpyrimidine

[001258] A solution of 2-chloro-4-methylsulfanylpyrimidine (1 g, 6.226 mmol), Na ₂ CO ₃ (9.3 ml of 2M aqueous solution, 18.60 mmol) and 2-[(E)-2-ethoxyvinyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.35 g, 6.816 mmol) in 1,2-dimethoxyethane (15 ml) was degassed with nitrogen. Pd(PPh ₃ ) ₄ (600 mg, 0.519 mmol) was added and the mixture was re-degassed with nitrogen. The mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature, partitioned between EtOAc/water and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica, EtOAc/petroleum ether gradient) to give 2-[(E)-2-ethoxyvinyl]-4-methylsulfanylpyrimidine (1.10 g, 90%); ¹ H NMR (500 MHz, chloroform-d) δ 8.19 (d, 1H), 7.94 (d, 1H), 6.85 (d, 1H), 5.90 (d, 1H), 4, 02 (q, 2H), 2.56 (s, 3H), 1.40 (t, 3H); ESVI-MS m/z 197.1 (M+H).

[001259] Synthesis 202: 5-(4-Chloropyrimidin-2-yl)-2-(difluoromethyl)imidazo[2,1-b]thiazole

[001260] Step 1: Ethyl 5-(4-methylsulfanylpyrimidin-2-yl)imidazo[2,1-b]thiazole-2-carboxylate

[001261] NBS (230 mg, 1.29 mmol) was added with stirring to a solution of 2-[(E)-2-ethoxyvinyl]-4-methylsulfanylpyrimidine (250 mg, 1.27 mmol) in dioxane (8 ml)/ water (3 ml) and the reaction mixture was stirred at ambient temperature for 15 minutes. Ethyl 2-aminothiazole-5-carboxylate (440 mg, 2.56 mmol) was added and the reaction mixture was heated at 65°C for 1 hour, then at 100°C for 19 hours. The mixture was cooled to ambient temperature and the resulting the precipitate was separated by filtration and washing with dioxane. The filtrate was concentrated in vacuo and purified by column chromatography (silica, EtOAc/petroleum ether gradient). The desired fractions were combined with the initial residue and concentrated in vacuo to give the title compound as a yellow solid (175 mg, 43%); ¹ H NMR (500 MHz, chloroform-d) δ 9.30 (s, 1H), 8.38 (d, 1H), 8.26 (s, 1H), 7.01 (d, 1H), 4, 45 (q, 2H), 2.69 (s, 3H), 1.45 (t, 3H); MS m/z: 321.1 (M+H) ⁺ .

[001262] Step 2: [5-(4-Methylsulfanylpyrimidin-2-yl)imidazo[2,1-b]thiazol-2-yl]methanol

[001263] Ethyl 5-(4-methylsulfanylpyrimidin-2-yl)imidazo[2,1-b]thiazole-2-carboxylate (175 mg, 0.546 mmol) was dissolved in dry THF (20 ml) and cooled in an ice bath . 2M LiAlH ₄ in THF (185 μL, 0.370 mmol) was added dropwise and the reaction mixture was allowed to warm to ambient temperature over 30 minutes. The reaction was stopped by sequentially adding 15 μl of water, 15 μl of 15% NaOH and 60 μl of water. The resulting solid was removed by filtration, washed with EtOAc and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (152 mg, 100%) which was used immediately without further purification; ¹ H NMR (500 MHz, chloroform-d) δ 8.46 (s, 1H), 8.24 (d, 1H), 8.08 (s, 1H), 6.86 (d, 1H), 4, 78 (s, 2H), 2.56 (s, 3H); MS m/z: 279.1 (M+H) ⁺ .

[001264] Step 3: 5-(4-Methylsulfanylpyrimidin-2-yl)imidazo[2,1-b]thiazole-2-carbaldehyde

[001265] MnO ₂ (485 mg, 5.58 mmol) was added to a solution of [5-(4-methylsulfanylpyrimidin-2-yl)imidazo[2,1-b]thiazol-2-yl]methanol (152 mg, 0.546 mmol) in THF (30 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was filtered through a pad of celite (THF wash) and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (128 mg, 85%); ¹ H NMR (500 MHz, chloroform-d) δ 9.95 (s, 1H), 9.25 (s, 1H), 8.29 (d, 1H), 8.19 (s, 1H), 6, 94 (d, 1H), 2.58 (s, 3H); MS m/z: 277.1 (M+H) ⁺ .

[001266] Step 4: 2-(Difluoromethyl)-5-(4-methylsulfanylpyrimidin-2-yl)imidazo[2,1-b]thiazole

[001267] Deoxofluor (130 μl, 0.705 mmol) was added to a solution of 5-(4-methylsulfanylpyrimidin-2-yl)imidazo[2,1-b]thiazole-2-carbaldehyde (127 mg, 0.460 mmol) in DCM (10 ml ) at 0°C and the mixture was warmed to ambient temperature for 20 hours. Another portion of Deoxofluor (130 μl, 0.705 mmol) was added and the reaction mixture was stirred at ambient temperature for another 24 hours. A saturated aqueous NaHCO ₃ solution was added dropwise and the reaction mixture was stirred for 30 minutes. The layers were separated and the aqueous phase was extracted with DCM (×2). The combined organic extracts were washed with brine (×1) and dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, EtOAc/petroleum ether gradient) to give the title compound as a white solid (71 mg, 52%); ¹ H NMR (500 MHz, chloroform-d) δ 8.89 (t, 1H), 8.36 (d, 1H), 8.23 (s, 1H), 7.01-6.77 (m, 1H ), 7.00 (d, 1H), 2.67 (s, 3H); ¹⁹ F NMR (471 MHz, chloroform-d) δ -105.56; MS m/z: 299.1 (M+H) ⁺ .

[001268] Step 5: 5-(4-Chloropyrimidin-2-yl)-2-(difluoromethyl)imidazo[2,1-b]thiazole

[001269] 2-(Difluoromethyl)-5-(4-methylsulfanylpyrimidin-2-yl)imidazo[2,1-b]thiazole (70 mg, 0.235 mmol) was dissolved in MeCN (6 ml) and concentrated HCl (20 μl) was added , 0.365 mmol). Sulfuryl chloride (80 μL, 0.988 mmol) was added and the reaction mixture was stirred at ambient temperature for 5 minutes. Cold saturated aqueous NaHCO ₃ solution was added dropwise and the mixture was stirred at ambient temperature for 10 minutes. The resulting precipitate was isolated by filtration, washed with water and dried to give the title compound as a white solid (39 mg, 58%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.05 (t, 1H), 8.85 (d, 1H), 8.21 (s, 1H), 7.57 (d, 1H), 7 .56 (t, 1H); 19F NMR (471 MHz, DMSO-d ₆ ) δ -104.83; MS m/z: 287.0 (M+H) ⁺ .

[001270] Synthesis 203: 5-(4-Chloropyrimidin-2-yl)-2-(trifluoromethyl)imidazo[2,1-b]thiazole

[001271] Step 1: 5-(4-Methylsulfanylpyrimidin-2-yl)-2-(trifluoromethyl)imidazo[2,1-b]thiazole

[001272] NBS (1.08 g, 6.07 mmol) was added with stirring to a solution of 2-[(E)-2-ethoxyvinyl]-4-methylsulfanylpyrimidine (1.16 g, 5.91 mmol) in a mixture of dioxane ( 20 ml)/water (7.5 ml) and the reaction mixture was stirred at ambient temperature for 15 minutes. 5-(trifluoromethyl)thiazol-2-amine (564 mg, 3.35 mmol) in dioxane (1 ml) was added and the reaction mixture was heated at 100°C for 22 hours. The mixture was cooled to ambient temperature and the solvent was removed in vacuo . The residue was partitioned between DCM and saturated aqueous NaHCO ₃ and the layers were separated. The aqueous layer was extracted with DCM (×2) and 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 the title compound as a white solid (137 mg, 13%); 1H NMR (500 MHz, chloroform-d) δ 9.19 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 8.40 (s, 1H), 7.14 (d , J=5.6 Hz, 1H), 2.69 (s, 3H); NMR (471 MHz, CDCl3) δ -56.87; MS m/z: 317.0 (M+H) ⁺ .

[001273] Step 2: 5-(4-Chloropyrimidin-2-yl)-2-(trifluoromethyl)imidazo[2,1-b]thiazole

[001274] 5-(4-Methylsulfanylpyrimidin-2-yl)-2-(trifluoromethyl)imidazo[2,1-b]thiazole (137 mg, 0.433 mmol) was dissolved in MeCN (15 ml) and concentrated HCl (40 μl) was added , 0.731 mmol). Sulfuryl chloride (150 µl, 1.85 mmol) was added and the reaction mixture was stirred at ambient temperature for 55 minutes. Cold saturated aqueous NaHCO ₃ solution was added dropwise and the mixture was stirred at ambient temperature for 10 minutes. The resulting precipitate was isolated by filtration, washed with water and dried to give the title compound as a beige solid (61 mg, 46%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.11 (q, 1H), 8.88 (d, 1H), 8.25 (s, 1H), 7.59 (d, 1H); 19F NMR (471 MHz, DMSO-d ₆ ) δ -55.63; MS m/z: 305.0 (M+H) ⁺ .

[001275] Synthesis 204: 2-(1H-Pyrazol-4-yl)morpholine

[001276] Step 1: tert-Butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate ***

[001277] A mixture of tert-butyl 2-(2-oxoethyl)morpholine-4-carboxylate (5.77 g, 25.17 mmol) and DMF-DMA (6.7 mL, 50.06 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 ethanol (100 ml) and hydrazine hydrate (1.3 ml, 26.51 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, EtOAc/petroleum ether gradient) to give tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate (2, 35 g, 9.29 mmol, 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] ⁺ .

[001278] Step 2: 2-(1H-pyrazol-4-yl)morpholine

[001279] 3M HCl in methanol (45 ml of 3M, 135.0 mmol) was added to a solution of tert-butyl 2-(1H-pyrazol-4-yl)morpholine-4-carboxylate (2.35 g, 9. 29 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, 8.29 mmol, 89%) as an orange solid; 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), 2.93-2.88 (m, 2H); MS m/z: 154.2 [M+H] ⁺ . The product was used in the next reaction without further purification.

[001280] Synthesis 205: 2,5-Dimethyl-3-((methylsulfinyl)methyl)piperidine

[001281] Step 1: 1-(tert-Butyl) 3-methyl-2,5-dimethylpiperidine-1,3-dicarboxylate

[001282] 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 overnight, 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 overnight, 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) to give 1-(t-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) .

[001283] Step 2: tert-Butyl 3-(hydroxymethyl)-2,5-dimethylpiperidine-1-carboxylate

[001284] O1-tert-Butyl-O3-methyl-2,5-dimethylpiperidine-1,3-dicarboxylate (1.4 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 at 50°C and stirred overnight. The reaction mixture was cooled to ambient temperature, 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).

[001285] Step 3: tert-Butyl-2,5-dimethyl-3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate

[001286] 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 minutes, the reaction was stopped with saturated aqueous NaHCO ₃ solution, stirred for 5 minutes 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.

[001287] Step 4: tert-Butyl-2,5-dimethyl-3-((methylthio)methyl)piperidine-1-carboxylate

[001288] Sodium thiomethoxide (9.939 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, 0-12.5% MeOH/DCM gradient ) 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).

[001289] Step 5: tert-Butyl 2,5-dimethyl-3-((methylsulfinyl)methyl)piperidine-1-carboxylate

[001290] 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 a further 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.

[001291] Step 6: 2,5-Dimethyl-3-((methylsulfinyl)methyl)piperidine

[001292] 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) ⁺ .

[001293] The following compound was prepared using a procedure similar to that exemplified in Synthesis 205:

3-((Methylsulfinyl)methyl)piperidine

[001294] Synthesis 206: N-(((3S,5S)-4,4-Difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

[001295] Step 1: Benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4-oxopiperidine-1-carboxylate

[001296] Benzyl 3-methyl-4-oxopiperidine-1-carboxylate (20 g, 0.081 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, 0.101 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, 0.121 mol) in THF (200 ml) was added dropwise over 25 min, keeping the 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, EtOAc/petroleum ether gradient). 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%).

[001297] Step 2: Benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[001298] Benzyl 3-((1,3-dioxoisoindolin-2-yl)methyl)-5-methyl-4-oxopiperidine-1-carboxylate (60 g, 0.148 mol) was placed in the flask and cooled in an ice/water bath . DAST (325 mL, 2.460 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 warmed to room temperature and the layers were separated. The aqueous phase was extracted with DCM (2 L). The combined organics were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was purified by chromatography (silica, eluting with EtOAc/PE). 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 glassy solid (32.5 g, 0.08 mol , 51%); ¹ H NMR (300 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. 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-dioxoisoindoline-2 -yl)methyl]-4,4-difluoro-5-methylpiperidine-1-carboxylate, (98.7% ee).

[001299] Step 3: Benzyl-(3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate

[001300] 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 .41 mmol) in ethanol (144 ml) was added hydrazine hydrate (8.5 ml, 112.0 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 2M methanol 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); 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] ⁺ , which was immediately used in the next reaction.

[001301] Step 4: Benzyl-(3S,5S)-4,4-difluoro-3-(methanesulfonamidomethyl)-5-methylpiperidine-1-carboxylate

[001302] Benzyl (3R,5S)-3-(aminomethyl)-4,4-difluoro-5-methylpiperidine-1-carboxylate (6.60 g, 22.12 mmol) was dissolved in DCM (66 ml) and cooled in an ice bath. The internal temperature reached 3°C. Et ₃ N (3.39 mL, 24.33 mmol) was added with stirring. Methanesulfonyl chloride (1.88 mL, 24.33 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). 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] ⁺ .

[001303] Step 5: N-(((3S,5S)-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide

[001304] To a solution of benzyl (3S,5S)-4,4-difluoro-3-(methanesulfonamidomethyl)-5-methylpiperidine-1-carboxylate (7.54 g, 20.03 mmol) in DCM (113 ml) Et ₃ N (8.38 ml, 60.09 mmol), then Pd(OAc) ₂ (1.799 g, 8.012 mmol) was added. Et ₃ SiH (19.20 ml, 120.2 mmol) for 5 min. 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 MeOH. The filtrates were discarded. The cartridges were washed with 2M methanol ammonia solution. The filtrates were combined and concentrated in vacuo. The residue was azeotroped with DCM, then taken up in 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 [M+H] ⁺ .

[001305] Synthesis 207: 4-Pyrrolidin-3-yl-1H-pyrazole

[001306] Step 1: tert-Butyl 3-(1H-pyrazol-4-yl)-2,5-dihydropyrrole-1-carboxylate

[001307] 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, 2.6 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 for 16 hours. 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). The product fractions were combined and concentrated to give the product as a pale yellow film-like substance (65 mg, 33%), which was immediately used in the next reaction. ESVI-MS m/z 236.0 (M+1) ⁺ .

[001308] Steps 2 and 3: 4-Pyrrolidin-3-yl-1H-pyrazole

[001309] 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) ESVI-MS m/z 136.0 (M+1) ⁺ .

[001310] Synthesis 208: 2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazine

[001311] Step 1: 2,5-Dimethyl-3-(1H-pyrazol-4-yl)pyrazine

[001312] 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)pyrazole-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% 2 M methanol ammonia]-petroleum ether gradient). 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) ⁺ .

[001313] Step 2: 2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazine

[001314] 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.

[001315] Synthesis 209: (5-(1H-Pyrazol-4-yl)piperidin-3-yl)dimethylphosphine oxide (hydrochloride)

[001316] Step 1: 3-(1-Benzylpyrazol-4-yl)-5-bromopyridine

[001317] 3-Bromo-5-iodopyridine (2.02 g, 7.115 mmol), iron; cyclopenta-1,4-dien-1-yl(diphenyl)phosphane; dichloromethane; dichloropalladium (290 mg, 0.355 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.12 g, 7.461 mmol) and carbonate sodium (7.1 ml 2M, 14.20 mmol) in 1,4-dioxane (70 ml) was degassed and then heated at 85°C for 16 hours. The reaction vessel was cooled to ambient temperature, diluted with ethyl acetate, washed brine, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a brown residue. The crude product was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether) to give 3-(1-benzylpyrazol-4-yl)-5-bromopyridine (1.24 g, 55%); ¹ H NMR (500 MHz, chloroform-d) δ 8.72 (s, 1H), 8.54 (s, 1H), 8.06 (s, 1H), 7.86 (s, 1H), 7, 74 (s, 1H), 7.43-7.33 (m, 3H), 7.33-7.27 (m, 2H), 5.36 (s, 2H). MS m/z 316.1 (M+H) ⁺ .

[001318] Step 2: 3-(1-Benzylpyrazol-4-yl)-5-dimethylphosphorylpyridine

[001319] 3-(1-Benzylpyrazol-4-yl)-5-bromopyridine (624 mg, 1.986 mmol), methylphosphonoylmethane (170.5 mg, 2.185 mmol), Xantphos (68.9 mg, 0.119 mmol), palladium acetate (II) (22.3 mg, 0.099 mmol) and K ₃ PO ₄ (505.8 mg, 2.383 mmol) in DMF (10 ml) were degassed and heated at 100°C for 16 hours. The reaction mixture was cooled to ambient temperature medium, filtered and washed with methanol and then immediately concentrated on silica gel. Purification by column chromatography (silica, 0-15% MeOH/CH ₂ Cl ₂ gradient) gave 3-(1-benzylpyrazol-4-yl)-5-dimethylphosphorylpyridine (200 mg, 32%); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 8.97 (t, J=2.2 Hz, 1H), 8.74 (dd, J=6.1, 1.9 Hz, 1H), 8 .34 (dt, J=12.1, 2.1 Hz, 1H), 8.29 (d, J=0.8 Hz, 1H), 8.06 (d, J=0.8 Hz, 1H) , 7.39-7.33 (m, 2H), 7.33-7.25 (m, 3H), 5.40 (s, 2H), 1.87 (d, J=13.6 Hz, 6H ). MS m/z 312.2 (M+H) ⁺ .

[001320] Step 3: (5-(1H-Pyrazol-4-yl)piperidin-3-yl)dimethylphosphine oxide

[001321] PtO ₂ (30 mg, 0.132 mmol) was added to a pressure vessel under a nitrogen atmosphere, then a solution of 3-(1-benzylpyrazol-4-yl)-5-dimethylphosphorylpyridine (200 mg, 0.642 mmol) in methanol (12) was added .9 ml). HCl in MeOH (3 mL 3M, 9 mmol) was added, then the vessel was transferred to a Parr hydrogenator. The reaction mixture was shaken at 60 ^psi hydrogen pressure for 16 hours. At this time, additional PtO ₂ (30 mg, 0.132 mmol) was added and the reaction mixture was shaken at 60 psi hydrogen pressure ² for another 24 hours. The reaction mixture was filtered and concentrated to give 3-dimethylphosphoryl-5-(1H-pyrazol-4-yl)piperidine (hydrochloride) (240 mg, 34%); MS m/z 147.1 (M+H) ⁺ . This substance was used without further purification.

[001322] Synthesis 210: Dimethyl(piperidin-3-ylimino)-λ6-sulfanone

The compound was prepared as in Tetrahedron, 2014, 70, 6613-6622.

Example 1: N-[[(3S,5S)-1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-4,4-difluoro -5-methyl-3-piperidyl]methyl]methanesulfonamide, II-36

[001323] 3-(6-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (511.5 mg, 1.82 mmol), N-[[(3S,5S) -4,4-difluoro-5-methyl-3-piperidyl]methyl]methanesulfonamide (400 mg, 1.65 mmol) and DIPEA (426.8 mg, 575.2 μl, 3.30 mmol) were combined in NMP (5 ml) and stirred at 80°C for 16 hours. The mixture was filtered through a Whatman filter, washed with DMSO (8 ml) and the resulting solution was purified using reverse phase chromatography (C18, MeCN/water/0.05% TFA in as eluent). The pure fractions were then passed through bicarbonate resin cartridges, combined and the resulting solution lyophilized to give N-[[(3S,5S)-1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3 -yl]pyrimidin-4-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]methanesulfonamide as an off-white solid (428 mg, 53%).

[001324] The following compounds were prepared using a methodology similar to that described in Example 1:

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide II -1;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide II -2;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-yl)methyl)methanesulfonamide II-3 ;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)morpholine II-4;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-hydroxy-5-methylpiperidin-3-yl)methyl) methanesulfonamide II-5;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-hydroxy-5-methylpiperidin-3-yl)methyl) methanesulfonamide II-6;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)indolin-3-yl)methyl)methanesulfonamide II-11;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,4-diazepan-5-one II-15;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)indoline-3-carboxamide II-16;

6-(Difluoromethyl)-3-(6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-19;

6-(Difluoromethyl)-3-(6-(indolin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-20;

6-(Difluoromethyl)-3-(6-(4-(methylsulfonyl)-1,4-diazepan-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-22;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,4-diazepan-1-sulfonamide II-24;

(1-(tert-Butyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methanol II-43;

7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one II-46 ;

(S)-7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)hexahydro-3H-oxazolo[3,4-a]pyrazin-3 -on II-47;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide II-50;

7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one II-51;

7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,7-diazaspiro[3.5]nonan-2-one II-52;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxypiperidin-3-yl)methyl)methanesulfonamide II-112 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-hydroxypyrrolidin-3-yl)methyl)methanesulfonamide II-137 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)methyl)methanesulfonamide II-140 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxypyrrolidin-3-yl)methyl)methanesulfonamide II-152 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-hydroxypiperidin-3-yl)methyl)methanesulfonamide II-158 ;

N-(1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide II-159;

N-(1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide II-177;

1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one II-186;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide II-190;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-N-(2-hydroxyethyl)piperidine-3-carboxamide II-191;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-sulfonamide II-192;

(S)-N-((4-(6-(6-Ethylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II-196;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methoxypiperidin-3-yl)methyl)methanesulfonamide II-198 ;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanesulfonamide II-199;

5-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)octahydro-3H-pyrrolo[3,4-c]pyridin-3-one II- 200;

(6R)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylmorpholine-2-carboxamide II-201;

1-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)sulfuric acid diamide II-202;

3-(6-(3-(1H-imidazol-4-yl)pyrrolidin-1-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-203;

3-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-pyrazol-5-carboxamide II- 205;

N-(2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethyl)-2-methoxyacetamide II -209;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,4-oxazepan-6-carboxamide II-210;

9-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,9-diazaspiro[5.5]undecan-3-one II-211;

3-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-4-yl)propanamide II-212;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-dimethylpyrrolidin-3-yl)methyl)methanesulfonamide II -213;

3-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)propanamide II-214;

1-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)urea II-215;

1-Cyclopropyl-3-(1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)urea II-216;

3-(6-(4-((1H-Pyrazol-5-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-217 ;

N-(2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-5-yl)acetamide II-218;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide II-219;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)methanesulfonamide II-221 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxy-4-methylpiperidin-3-yl)methyl) methanesulfonamide II-239;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxy-4-methylpiperidin-3-yl)methyl) methanesulfonamide II-240;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpyrrolidin-3-yl)methyl)methanesulfonamide II-243 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpyrrolidin-3-yl)methyl)methanesulfonamide II-244 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-yl)methyl)methanesulfonamide II-245 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-yl)methyl)methanesulfonamide II-246 ;

N-(((3S,6R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-yl) methyl)methanesulfonamide II-247;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-yl)methyl)methanesulfonamide II-248 ;

(S)-N-((4-(6-(6-Cyclopropylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II-249;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholine II-251;

6-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-oxa-6-azaspiro[3.3]heptane II-252;

6-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-(methylsulfonyl)-2,6-diazaspiro[4.5]decane II-256 ;

(R)-N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6,6-dimethylmorpholin-2-yl) methyl)methanesulfonamide II-257;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,5-difluoropiperidin-3-yl)methyl)methanesulfonamide II -258;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(dimethylamino)-4,4-difluoropiperidin-3- yl)methyl)methanesulfonamide II-259;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(dimethylamino)-4,4-difluoropiperidin-3- yl)methyl)methanesulfonamide II-260;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)acetamide II-261;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,6-dimethylpiperidin-3-yl)methyl)methanesulfonamide II -268;

N-[[(3S,5S)-1-[2-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-5-fluoro-4-pyridyl]-4,4-difluoro -5-methyl-3-piperidyl]methyl]methanesulfonamide II-270;

N-[[1-[2-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-5-fluoro-4-pyridyl]-6-methyl-3-piperidyl]methyl]methanesulfonamide II-271;

3-(6-(7,7-Difluoro-3-azabicyclo[4.1.0]heptan-3-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-274 ;

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-2-yl)ethane-1-sulfonamide II-283;

(S)-N-((1-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide II- 291;

(S)-N-((4-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II- 292;

N-((4,4-Difluoro-5-methyl-1-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl )methyl)methanesulfonamide II-293;

N-((4,4-Difluoro-5-methyl-1-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl )methyl)methanesulfonamide II-294;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)thiomorpholine 1,1-dioxide II-295;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)thiomorpholine-1-oxide II-296;

((2S,6S)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(trifluoromethyl)morpholin-2-yl) methanol II-297;

((2R,6S)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(trifluoromethyl)morpholin-2-yl) methanol II-298;

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetonitrile II-299;

(S)-N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide II- 300;

5-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-oxa-5-azabicyclo[4.1.0]heptane II-301;

6-(Difluoromethyl)-3-(6-(piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-308;

11-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,8-dioxa-4,11-diazaspiro[5.6]dodecane-3- he II-309;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl)methanesulfonamide II-313 ;

((3R,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(trifluoromethyl)piperidin-3-yl) methanol II-314;

((3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(trifluoromethyl)piperidin-3-yl) methanol II-315;

diamide 1-(((3S,5S)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5 -methylpiperidin-3-yl)methyl)sulfuric acid II-316;

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethane-1-sulfonamide II-317;

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethane-1-sulfonamide II-318;

N-(((3S,5S)-1-(6-(6-(1,1-Difluoroethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4- difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide II-321;

(S)-N-((4-(6-(6-(1,1-Difluoroethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl )methanesulfonamide II-322;

(S)-6-(Difluoromethyl)-3-(6-(2-methylpiperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-323;

(R)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholine II-324;

(S)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholine II-325;

2-((1H-1,2,4-Triazol-1-yl)methyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4- yl)morpholine II-326;

3-(6-(3-((1H-1,2,3-Triazol-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2- b]pyridazine II-327;

(S)-N-((4-(6-(6-Methylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II-328;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,5-difluoro-2-methylpiperidin-3-yl) methyl)methanesulfonamide II-329;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl)methanesulfonamide II-336 ;

3-(6-(3-((1H-1,2,4-Triazol-1-yl)methyl)piperidin-1-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2- b]pyridazine II-339;

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methanol II-341;

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methanol II-342;

(8-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dioxa-8-azaspiro[3.5]nonan-6-yl )methanol II-343;

1-(2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethyl)pyrrolidin-3-ol II-351;

1'-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-[1,3'-bipyrrolidin]-3-ol II-352;

4-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)piperazin-2-one II- 353;

(R)-6-(Difluoromethyl)-3-(6-(2-methylpiperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-354;

(7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-oxa-7-azaspiro[2.5]octan-5-yl)methanol II-359;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide II-362;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxy-4,6-dimethylpiperidin-3-yl) methyl)methanesulfonamide II-365;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxy-2,4-dimethylpiperidin-3-yl) methyl)methanesulfonamide II-366;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxy-4,6-dimethylpiperidin-3-yl) methyl)methanesulfonamide II-367;

1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-1-yl)ethan-1-one II- 368;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanol II-373;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-sulfonamide II-376;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide II-378;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-1,1,1- trifluoromethanesulfonamide II-379;

6-(Difluoromethyl)-3-(6-(2-(trifluoromethyl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-380;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,5-difluoro-4-methylpiperidin-3-yl) methyl)methanesulfonamide II-381;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,5-difluoro-4-methylpiperidin-3-yl) methyl)methanesulfonamide II-382;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-methoxypiperidin-3-yl)methyl)methanesulfonamide II-390 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-ethylpiperidin-3-yl)methyl)methanesulfonamide II-391 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)methanesulfonamide II-394;

6-(Difluoromethyl)-3-(6-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-395;

6-(Difluoromethyl)-3-(6-(3-((methylsulfonyl)methyl)pyrrolidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-396;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)methyl)methanesulfonamide II-397 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)methyl)methanesulfonamide II-398 ;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-carboxamide II-399;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-7-oxa-4-azaspiro[2.5]octane II-400;

3-(6-(4-Azaspiro[2.5]octan-4-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II-401;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3,3-dimethylmorpholine II-402;

(S)-N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6,6-dimethylmorpholin-2-yl) methyl)methanesulfonamide II-403;

(S)-Dimethyl(((4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)imino)- λ6-sulfanone II-406;

Dimethyl((1-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone II-407;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone II-408;

(((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperazin-2-yl)methyl)imino)dimethyl-λ6 -sulfanone II-411;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanesulfonamide II-424;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3,6-dimethylpiperazin-2-yl)methyl)methanesulfonamide II -427;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(3-fluoroazetidin-1-yl)piperidin-3 -yl)methyl)methanesulfonamide II-428;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(3-fluoroazetidin-1-yl)piperidin-3 -yl)methyl)methanesulfonamide II-429;

6-(Difluoromethyl)-3-(6-(3-((methylsulfonyl)methyl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-430;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2-methylpiperidin-3-yl) methyl)methanesulfonamide II-431;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2-methylpiperidin-3-yl) methyl)methanesulfonamide II-432;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-6-methylpiperidin-3-yl) methyl)methanesulfonamide II-433;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-6-methylpiperidin-3-yl) methyl)methanesulfonamide II-434;

(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol II- 438;

N-((3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)methanesulfonamide II-449;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide II-450;

3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-oxa-3-azabicyclo[3.1.1]heptane II-451;

8-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methyl-2-(methylsulfonyl)-2,5,8-triazaspiro[ 3.5]nonane II-452;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-carboxamide II-453;

(S)-1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)cyclopropan-1-ol II -454;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-N-methylmethanesulfonamide II-455;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,5-dimethylmorpholin-2-yl)methyl)methanesulfonamide II -457;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-461;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-462;

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-yl)methanesulfonamide II-464;

N-(1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethyl)methanesulfonamide II-465;

N-((3-Methyl-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methyl)methanesulfonamide II- 466;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-475;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-476;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-carboxamide II-477;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-N-methylpiperidin-3-sulfonamide II-480;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,4-oxazepan-6-yl)methyl)methanesulfonamide II -481;

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)acetamide II-483;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-fluoro-2,5-dimethyl-1,2, 5,6-tetrahydropyridin-3-yl)methyl)methanesulfonamide II-491;

6-(Difluoromethyl)-3-(6-(3-(2-(methylsulfonyl)ethyl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-493;

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)ethan-1-ol II-496;

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethan-1-ol II-497;

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethan-1-ol II-498;

2-(1-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethan-1-ol II-499;

2-(4-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethan-1-ol II-500;

2-(1-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetonitrile II-501;

(S)-1-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidine-3-carboxylic acid II-504;

(S)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidine-3-carboxylic acid II-505;

(R)-1-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidine-3-carboxylic acid II-506;

(R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidine-3-carboxylic acid II-508;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide II -511;

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)acetonitrile II-512;

2-(4-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)acetonitrile II-513;

(S)-(1-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol II-516;

(R)-(1-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol II-517;

(4-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methanol II-518;

(S)-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol II-519;

(R)-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol II-520;

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methanol II-521;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)(imino)(methyl)-λ6-sulfanone II- 522;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl-d2)methanesulfonamide II-524;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methyl-4-oxopiperidin-3-yl)methyl) methanesulfonamide II-525;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methyl-4-oxopiperidin-3-yl)methyl) methanesulfonamide II-526;

N-((8-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-10-methyl-1,4-dioxa-8-azaspiro[ 4.5]decan-6-yl)methyl)methanesulfonamide II-527;

N-((5-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-8,8-difluoro-5-azaspiro[2.5]octan- 7-yl)methyl)methanesulfonamide II-528;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholine-2-carbonitrile II-531;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-carbonitrile II-532;

4-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholine-2-carbonitrile II-533;

1-(6-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-carbonitrile II-534;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-fluoro-5-methyl-1,2,5, 6-tetrahydropyridin-3-yl)methyl)methanesulfonamide II-537;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-fluoro-5-methyl-1,2,3, 6-tetrahydropyridin-3-yl)methyl)methanesulfonamide II-538;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,6-dimethylpiperidin-3-yl)methyl)methanesulfonamide II -544;

7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-8-methylhexahydro-3H-oxazolo[3,4-a]pyrazin-3- he II-547;

6-(Difluoromethyl)-3-(6-(2,3-dimethylpiperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-548;

N-((5-Cyano-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide II- 553;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanol II-554;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanol II-555;

(1-(tert-Butyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methanol II-556;

(1-(tert-Butyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methanol II-557;

(1-(tert-Butyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methanol II-558;

N-(((8aS)-2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)octahydropyrrolo[1,2-a]pyrazin-4 -yl)methyl)methanesulfonamide II-560;

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)tetrahydrothiophene 1,1-dioxide II-563;

N-((6-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-azaspiro[2.5]octan-4-yl)methyl) methanesulfonamide II-566;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6,6-dimethylpiperazin-2-yl)methyl)methanesulfonamide II -567;

N-(((7S,8aS)-2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-7-fluoroctahydropyrrolo[1,2- a]pyrazin-4-yl)methyl)methanesulfonamide II-568;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6,6-dimethylpiperazin-2-yl)methyl)methanesulfonamide II -569;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6,6-dimethylpiperazin-2-yl)methyl)methanesulfonamide II -570;

N-(1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)propyl)methanesulfonamide II-571;

N-(1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)propyl)methanesulfonamide II-572;

(((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)imino)dimethyl-λ6-sulfanone II -573;

(((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)imino)dimethyl-λ6-sulfanone II -574;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methanol II-577;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -578;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -579;

(((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)imino)dimethyl-λ6 -sulfanone II-583;

(((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)imino)dimethyl-λ6 -sulfanone II-584;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,6-dimethylpiperidin-3-yl)methyl)methanesulfonamide II -591;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,6-dimethylpiperidin-3-yl)methyl)methanesulfonamide II -592;

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)propan-2-ol II-608;

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylmorpholin-2-yl)methanol II-615;

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylmorpholin-2-yl)methanol II-616;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxy-2,4,5-trimethylpiperidin-3- yl)methyl)methanesulfonamide II-617;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-hydroxy-2,4,5-trimethylpiperidin-3- yl)methyl)methanesulfonamide II-618;

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-3-methylbutan-2-ol II- 621;

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-3-methylbutan-2-ol II- 622;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5-methylpiperidin-3-yl)methanol II- 623;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5-methylpiperidin-3-yl)methanol II- 624;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)diethyl-λ6-sulfanone II -627;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -629;

Cyclopropyl((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(methyl)-λ6 -sulfanone II-634;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(ethyl)(methyl) -λ6-sulfanone II-635;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-ethylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -648;

1-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)tetrahydro-1H- 1-λ6-thiophene-1-oxide II-649;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)imino)dimethyl-λ6 -sulfanone II-654;

[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5,5-difluoro-2-methyl-3-piperidyl]methanol II- 684;

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-ethylmorpholin-2-yl)methanol II-685;

2-[4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-methylpiperazin-2-yl]ethanol II-686;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperazin-2-yl)methyl)methanesulfonamide II-687 ;

(S)-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)methanol II-688;

cis-[6-Cyclopropyl-4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methanol II-689;

[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-(2-methoxyethoxy)-3-piperidyl]methanol II-690;

N-[[1-[6-(6-Cyanoimidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl]-3-piperidyl]methyl]methanesulfonamide II-692;

3-[6-[2,5-Dimethyl-3-(1H)-pyrazol-4-yl)piperazin-1-yl]pyrimidin-4-yl]imidazo[1,2-b]pyridazin-6-carbonitrile II -693;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)imino)dimethyl-λ6 -sulfanone II-694;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(trifluoromethyl)piperidin-3-yl)imino)dimethyl-λ6 -sulfanone II-695;

[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-6-methyl-3-piperidyl]iminodimethyl-λ6-sulfanone II-696;

[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-6-methyl-3-piperidyl]iminodimethyl-λ6-sulfanone II-697;

3-[6-[2,5-Dimethyl-3-(1H)-pyrazol-4-yl)piperazin-1-yl]pyrimidin-4-yl]-6-(trifluoromethyl)imidazo[1,2-b] pyridazine II-698;

3-(6-(6-Oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-carbonitrile II-699;

[2-(Difluoromethyl)-1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]iminodimethyl-λ6-sulfanone II- 700;

[2-(Difluoromethyl)-1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]iminodimethyl-λ6-sulfanone II- 701;

3-(6-(3-((Dimethyl(oxo)-λ6-sulfanylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine-6-carbonitrile II -702;

3-(6-(3-((Dimethyl(oxo)-λ6-sulfanylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine-6-carbonitrile II -703;

3-(6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II-704;

3-(6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II-705;

3-(6-(2-Methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II- 706;

3-(6-(3-Methyl-2-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II- 707;

6-(Difluoromethyl)-3-[6-(3-dimethylphosphoryl-5-methyl-1-piperidyl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine II-710;

6-(Difluoromethyl)-3-[6-(3-dimethylphosphoryl-5-methyl-1-piperidyl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine II-711;

3-[6-(3-Dimethylphosphoryl-5-methyl-1-piperidyl)pyrimidin-4-yl]-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II-712;

3-[6-(3-Dimethylphosphoryl-5-methyl-1-piperidyl)pyrimidin-4-yl]-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II-713;

3-(6-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-714;

3-(6-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-715;

2,5-Dimethyl-1-[6-[6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]piperidin-3-carboxamide (racemic pair of diastereoisomers, 2 compounds) II-719;

2,5-Dimethyl-1-[6-[6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]piperidin-3-carboxamide (racemic pair of diastereoisomers, 2 compounds) II-720;

2,5-Dimethyl-1-[6-[6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]piperidine-3-carboxylic acid II-721;

3-(6-(3-((Dimethyl(oxo)-λ6-sulfanylidene)amino)-5-methylpiperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine-6-carboxamide II -726;

3-[6-(6-Oxo-3,4,7,8,9,9a-hexahydro-1H-pyrido[1,2-a]pyrazin-2-yl)pyrimidin-4-yl]imidazo[1, 2-b]pyridazine-6-carboxamide II-727;

3-[6-[2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-4-yl]imidazo[1,2-b]pyridazin-6-carboxamide II- 728;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-5-fluoropyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II-729 ;

N-((1-(5-Chloro-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II- 730

[001325] The following compounds were prepared using a methodology similar to that described in Example 1 and were further purified using chiral SFC:

N-(2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-7-yl)methanesulfonamide II- 95 (one stereoisomer, isolated using chiral SFC);

N-(2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-7-yl)methanesulfonamide II- 100 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methoxypiperidin-3-yl)methyl)methanesulfonamide II-233 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)methanesulfonamide II-263 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)methanesulfonamide II-264 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)methanesulfonamide II-265 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)methanesulfonamide II-266 (one stereoisomer, isolated using chiral SFC);

diamide (S)-1-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)sulfuric acid (one stereoisomer, isolated using chiral SFC) and diamide (R)-1-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl )piperidin-3-yl)methyl)sulfuric acid (one stereoisomer, isolated using chiral SFC); II-277 and II-278 (in no particular order)

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2-methylpiperidin-3-yl) methyl)methanesulfonamide II-302 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2-methylpiperidin-3-yl) methyl)methanesulfonamide II-303 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-6-methylpiperidin-3-yl) methyl)methanesulfonamide II-304 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-6-methylpiperidin-3-yl) methyl)methanesulfonamide II-305 (one stereoisomer, isolated using chiral SFC);

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylthiomorpholine-1-oxide II-355 (one stereoisomer, isolated using chiral SFC);

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylthiomorpholine-1-oxide II-356 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,5-difluoro-2-methylpiperidin-3-yl) methyl)methanesulfonamide II-360 (one stereoisomer, isolated using chiral SFC);

N-(((2S,3R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5,5-difluoro-2- methylpiperidin-3-yl)methyl)methanesulfonamide II-361 (one stereoisomer, isolated using chiral SFC);

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methyl)methanesulfonamide II-371 (one stereoisomer, isolated using chiral SFC);

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methyl)methanesulfonamide II-372 (one stereoisomer, isolated using chiral SFC);

((2S,3S)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanol II- 392 (one stereoisomer, isolated using chiral SFC);

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanol II-393 (one stereoisomer, isolated using chiral SFC);

(S)-N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide II-404 (one stereoisomer, isolated using chiral SFC);

(R)-N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide II-405 (one stereoisomer, isolated using chiral SFC);

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methanol II-413 (one stereoisomer, isolated using chiral SFC);

(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methanol II-414 (one stereoisomer, isolated using chiral SFC);

(((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-ethylpiperidin-3-yl)methyl)imino)dimethyl-λ6 -sulfanone II-416 (one stereoisomer, isolated using chiral SFC);

(((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-ethylpiperidin-3-yl)methyl)imino)dimethyl-λ6 -sulfanone II-417 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)methyl)methanesulfonamide II-436 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)methyl)methanesulfonamide II-437 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-467 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-468 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-469 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-470 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-2,5-dimethylpiperidin-3- yl)methyl)methanesulfonamide II-471 (one stereoisomer, isolated using chiral SFC);

N-(((2S,3R,5S)-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro- 2,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide II-472 (one stereoisomer, isolated using chiral SFC);

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3,6,6-trimethylmorpholin-2-yl)methyl) methanesulfonamide II-484 (one stereoisomer, isolated using chiral SFC);

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3,6,6-trimethylmorpholin-2-yl)methyl) methanesulfonamide II-489 (one stereoisomer, isolated using chiral SFC);

N-(((2R,3S)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3,6,6-trimethylmorpholine- 2-yl)methyl)methanesulfonamide II-490 (one stereoisomer, isolated using chiral SFC);

(S)-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone II-502 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone II-503 ( one stereoisomer, isolated using chiral SFC);

N-((S)-1-((S)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl )ethyl)methanesulfonamide II-509 (one stereoisomer, isolated using chiral SFC);

N-(-1-((R)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl) methanesulfonamide II-510 (one stereoisomer, isolated using chiral SFC);

6-(Difluoromethyl)-3-(6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-529 (one stereoisomer, isolated using chiral SFC );

6-(Difluoromethyl)-3-(6-(3-(methylsulfonyl)piperidin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-530 (one stereoisomer, isolated using chiral SFC );

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -540 (one stereoisomer, isolated using chiral SFC);

(((3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino) dimethyl-λ6-sulfanone II-541 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide II -545 (one stereoisomer, isolated using chiral SFC);

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)methanesulfonamide II -546 (one stereoisomer, isolated using chiral SFC);

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)acetonitrile II-564 (one stereoisomer, isolated with using chiral SFC);

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)acetonitrile II-565 (one stereoisomer, isolated with using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -581 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -582 (one stereoisomer, isolated using chiral SFC);

((2S,3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl )methanol II-585 (one stereoisomer, isolated using chiral SFC);

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methanol II-586 (one stereoisomer , isolated using chiral SFC);

(((2S,3S)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)imino) dimethyl-λ6-sulfanone II-593 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -594 (one stereoisomer, isolated using chiral SFC);

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)propan-2-ol II-613 (one stereoisomer, isolated using chiral SFC);

2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)propan-2-ol II-614 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)imino)dimethyl-λ6- sulfanone II-630 (one stereoisomer, isolated using chiral SFC);

(((2S,3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3- yl)imino)dimethyl-λ6-sulfanone II-631 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -632 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -633 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-636 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-637 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-638 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-639 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(ethyl)(methyl) -λ6-sulfanone II-640 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(ethyl)(methyl) -λ6-sulfanone II-641 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(ethyl)(methyl) -λ6-sulfanone II-642 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(ethyl)(methyl) -λ6-sulfanone II-643 (one stereoisomer, isolated using chiral SFC);

Cyclopropyl((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(methyl)-λ6 -sulfanone II-644 (one stereoisomer, isolated using chiral SFC);

Cyclopropyl((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(methyl)-λ6 -sulfanone II-645 (one stereoisomer, isolated using chiral SFC);

Cyclopropyl((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(methyl)-λ6 -sulfanone II-646 (one stereoisomer, isolated using chiral SFC);

Cyclopropyl((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)(methyl)-λ6 -sulfanone II-647 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-ethylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -650 (one stereoisomer, isolated using chiral SFC);

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-ethylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -651 (one stereoisomer, isolated using chiral SFC);

6-(Difluoromethyl)-3-(6-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-652 (one stereoisomer, isolated using chiral SFC);

6-(Difluoromethyl)-3-(6-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-653 (one stereoisomer, isolated using chiral SFC);

2,5-Dimethyl-1-[6-[6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]piperidin-3-carboxamide II-717 (one stereoisomer, isolated using chiral SFC);

2,5-Dimethyl-1-[6-[6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]piperidin-3-carboxamide II-718 (one stereoisomer, isolated using chiral SFC);

((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-5-fluoropyridin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6 -sulfanone II-722 (one stereoisomer, isolated using chiral SFC);

((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-5-fluoropyridin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6 -sulfanone II-723 (one stereoisomer, isolated using chiral SFC);

((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -724 (one stereoisomer, isolated using chiral SFC);

((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -725 (one stereoisomer, isolated using chiral SFC);

Example 2: 2-((4H-1,2,4-Triazol-4-yl)methyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidine -4-yl)morpholine, II-29

[001326] Mixture of 2-(1,2,4-triazol-4-ylmethyl)morpholine (trifluoroacetate) (15 mg, 0.053 mmol), 6-(difluoromethyl)-3-(6-fluoropyrimidin-4-yl)imidazo[ 1,2-b]pyridazine (14.1 mg, 0.053 mmol) and K ₂ CO ₃ (40 mg, 0.289 mmol) in NMP (1 ml) were stirred at 90°C in a sealed tube for 24 hours. The crude mixture was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). The pure fractions were combined and lyophilized to give 2-((4H-1,2,4-triazol-4-yl)methyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3 -yl)pyrimidin-4-yl)morpholine as a pale yellow solid (10 mg, 45%).

[001327] The following compounds were prepared using a methodology similar to that described in Example 2:

(S)-N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methyl-6-oxopiperazine-2- yl)methyl)methanesulfonamide II-7;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpyrrolidin-3-yl)methyl)methanesulfonamide II-8 ;

(S)-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methanol II-9;

[(2S)-4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyliminodimethyloxosulfan II-10;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-hydroxypiperidin-3-yl)methyl)methanesulfonamide II-12 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-hydroxypiperidin-3-yl)methyl)methanesulfonamide II-13 ;

N-(2-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)ethyl)methanesulfonamide II-17;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-methylpyrrolidin-3-yl)methyl)methanesulfonamide II-18 ;

N-(((S)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonimidamide II- 23;

(S)-N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-oxopiperazin-2-yl)methyl) methanesulfonamide II-25;

[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]methylmethylmethyliminooxosulfan II-26;

3-(6-(1H-Pyrrolo[3,4-c]pyridin-2(3H)-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-28;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylmorpholin-2-yl)methyl)methanesulfonamide II-31 ;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylmorpholin-2-yl)methyl)methanesulfonamide II-32 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5-methylpiperidin-3-yl) methyl)methanesulfonamide II-35;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylmorpholin-2-yl)methyl)methanesulfonamide II-33 ;

(S)-N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II- 34;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5-methylpiperidin-3-yl) methyl)methanesulfonamide II-45;

4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-2-one II-62.

Example 3: N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide, II- 59

[001328] To 6-(difluoromethyl)-3-iodimidazo[1,2-b]pyridazine (65 mg, 0.22 mmol) in dry 1,4-dioxane (4 ml) was added tributyl(tributylstannyl)stannane (255, 6 mg, 0.44 mmol), LiCl (46.72 mg, 1.1 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.7 mg, 0.011 mmol). The mixture was heated at 105°C under nitrogen for 15 hours. N-[[1-(6-bromopyrimidin-4-yl)-3-piperidyl]methyl]methanesulfonamide (38 mg, 0.11 mmol) and Pd were added sequentially (PPh ₃ ) ₂ Cl ₂ (15.5 mg, 0.022 mmol) and the mixture was stirred at 140°C in a sealed tube for 4 hours. Another portion of N-[[1-(6-bromopyrimidin-4-yl) was added -3-piperidyl]methyl]methanesulfonamide (76 mg, 0.22 mmol) and the mixture was stirred at 140°C for an additional 4 hours. The mixture was purified by reverse phase chromatography (C18, MeCN/water 0.05% TFA in as eluent) and obtained N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide ( 6.6 mg, 5.4%).

Example 4: N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(methylamino)pyridin-4-yl)piperidin-3-yl) methyl)methanesulfonamide, II-60

[001329] A solution of tributyl-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]stannane (82 mg, 0.179 mmol) in DMF (5 ml) was degassed using several vacuum/N ₂ cycles. then N-[[1-[2-bromo-6-(methylamino)-4-pyridyl]-3-piperidyl]methyl]methanesulfonamide (67.5 mg, 0.179 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ ( 18.8 mg, 0.027 mmol). The mixture was further degassed, then heated at 90°C under nitrogen for 2 hours. The mixture was loaded into a 5 g SCX-2 cartridge and washed with DCM/MeOH mixtures. The product was eluted with 2 M NH ₃ in MeOH and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water 0.05% TFA as eluent) to give N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin- 3-yl)-6-(methylamino)pyridin-4-yl)piperidin-3-yl)methyl)methanesulfonamide (5.3 mg, 4.6%).

Example 5: N-[[(2S)-4-[4-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]morpholin-2-yl]methyl]methanesulfonamide , II-121

[001330] Solution of 6-(difluoromethyl)-3-(2-fluoro-4-pyridyl)imidazo[1,2-b]pyridazine (124 mg, 0.469 mmol), N-[[(2S)-morpholine-2- yl]methyl]methanesulfonamide (1.85 ml 0.51 M, 0.943 mmol) and DIPEA (245 μl, 1.41 mmol) in NMP (0.15 ml) were heated at 160°C for 16 hours. The reaction mixture was cooled to ambient temperature and immediately purified by reverse phase chromatography (C18, MeCN/water - 0.1% ammonium hydroxide eluent). Fractions were collected and freeze-dried to yield N-[[(2S)-4-[4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]morpholin-2-yl ]methyl]methanesulfonamide as a beige solid (38 mg, 18%).

[001331] The following compounds were prepared using a methodology similar to that described in Example 5:

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-5-hydroxypiperidin-3-yl)methyl)methanesulfonamide II-39 ;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-5-hydroxypiperidin-3-yl)methyl)methanesulfonamide II-40 ;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-4,4-difluoro-5-methylpiperidin-3-yl) methyl)methanesulfonamide II-57;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-4,4-difluoro-5-methylpiperidin-3-yl) methyl)methanesulfonamide II-58;

4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholine II-76;

4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)thiomorpholine 1,1-dioxide II-77;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-4,4-difluoro-5-methylpiperidin-3-yl) methyl)methanesulfonamide II-78;

7-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)- he II-88;

N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-2-yl)methyl)methanesulfonamide II-90;

(4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-yl)methanol II-97;

N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1,4-oxazepan-6-yl)methyl)methanesulfonamide II -99;

[(2S)-4-[4-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]morpholin-2-yl]methyliminodimethyloxosulfan II-102;

N-(1-(4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholin-2-yl)ethyl)methanesulfonamide II-106;

4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-2-(1H-pyrazol-4-yl)morpholine II-107;

4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-2-(1H-pyrazol-4-yl)morpholine II-108;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)-N-methylmethanesulfonamide II-109 ;

N-(2-(1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)propan-2-yl)methanesulfonamide II-114;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-3-methylpiperidin-3-yl)methyl)methanesulfonamide II-115 ;

N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-6-methylmorpholin-2-yl)methyl)methanesulfonamide II-118 ;

N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-6-methylmorpholin-2-yl)methyl)methanesulfonamide II-119 ;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)pyrrolidin-3-yl)methyl)methanesulfonamide II-123;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)oxy)methanesulfonamide II-124;

6-(Difluoromethyl)-3-(2-(3-(2-(methylsulfonyl)ethyl)piperidin-1-yl)pyridin-4-yl)imidazo[1,2-b]pyridazine II-128;

N-(1-(1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)ethyl)methanesulfonamide II-133;

N-(1-(1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)ethyl)methanesulfonamide II-134;

4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholine-2-carboxamide II-135;

6-(Difluoromethyl)-3-(2-(2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)pyridin-4-yl)imidazo[1,2-b]pyridazine II-136 ;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-3-fluoropiperidin-3-yl)methyl)methanesulfonamide II-139 ;

(S)-1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-carboxamide II-143;

(1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methanesulfonamide II-144;

2-(1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)acetamide II-145;

2-(4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholin-2-yl)ethanol II-146;

4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-2-(1H-pyrazol-4-yl)morpholine II-147;

(R)-N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-6,6-dimethylmorpholin-2-yl) methyl)methanesulfonamide II-148;

N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholin-2-yl)methyl)methanesulfonamide II-149;

6-(Difluoromethyl)-3-(2-(3-((methylsulfinyl)methyl)piperidin-1-yl)pyridin-4-yl)imidazo[1,2-b]pyridazine II-151;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide II -153;

(S)-N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II- 154;

(R)-N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II- 155;

7-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-2,7-diazaspiro[4.5]decan-1-one II-156;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II-157;

7-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-4,7-diazaspiro[2.5]octan-5-one II-160;

(1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methanol II-162;

1-(4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1,4-diazepan-1-yl)ethanone II-163;

1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1,4-diazepan-5-one II-164;

2-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one II-167 ;

2-(1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)ethanol II-168;

1-(4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-methoxyethanone II-170;

7-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one II-172 ;

7-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one II-173 ;

7-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo [4,3-a]pyrazine II-174;

7-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one II-175 ;

1-(4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone II-176;

(S)-N-((4-(4-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholin-2-yl)methyl)methanesulfonamide II- 224;

2-(1H-Pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholine II-225;

(S)-7'-(4-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)tetrahydrospiro[cyclopropane-1,1'-oxazolo[3,4 -a]pyrazine]-3'(5'H)-one II-226;

3-(2-(3-((Methylsulfonyl)methyl)piperidin-1-yl)pyridin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II-227;

3-(2-(3-(Methylsulfonyl)piperidin-1-yl)pyridin-4-yl)-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II-228;

2-(1H-Pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholine II-229 (one stereoisomer , isolated using chiral SFC);

2-(1H-Pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholine II-230 (one stereoisomer , isolated using chiral SFC);

N-(1-(4-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methanesulfonamide II-231;

N-((4-(4-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1,4-oxazepan-6-yl)methyl)methanesulfonamide II -232;

((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -716;

((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6-sulfanone II -691.

Example 6: 2-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)octahydro-1H-pyrazino[1,2-a]pyrazine, II- 38

[001332] TFA (500 μl, 6.49 mmol) was added to the solution of tert-butyl-8-[4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2- with stirring pyridyl]-3,4,6,7,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine-2-carboxylate (55.1 mg, 0.113 mmol, prepared according to a procedure similar to that used in example 5) in DCM (5 ml) and the reaction mixture was stirred at ambient temperature for 22 hours. The solvent was removed in vacuo and the residue was azeotroped with DCM (×2) and diethyl ether (×2). The substance was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). Pure fractions were collected and freeze-dried to yield 2-[4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]-1,3,4,6,7,8 ,9,9a-octahydropyrazino[1,2-a]pyrazine (28.1 mg, 39.5%) as a beige solid.

[001333] The following compounds were prepared using a methodology similar to that described in Example 6:

3-(2-(2,6-Diazaspiro[3.3]heptan-2-yl)pyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-79;

3-(2-(3,9-Diazaspiro[5.5]undecan-3-yl)pyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-161;

3-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)pyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II -165;

3-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)pyridin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II -166;

(S)-(4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-2-yl)methanol II-169.

Example 7: 2-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-8-(methylsulfonyl)octahydro-1H-pyrazino[1,2- a]pyrazine, II-37

[001334] 2-[4-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]-1,3,4,6,7,8,9,9a- Octahydropyrazino[1,2-a]pyrazine (bis-trifluoroacetate) (28.1 mg, 0.045 mmol, prepared according to the same procedure as Example 6) was dissolved in DMF (1 ml) and Et ₃ N (35 µl) was added , 0.251 mmol), then methanesulfonyl chloride (6 μl, 0.077 mmol). The reaction mixture was stirred at ambient temperature for 1.5 hours. Water (200 μl) was added and the reaction mixture was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). Pure fractions were collected and freeze-dried to yield 8-[4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]-2-methylsulfonyl-3,4,6,7 ,9,9a-hexahydro-1H-pyrazino[1,2-a]pyrazine) (10.1 mg, 38%) as a beige solid.

[001335] The following compounds were prepared using a methodology similar to that described in Example 7:

6-(Difluoromethyl)-3-(6-(6-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-279 ;

2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-8-(methylsulfonyl)-5-oxa-2,8-diazaspiro[3.5] nonane II-280;

6-(Difluoromethyl)-3-(6-(2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-281 ;

6-(Difluoromethyl)-3-(6-(5-(methylsulfonyl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II -282;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-N-methylmethanesulfonamide II-310 ;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(methylsulfonyl)octahydropyrrolo[3,4-b][1,4] oxazine II-319;

6-(Difluoromethyl)-3-(6-(6-(methylsulfonyl)octahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-320;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(methylsulfonyl)octahydro-1H-pyrido[3,4-b][ 1,4]oxazine II-369;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoropiperidin-3-yl)methanesulfonamide II-589;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoropiperidin-3-yl)methanesulfonamide II-596;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoropiperidin-3-yl)methanesulfonamide II-597;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanesulfonamide II-600;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanesulfonamide II-601;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanesulfonamide II-602;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanesulfonamide II-603;

N-(1-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethyl)methanesulfonamide II-619;

N-(1-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethyl)methanesulfonamide II-620.

Example 8: N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1-(oxetan-3-yl)piperazin- 2-yl)methyl)methanesulfonamide, II-81

[001336] Mixture of N-((4-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-2-yl)methyl)methanesulfonamide (trifluoroacetate) ) (80 mg, 0.135 mmol), acetic acid (15 µl, 0.264 mmol) and oxetan-3-one (25 mg, 0.347 mmol) in THF (3 ml) were stirred at ambient temperature for 90 min, then cyanoborohydride was added sodium (15 mg, 0.239 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent ). Pure fractions were collected and freeze-dried to give the title compound (20 mg, 22%).

Example 9: N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-fluoropyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide , II-122

[001337] 6-(Difluoromethyl)-3-(2,6-difluoro-4-pyridyl)imidazo[1,2-b]pyridazine (478 mg, 1.694 mmol), N-(3-piperidylmethyl)methanesulfonamide (325, 7 mg, 1.694 mmol) and DIPEA (875.8 mg, 1.18 mL, 6.776 mmol) were heated in NMP (10 mL) at 120°C for 3 hours. The reaction mixture was cooled to ambient temperature and partitioned between EtOAc and brine. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give N-((1-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-fluoropyridin-2-yl )piperidin-3-yl)methyl)methanesulfonamide as a brown solid (593 mg, 77%).

Example 10: N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-morpholinopyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide , II-66

[001338] N-[[1-[4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-6-fluoro-2-pyridyl]-3-piperidyl]methyl]methanesulfonamide mixture (36 mg, 0.079 mmol), morpholine (100 µl, 1.147 mmol) and DIPEA (50 µl, 0.287 mmol) in NMP (0.5 ml) were heated at 170°C for 16 h. The reaction mixture was cooled to ambient temperature and purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). The pure fractions were freeze-dried to give N-((1-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-morpholinopyridin-2-yl)piperidin-3-yl) methyl)methanesulfonamide (24.1 mg, 35%).

[001339] The following compounds were prepared using a methodology similar to that described in Example 10:

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl )pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II-72;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridine -2-yl)piperidin-3-yl)methyl)methanesulfonamide II-83;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(3-hydroxyazetidin-1-yl)pyridin-2-yl)piperidin-3 -yl)methyl)methanesulfonamide II-85;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(1-oxa-6-azaspiro[3.3]heptan-6-yl)pyridine -2-yl)piperidin-3-yl)methyl)methanesulfonamide II-86;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-((2-methoxyethyl)amino)pyridin-2-yl)piperidin-3- yl)methyl)methanesulfonamide II-89;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-((2-hydroxyethyl)amino)pyridin-2-yl)piperidin-3- yl)methyl)methanesulfonamide II-91;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(piperazin-1-yl)pyridin-2-yl)piperidin-3-yl )methyl)methanesulfonamide II-96;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(methylamino)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II-116.

Example 11: N-[[1-[6-(2,6-Diazaspiro[3.3]heptan-2-yl)-4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl] -2-pyridyl]-3-piperidyl]methyl]methanesulfonamide, II-92

[001340] N-[[1-[4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-6-fluoro-2-pyridyl]-3-piperidyl]methyl]methanesulfonamide suspension (50 mg, 0.11 mmol), tert-butyl-2,6-diazaspiro[3.3]heptane-2-carboxylate (65.4 mg, 0.33 mmol) and Cs ₂ CO ₃ (179.2 mg, 0 .55 mmol) in 1,4-dioxane (730 µl) was heated at 120°C for 16 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in DCM, then TFA (1.254 g, 847 µl, 11 mmol) was added. The mixture was stirred at ambient temperature for 1 hour, then the solution was concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-[[1-[6-(2,6-diazaspiro[3.3]heptan-2-yl) -4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]-3-piperidyl]methyl]methanesulfonamide (15.2 mg, 19%).

[001341] The following compounds were prepared using a methodology similar to that described in Example 11:

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(1,6-diazaspiro[3.3]heptan-6-yl)pyridin-2 -yl)piperidin-3-yl)methyl)methanesulfonamide II-67;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(2-(methylamino)ethoxy)pyridin-2-yl)piperidin-3- yl)methyl)methanesulfonamide II-74;

N-((1-(6-(Azetidin-3-yloxy)-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl )methyl)methanesulfonamide II-84.

Example 12: N-((1-(6-(6-Acetyl-2,6-diazaspiro[3.3]heptan-2-yl)-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin- 3-yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide, II-55

[001342] Acetyl chloride (2.4 mg, 2.2 μl, 0.031 mmol) and DMAP (0.13 mg, 0.001 mmol) were sequentially added to a solution of N-[[1-[6-(2,6-diazaspiro[3.3 ]heptan-2-yl)-4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]-3-piperidyl]methyl]methanesulfonamide (13.3 mg, 0.021 mmol) and Et ₃ N (8.4 mg, 11.56 µl, 0.083 mmol) in DCM (300 µl). After 1 hour, MeOH was added to stop the reaction and the mixture was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-((1-(6-(6-acetyl-2 ,6-diazaspiro[3.3]heptan-2-yl)-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl) methanesulfonamide (4.5 mg, 27%).

Example 13: (S)-N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(methylamino)pyridin-2-yl)piperidin- 3-yl)methyl)methanesulfonamide, II-68

[001343] Mixture of 6-(difluoromethyl)-3-(2,6-difluoro-4-pyridyl)imidazo[1,2-b]pyridazine (100 mg, 0.354 mmol), N-[[(3S)-3- piperidyl]methyl]methanesulfonamide (68.1 mg, 0.354 mmol) and DIPEA (183.3 mg, 247 μl, 1.418 mmol) were heated in NMP (1.8 ml) at 120°C. After 3 hours, methylamine (500 μL 40% w/v, 6.44 mmol) was added and the reaction mixture was heated at 150°C for 16 hours. Additional methylamine (500 μL 40% w/v, 6.44 mmol) and the reaction mixture was heated at 170°C for 6 hours. The crude reaction mixture was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give (S)- N-((1-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(methylamino)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide (13.1 mg, 8%).

[001344] The following compounds were prepared using a methodology similar to that described in Example 13:

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(methylamino)pyridin-2-yl)-4,4-difluoro-5- methylpiperidin-3-yl)methyl)methanesulfonamide II-64;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(methylamino)pyridin-2-yl)-4,4-difluoro-5- methylpiperidin-3-yl)methyl)methanesulfonamide II-65;

(S)-N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(methylamino)pyridin-2-yl)morpholin-2-yl )methyl)methanesulfonamide II-69;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(methylamino)pyridin-2-yl)-4,4-difluoropiperidin-3- yl)methyl)methanesulfonamide II-71.

Example 14: N-((1-(6-Cyano-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl) methanesulfonamide, II-130

[001345] Mixture of 6-chloro-4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyridin-2-carbonitrile (40 mg, 0.073 mmol), N-(3-piperidylmethyl) methanesulfonamide (28.2 mg, 0.147 mmol) and DIPEA (37.9 mg, 51.0 µl, 0.293 mmol) were heated in NMP (375 µl) at 150°C for 3 hours. The crude reaction mixture was purified by chromatography with reverse phase (C18, MeCN/water/0.05% TFA as eluent) to obtain N-((1-(6-cyano-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazine-3 -yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide as a beige solid (14.3 mg, 33%).

[001346] The following compounds were prepared using a methodology similar to that described in Example 14:

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-methylpyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II-129 .

Example 15: N-((1-(6-(Aminomethyl)-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl) methyl)methanesulfonamide, II-80

[001347] Methanol (16.9 mL) then HCl (100 μL 12 M, 1.2 mmol) was added to N-[[1-[6-cyano-4-[6-(difluoromethyl)imidazo[1,2 -b]pyridazin-3-yl]-2-pyridyl]-3-piperidyl]methyl]methanesulfonamide (35 mg, 0.076 mmol) and Pd(OH) ₂ on carbon (10.6 mg, 0.076 mmol). The suspension was stirred with H ₂ supplied from a balloon for 5 hours, then the catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-((1-(6-(aminomethyl)-4-(6-(difluoromethyl)imidazo[1 ,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide (7.8 mg, 15%).

Example 16: N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl) methyl)methanesulfonamide, II-63

[001348] Mixture of 3-[2-chloro-6-(trifluoromethyl)-4-pyridyl]-6-(difluoromethyl)imidazo[1,2-b]pyridazine (40 mg, 0.115 mmol), N-(3-piperidylmethyl )methanesulfonamide (33.1 mg, 0.172 mmol) and DIPEA (59.3 mg, 79.9 μl, 0.459 mmol) in NMP (570 μl) were heated at 150°C for 16 h. After cooling, the reaction mixture was purified using reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to obtain N-((1-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl )-6-(trifluoromethyl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide (10.1 mg, 13%).

Example 17: N-((1-(6-Chloro-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl) methanesulfonamide, II-61

[001349] Mixture of 3-(2,6-dichloro-4-pyridyl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (40 mg, 0.127 mmol), N-(3-piperidylmethyl)methanesulfonamide (26 .8 mg, 0.140 mmol) and DIPEA (65.6 mg, 88.4 µl, 0.508 mmol) in NMP (630 µl) were heated at 150°C for 16 hours. After cooling, the reaction mixture was purified using reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to obtain N-((1-(6-chloro-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl )pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide (17.5 mg, 21%).

Example 18: N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-4,4-difluoro-5-methylpiperidin-3 -yl)methyl)methanesulfonamide, II-75

[001350] 6-(Difluoromethyl)-3-(4-fluoro-2-pyridyl)imidazo[1,2-b]pyridazine (18 mg, 0.068 mmol), DIPEA (26.4 mg, 35.6 µl, 0.204 mmol) and N-[(4,4-difluoro-5-methyl-3-piperidyl)methyl]methanesulfonamide (24.8 mg, 0.102 mmol) were added to NMP (225 μl) and heated at 150°C for 13 h After cooling, the crude reaction mixture was filtered and purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-[[1-[2-[6-(difluoromethyl)imidazo[ 1,2-b]pyridazin-3-yl]-4-pyridyl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]methanesulfonamide (2.2 mg, 6.8%).

[001351] The following compounds were prepared using a methodology similar to that described in Example 18:

N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-4,4-difluoro-5-methylpiperidin-3-yl) methyl)methanesulfonamide II-93;

N-((4-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-6-methylmorpholin-2-yl)methyl)methanesulfonamide II-94 ;

N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)-4,4-difluoropiperidin-3-yl)methyl)methanesulfonamide II -103;

N-(1-(4-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide II-105;

(S)-N-((4-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II- 110;

N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)piperidin-3-yl)methyl)methanesulfonamide II-125;

1-(4-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-4-yl)piperazin-1-yl)ethanone II-127.

Example 19: 6-(Difluoromethyl)-3-(6-(1-(methylsulfonyl)azepan-4-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine, II-14

Step 1: 6-(Difluoromethyl)-3-[6-(2,3,6,7-tetrahydro-1H-azepin-4-yl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine

[001352] 3-(6-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (100 mg, 0.355 mmol), tert-butyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,6,7-tetrahydroazepine-1-carboxylate (172.2 mg, 0.533 mmol) and aqueous solution of K ₂ CO ₃ (888 μl 2 M, 1.776 mmol) were combined in 1,4-dioxane (1.5 ml) and the mixture was degassed (×2 cycles vacuum - N ₂ ). Pd(dppf)Cl ₂ DCM (14.5 mg, 0.018 mmol) was added and the mixture was re-degassed (×2 cycles), then heated at 130°C for 45 min in a microwave oven. The reaction mixture was partitioned between EtOAc and water. The organic extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc/PE gradient elution). The pure fractions were concentrated to give a yellow solid. The solid was taken up in DCM (2 ml) and TFA (1 ml) was added. After 1 hour at ambient temperature, the reaction mixture was concentrated in vacuo to give 6-(difluoromethyl)-3-[6-(2,3,6,7-tetrahydro-1H-azepin-4-yl)pyrimidin-4-yl] imidazo[1,2-b]pyridazine (120 mg, 99%); MS m/z: 343.0 (M+H) ⁺ .

Step 2: 6-(Difluoromethyl)-3-(6-(1-(methylsulfonyl)-2,3,6,7-tetrahydro-1H-azepin-4-yl)pyrimidin-4-yl)imidazo[1,2 -b]pyridazine

[001353] DIPEA (170 mg, 229.1 μl, 1.315 mmol) was added to 6-(difluoromethyl)-3-[6-(2,3,6,7-tetrahydro-1H-azepin-4-yl)pyrimidin- 4-yl]imidazo[1,2-b]pyridazine (90 mg, 0.263 mmol) in NMP (0.5 ml). The solution was cooled in an ice bath and methanesulfonyl chloride (30.1 mg, 20.35 μL, 0.263 mmol) was added. After 5 min, the reaction was stopped by adding water. The reaction mixture was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluant) and the pure fractions were combined and concentrated to give 6-(difluoromethyl)-3-[6-(1-methylsulfonyl-2 ,3,6,7-tetrahydroazepin-4-yl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine as a tan solid (39 mg, 35%); MS m/z: 421.0 (M+H) ⁺ .

Step 3: 6-(Difluoromethyl)-3-[6-(1-methylsulfonylazepan-4-yl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine

[001354] 6-(Difluoromethyl)-3-[6-(1-methylsulfonyl-2,3,6,7-tetrahydroazepin-4-yl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine (39 mg, 0.093 mmol) was suspended in MeOH (5 ml). The mixture was degassed (×5 cycles vacuum - N ₂ ), then Pd on C, wet, Degussa (1.9 mg, 0.018 mmol) was added and the mixture was degassed with N ₂ (×5 cycles). The reaction mixture was hydrogenated for 16 hours at ambient temperature with H ₂ supplied from a cylinder. The catalyst was filtered off and the filtrate was concentrated in vacuo to obtain 6-(difluoromethyl)-3-(6-(1-(methylsulfonyl)azepan-4-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine as a pale -yellow solid (17.6 mg, 43%).

[001355] The following enantiomers were prepared using a methodology similar to that described in Example 19 and isolated using chiral SFC:

(R)-6-(Difluoromethyl)-3-(6-(1-(methylsulfonyl)azepan-4-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine and (S)-6-( Difluoromethyl)-3-(6-(1-(methylsulfonyl)azepan-4-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine; II-275 and II-276 (in no particular order).

Example 20: 6-(Difluoromethyl)-3-(6-(1-(methylsulfonyl)piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine, II-21

Step 1: 6-(Difluoromethyl)-3-(6-(1,2,5,6-tetrahydropyridin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine

[001356] 3-(6-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (100 mg, 0.355 mmol), tert-butyl-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (109.8 mg, 0.355 mmol) and aqueous solution of K ₂ CO ₃ (888 µl 2 M, 1.776 mmol) were combined in 1,4-dioxane (1.5 ml). Pd(dppf)Cl ₂ .DCM (14.5 mg, 0.018 mmol) was added and the mixture was degassed (×2 vacuum - N ₂ cycles), then the reaction mixture was heated at 130°C for 45 min in a microwave oven. The reaction mixture was partitioned between EtOAc and water. The organic extract was washed with brine, dried and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% EtOAc/PE gradient elution). The pure fractions were concentrated in vacuo, the residue was taken up in DCM (2 ml) and TFA (607.4 mg, 410 µl, 5.326 mmol) was added. The reaction mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was loaded into an SCX-2 cartridge and washed with DCM-MeOH mixtures. The product was eluted with 2 M NH ₃ in MeOH. The filtrate was concentrated in vacuo to give 6-(difluoromethyl)-3-(6-(1,2,5,6-tetrahydropyridin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine (55 mg , 47%); MS m/z: 329.2 (M+H) ⁺ .

Step 2: 6-(Difluoromethyl)-3-(6-(piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine

[001357] Pd on C, wet, Degussa (45.4 mg, 0.426 mmol) was added to 6-(difluoromethyl)-3-[6-(1,2,3,6-tetrahydropyridin-5-yl)pyrimidin-4 -yl]imidazo[1,2-b]pyridazine (200 mg, 0.61 mmol) and the mixture was dissolved in MeOH (26 ml). The mixture was degassed (×5 cycles), then hydrogenated for 16 hours (H ₂ under pressure from a cylinder). The catalyst was filtered off and the filtrate was evaporated in vacuo to give 6-(difluoromethyl)-3-(6-(piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine; MS m/z: 331.3 (M+H) ⁺ .

Step 3: 6-(Difluoromethyl)-3-(6-(1-(methylsulfonyl)piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine

[001358] To a solution of 6-(difluoromethyl)-3-(6-(piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine (7.7 mg, 0.023 mmol) and DIPEA ( 20.2 µl, 0.116 mmol) in acetonitrile (0.2 ml), methanesulfonyl chloride (2.7 mg, 2 µl, 0.023 mmol) was added and the mixture was stirred at ambient temperature for 1 hour. The reaction was stopped with water and purified by chromatography with reverse phase (C18, MeCN/water/0.05% TFA as eluent) to give 6-(difluoromethyl)-3-(6-(1-(methylsulfonyl)piperidin-3-yl)pyrimidin-4-yl) imidazo[1,2-b]pyridazine (6 mg, 58%).

[001359] The following compound was prepared using a methodology similar to that described in Example 20:

6-(Difluoromethyl)-3-(6-(1-(methylsulfonyl)pyrrolidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-250.

[001360] The following compounds were prepared in accordance with Step 1 and Step 2 of Example 20:

6-(Difluoromethyl)-3-(6-(3,6-dihydro-2H-pyran-4-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-357;

6-(Difluoromethyl)-3-(6-tetrahydropyran-4-ylpyrimidin-4-yl)imidazo[1,2-b]pyridazine II-358.

Example 21: 6-(Difluoromethyl)-3-(5-(7-(methylsulfonyl)-1,7-diazaspiro[3.5]nonan-1-yl)pyridin-3-yl)imidazo[1,2-b]pyridazine , II-42

Step 1: 3-(5-Bromopyridin-3-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine

[001361] Mixture of 6-(difluoromethyl)-3-iodimidazo[1,2-b]pyridazine (250 mg, 0.847 mmol), 3-bromo-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyridine (200.5 mg, 0.706 mmol), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (57.7 mg, 0.071 mmol) and Na ₂ CO ₃ (706 μl 2 M, 1.412 mmol) in THF (3.5 ml) was degassed with nitrogen for 10 min. The suspension was heated at 65°C for 20 hours. The reaction mixture was cooled to ambient temperature and partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give 3-(5-bromopyridin-3-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine as a light brown solid, which was used for next stage without additional purification; MS m/z: 325.0 (M+H) ⁺ .

Step 2: 6-(Difluoromethyl)-3-(5-(7-(methylsulfonyl)-1,7-diazaspiro[3.5]nonan-1-yl)pyridin-3-yl)imidazo[1,2-b]pyridazine

[001362] Mixture of 3-(5-bromo-3-pyridyl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (50 mg, 0.154 mmol), 7-methylsulfonyl-1,7-diazaspiro[3.5] nonane (47.1 mg, 0.231 mmol), Cs ₂ CO ₃ (100.2 mg, 0.308 mmol), Pd ₂ (dba) ₃ (7.0 mg, 0.008 mmol) and Xantphos (8.9 mg, 0.015 mmol ) in 1,4-dioxane (737 µl) was degassed with nitrogen. The suspension was then heated at 120°C for 16 hours. After cooling to ambient temperature, the reaction mixture was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 6-(difluoromethyl) -3-(5-(7-(methylsulfonyl)-1,7-diazaspiro[3.5]nonan-1-yl)pyridin-3-yl)imidazo[1,2-b]pyridazine (3.41 mg, 3% ).

[001363] The following compounds were prepared using a methodology similar to that described in Example 21:

N-((1-(5-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl)piperidin-3-yl)methyl)methanesulfonamide II-87;

6-(Difluoromethyl)-3-(5-(2-(methylsulfonyl)-2,6-diazaspiro[3.5]nonan-6-yl)pyridin-3-yl)imidazo[1,2-b]pyridazine II-101 ;

1-(4-(5-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl)piperazin-1-yl)ethanone II-171.

Example 22: N-((1-(5-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-2-methylpyridin-3-yl)piperidin-3-yl)methyl)methanesulfonamide , II-49

Step 1: 3-(5-Bromo-6-methylpyridin-3-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine and 3-(5-bromo-2-methylpyridin-3-yl)-6 -(difluoromethyl)imidazo[1,2-b]pyridazine

[001364] A mixture of tributyl-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]stannane (104 mg, 0.227 mmol), 3,5-dibromo-2-methylpyridine (62.6 mg, 0.250 mmol) and PdCl ₂ (PPh ₃ ) ₂ (15.9 mg, 0.023 mmol) in DMF (1.5 ml) were degassed with nitrogen and then heated at 80°C for 16 hours. The mixture was diluted with EtOAc and washed successively saturated aqueous solutions of NH ₄ Cl, NaHCO ₃ and brine. The organic extract was dried (MgSO ₄ ) and concentrated in vacuo to obtain a mixture of 3-(5-bromo-6-methylpyridin-3-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine and 3-(5- bromo-2-methylpyridin-3-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine as a yellow solid, which was used in the next step without further purification.

Step 2: N-((1-(5-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-2-methylpyridin-3-yl)piperidin-3-yl)methyl)methanesulfonamide and N-((1-(5-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-methylpyridin-3-yl)piperidin-3-yl)methyl)methanesulfonamide

[001365] Mixture of 3-(5-bromo-6-methylpyridin-3-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine and 3-(5-bromo-2-methylpyridin-3-yl) -6-(difluoromethyl)imidazo[1,2-b]pyridazine, N-(3-piperidylmethyl)methanesulfonamide (27.2 mg, 0.141 mmol), Pd ₂ (dba) ₃ (3.4 mg, 0.006 mmol), Xantphos (6.8 mg, 0.012 mmol) and Cs ₂ CO ₃ (76.8 mg, 0.236 mmol) in 1,4-dioxane (589 μl) were degassed with nitrogen. The suspension was then heated at 120°C for 16 hours. The reaction mixture was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 2 separable regioisomeric products. Pure fractions were lyophilized to give N-((1-(5-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-2-methylpyridin-3-yl)piperidin-3-yl)methyl )methanesulfonamide (4 mg, 3.8%) and N-((1-(5-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-methylpyridin-3-yl) piperidin-3-yl)methyl)methanesulfonamide (2.3 mg, 2.0%).

[001366] The following compounds were prepared using a methodology similar to that described in Example 22:

6-(Difluoromethyl)-3-(6-methyl-5-(7-(methylsulfonyl)-1,7-diazaspiro[3.5]nonan-1-yl)pyridin-3-yl)imidazo[1,2-b] pyridazine II-44;

N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-5-methylpyridin-4-yl)piperidin-3-yl)methyl)methanesulfonamide II-53 .

Example 23: 1-(4-(3-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)phenyl)piperazin-1-yl)ethanone, II-150

Step 1: 6-(Difluoromethyl)-3-(3-(piperazin-1-yl)phenyl)imidazo[1,2-b]pyridazine

[001367] Mixture of 6-(difluoromethyl)-3-iodimidazo[1,2-b]pyridazine (82 mg, 0.278 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)phenyl)piperazine (80 mg, 0.278 mmol), Pd(PPh ₃ ) ₄ (16.1 mg, 0.014 mmol) and Na ₂ CO ₃ (416.8 μl 2 M, 0.834 mmol) in 1,4-dioxane (1.4 ml) was degassed with N ₂ and then heated at 80°C for 16 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give 6-(difluoromethyl)-3-(3-piperazin-1-ylphenyl)imidazo[1,2-b]pyridazine as a yellow oil, which was used in the next step without additional cleaning; MS m/z: 330.2 (M+H) ⁺ .

Step 2: 1-(4-(3-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)phenyl)piperazin-1-yl)ethanone

[001368] Acetyl chloride (32.7 mg, 29.6 μl, 0.417 mmol) and DMAP (1.7 mg, 0.014 mmol) were added sequentially to a solution of 6-(difluoromethyl)-3-(3-piperazin-1-ylphenyl) imidazo[1,2-b]pyridazine (91.6 mg, 0.278 mmol) and Et ₃ N (112.5 mg, 155 μl, 1.112 mmol) in DCM (2 ml) and the mixture was stirred at ambient temperature for 1 h. MeOH was added and then the reaction mixture was concentrated in vacuo. The reaction mixture was purified by reverse phase chromatography (C18, MeCN/water 0.05% TFA as eluent) to give 1-(4-(3-(6-(difluoromethyl)imidazo[1,2-b]pyridazin- 3-yl)phenyl)piperazin-1-yl)ethanone (20.3 mg, 13%).

[001369] The following compound was prepared using a methodology similar to that described in Example 23:

6-Chloro-3-(2-phenylpyridin-4-yl)imidazo[1,2-b]pyridazine II-27.

Example 24: N-((1-(2-Cyano-5-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)phenyl)piperidin-3-yl)methyl)methanesulfonamide, II- 82

[001370] N-(3-Piperidylmethyl)methanesulfonamide (150 mg, 0.78 mmol), 4-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-fluorobenzonitrile (75 mg , 0.26 mmol) and K ₂ CO ₃ (71.9 mg, 0.52 mmol) were combined in DMF (5 ml) and heated at 90°C for 16 hours. The solid was filtered and the filtrate was purified by chromatography with reverse phase (C18, MeCN/water 0.05% TFA as eluent) to obtain N-((1-(2-cyano-5-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3- yl)phenyl)piperidin-3-yl)methyl)methanesulfonamide (46 mg, 37%).

Example 25: N-((1-(2-Cyano-5-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl)piperidin-3-yl)methyl) methanesulfonamide, II-117

[001371] 5-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-3-fluoropyridin-2-carbonitrile (40 mg, 0.138 mmol), N-(3-piperidylmethyl)methanesulfonamide ( 53.2 mg, 0.277 mmol) and DIPEA (96.4 µl, 0.553 mmol) were heated in NMP (800 µl) at 120°C for 4 hours. The reaction mixture was purified by reverse phase chromatography (C18, MeCN/water 0.05% TFA as eluent) to obtain N-((1-(2-cyano-5-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl) piperidin-3-yl)methyl)methanesulfonamide (27.5 mg, 31%).

Example 26: N-((1-(2-(Aminomethyl)-5-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl)piperidin-3-yl) methyl)methanesulfonamide, II-73

[001372] MeOH (0.8 ml) and HCl (114.2 µl 12 M, 1.371 mmol) were added to N-[[1-[2-cyano-5-[6-(difluoromethyl)imidazo[1,2- b]pyridazin-3-yl]-3-pyridyl]-3-piperidyl]methyl]methanesulfonamide (40 mg, 0.087 mmol) and Pd(OH) ₂ on carbon (12.2 mg, 0.087 mmol). The suspension was stirred under excess hydrogen pressure (under pressure from a cylinder) for 6 hours, then the catalyst was filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water 0.05% TFA as eluent) to give N-((1-(2-(aminomethyl)-5-(6-(difluoromethyl )imidazo[1,2-b]pyridazin-3-yl)pyridin-3-yl)piperidin-3-yl)methyl)methanesulfonamide (15.2 mg, 24%).

Example 27: N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-methoxypyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide , II-142 and N-((1-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-oxo-1,6-dihydropyridin-2-yl)piperidine -3-yl)methyl)methanesulfonamide, II-141

And

[001373] N-(3-Piperidylmethyl)methanesulfonamide (34.6 mg, 0.18 mmol), 3-(2-chloro-6-methoxy-4-pyridyl)-6-(difluoromethyl)imidazo[1,2- b]pyridazine (28.0 mg, 0.09 mmol) and DIPEA (46.5 mg, 62.7 μl, 0.36 mmol) were heated in NMP (700 μl) at 190°C for 16 h. The mixture was purified with using reverse phase chromatography (C18, MeCN/water 0.05% TFA as eluent) to obtain N-((1-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl )-6-methoxypyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide (16.5 mg, 28%) and N-((1-(4-(6-(difluoromethyl)imidazo[1,2- b]pyridazin-3-yl)-6-oxo-1,6-dihydropyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide (11.9 mg, 21%).

[001374] The following compounds were prepared using a methodology similar to that described in Example 27:

(S)-N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-oxo-1,6-dihydropyridin-2-yl)piperidin- 3-yl)methyl)methanesulfonamide II-111;

(S)-N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-6-methoxypyridin-2-yl)piperidin-3-yl)methyl) methanesulfonamide II-120.

Example 28: N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-4,4-difluoropiperidin-3-yl)methyl )-N-hydroxymethanesulfonamide, II-131 and

2-(4,4-difluoro-3-(methylsulfonamidomethyl)piperidin-1-yl)-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-1-oxide, II -132

And

[001375] N-[[1-[4-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]-2-pyridyl]-4,4-difluoro-3-piperidyl]methyl] methanesulfonamide (50 mg, 0.106 mmol) (II-153) and m-CPBA (20 mg, 0.106 mmol) were combined in DCM (15 ml) and stirred at ambient temperature for 2.5 h. The solvent was removed in vacuo and the residue purified by reverse phase chromatography (C18, MeCN/water 0.05% TFA as eluent) to give N-[[1-[4-[6-(difluoromethyl)imidazo[1,2-b]pyridazine-3 -yl]-2-pyridyl]-4,4-difluoro-3-piperidyl]methyl]-N-hydroxymethanesulfonamide (2.4 mg) and N-[[1-[4-[6-(difluoromethyl)imidazo[1 ,2-b]pyridazin-3-yl]-1-oxidopyridin-1-ii-2-yl]-4,4-difluoro-3-piperidyl]methyl]methanesulfonamide (2.2 mg)

Example 29: N-((4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-yl)methyl)methanesulfonamide ,II-98

[001376] To a solution of (4-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1-methylpiperazin-2-yl)methanol (17 mg , 0.045 mmol, was synthesized in accordance with a procedure similar to that used in example 5), tert-butyl-N-methylsulfonylcarbamate (16 mg, 0.082 mmol) and PPh ₃ (37 mg, 0.141 mmol) in THF (1 ml) were added dropwise DEAD (15 μl, 0.095 mmol) and the reaction mixture was stirred at ambient temperature under nitrogen for 18 hours. The solution was partitioned between DCM and saturated aqueous NaHCO ₃ solution. The organic layer was dried and concentrated in vacuo. The residue was taken up in DCM (1 ml) and TFA (1 ml) and stirred at ambient temperature for 3 hours, then concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-((4-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazine -3-yl)pyridin-2-yl)-1-methylpiperazin-2-yl)methyl)methanesulfonamide (10 mg, 49%).

Example 30: 2-(4-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1H-pyrazol-1-yl)ethanol, II- 113

[001377] (2-Chloro-4-pyridyl)boronic acid (64 mg, 0.407 mmol) was added to a solution of 6-(difluoromethyl)-3-iodimidazo[1,2-b]pyridazine (100 mg, 0.339 mmol), a complex 1,1'-bis(diphenylphosphino)ferrocene palladium(II) chloride with dichloromethane (27.7 mg, 0.034 mmol) and Na ₂ CO ₃ (508.5 μl 2 M, 1.017 mmol) in 1,4-dioxane (6 ml ) and the mixture was heated at 70°C for 16 hours. After cooling to ambient temperature, 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was added to the mixture. pyrazol-1-yl]ethanol (40.4 mg, 0.169 mmol), then Pd(PPh ₃ ) ₄ (19.6 mg, 0.017 mmol). The mixture was heated in a microwave oven for 30 min at 140°C, then concentrated in vacuo and the residue purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 2-(4- (4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1H-pyrazol-1-yl)ethanol (4.5 mg, 3.7%) .

Example 31: 1-(4-(4-(6-(Trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone, II-223

Step 1: 1-(4-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethanone

[001378] Acetyl chloride (280 μl, 3.938 mmol) was added to a solution of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (750 mg, 2.59 mmol) and Et ₃ N (900 μl, 6.46 mmol) in DCM (7.5 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The residue was immediately purified by passing it through cartridge 10 d Florisil eluting with 0 to 50% EtOAc/petroleum ether. The pure fractions were combined and concentrated in vacuo to give 1-[4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazin-1-yl ]ethanone (693.3 mg, 81%) as an off-white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.16 (dd, J=4.8, 0.9 Hz, 1H), 6.98 (s, 1H), 6.85 (dd, J= 4.8, 0.7 Hz, 1H), 3.55-3.52 (m, 6H), 3.48-3.46 (m, 2H), 2.04 (s, 3H), 1.31 (s, 12H); MS m/z: 332.2 (M+H) ⁺ .

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

[001379] Mixture of 3-iodo-6-(trifluoromethyl)imidazo[1,2-b]pyridazine (45.4 mg, 0.145 mmol), 1-[4-[4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazin-1-yl]ethanone (40 mg, 0.121 mmol), Pd(PPh ₃ ) ₄ (7 mg, 0.006 mmol) and Na ₂ CO ₃ (185 µl 2 M) in 1,4-dioxane (1.2 ml) and H ₂ O (0.3 ml) was stirred at 80°C for 18 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed in nitrogen flow. The residue was dissolved in DMSO and purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). Pure fractions were collected, passed through a sodium bicarbonate cartridge, and freeze-dried to yield 1-(4-(4-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazine -1-yl)ethanone (14.7 mg, 31%).

Example 32: N-((1-(4-(6-Methylimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide, II-183

[001380] N-(3-Piperidylmethyl)methanesulfonamide (42.1 mg, 0.219 mmol), 3-(2-fluoro-4-pyridyl)-6-methylimidazo[1,2-b]pyridazine (25 mg, 0.109 mmol ) and DIPEA (42.5 mg, 57.2 μl, 0.328 mmol) were combined in NMP (830 μl) and heated at 140°C in a sealed tube for 16 h. The crude mixture was purified using reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to obtain N-((1-(4-(6-methylimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3 -yl)methyl)methanesulfonamide (15 mg, 17%).

[001381] The following compounds were prepared using a methodology similar to that described in Example 32:

N-((1-(4-(6-(Methylamino)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide II-179;

N-((4-(4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholin-2-yl)methyl)methanesulfonamide II-184;

1-(4-(4-(6-Methylimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone II-193;

2-(4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)hexahydro-1H-pyrido[1,2-a]pyrazin-6(2H)-one II- 207.

Example 33: 1-(4-(4-(6-(Hydroxymethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone, II-185

Step 1: Ethylimidazo[1,2-b]pyridazine-6-carboxylate

[001382] 2-Bromo-1,1-diethoxyethane (16.55 g, 12.63 mL, 84 mmol) was dissolved in hydrogen bromide (3.52 mL 48% w/v, 20.88 mmol) and stirred at 120°C for 30 min. The reaction mixture was allowed to cool to ambient temperature and EtOH (100 mL) was added, followed by NaHCO ₃ (3.196 g, 38.04 mmol) and ethyl 6-aminorpyridazine-3-carboxylate (2 g, 12 mmol). The resulting mixture was stirred at 80°C for 1.5 hours. The dark brown reaction mixture was allowed to cool to ambient temperature and concentrated under reduced pressure to give a dark brown gum. This material was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc (3×20 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a brown oil, which was purified by column chromatography (silica, 3% MeOH in EtOAc) to give a brown solid. This material was recrystallized from EtOAc/hexane mixtures to give ethyl imidazo[1,2-b]pyridazine-6-carboxylate as a light brown powder (1.1 g, 48%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (s, 1H), 8.28 (d, J=9.5 Hz, 1H), 7.98 (d, J=1.2 Hz , 1H), 7.73 (d, J=9.5 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H ).

Step 2: Ethyl 3-iodimidazo[1,2-b]pyridazine-6-carboxylate

[001383] Ethyl imidazo[1,2-b]pyridazine-6-carboxylate (500 mg, 2.615 mmol) was dissolved in 1 M iodine monochloride (9.153 mL 1 M, 9.153 mmol) in a high-pressure tube and cooled in an ice bath. Pyridine (2.5 mL) was slowly added dropwise and a dark yellow solid began to precipitate from the reaction mixture immediately after addition was completed. This mixture was stirred at 50°C for 48 hours, then allowed to cool to ambient temperature, diluted with DCM and washed with saturated Na ₂ S ₂ O ₃ solution. The aqueous layer was extracted with DCM (3×20 ml) and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to give a bright yellow solid. This material was triturated with ether and the suspended solid was collected by filtration and washed with pentane (3 x 2 ml) to obtain ethyl 3-iodimidazo[1,2-b]pyridazine-6-carboxylate as a bright yellow powder (689.8 mg, 83%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J=9.4 Hz, 1H), 8.10 (s, 1H), 7.76 (d, J=9.4 Hz , 1H), 4.46 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).

Step 3: 3-(2-(4-Acetylpiperazin-1-yl)pyridin-4-yl)imidazo[1,2-b]pyridazin-6-carboxylic acid

[001384] A mixture of ethyl 3-iodimidazo[1,2-b]pyridazine-6-carboxylate (114.9 mg, 0.362 mmol), 1-[4-[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazin-1-yl]ethanone (100 mg, 0.302 mmol, see example 31, step 1), Pd(PPh ₃ ) ₄ (18 mg, 0.016 mmol) and Na ₂ CO ₃ (454.8 µl 2 M, 0.910 mmol) in 1,4-dioxane (1.5 ml) and H ₂ O (500 µl) were stirred at 80°C for 22 hours. The reaction the mixture was cooled to ambient temperature and the solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO and TFA and purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). Pure fractions were collected and lyophilized to yield 3-[2-(4-acetylpiperazin-1-yl)-4-pyridyl]imidazo[1,2-b]pyridazine-6-carboxylic acid as a yellow solid (72.9 mg , 49%).

Step 4: 1-(4-(4-(6-(Hydroxymethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone, II-185

[001385] Et ₃ N (50 μl, 0.359 mmol) was added to a suspension of 3-[2-(4-acetylpiperazin-1-yl)-4-pyridyl]imidazo[1,2-b]pyridazine-6-carboxylic acid ( salt with TFA) (68 mg, 0.137 mmol) in THF (5 ml) and the mixture was cooled to -20°C. Isobutyl chloroformate (27 µl, 0.208 mmol) was added and the reaction mixture was stirred at this temperature for 30 minutes. Sodium borohydride (8 mg, 0.211 mmol) was added followed by methanol (2 ml) and the reaction mixture was stirred at -20°C for a further 30 minutes. The reaction was stopped by adding saturated aqueous NaHCO ₃ solution and allowed to warm to ambient temperature. Water was added to dissolve the solids and the mixture was extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated in vacuo. The material was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 1-(4-(4-(6-(hydroxymethyl)imidazo[1,2-b]pyridazin- 3-yl)pyridin-2-yl)piperazin-1-yl)ethanone as a white solid (22.8 mg, 35%).

[001386] The following compounds were prepared using a methodology similar to Step 3 described in Example 33:

1-(4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)-1,4-diazepan-5-one II-187;

(S)-1-(4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-carboxamide II-189;

4-(4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholine II-194;

6-Chloro-3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)imidazo[1,2-b]pyridazine II-195;

1-(4-(4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone II-208;

6-Chloro-3-(2-(piperazin-1-yl)pyridin-4-yl)imidazo[1,2-b]pyridazine II-220.

Example 34: N-(((2S,5R)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylmorpholine-2 -yl)methyl)methanesulfonamide, II-197 and N-(((2R,5S)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4- yl)-5-methylmorpholin-2-yl)methyl)methanesulfonamide, II-234

Step 1: (4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylmorpholin-2-yl)methylmethanesulfonate.

[001387] Under an N ₂ atmosphere, Et ₃ N (200 μL, 1.43 mmol) and methanesulfonyl chloride (80 μL, 1.03 mmol) were added sequentially to an ice-cooled solution of [4-[6-[6-(difluoromethyl)imidazo [1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-methylmorpholin-2-yl]methanol (300 mg, 0.79 mmol, prepared according to a methodology similar to that described in Example 1) in DCM (5 ml). The mixture was stirred for 5 minutes at 0°C, then the ice bath was removed and the suspension was stirred at ambient temperature. After 18 hours, DMF (2 ml) was added, followed by Et ₃ N (200 µl, 1.43 mmol) and methanesulfonyl chloride (80 µl, 1.03 mmol) and the mixture was stirred at ambient temperature for 24 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO ₃ solution. The combined organics were dried (MgSO ₄ ), filtered and concentrated in vacuo and immediately used in the next step.

Step 2: N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylmorpholin-2-yl)methyl)methanesulfonamide .

[001388] DMF (5 ml), methanesulfonamide (300 mg, 3.15 mmol) and solid K ₂ CO ₃ (500 mg, 3.62 mmol) were added to the crude material obtained in step 1 and the reaction mixture was stirred at 80 °C for 3 days in N ₂ atmosphere. The crude mixture was first purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent), then the stereoisomers were separated by chiral SFC to give N-(((2S,5R)-4-(6 -(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylmorpholin-2-yl)methyl)methanesulfonamide II-197 (33 mg, 9.1% ) and N-(((2R,5S)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylmorpholine-2- yl)methyl)methanesulfonamide II-234 (27 mg, 7.4%).

[001389] The following compounds were prepared using a methodology similar to that described in Example 34:

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methyl)methanesulfonamide II-345 ;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methyl)methanesulfonamide II-346 ;

N-((7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-oxa-7-azaspiro[2.5]octane-5- yl)methyl)methanesulfonamide II-375;

N-((7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-oxa-7-azaspiro[2.5]octane-5- yl)methyl)methanesulfonamide II-383;

N-((7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-oxa-7-azaspiro[2.5]octane-5- yl)methyl)methanesulfonamide II-384;

(S)-(((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-yl)methyl)imino )dimethyl-λ6-sulfanone II-410;

N-((6-Cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II- 440;

N-((6-Cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II- 441;

N-((6-Cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II- 443;

N-((6-Cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide II- 444;

N-((3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl) methyl)methanesulfonamide II-447;

N-[[4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3,6,6-trimethylmorpholin-2-yl]methyl] methanesulfonamide II-458;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(2-methoxyethoxy)piperidin-3-yl)methyl )methanesulfonamide II-549;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-(2-methoxyethoxy)piperidin-3-yl)methyl )methanesulfonamide II-550;

N-((1-(tert-Butyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2- yl)methyl)methanesulfonamide II-559.

Example 35: N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,3-dimethylpiperazin-2-yl)methyl )methanesulfonamide, II-312 (mixture of stereoisomers),

N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,3-dimethylpiperazin-2-yl)methyl)methanesulfonamide, II-363 (one stereoisomer) and N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,3-dimethylpiperazin- 2-yl)methyl)methanesulfonamide, II-364 (one stereoisomer)

one stereosomer one stereosomer

[001390] Mixture of N-[[4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-methylpiperazin-2-yl]methyl] methanesulfonamide (500 mg, 1 mmol, prepared according to a methodology similar to that described in Example 1), formic acid (2 ml 50% w/w, 24.3 mmol) and formaldehyde (2 ml 37% w/v ., 24.65 mmol) in MeOH (2 ml) in a sealed vessel was stirred at 100°C. After 12 h, the mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). Pure fractions were freeze-dried to give N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,3-dimethylpiperazin-2- yl)methyl)methanesulfonamide II-312.

[001391] Stereoisomers were separated using chiral SFC to give N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,3 -dimethylpiperazin-2-yl)methyl)methanesulfonamide II-363 (58.9 mg, 69%) and N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3- yl)pyrimidin-4-yl)-1,3-dimethylpiperazin-2-yl)methyl)methanesulfonamide II-364 (63.3 mg, 74%).

[001392] The following compounds were prepared using a methodology similar to that described in Example 35:

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethyl-3-methylpiperazin-2-yl)methyl) methanesulfonamide II-340;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,6-dimethylpiperazin-2-yl)methyl)methanesulfonamide II -418;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,5-dimethylpiperazin-2-yl)methyl)methanesulfonamide II -423;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,3,6-trimethylpiperazin-2-yl)methyl) methanesulfonamide II-448;

(S)-1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-yl)cyclopropan-1 -ol II-459;

N-((1-Cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl) methanesulfonamide II-463;

N-(1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-yl)ethyl)methanesulfonamide II -473;

N-(1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-yl)ethyl)methanesulfonamide II -474;

N-((1-Cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl) methanesulfonamide II-478 (one stereoisomer, isolated using chiral SFC);

N-((1-Cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl)methyl) methanesulfonamide II-479 (one stereoisomer, isolated using chiral SFC);

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-yl)acetamide II-492;

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-yl)ethan-1-ol II- 514;

2-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1,3-dimethylpiperazin-2-yl)ethan-1-ol II-536.

Example 36: 2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-6-sulfonamide, II -284;

[001393] Mixture of 3-(6-(2,6-diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (50 mg, 0 .13 mmol was prepared according to a procedure similar to that described in Example 59) and the sulfonamide (129 mg, 1.34 mmol) in 1,4-dioxane (2 ml) was heated in an Anton-Parr microwave oven at 120°C for 30 min. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 2-(6-(6-(difluoromethyl)imidazo[1,2-b ]pyridazin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-6-sulfonamide II-284 (4 mg, 6.6%).

[001394] The following compounds were prepared using a methodology similar to that described in Example 36:

2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane-8-sulfonamide II -285;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-sulfonamide II-286 ;

1-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-1-methylsulfuric acid diamide II -311;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H) -sulfonamide II-332;

6-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-2-sulfonamide II-333;

8-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-oxa-2,8-diazaspiro[3.5]nonane-2-sulfonamide II -334;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)octahydro-6H-pyrrolo[3,4-b]pyridine-6-sulfonamide II- 335;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)octahydro-6H-pyrrolo[2,3-c]pyridine-6-sulfonamide II- 344;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)sulfuric acid diamide II-347;

6-(Difluoromethyl)-3-[6-[2-methyl-3-[(sulfamoylamino)methyl]-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine II-387.

Example 37: 3-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-1 diamide, 1-dimethylsulfuric acid, II-348

[001395] [1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]methanamine (7.5 mg, 0.02 mmol was prepared according to a procedure similar to that used in Example 59) and DIPEA (8.1 mg, 11 µl, 0.062 mmol) was combined in NMP (1 ml) and N,N-dimethylsulfamoyl chloride (3 mg, 2.24 µl) was added , 0.021 mmol). The mixture was kept overnight at ambient temperature, then purified by reverse phase chromatography (C18, MeCN/water - 0.1% ammonium hydroxide as eluent) to give diamide 3-((1-(6-(6- (difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-1,1-dimethylsulfuric acid II-348 as a white solid (3.67 mg, 37%).

[001396] The following compounds were prepared using a methodology similar to that described in Example 37:

3-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)-1,1-dimethylsulfur diamide acids II-349;

1-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-3-methylsulfuric acid diamide II -385;

1-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)-3-methylsulfuric acid diamide II -386;

1-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)sulfuric acid diamide II-415.

Example 38: N-[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-2-methyl-3-piperidyl]methanesulfonamide, II- 377 and II-374

[001397] To a solution of 1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-amine (prepared according to the procedure similar to that used in Example 59), Et ₃ N (108 mg, 150 μL, 1.06 mmol) was added to DCM (2 ml), followed by methanesulfonyl chloride (57 mg, 39 μL, 0.50 mmol). The mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-[1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin- 3-yl]pyrimidin-4-yl]-2-methyl-3-piperidyl]methanesulfonamide II-377 and N-[1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3- yl]pyrimidin-4-yl]-2-methyl-3-piperidyl]methanesulfonamide II-374.

[001398] The following compounds were prepared using a methodology similar to that described in Example 38:

2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-8-(methylsulfonyl)-2,8-diazaspiro[4.5]decane II-54 ;

7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-(methylsulfonyl)-2,7-diazaspiro[4.5]decane II-56 ;

6-(Difluoromethyl)-3-(6-(1-(methylsulfonyl)-1,6-diazaspiro[3.5]nonan-6-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-70 ;

6-(Difluoromethyl)-3-(6-(8-(methylsulfonyl)-3,8-diazabicyclo[4.2.0]octan-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II -181;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)(4-(methylsulfonyl)piperazin-1-yl) methanone II-206;

N-(((3R,4R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-methylpyrrolidin-3-yl) methyl)methanesulfonamide II-237;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-methylpyrrolidin-3-yl)methyl)methanesulfonamide II-238 ;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)cyclopropanesulfonamide II-262;

8-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-(methylsulfonyl)-5-oxa-2,8-diazaspiro[3.5] nonane II-273;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-9-(methylsulfonyl)-1-oxa-4,9-diazaspiro[5.5] undecane II-287;

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-8-(methylsulfonyl)-1-oxa-4,8-diazaspiro[5.5] undecane II-288;

N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)oxetane-3-sulfonamide II- 289;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanamine II-409 (using only step 1 of Example 38 );

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperidin-3-yl)methanesulfonamide II-412;

(S)-N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)oxetane-3-sulfonamide II -419;

(S)-1-Cyclopropyl-N-(1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide II -420;

(S)-N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethanesulfonamide II-421;

(S)-1-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-3-methylsulfuric acid diamide II-422;

N-(1-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)cyclopropyl)methanesulfonamide II-439;

(S)-N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)cyclopropanesulfonamide II-442;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperidin-3-yl)methanesulfonamide II-445;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperidin-3-yl)methanesulfonamide II-446;

8-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methyl-2,5,8-triazaspiro[3.5]nonan-2- sulfonamide II-535;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-yl)methanesulfonamide II-551;

N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-yl)methanesulfonamide II-552.

Example 39: 1-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-N-methylmethanesulfonamide, II- 236

[001399] Mixture of [1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]methanesulfonamide (8 mg, prepared according to method similar to that used in example 1), K ₂ CO ₃ (2.6 mg, 0.019 mmol) and iodomethane (2.7 mg, 1.2 μl, 0.019 mmol) in DMF (0.5 ml) were stirred at ambient temperature medium for 16 hours. K ₂ CO ₃ (2.6 mg, 0.019 mmol) and iodomethane (2.7 mg, 1.2 μl, 0.019 mmol) were added and the mixture was stirred at ambient temperature for another 6 hours. Insoluble the material was filtered off and the filtrate was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 1-(1-(6-(6-(difluoromethyl)imidazo[1,2-b ]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-N-methylmethanesulfonamide II-236 (1.2 mg, 2.9%).

Example 40: N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-fluoro-4-methylpiperidin-3-yl )methyl)methanesulfonamide, II-350, II-388, II-389

II-350 II-388 II-389

[001400] Solution of N-[[1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-4-hydroxy-4-methyl-3- piperidyl]methyl]methanesulfonamide (200 mg, 0.43 mmol) in DCM (10 ml) was cooled to -78°C under nitrogen, then DAST (150 μl, 1.13 mmol) was added dropwise. The mixture was stirred at this temperature for 10 minutes, then the cooling bath was removed. The mixture was carefully poured into cold saturated aqueous NaHCO ₃ solution, then extracted with EtOAc (×2). The combined organic layers were dried (MgSO ₄ ), filtered and evaporated. The residue was purified by reverse phase chromatography (C18, MeCN/water - 0.1% ammonium hydroxide eluent) to give a racemic mixture of N-((1-(6-(6-(difluoromethyl)imidazo[1,2- b]pyridazin-3-yl)pyrimidin-4-yl)-4-fluoro-4-methylpiperidin-3-yl)methyl)methanesulfonamide II-350, which was further purified by chiral SFC to give enantiomerically pure N-((1 -(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-fluoro-4-methylpiperidin-3-yl)methyl)methanesulfonamide II-388 ( 19 mg, 9.5%) and N-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4-fluoro-4 -methylpiperidin-3-yl)methyl)methanesulfonamide II-389 (6.6 mg, 3.3%).

Example 41: N-(((2S,6R)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(trifluoromethyl) morpholin-2-yl)methyl)methanesulfonamide, II-331

[001401] To a solution of [(2S,6S)-4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-6-(trifluoromethyl)morpholine -2-yl]methanol (68.4 mg, 0.16 mmol, prepared in accordance with a procedure similar to that used in example 1), tert-butyl-N-methylsulfonylcarbamate (45 mg, 0.23 mmol) and PPh ₃ ( 125 mg, 0.47 mmol) in THF (5 mL), DEAD (55 μL, 0.35 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature under nitrogen for 16 h. The solvent was removed in vacuo and the residue was recycled dissolved in DCM (5 ml) and TFA (1 ml, 13 mmol). The reaction mixture was stirred at ambient temperature for 4.5 hours and the solvent was removed in vacuo. The substance was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). Fractions containing the product were collected, passed through a sodium bicarbonate cartridge and freeze-dried to yield N-[[(2S,6S)-4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazine-3 -yl]pyrimidin-4-yl]-6-(trifluoromethyl)morpholin-2-yl]methyl]methanesulfonamide II-331 (46.3 mg, 57%) as a white solid.

[001402] The following compounds were prepared using a methodology similar to that described in Example 41:

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-ethylmorpholin-2-yl)methyl)methanesulfonamide II-267 ;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-ethylmorpholin-2-yl)methyl)methanesulfonamide II-269 ;

N-(((2R,6S)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(trifluoromethyl)morpholine-2 -yl)methyl)methanesulfonamide II-306;

N-(((2S,6S)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(trifluoromethyl)morpholine-2 -yl)methyl)methanesulfonamide II-307;

N-(((2R,6R)-4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(trifluoromethyl)morpholine-2 -yl)methyl)methanesulfonamide II-330.

Example 42: 3-(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-1-yl)-3-oxopropanenitrile, II- thirty

[001403] A solution of 6-(difluoromethyl)-3-(6-(piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine (20 mg, 0.06 mmol, prepared using step 1 and step 2 of Example 20) in MeCN (0.6 ml) was added to a solution of 2-cyanoacetic acid (5.2 mg, 0.06 mmol), (dimethylamino)-N,N-dimethyl(3H-[1,2 ,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (25.3 mg, 0.066 mmol) and DIPEA (42 µl, 0.24 mmol) in MeCN (0.4 ml) and reaction mixture stirred at ambient temperature for 16 hours. The reaction mixture was immediately purified using reverse phase (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give 3-(3-(6-(6-( difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-1-yl)-3-oxopropanenitrile II-30 (11 mg, 44%).

[001404] The following compounds were prepared using a methodology similar to that described in Example 42:

(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-1-yl)(1-methyl-1H-pyrazol-4-yl )methanone II-41;

1-(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-1-yl)ethan-1-one II-222;

1-(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-1-yl)ethan-1-one II-253.

Example 43: 6-(Difluoromethyl)-3-(6-(1-(oxetan-3-yl)piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine, II-180

[001405] 6-(Difluoromethyl)-3-(6-(piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine (20 mg, 0.06 mmol, prepared using step 1 and step 2 of example 20) were dissolved in THF (200 μl) and oxetan-3-one (6.5 mg, 0.091 mmol) was added. After 10 minutes, the reaction mixture was cooled to approximately 10°C, then sodium triacetoxyborohydride (25.7 mg, 0.12 mmol) was added in portions and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was partitioned between saturated aqueous NaHCO ₃ and EtOAc. The layers were separated and the organic layer was washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was immediately purified using reverse phase (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give 6-(difluoromethyl)-3-(6-(1-(oxetan-3-yl)piperidin- 3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-180 (11 mg, 38%).

[001406] Enantiomers were separated using chiral SFC to obtain:

(R)-6-(Difluoromethyl)-3-(6-(1-(oxetan-3-yl)piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine and (S) -6-(Difluoromethyl)-3-(6-(1-(oxetan-3-yl)piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine; II-241 and II-242 (in no particular order).

Example 44: 3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-N-(2-hydroxyethyl)piperidine-1-carboxamide, II- 178

[001407] bis-(Trichloromethyl) carbonate (14.4 mg, 0.048 mmol) was added to a solution of 6-(difluoromethyl)-3-(6-(piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2 -b]pyridazine (20 mg, 0.06 mmol, prepared using step 1 and step 2 of example 20) and DIPEA (39 mg, 53 μl, 0.30 mmol) in DCM (750 μl) and the reaction mixture was stirred at temperature environment for 10 minutes. Ethanolamine (4.4 mg, 4.4 μL, 0.072 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 16 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO ₃ and the organic layer was dried and concentrated in vacuo . The residue was immediately purified using reverse phase (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give 3-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3- yl)pyrimidin-4-yl)-N-(2-hydroxyethyl)piperidine-1-carboxamide II-178 (10 mg, 38%).

[001408] The following compound was prepared using a methodology similar to that described in Example 44:

3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-N-(2-hydroxyethyl)pyrrolidine-1-carboxamide II-254.

Example 45: 6-(Difluoromethyl)-3-(6-(1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine, II-48

[001409] 1-Methysulfonylethylene (8.8 mg, 7.3 μl, 0.083 mmol) was added to a solution of 6-(difluoromethyl)-3-(6-(piperidin-3-yl)pyrimidin-4-yl)imidazo[1 ,2-b]pyridazine (25 mg, 0.075 mmol, prepared using Step 1 and Step 2 of Example 20) in ethanol (625 μl) and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). Pure fractions were lyophilized to obtain 6-(difluoromethyl)-3-(6-(1-(2-(methylsulfonyl)ethyl)piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II- 48 (6.9 mg, 16%).

[001410] The following compound was prepared using a methodology similar to that described in Example 45:

6-(Difluoromethyl)-3-(6-(1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-255.

Example 46: N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethyl-3-methylpiperazin-2-yl )methyl)methanesulfonamide, II-542 and N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethyl-3 -methylpiperazin-2-yl)methyl)methanesulfonamide, II-543

(one stereoisomer) (one stereoisomer) II-542 II-543

[001411] N-[[4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-methylpiperazin-2-yl]methyl]methanesulfonamide II-313 (200 mg, 0.44 mmol) was dissolved in DMF (1.8 ml), then ethyl iodide (138 mg, 71 μl, 0.88 mmol) was added, then potassium carbonate (92 mg, 0.66 mmol) . The solution was then heated at 60°C for 7 hours. The reaction mixture was diluted with DMSO (3 ml) and the insoluble material was filtered off. The filtrate was immediately purified using reverse phase (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b] pyridazin-3-yl)pyrimidin-4-yl)-1-ethyl-3-methylpiperazin-2-yl)methyl)methanesulfonamide II-482 (130 mg, 62%).

[001412] Enantiomers were separated using chiral SFC to give:

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-ethyl-3-methylpiperazin-2-yl)methyl) methanesulfonamide II-542 (50 mg, 47%) and N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1- ethyl-3-methylpiperazin-2-yl)methyl)methanesulfonamide II-543 (45 mg, 41%).

[001413] The following compounds were prepared using a methodology similar to that described in Example 46:

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-(2-methoxyethyl)-3-methylpiperazin-2- yl)methyl)methanesulfonamide II-494;

N-((1-(Cyclopropylmethyl)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl) methyl)methanesulfonamide II-495;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-isopropyl-3-methylpiperazin-2-yl)methyl) methanesulfonamide II-507;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methyl-1-(methyl-d3)piperazine-2 -yl)methyl)methanesulfonamide II-523;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methyl-1-(methyl-d3)piperazine-2 -yl)methyl)methanesulfonamide II-561;

N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methyl-1-(methyl-d3)piperazine-2 -yl)methyl)methanesulfonamide II-562.

Example 47: N-[[3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]phenyl]methyl]methanesulfonamide, II-576

[001414] A mixture of Pd(PPh ₃ ) ₄ (8 mg, 0.007 mmol), Na ₂ CO ₃ (213 μl 2 M, 0.42 mmol), [3-(methanesulfonamidomethyl)phenyl]boronic acid (42.3 mg, 0.185 mmol) and 3-(6-chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (40 mg, 0.14 mmol) in 1,4-dioxane (2.4 ml ) was stirred at 60°C for 1 hour. The reaction mixture was partitioned between DCM and water, the layers were separated and the organic layer was dried and concentrated in vacuo. The residue was triturated with 2 ml MeOH. The insoluble material was filtered and collected to give N-[[3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]phenyl]methyl]methanesulfonamide II-576 (9 mg, 14%).

[001415] The following compounds were prepared according to a procedure similar to that used in Example 47:

3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-methylbenzaldehyde;

[3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-methylphenyl]methanol II-655;

1-(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)phenyl)ethan-1-ol II-656;

3-(6-(3-Bromophenyl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine;

6-(Difluoromethyl)-3-[6-[3-(methylsulfanylmethyl)phenyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine;

3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylbenzaldehyde;

3-[6-(1-Tetrahydropyran-4-ylpyrazol-4-yl)pyrimidin-4-yl]-6-(trifluoromethyl)imidazo[1,2-b]pyridazine II-708;

6-(Difluoromethyl)-3-[6-(1-tetrahydropyran-4-ylpyrazol-4-yl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine II-709.

Example 48: N-[[3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-2-methylphenyl]methyl]methanesulfonamide, II-575

Step 1: [3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-2-methylphenyl]methanol

[001416] Sodium borohydride (1.7 mg, 0.044 mmol) was added to the 3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-2 suspension α-methylbenzaldehyde (32 mg, 0.09 mmol, prepared according to a procedure similar to that used in Example 47) in MeOH (2 ml) and DCM (1 ml). After 1 min, the reaction was stopped with 1 drop of 1 M HCl and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were dried (MgSO ₄ ) and concentrated in vacuo to give [3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4 -yl]-2-methylphenyl]methanol (32 mg, 99%).

Step 2: N-[[3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-2-methylphenyl]methyl]methanesulfonamide, II-575

[001417] Isopropyl-N-isopropoxycarbonyliminocarbamate (30 μl, 0.15 mmol) in DCM (0.5 ml) was slowly added to the [3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazine suspension -3-yl]pyrimidin-4-yl]-2-methylphenyl]methanol (31 mg, 0.08 mmol), tert-butyl-N-methylsulfonylcarbamate (33 mg, 0.17 mmol) and PS-PPh ₃ (80 mg 2.11 mmol/g, 0.17 mmol) in DCM (3 ml) and the mixture was stirred at ambient temperature for 2 hours. Additional PS-PPh ₃ (80 mg 2.11 mmol/g, 0.17) was added mmol) and tert-butyl-N-methylsulfonylcarbamate (33 mg, 0.17 mmol), then a solution of isopropyl-N-isopropoxycarbonyliminocarbamate (30 μl, 0.15 mmol) in DCM (0.5 ml) and the reaction mixture was stirred at temperature environment for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). The pure fractions were combined and concentrated and the remaining solid was dried overnight at 60°C using a piston dryer to give N-[[3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3- yl]pyrimidin-4-yl]-2 - methylphenyl]methyl]methanesulfonamide (13 mg, 35%).

Example 49: ((3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)benzyl)imino)dimethyl-λ6-sulfanone, II-595

[001418] A mixture of (3-bromophenyl)methyliminodimethyloxo-λ6-sulfane (139 mg, 0.53 mmol, prepared according to a procedure similar to that used in Example 47), potassium acetate (260 mg, 2.7 mmol), 4, 4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (202 mg, 0.8 mmol) and Pd(dppf)Cl ₂ .DCM (44 mg, 0.05 mmol) in DMF (3 ml) were stirred at 100°C for 1 hour. The mixture was concentrated in vacuo and the residue was dissolved in 1,4-dioxane (4 ml ). Na ₂ CO ₃ (795 μl 2 M, 1.6 mmol), Pd(PPh ₃ ) ₄ (30.6 mg, 0.03 mmol) and 3-(6-chloropyrimidin-4-yl)-6-( difluoromethyl)imidazo[1,2-b]pyridazine (134 mg, 0.48 mmol) and the reaction mixture was stirred at 100°C for 4 hours. The mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN /water/0.05% TFA as eluent) to obtain ((3-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)benzyl)imino )dimethyl-λ6-sulfanone (14 mg, 5%).

Example 50: [3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]phenyl]iminodimethyloxo-λ6-sulfane, II-599

[001419] 3-[6-(3-Bromophenyl)pyrimidin-4-yl]-6-(difluoromethyl)imidazo[1,2-b]pyridazine (110 mg, 0.27 mmol) (prepared according to the procedure similar to that used in example 47), iminodimethyloxo-λ6-sulfane (32 mg, 0.34 mmol), di-tert-butyl-(2-phenylphenyl)phosphane (23 mg, 0.078 mmol), tris(dibenzylideneacetone)dipalladium(0) (25 mg, 0.027 mmol), 2-methylpropan-2-olate (sodium salt) (39 mg, 0.4 mmol) in 1,4-dioxane (4 ml) was degassed ( _N2 ), then heated at 90°C within 15 min. The mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). The pure fractions were combined and freeze-dried to give [3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]phenyl]iminodimethyloxo-λ6-sulfane (41 mg , 36%).

Example 51: N-[1-[3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]phenyl]ethyl]methanesulfonamide, II-609

[001420] When stirred to a solution of 1-[3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]phenyl]ethanol (130 mg, 0. 35 mmol, prepared in accordance with a procedure similar to that used in example 47), tert-butyl-N-methylsulfonylcarbamate (138.2 mg, 0.7 mmol) and PS-PPh ₃ (334 mg, 0.7 mmol) was added DIAD (103 μl, 0.5 mmol) and the mixture was stirred at ambient temperature for 16 h. Additionally, tert-butyl-N-methylsulfonylcarbamate (138 mg, 0.7 mmol), PS-PPh ₃ (334 mg 2, 12 mmol/g, 0.7 mmol) and DIAD (103 μl, 0.5 mmol) and the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in MeOH and DCM and loaded into an SCX-2 cartridge, washed with DCM/MeOH mixtures. The product was eluted with 2 M NH ₃ in MeOH and the main eluent was concentrated in vacuo. DCM (5 ml) was added to the residue, followed by TFA (3 ml). The mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-[1-[3-[6-[6-(difluoromethyl)imidazo[1,2-b ]pyridazin-3-yl]pyrimidin-4-yl]phenyl]ethyl]methanesulfonamide (12.9 mg, 7%)

[001421] The following compound was prepared according to a procedure similar to that used in Example 51:

N-(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylbenzyl)methanesulfonamide II-612.

Example 52: [3-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-methylphenyl]methyliminodimethyloxo-λ6-sulfane, II-610 and 3-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-N-(dimethyl(oxo)-λ6-sulfanylidene)-5-methylbenzamide, II -611

[001422] A solution of 3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-methylbenzaldehyde (130 mg, 0.36 mmol, prepared in following a procedure similar to that used in Example 47), iminodimethyl-λ6-sulfanone (100 mg, 1 mmol) and NaBH(OAc) ₃ (150 mg, 0.7 mmol) in DCE (5 ml) were stirred at ambient temperature in for 4 hours. Additional iminodimethyl-λ6-sulfanone (100 mg, 1 mmol) and NaBH(OAc) ₃ (150 mg, 0.7 mmol) were added and the mixture was stirred at ambient temperature for 4 hours. Iminodimethyl-λ6- sulfanone (99.4 mg, 1.1 mmol) and NaBH(OAc) ₃ (150 mg, 0.7 mmol) and the mixture was stirred at ambient temperature for an additional 16 hours. The mixture was partitioned between DCM and saturated aqueous NaHCO ₃ . The layers were separated and the organic layer was dried and concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give [3-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3- yl]pyrimidin-4-yl]-5-methylphenyl]methyliminodimethyloxo-λ6-sulfane II-610 (30.8 mg, 14%) and 3-(6-(6-(difluoromethyl)imidazo[1,2-b] pyridazin-3-yl)pyrimidin-4-yl)-N-(dimethyl(oxo)-λ6-sulfanylidene)-5-methylbenzamide II-611 (5 mg, 3%).

Example 53: 6-(Difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfonylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine, II-587 and 6-(difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfonylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine, II-588

II-588 II-625 II-626

Step 1: 6-(Difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfanylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine

[001423] Sodium methanethiolate (683 mg, 9.7 mmol) was added to a solution of [1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]- 2,5-dimethyl-3-piperidyl]methylmethanesulfonate (757 mg, 1.6 mmol, prepared according to a procedure similar to that described in synthesis 149) in EtOH (11 ml) and stirred at 0°C. The cooling bath was removed and the reaction mixture was heated at 60°C overnight. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 5% DCM/MeOH eluting gradient) to give 6-(difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfanylmethyl)- 1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine (520 mg, 77%).

Step 2: 6-(Difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfonylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine

[001424] mCPBA (44 mg, 0.18 mmol) was added portionwise to an ice-cold solution of 6-(difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfanylmethyl)-1-piperidyl]pyrimidine-4 -yl]imidazo[1,2-b]pyridazine (30 mg, 0.07 mmol) in DCM (615 µl). The reaction mixture was stirred for 4 hours, then the reaction was stopped with an aqueous solution of Na ₂ S ₂ O ₃ (20 ml). The mixture was partitioned between DCM and water and the organic layer was washed with NaHCO ₃ (×2), dried (MgSO ₄ ) and concentrated in vacuo. The residue was immediately purified using reverse phase (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give 6-(difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfonylmethyl) -1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine II-587 (5 mg, 15%) and 6-(difluoromethyl)-3-[6-[2,5-dimethyl-3 -(methylsulfonylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine II-588 (1.9 mg, 5.9%).

[001425] Enantiomers of II-587 were separated using chiral SFC to give:

6-(Difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfonylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine II-625 and

6-(difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfonylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine II-626.

[001426] The following compound was prepared according to a procedure similar to that used in Example 53:

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methyl-2-((methylsulfonyl)methyl)morpholine II-426.

Example 54: 1-(4-(4-(6-Methoxyimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one trifluoroacetate, II-204

Step 1: 6-Chloro-3-(2-(piperazin-1-yl)pyridin-4-yl)imidazo[1,2-b]pyridazine

[001427] To a solution of 6-chloro-3-iodimidazo[1,2-b]pyridazine (440 mg, 1.57 mmol) in 1,4-dioxane (6 ml) and H ₂ O (2 ml) was added 1- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine (350 mg, 1.21 mmol), Pd(PPh ₃ ) ₄ (98 mg, 0.084 mmol) and Na ₂ CO ₃ (1.82 ml 2 M, 3.63 mmol). The reaction mixture was stirred at 100°C for 45 minutes. The mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO ₃ and brine. The organic layer was dried (MgSO ₄ ) and concentrated to give 6-chloro-3-(2-(piperazin-1-yl)pyridin-4-yl)imidazo[1,2-b]pyridazine, which was immediately used in the next step.

Step 2: 1-(4-(4-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one

[001428] To a solution of 6-chloro-3-(2-piperazin-1-yl-4-pyridyl)imidazo[1,2-b]pyridazine (700 mg, 2.22 mmol) in DCM (10 ml) was added N , N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (714 mg, 2.22 mmol), acetic acid (200 mg, 190 μl, 3.34 mmol) and triethylamine (450 mg , 620 µl, 4.45 mmol). The reaction mixture was stirred at ambient temperature for 3 hours and then at 100°C for 45 minutes. The mixture was diluted with EtOAc and washed successively with 10% aqueous citric acid and brine. The organic layer was dried (Na ₂ SO ₄ ) and concentrated to give a yellow oil, which was purified by column chromatography (silica, 5 to 15% MeOH/NH ₃ in DCM with gradient elution) to give 1-[4- [4-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-2-pyridyl]piperazin-1-yl]ethanone (760 mg, 96%) as a yellow solid; MS m/z: 357.2 (M+H) ⁺ .

Step 3: 1-(4-(4-(6-Methoxyimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one trifluoroacetate, II-204

[001429] To a solution of 1-[4-[4-(6-chloroimidazo[1,2-b]pyridazin-3-yl)-2-pyridyl]piperazin-1-yl]ethanone (50 mg, 0.14 mmol ) in MeOH (7 ml) was added NaOMe (22.7 mg, 0.42 mmol). The reaction mixture was stirred at 120°C for 90 min, then immediately purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 1-(4-(4-(6- methoxyimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one trifluoroacetate (1 mg, 1.4%).

Example 55: N-(((3S,5S)-4,4-Difluoro-1-(6-(6-(1-hydroxyethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4- yl)-5-methylpiperidin-3-yl)methyl)methanesulfonamide, II-337

Step 1: N-(((3S,5S)-1-(6-(6-acetylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5- methylpiperidin-3-yl)methyl)methanesulfonamide

[001430] N-(((3S,5S)-1-(6-(6-acetylimidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5- Methylpiperidin-3-yl)methyl)methanesulfonamide was prepared from 1-(3-(6-chloropyrimidin-4-yl)imidazo[1,2-b]pyridazin-6-yl)ethan-1-one using a procedure similar to that used in example 1; MS m/z: 480.1 (M+H) ⁺ .

Step 2: N-(((3S,5S)-4,4-Difluoro-1-(6-(6-(1-hydroxyethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4- yl)-5-methylpiperidin-3-yl)methyl)methanesulfonamide, II-337

[001431] NaBH ₄ (0.15 mg, 0.004 mmol) was added to the suspension of N-(((3S,5S)-1-(6-(6-acetylimidazo[1,2-b]pyridazin-3-yl)pyrimidine -4-yl)-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide (2 mg, 0.004 mmol) in MeOH (1 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was immediately purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-(((3S,5S)- 4,4-difluoro-1-(6-(6-(1-hydroxyethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)methyl) methanesulfonamide (1.8 mg, 69%).

[001432] The following compound was prepared according to a procedure similar to that used in Example 55:

N-(((2S)-4-(6-(6-(1-Hydroxyethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide trifluoroacetate II-338.

Example 56: [4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-methylmorpholin-2-yl]methanol, II-657

[001433] Mixture of (5-methylmorpholin-2-yl)methanol (250 mg, 1.906 mmol), 3-(6-chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (250 mg, 0.888 mmol) and DIPEA (300 µl, 1.722 mmol) in DMF (2 ml) were stirred at 90°C for 18 hours. The solution was diluted with DCM and saturated aqueous NaHCO ₃ solution. After stirring for 5 minutes, the organic layer was isolated using a phase separation cartridge and concentrated. Purification by column chromatography (silica, eluting with EtOAc/MeOH/petroleum ether) gave [4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl ]-5-methylmorpholin-2-yl]methanol (305 mg, 91%); MS m/z: 377.3 (M+H) ⁺ .

Example 57: 6-(Difluoromethyl)-3-[6-(2,5-dihydro-1H-pyrrol-3-yl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine, II-658

Step 1: tert-Butyl-3-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dihydro-1H-pyrrole-1 -carboxylate

[001434] 3-(6-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (300 mg, 1.07 mmol), tert-butyl-3-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (314 mg, 1.07 mmol) and 2 M aqueous solution of K ₂ CO ₃ (2.66 ml 2 M, 5.33 mmol) were combined in 1,4-dioxane (4.5 ml) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane complex (43 mg, 0.05 mmol) was added . The mixture was degassed and the reaction mixture was heated in a microwave oven at 130°C for 45 minutes. The reaction mixture was diluted with EtOAc and water and filtered. The layers were separated and the aqueous phase was extracted with EtOAc (×2). The combined organics were washed with brine, dried (MgSO ₄ ) and concentrated. Purification by column chromatography (silica, 50-100% ethyl acetate in petroleum ether with gradient elution) gave tert-butyl-3-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3 -yl)pyrimidin-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate as a fine white powder (150 mg, 32%); 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.30-9.15 (m, 1H), 8.82-8.67 (m, 2H), 8.58 (d, J=9.4 Hz , 1H), 7.76 (d, J=9.5 Hz, 1H), 7.42 (t, J=53.7 Hz, 1H), 7.13 (s, 1H), 4.55 (s , 2H), 4.38 (s, 2H), 1.52-1.40 (m, 9H); MS m/z: 415.1 (M+H) ⁺ .

Step 2: 6-(Difluoromethyl)-3-[6-(2,5-dihydro-1H-pyrrol-3-yl)pyrimidin-4-yl]imidazo[1,2-b]pyridazine

[001435] tert-Butyl-3-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dihydro-1H-pyrrole-1 α-carboxylate (150 mg, 0.32 mmol) was dissolved in DCM (6 ml) and TFA (1.2 ml, 16.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated in vacuo. The residue was passed through an SCX-2 cartridge, the product was eluted with 2 M ammonia in MeOH and the main wash solution was concentrated to give 6-(difluoromethyl)-3-(6-(2,5-dihydro-1H-pyrrol-3-yl)pyrimidin- 4-yl)imidazo[1,2-b]pyridazine as a pale yellow solid (100 mg, 100%); MS m/z: 315.0 (M+H) ⁺ .

Step 3: 6-(Difluoromethyl)-3-(6-pyrrolidin-3-ylpyrimidin-4-yl)imidazo[1,2-b]pyridazine II-658

[001436] Palladium (10% on carbon, 23.7 mg, 0.22 mmol) was added to 6-(difluoromethyl)-3-(6-(2,5-dihydro-1H-pyrrol-3-yl)pyrimidin- 4-yl)imidazo[1,2-b]pyridazine (100 mg, 0.32 mmol) and MeOH (12.8 ml) was added. The mixture was degassed and stirred with hydrogen supplied from a cylinder. After 16 h, the reaction mixture was filtered through celite and concentrated to give 6-(difluoromethyl)-3-[6-(2,5-dihydro-1H-pyrrol-3-yl)pyrimidin-4-yl]imidazo[1,2- b]pyridazine II-658 (100 mg, 85%).

[001437] The following compound was prepared according to a procedure similar to that used in Example 57:

6-(Difluoromethyl)-3-(6-(piperidin-3-yl)pyrimidin-4-yl)imidazo[1,2-b]pyridazine II-659.

Example 58: 1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl )ethan-1-one, II-539

Step 1: 1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl )ethan-1-one

[001438] 3-(6-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (101 mg, 0.36 mmol), 1-[4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-yl]ethanone (135 mg, 0.54 mmol) and 2 M saturated aqueous solution of K ₂ CO ₃ (900 µl 2 M, 1.80 mmol) was combined in 1,4-dioxane (1.5 ml). The mixture was degassed, Pd(dppf)Cl ₂ DCM (15 mg, 0.018 mmol) was added and the mixture was degassed again, then heated at 130°C for 45 min in a microwave oven. The reaction mixture was diluted with EtOAc and water and filtered through celite. The layers were separated and the aqueous phase was extracted with ethyl acetate (×2). The combined organics were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. The residue was dissolved in DMSO, filtered and purified by reverse phase chromatography (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give 1-[4-[6-[6-(difluoromethyl)imidazo[ 1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3,6-dihydro-2H-pyridin-1-yl]ethanone as a pale yellow solid (23 mg, 17%); MS m/z: 371.0 (M+H) ⁺ .

Step 2: 1-(4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-1-yl)ethan-1-one

[001439] Mixture of 1-[4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3,6-dihydro-2H-pyridin-1 -yl]ethanone (23 mg, 0.062 mmol) [mixture of isomers] and Pd on C, wet, Degussa (28 mg 10% w/w, 0.026 mmol) were stirred at ambient temperature with H ₂ supplied from a cylinder. After 3 hours, the catalyst was filtered through celite, the filtrate was concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give 1-(4-(6-( 6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl)ethan-1-one II-539 as white solids (8 mg, 32%)

Example 59: 3-[6-(2,8-Diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl]-6-(difluoromethyl)imidazo[1,2-b]pyridazine, II-660

Step 1: tert-Butyl-2-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonan-6 -carboxylate

[001440] 3-(6-Chloropyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine (60 mg, 0.21 mmol), tert-butyl-2,6-diazaspiro[3.5 ]nonane-6-carboxylate (96 mg, 0.43 mmol) and DIPEA (185 µl, 1.07 mmol) were combined in NMP (2 ml) and heated in the microwave for 35 min at 120°C, then cooled to ambient temperature and purified by reverse phase chromatography (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give tert-butyl-2-(6-(6-(difluoromethyl)imidazo[1, 2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-6-carboxylate, which was immediately used in the next step.

Step 2: 3-[6-(2,8-Diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl]-6-(difluoromethyl)imidazo[1,2-b]pyridazine, II-660

[001441] tert-Butyl-2-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.5]nonane-6 The β-carboxylate was dissolved in DCM (3 ml) and TFA (1 ml). After stirring for 2 hours at ambient temperature, the mixture was concentrated. The residue was taken up in MeOH, passed through bicarbonate SPE cartridges and concentrated to give 3-[6-(2,8-Diazaspiro[3.5]nonan-2-yl)pyrimidin-4-yl]-6-(difluoromethyl)imidazo[1 ,2-b]pyridazine as a white solid (100 mg, 100%); MS m/z: 372.1 (M+H) ⁺ .

[001442] The following compounds were prepared according to a procedure similar to that used in Example 59:

1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinoxalin-5-ol II-628;

(3S)-1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]piperidin-3-amine II-661;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)octahydro-1H-pyrido[3,4-b][1,4]oxazine II -662;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-amine II-663;

2-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-oxa-2,8-diazaspiro[3.5]nonane II-664;

3-[6-(3,3a,4,5,6,6a-Hexahydro-2H-pyrrolo[2,3-c]pyrrol-1-yl)pyrimidin-4-yl]-6-(difluoromethyl)imidazo[ 1,2-b]pyridazine II-665;

1-[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]-N-methylmethanamine II-666;

4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3,4a,5,6,7,7a-hexahydro-2H-pyrrolo[ 3,4-b][1,4]oxazine II-667;

3-[6-(2,6-Diazaspiro[3.5]nonan-6-yl)pyrimidin-4-yl]-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-668;

8-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-5-oxa-2,8-diazaspiro[3.5]nonane II-669;

3-[6-(2,3,4,4a,5,6,7,7a-Octahydropyrrolo[3,4-b]pyridin-1-yl)pyrimidin-4-yl]-6-(difluoromethyl)imidazo[ 1,2-b]pyridazine II-670;

[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]methanamine II-671;

[4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methanamine II-672;

2-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane II-673;

3-(6-(1,6-Diazaspiro[3.5]nonan-6-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-674;

7-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[4.5]decane II-675;

3-(6-(3,8-Diazabicyclo[4.2.0]octan-3-yl)pyrimidin-4-yl)-6-(difluoromethyl)imidazo[1,2-b]pyridazine II-677;

1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperidin-3-amine II-678;

3-[6-(2,3,3a,4,5,6,7,7a-Octahydropyrrolo[2,3-c]pyridin-1-yl)pyrimidin-4-yl]-6-(difluoromethyl)imidazo[ 1,2-b]pyridazine II-679;

1-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethan-1-amine II-680;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanamine II-681;

1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-4,4-difluoropiperidin-3-amine II-682.

4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-1-oxa-4,8-diazaspiro[5.5]undecane II-683.

Example 60: (((2S,3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidine -3-yl)methyl)(imino)(methyl)-λ6-sulfanone, II-607

Step 1: [1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-2,5-dimethyl-3-piperidyl]methylmethanesulfonate

[001443] Methanesulfonyl chloride (188 μl, 2.43 mmol) was added to the cooled solution of [1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]- 2,5-dimethyl-3-piperidyl]methanol (630 mg, 1.62 mmol) and triethylamine (452 μl, 3.24 mmol) in DCM (12.6 ml) and stirred under nitrogen atmosphere. After 15 min at 0°C, the reaction was stopped with a saturated aqueous solution of NaHCO ₃ . After stirring for 10 min, the layers were separated using a phase separation cartridge and the organic layer was concentrated to give [1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4- yl]-2,5-dimethyl-3-piperidyl]methylmethanesulfonate as a colorless oil, which was immediately used in the next step; MS m/z: 467.1 (M+H) ⁺ .

Step 2: 6-(Difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfanylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine

[001444] Sodium methanethiolate (683 mg, 9.74 mmol) was added to a solution of [1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]- 2,5-dimethyl-3-piperidyl]methylmethanesulfonate (757 mg, 1.62 mmol) in EtOH (11.2 ml) was stirred at 0°C. The cooling bath was removed and the reaction mixture was heated at 60°C for 16 hours, then cooled to ambient temperature and evaporated in vacuo. The residue was purified by column chromatography (silica, 0-5% MeOH in DCM, eluting gradient) to give 6-(difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfanylmethyl)-1 -piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine (520 mg, 77% in two stages); MS m/z: 419.3 (M+H) ⁺ .

Step 3: 6-(Difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfinylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine

[001445] mCPBA (276 mg, 1.12 mmol) was added to an ice-cold solution of 6-(difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfanylmethyl)-1-piperidyl]pyrimidine-4- yl]imidazo[1,2-b]pyridazine (520 mg, 1.24 mmol) in DCM (10.7 ml). After 5 min, the reaction was stopped with a saturated aqueous solution of Na ₂ S ₂ O ₃ (20 ml) and stirred for 5 min, then the layers were separated. The aqueous layer was extracted with DCM, then the combined organic layers were washed with saturated aqueous NaHCO ₃ (2×20 ml), dried (MgSO ₄ ) and concentrated to give 6-(difluoromethyl)-3-[6-[2,5-dimethyl -3-(methylsulfinylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine as a colorless resinous substance (530 mg, 98%); MS m/z: 435.3 (M+H) ⁺ .

Step 4: (((2S,3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidine -3-yl)methyl)(imino)(methyl)-λ6-sulfanone, II-607

[001446] 6-(Difluoromethyl)-3-[6-[2,5-dimethyl-3-(methylsulfinylmethyl)-1-piperidyl]pyrimidin-4-yl]imidazo[1,2-b]pyridazine (340 mg, 0.78 mmol), ammonium carbamate (244 mg, 3.13 mmol) and iodobenzene diacetate (756 mg, 2.35 mmol) were dissolved in MeOH (1.6 ml) and stirred in an open flask. After 40 minutes, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica, 0-10% MeOH in DCM gradient eluting) to give a mixture of four stereoisomers as a pale yellow solid. This solid was dissolved in DMSO and purified by reverse phase chromatography (C18, MeCN/water/0.1% NH ₄ OH as eluent). Pure fractions were lyophilized to obtain two sets of two isomers each.

[001447] Chiral resolution using SFC gave:

(((2S,3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3- yl)methyl)(imino)(methyl)-λ6-sulfanone II-607 as a yellow solid (25 mg, 23%); MS m/z: 450.1 (M+H) ⁺ .

(((2R,3R,5S)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3- yl)methyl)(imino)(methyl)-λ6-sulfanone II-604; MS m/z: 450.1 (M+H) ⁺ .

(((2R,3R,5S)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3- yl)methyl)(imino)(methyl)-λ6-sulfanone II-605; MS m/z: 450.1 (M+H) ⁺ and

(((2S,3S,5R)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3- yl)methyl)(imino)(methyl)-λ6-sulfanone II-606; MS m/z: 450.1 (M+H) ⁺ .

[001448] The following compounds were prepared using a procedure similar to that used in Example 60:

((1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-138;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-370;

((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylmorpholin-2-yl)methyl)(imino)(methyl) -λ6-sulfanone II-425;

(S)-(((2S,3S)-1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3- yl)methyl)(imino)(methyl)-λ6-sulfanone II-485;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)(imino)(methyl) -λ6-sulfanone II-486;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)(imino)(methyl) -λ6-sulfanone II-487;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methyl)(imino)(methyl) -λ6-sulfanone II-488;

(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)(imino)(methyl)-λ6-sulfanone II- 522;

(2-(1-(4-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl)ethyl)(imino)(methyl)- λ6-sulfanone II-104;

(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)phenyl)(imino)(methyl)-λ6-sulfanone II-580;

(3-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)benzyl)(imino)(methyl)-λ6-sulfanone II-598;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-636;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-637;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-638;

((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone II-639.

Example 61: 1-[4-[6-(6-Chloroimidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl]piperazin-1-yl]ethanone, II-590

[001449] N-Bromosuccinimide (30.5 mg, 0.17 mmol) was added to the 1-[4-[6-[(E)-2-ethoxyvinyl]pyrimidin-4-yl]piperazin-1-yl solution with stirring ]ethanone (45 mg, 0.16 mmol) in 1,4-dioxane (1 ml) and water (375 μl). The reaction mixture was stirred at ambient temperature for 1 hour, then a solution of 6-chloropyridazin-3-amine (21 mg, 0.16 mmol) in 1,4-dioxane (63 μl) was added. The reaction mixture was heated at 80°C for 16 hours, then cooled to ambient temperature and immediately purified using reverse phase (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give 1-[4- [6-(6-chlorimidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl]piperazin-1-yl]ethanone (0.9 mg, 2%).

Example 62: N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-hydroxypiperidin-3-yl)methyl)- N-methylmethanesulfonamide, II-235

[001450] NaH (4 mg, 0.1 mmol) was added to the ice-cooled suspension of N-[[1-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4 -yl]-5-hydroxy-3-piperidyl]methyl]methanesulfonamide (40 mg, 0.088 mmol, prepared according to the same procedure as in Example 1) in DMF (1 ml) and stirred under nitrogen. After 10 min, MeI (6 µl, 0.096 mmol) was added and the reaction mixture was stirred at ambient temperature for 18 h. The reaction was stopped by adding methanol (0.1 ml) and the crude mixture was purified by reverse phase chromatography (C18, MeCN /water/0.05% TFA as eluent) to obtain N-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)- 5-Hydroxypiperidin-3-yl)methyl)-N-methylmethanesulfonamide (30 mg, 47%).

[001451] The following compound was prepared according to a procedure similar to that used in Example 62:

(S)-N-((4-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)-N- methylmethanesulfonamide II-290.

Example 63: N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)azetidine-3- sulfonamide, II-272

Step 1: tert-Butyl-3-(N-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl )methyl)sulfamoyl)azetidine-1-carboxylate

[001452] DIPEA (65 μl, 0.38 mmol) and tert-butyl-3-chlorosulfonylasetidine-1-carboxylate (21 mg, 0.08 mmol) were added to the [1-[6-[6-(difluoromethyl)imidazo solution [1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]methanamine (30 mg, 0.08 mmol, prepared according to the same procedure as Example 59) in acetonitrile (600 µl). The reaction mixture was stirred at ambient temperature for 24 hours, then diluted in DMSO and purified by reverse phase chromatography (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give tert-butyl-3- (N-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)sulfamoyl)azetidine-1- carboxylate (50 mg, 100%); MS m/z: 579.1 (M+H) ⁺ .

Step 2: N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)azetidine-3- sulfonamide

[001453] TFA (148 mg, 100 μl, 1.3 mmol) was added to the solution of tert-butyl-3-(N-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazine -3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)sulfamoyl)azetidine-1-carboxylate (50 mg, 0.086 mmol) in DCM (1 ml) and the reaction mixture was stirred at ambient temperature for 45 min. The reaction mixture was concentrated in vacuo and the residue was loaded into an SCX-2 cartridge, washed with DCM/MeOH and the product eluted with 2 M NH ₃ in MeOH. The stock washes were concentrated in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.1% NH ₄ OH as eluent) to give N-((1-(6-(6-(difluoromethyl) imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)azetidine-3-sulfonamide (7.5 mg, 17%).

[001454] The following compound was prepared according to a procedure similar to that used in Example 63:

(S)-N-(1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)azetidine-3-sulfonamide II -435.

Example 64: 1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-N-(methylsulfonyl)piperidine-3-carboxamide, II-460

[001455] 3-(Ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine hydrochloride (9 mg, 0.046 mmol) was added to a suspension of methanesulfonamide (6 mg, 0.066 mmol), DMAP (12 mg, 0.1 mmol) and 1- [6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]piperidine-3-carboxylic acid (ditrifluoroacetate) (20 mg, 0.033 mmol, prepared according to the procedure similar to that used in Example 1) in CH ₃ CN (2 ml) and the mixture was stirred at ambient temperature for 24 hours. The solvent was removed in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.05 % TFA as eluent to obtain 1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-N-(methylsulfonyl)piperidine-3-carboxamide II -460 (14 mg, 64%).

Example 65: N-((1-(6-(6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-2-( dimethylamino)-N-(methylsulfonyl)acetamide, II-456

[001456] N-[[1-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-piperidyl]methyl]methanesulfonamide (50 mg, 0.114 mmol) was suspended in THF (2 ml) and NaH (9 mg, 0.23 mmol) was added. After 5 minutes, 2-bromoacetyl bromide (23 mg, 0.11 mmol) was added and the mixture was stirred at ambient temperature for 5 minutes. 2-bromoacetyl bromide (23 mg, 0.11 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 5 minutes. The reaction mixture was partitioned between saturated aqueous NH ₄ Cl and DCM. The organic layer was dried and concentrated in vacuo. The residue was dissolved in 2 M HNMe ₂ in THF (4 ml) and the mixture was stirred at ambient temperature for 5 min, then concentrated in vacuo. Purification by reverse phase chromatography (C18, MeCN/water/0.05% TFA eluent) gave N-((1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazine-3 -yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-2-(dimethylamino)-N-(methylsulfonyl)acetamide II-456 (15 mg, 14%).

Example 66: N-((1-Acetyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin-2-yl )methyl)methanesulfonamide, II-515

[001457] N-[[4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-3-methylpiperazin-2-yl]methyl]methanesulfonamide (25 mg, 0.055 mmol) was dissolved in DCM (550 µl), then triethylamine (9 mg, 12 µl, 0.083 mmol) was added, followed by acetyl chloride (5 mg, 5 µl, 0.072 mmol). The solution was stirred at ambient temperature for 30 minutes, then concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-[[1-acetyl-4-[6-[6-(difluoromethyl)imidazo[1,2 -b]pyridazin-3-yl]pyrimidin-4-yl]-3-methylpiperazin-2-yl]methyl]methanesulfonamide II-515 as a white solid (17 mg, 62%).

Example 67: 4-[6-[6-(Difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-1-imino-1,4-thiazinan-1-oxide, II -676

[001458] To a solution of 4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-1,4-thiazinan-1-oxide (166 mg, 0.45 mmol was prepared in accordance with a procedure similar to that used in example 1) carbamic acid (144 mg, 1.8 mmol) and iodobenzene diacetate (450 mg, 1.4 mmol) were added to MeOH (1.5 ml). The cloudy solution was stirred for 18 hours, then 2 ml of MeOH was added. After 5 days, 2 ml of DCM was added, followed by 2 ml of toluene and the mixture was heated at 60°C for 4 hours. The solution was filtered, the solvent was removed in vacuo and the residue was purified by reverse phase chromatography (C18, MeCN/water/0.1 % NH ₄ OH as eluent) and obtained 4-[6-[6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl]pyrimidin-4-yl]-1-imino-1,4- Thiazinan 1-oxide (tritrifluoroacetate) (6.2 mg, 2%).

Example 68: 1-[4-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethanone, III-1

[001459] Mixture of 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)-2-iodopyrazolo[1,5-a]pyrimidine (50 mg, 0.123 mmol), 1-piperazin-1-ylethanone (16 mg, 0.123 mmol) and DIPEA (32 mg, 43 μl, 0.245 mmol) in NMP (3 ml) were heated at 100°C in a microwave oven for 1 h. The mixture was immediately purified using reverse phase chromatography (C18, MeCN/ water/0.05%TFA as eluent). The desired fractions were combined in vacuo and the residue was dissolved in MeOH (10 ml). Pd on C, wet, Degussa (50 mg, 0.470 mmol) was added and the mixture was placed under a hydrogen cylinder atmosphere and stirred at ambient temperature for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give 1-[4-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin- 3-yl]pyrimidin-4-yl]piperazin-1-yl]ethanone (trifluoroacetate) as a white solid (1.7 mg, 3%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.54 (d, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.80 (d, 1H), 7 .55 (d, 1H), 7.35-7.07 (m, 1H), 3.90-3.61 (m, 8H), 2.08 (s, 3H); MS m/z: 374.1 (M+H) ⁺ .

[001460] The following compounds were prepared using a methodology similar to that described in Example 68:

N-[[1-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]-3-piperidyl]methyl]methanesulfonamide III-2;

1-[6-[5-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]-1,4-diazepan-5-one III-3.

Example 69: N-[[(2R)-4-[6-[5-(Difluoromethyl)-6-fluoropyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl ]methyl]methanesulfonamide, III-5

Step 1: N-[[(2R)-4-[6-[5-(Difluoromethyl)-6-fluoro-2-iodopyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholine -2-yl]methyl]methanesulfonamide

[001461] Mixture of 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)-6-fluoro-2-iodopyrazolo[1,5-a]pyrimidine (55 mg, 0.129 mmol), DIPEA (84 mg, 113 µl, 0.646 mmol) and N-[[(2R)-morpholin-2-yl]methyl]methanesulfonamide (30 mg, 0.154 mmol) in NMP (2 ml) were stirred at 80°C for 5 hours. The residue was immediately purified using reverse phase chromatography (C18, MeCN/water - 0.1% NH ₄ OH as eluent) to give N-[[(2R)-4-[6-[5-(difluoromethyl)-6-fluoro- 2-iodopyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide as an off-white solid, which was immediately used in the next step; MS m/z: 584.1 (M+H) ⁺ .

Step 2: N-[[(2R)-4-[6-[5-(Difluoromethyl)-6-fluoropyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl ]methyl]methanesulfonamide

[001462] N-[[(2R)-4-[6-[5-(Difluoromethyl)-6-fluoro-2-iodopyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholine -2-yl]methyl]methanesulfonamide (75 mg, 0.129 mmol) was suspended in MeOH (5 ml) and Pd on C, wet, Degussa (14 mg, 0.129 mmol) was added. The mixture was placed under a hydrogen cylinder atmosphere and stirred at ambient temperature for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-[[(2R)-4-[6-[5-(difluoromethyl)-6-fluoropyrazolo[ 1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide as a white solid (2.9 mg, 4%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.03 (d, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.77 (d, 1H), 7 .32 (t, 1H), 7.30 (t, 1H), 4.61-4.37 (m, 1H), 4.26 (s, 1H), 4.09-4.03 (m, 1H ), 3.65-3.55 (m, 2H), 3.16 (m, 3H), 2.96 (s, 3H), 2.95-2.87 (m, 1H); MS m/z: 458.1 (M+H) ⁺ .

[001463] The following compounds were prepared using a methodology similar to that described in Example 69:

N-[[(2S)-4-[6-[5-(Difluoromethyl)-6-fluoropyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl] methanesulfonamide III-10;

N-[[(3S,5S)-1-[6-[5-(Difluoromethyl)-6-fluoropyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]-4,4-difluoro -5-methyl-3-piperidyl]methyl]methanesulfonamide III-11.

Example 70: N-[[(2S)-4-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl] methanesulfonamide, III-4

Step 1: N-[[(2S)-4-[6-[2-Amino-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholine-2- yl]methyl]methanesulfonamide

[001464] DIPEA (436 mg, 587 μl, 3.37 mmol) was added to a solution of 3-(6-chloropyrimidin-4-yl)-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-2-amine ( 100 mg, 0.337 mmol) and N-[[(2S)-morpholin-2-yl]methyl]methanesulfonamide (72 mg, 0.371 mmol) in NMP (2 ml) and the mixture was stirred at 85°C for 16 hours. Reaction the mixture was cooled to ambient temperature and loaded onto a pre-wetted SCX-2 column. The column was washed with MeOH and the product was eluted with a 2 M solution of NH ₃ in MeOH. The eluent was concentrated in vacuo to give N-[[(2S)-4-[6-[2-amino-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholine -2-yl]methyl]methanesulfonamide as an off-white solid, which was immediately used in the next step; MS m/z: 455.2 (M+H) ⁺ .

Step 2: N-[[(2S)-4-[6-[5-(Difluoromethyl)-2-iodopyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl ]methyl]methanesulfonamide

[001465] NaNO ₂ (47 mg, 0.673 mmol) in water (0.5 ml) was slowly added to a solution of KI (140 mg, 0.842 mmol), p-toluenesulfonic acid (174 mg, 1.01 mmol) and N-[ [(2S)-4-[6-[2-Amino-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide ( 153 mg, 0.337 mmol) in acetonitrile (23 ml) and water (8 ml). The solution was stirred at ambient temperature for 4 hours, then further KI (140 mg, 0.842 mmol) and p-toluenesulfonic acid (174 mg, 1.01 mmol) in water (1 ml) were added. After 5 minutes, NaNO ₂ (47 mg, 0.673 mmol) in water (0.5 ml) was added and the mixture was stirred at ambient temperature for 16 hours. The reaction was stopped by adding saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ S ₂ O ₃ and the mixture was concentrated in vacuo. The aqueous phase was extracted with DCM (×3) and the combined organic extracts were dried (MgSO ₄ ), filtered and concentrated in vacuo. The crude mixture was purified by column chromatography (silica, DCM/MeOH as eluent, gradient mode) to give N-[[(2S)-4-[6-[5-(difluoromethyl)-2-iodopyrazolo[1. 5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide as an off-white solid, which was immediately used in the next step; MS m/z: 566.1 (M+H) ⁺ .

Step 3: N-[[(2S)-4-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl] methanesulfonamide, III-4

[001466] N-[[(2S)-4-[6-[5-(Difluoromethyl)-2-iodopyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl ]methyl]methanesulfonamide (190 mg, 0.337 mmol) was dissolved in MeOH (10 ml) and Pd on C, wet, Degussa (36 mg, 0.337 mmol) was added. The mixture was stirred with hydrogen supplied from a cylinder at ambient temperature for 30 minutes. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-[[(2S)-4-[6-[5-(Difluoromethyl)pyrazolo[1,5 -a]pyrimidin-3-yl]pyrimidin-4-yl]morpholin-2-yl]methyl]methanesulfonamide (bis-trifluoroacetate) as a white solid (6.4 mg, 3%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.58 (d, 1H), 9.08 (s, 1H), 8.79 (d, 1H), 7.81 (d, 1H), 7 .61 (d, 1H), 7.32 (t, 1H), 7.17 (t, 1H), 4.54 (s, 1H), 4.33 (s, 1H), 4.07 (ddd, 1H), 3.68-3.55 (m, 2H), 3.34-3.24 (m, 1H), 3.22-3.09 (m, 2H), 3.07-2.97 ( m, 1H), 2.97 (s, 3H); MS m/z: 440.2 (M+H) ⁺ .

Example 71: N-[[(3S,5S)-1-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]-4,4-difluoro -5-methyl-3-piperidyl]methyl]methanesulfonamide, III-12

[001467] 3-(6-Chloropyrimidin-4-yl)-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidine (13.2 mg, 0.047 mmol), N-[[(3S,5S)-4 ,4-difluoro-5-methyl-3-piperidyl]methyl]methanesulfonamide (11.4 mg, 0.047 mmol) and DIPEA (16.4 μL, 0.094 mmol) were heated in NMP (400 μL) at 90°C. After completion of the reaction, the mixture was cooled to ambient temperature, filtered and purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent) to give N-[[(3S,5S)-1- trifluoroacetate [6-[5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]-4,4-difluoro-5-methyl-3-piperidyl]methyl]methanesulfonamide (14, 7 mg, 47%).

[001468] The following compounds were prepared using a methodology similar to that described in Example 71:

N-[[1-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]-4,4-difluoro-2,5-dimethyl-3- piperidyl]methyl]methanesulfonamide III-13;

[1-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]-5-methyl-3-piperidyl]iminodimethyloxo-λ6-sulfane III-14.

Example 72: N-[[(2S)-4-[4-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-2-pyridyl]morpholin-2-yl]methyl]methanesulfonamide ,III-6

[001469] N-[[(2S)-Morpholin-2-yl]methyl]methanesulfonamide (44 mg, 0.227 mmol), 5-(difluoromethyl)-3-(2-fluoro-4-pyridyl)pyrazolo[1.5 -a]pyrimidine (40 mg, 0.151 mmol) and DIPEA (79 μl, 0.454 mmol) were heated in NMP (1 ml) by microwave radiation at 170°C for 2 h. The reaction mixture was cooled to ambient temperature and purified by chromatography with reverse phase (C18, MeCN/water - 0.1% NH ₄ OH as eluent) to give N-[[(2S)-4-[4-[5-(difluoromethyl)pyrazolo[1,5-a] pyrimidin-3-yl]-2-pyridyl]morpholin-2-yl]methyl]methanesulfonamide as a white solid (3.5 mg, 5%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.43 (d, 1H), 9.09 (s, 1H), 8.23-8.18 (m, 1H), 7.61 (s, 1H), 7.56 (d, 1H), 7.42 (d, 1H), 7.26-7.01 (m, 2H), 4.38-4.26 (m, 1H), 4.18 -4.07 (m, 1H), 4.02 (ddd, 1H), 3.69-3.55 (m, 2H), 3.14 (td, 2H), 3.02-2.88 (m , 4H), 2.72-2.59 (m, 1H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -116.51, - 116.62; MS m/z: 439.1 (M+H) ⁺ .

[001470] The following compound was prepared using a methodology similar to that described in Example 72:

N-[[1-[4-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]-2-pyridyl]-4,4-difluoro-5-methyl-3-piperidyl]methyl ]methanesulfonamide III-7.

Example 73: 1-[4-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethanone, III-8

[001471] To a solution of 3-bromo-5-(difluoromethyl)pyrazolo[1,5-a]pyrimidine (30 mg, 0.121 mmol) in 1,4-dioxane (1 ml) and water (333 μl) was added 1-[ 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazin-1-yl]ethanone (48 mg, 0.145 mmol), 2 M an aqueous solution of Na ₂ CO ₃ (182 μl, 0.363 mmol) and Pd(PPh ₃ ) ₄ (7 mg, 0.006 mmol) and the mixture was heated at 80°C for 16 hours. The reaction mixture was cooled to ambient temperature and purified using reverse phase chromatography (C18, MeCN/water - 0.1% NH ₄ OH as eluent) to obtain 1-[4-[6-[5-(difluoromethyl)pyrazolo[1,5-a]pyrimidine-3- yl]pyrimidin-4-yl]piperazin-1-yl]ethanone as a yellow solid (22 mg, 49%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.42 (d, 1H), 9.10 (s, 1H), 8.19 (dd, 1H), 7.61 (s, 1H), 7 .58-7.51 (m, 1H), 7.41 (d, 1H), 7.15 (t, 1H), 3.69-3.63 (m, 2H), 3.63-3.52 (m, 6H), 2.07 (s, 3H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -116.73, - 116.85; MS m/z: 373.1 (M+H) ⁺ .

Example 74: 1-[4-[6-[5-(Difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]piperazin-1-yl]ethanone, III-9

[001472] Mixture of 3-iodo-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (45 mg, 0.145 mmol), 1-[4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazin-1-yl]ethanone (40 mg, 0.121 mmol), Pd(PPh ₃ ) ₄ (7 mg, 0.006 mmol) and 2 M aqueous Na solution ₂ CO ₃ (185 µl, 0.370 mmol) in 1,4-dioxane (1.2 ml)/H ₂ O (0.3 ml) was stirred at 80°C for 18 hours. The reaction mixture was cooled to ambient temperature and the solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO and purified by reverse phase chromatography (C18, MeCN/water/0.05% TFA as eluent). Fractions were collected, passed through a sodium bicarbonate cartridge and lyophilized to yield 1-[4-[6-[5-(difluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]pyrimidin-4-yl]piperazin-1 -yl]ethanone as a yellow solid (15.9 mg, 34%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.55 (d, 1H), 9.18 (s, 1H), 8.22 (d, 1H), 7.61 (d, 1H), 7 .58 (s, 1H), 7.51 (dd, 1H), 3.66-3.64 (m, 2H), 3.60-3.55 (m, 6H), 2.07 (s, 3H ); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -67.26; MS m/z: 391.1 (M+H) ⁺ .

Table 5: Analysis data for compounds of formula II

[001473] The purity and retention time of the compounds of the present invention were determined using HPLC. Several methods were used and they are listed below.

Retention times (RT) marked * were determined according to method 1;

Retention times without the * mark were determined using method 2;

Method 1: 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). Duration of the study is 1.5 minutes.

Method 2: 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). Duration of the study is 5 minutes.

II-No. LCMS_Plus LCMS_RT NMR II-1 474 2.37 1H NMR (500MHz, DMSO-d6) δ 8.66 (d, 1H), 8.65 (d, 1H), 8.06 (d, 1H), 7.72 (d, 1H), 7.40- 7.10 (m, 2H), 4.65 (m, 1H), 4.50 (m, 1H), 3.40 (m, 1H), 3.15 (m, 1H), 2.96 (m , 4H), 2.30 (m, 2H), 2.06 (m, 1H), 1.20 (m, 1H). II-2 474 2.37 II-3 452.2 2.38 1H NMR (500MHz, DMSO-d6) δ 8.73 (d, 2H), 8.57 (d, 1H), 8.00 (s, 1H), 7.75 (d, 1H), 7.30 ( t, 1H), 7.19 (m, 1H), 3.05 (m, 6H), 2.85 (m, 1H), 1.80-1.60 (m, 5H), 1.51 (m , 1H), 1.25 (d, 3H). II-4 399.2 1.98 1H NMR (500MHz, DMSO-d6) δ 8.73 (d, 2H), 8.57 (d, 1H), 8.04 (s, 1H), 7.75 (d, 1H), 7.69 ( s, 2H), 7.45-7.23 (t, 1H), 4.63 (m, 1H), 4.54 (m, 1H), 4.34 (m, 1H), 4.07 (m , 1H), 3.75 (m, 1H), 3.33-3.25 (m, 2H). II-5 468.2 1.96 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57-8.49 (m, 2H), 8.03 (s, 1H), 7.68 (d, J= 9.5 Hz, 1H), 7.42-7.09 (m, 2H), 4.39 (s, 1H), 2.93 (s, 5H), 1.73 (d, J=12.8 Hz, 1H), 1.23 (d, J=17.9 Hz, 6H). II-6 468.2 1.87 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.59-8.47 (m, 2H), 8.01 (d, J=1.2 Hz, 1H), 7 .69 (d, J=9.4 Hz, 1H), 7.40-7.07 (m, 2H), 4.90 (s, 1H), 4.28 (d, J=109.2 Hz, 1H), 2.99-2.85 (m, 6H), 2.79-2.62 (m, 1H), 1.79 (d, J=11.3 Hz, 2H), 1.36 (t , J=12.7 Hz, 1H), 1.10 (s, 3H). II-7 467 1.7 II-8 438 2.16 II-9 363.1 1.84 II-10 437 1.81 II-11 472 2.54 1H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J=1.1 Hz, 1H), 8.71 (s, 1H), 8.57 (d, J=9.4 Hz, 1H ), 8.42 (br d, J=8.6 Hz, 1H), 8.18 (s, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.42-7, 21 (m, 4H), 7.06 (td, J=7.4, 1.0 Hz, 1H), 4.32 (dd, J=10.9, 9.6 Hz, 1H), 4.14 (dd, J=11.0, 5.0 Hz, 1H), 3.70 (tt, J=9.6, 5.1 Hz, 1H), 3.46-3.32 (m, 1H), 3.22-3.17 (m, 1H), 2.91 (s, 3H). II-12 454.2 1.81 1H NMR (500 MHz, methanol-d4) δ 8.61 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.37 (d, J=9.4 Hz, 1H ), 8.13 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.13 (t, J=53.9 Hz, 1H), 4.42 (s, 1H), 4.29 (s, 1H), 4.10 (s, 1H), 3.51 (dd, J=13.6, 2.5 Hz, 1H), 3.19 -3.00 (m, 3H), 2.97 (s, 3H), 2.26 (td, J=8.9, 4.3 Hz, 1H), 1.99-1.85 (m, 1H ), 1.70 (ddd, J=13.5, 10.4, 3.2 Hz, 1H). II-13 454.2 1.79 1H NMR (500 MHz, methanol-d4) δ 8.64 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.38 (d, J=9.5 Hz, 1H ), 8.13 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.15 (t, J=53.8 Hz, 1H), 4.57 (s, 1H), 3.69 (td, J=10.2, 4.9 Hz, 1H), 3.19-3.04 (m, 2H), 2.99 (s, 3H) , 2.80 (t, J=12.5 Hz, 2H), 2.21 (d, J=12.5 Hz, 1H), 1.89 (s, 1H), 1.41-1.19 ( m, 1H). II-14 423 2.21 1H NMR (500 MHz, DMSO-d6) δ 9.17 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.56 (d, J=9.4 Hz, 1H ), 8.52 (d, J=1.3 Hz, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.38 (t, J=52.5 Hz, 1H), 3.57 (ddd, J=14.0, 5.5, 3.9 Hz, 1H), 3.47 (dt, J=13.3, 4.6 Hz, 1H), 3.40-3, 33 (m, 1H), 3.28-3.26 (m, 1H), 3.13-2.99 (m, 1H), 2.93 (s, 3H), 2.12 (dq, J= 13.6, 4.3 Hz, 1H), 2.07-1.92 (m, 3H), 1.90-1.84 (m, 1H), 1.81-1.76 (m, 1H) . II-15 360 1.72 1H NMR (500 MHz, DMSO-d6) δ 8.68-8.59 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.01 (d, J=1, 2 Hz, 1H), 7.76-7.63 (m, 2H), 7.37 (t, J=53.7 Hz, 1H), 4.02-3.82 (m, 4H), 3, 29-3.327 (m, 2H), 2.64-2.55 (m, 2H). II-16 408 2.21 1H NMR (500 MHz, DMSO-d6) δ 8.86 (d, J=1.1 Hz, 1H), 8.74 (s, 1H), 8.57 (d, J=9.4 Hz, 1H ), 8.46 (brs, 1H), 8.17 (s, 1H), 7.93 (d, J=5.0 Hz, 1H), 7.74 (d, J=9.4 Hz, 1H ), 7.52-7.28 (m, 3H), 7.26 (brs, 1H), 7.07 (td, J=7.4, 1.0 Hz, 1H), 4.51-4, 41 (m, 1H), 4.39-4.27 (m, 2H). II-17 438.2 2.11 1H NMR (500MHz; dmso-d6) δ 8.71 (s, 1H), 8.67 (s, 1H), 8.57 (d, 1H), 7.75 (m, 2H), 7.32 ( t, 1H), 7.06 (br s, 1H), 3.92 (m, 1H), 3.80 (m, 1H), 3.71 (m, 1H), 3.52 (m, 1H) , 3.18 (m, 1H), 3.08 (m, 2H), 2.93 (s, 3H), 1.65 (m, 4H). II-18 438.1 1.79 II-19 409.7 2.08 1H NMR (400 MHz, DMSO-d6) δ 8.80-8.68 (m, 2H), 8.57 (d, J=9.4 Hz, 1H), 8.07 (d, J=1, 2 Hz, 1H), 7.75 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.7 Hz, 1H), 4.86 (s, 1H), 4.35 (s, 1H), 3.50-3.32 (m, 2H), 3.26 (t, J=12.6 Hz, 1H), 3.07 (s, 3H), 2.31-2, 13 (m, 1H), 1.92 (tq, J=19.0, 7.5, 5.7 Hz, 2H), 1.60 (t, J=12.4 Hz, 1H). II-20 365 2.98 1H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J=1.1 Hz, 1H), 8.71 (s, 1H), 8.56 (d, J=9.4 Hz, 1H ), 8.43 (brd, J=8.1 Hz, 1H), 8.14 (s, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.49-7.22 (m, 3H), 7.01 (td, J=7.4, 1.0 Hz, 1H), 4.23 (dd, J=9.1, 8.0 Hz, 2H). (peak water obscures some signals) II-21 409 2.24 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=1.3 Hz, 1H), 8.76 (s, 1H), 8.62 (d, J=1.4 Hz, 1H ), 8.57 (d, J=9.5 Hz, 1H), 7.75 (d, J=9.4 Hz, 1H), 7.40 (t, J=53.7 Hz, 1H), 3.81 (d, J=10.6 Hz, 1H), 3.59 (d, J=11.9 Hz, 1H), 3.21-2.99 (m, 2H), 2.92 (s , 3H), 2.88-2.76 (m, 1H), 2.09 (d, J=12.3 Hz, 1H), 1.89 (d, J=12.7 Hz, 1H), 1 .83-1.60 (m, 2H). II-22 424 2.07 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.61 (d, J=1.2 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.96 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.32 (t, J=55.0 Hz, 1H), 4.07-3.72 (m, 4H), 3.50 (brs, 2H), 2.87 (s, 3H), 1.96 (brs, 2H), water peak covers some signals. II-23 438 1.75 1H NMR (500MHz, DMSO-d6) 8.64 (s, 1H), 8.59 (s, 1H), 8.40 (m, 1H), 8.12 (s, 1H), 7.29-7 .02 (t, 1H), 4.52-4.41 (m, 3H), 4.13 (m, 1H), 3.74 (m, 3H), 3.06-2.98 (m, 5H ). II-24 425 1.9 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.95 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.32 (t, J=55.0 Hz, 1H), 6.76 (s, 2H ), 4.08-3.71 (m, 4H), 3.51-3.33 (m, 2H), 3.22-3.11 (m, 2H), 1.96 (br s, 2H) . II-25 453.1 1.66 1H NMR (500MHz, DMSO-d6) δ 8.70 (m, 2H), 8.55 (d, 1H), 8.29 (s, 1H), 7.96 (s, 1H), 7.73 (d, 1H), 7.41-7.25 (m, 2H), 4.35-4.10 (br m, 2H), 4.06 (m, 1H), 3.91 (m, 1H) , 3.60 (m, 1H), 3.15-3.12 (m, 1H), 3.07-3.04 (m, 1H), 2.92 (s, 3H). II-26 436.2 2.07 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.4 Hz, 1H), 8.58 (dd, J=2.0, 1.1 Hz, 1H), 8.52 (dd, J=9.4, 1.4 Hz, 1H), 7.99 (dd, J=9.9, 1.2 Hz, 1H), 7.69 (dd, J=9.4, 2 ,1 Hz, 1H), 7.43 (d, J=24.2 Hz, 1H), 4.45 (dd, J=72.8, 25.2 Hz, 2H), 3.25-3.00 (m, 4H), 2.97 (d, J=6.9 Hz, 3H), 2.62 (d, J=4.0 Hz, 3H), 2.20 (tqd, J=10.9, 7.5, 4.3 Hz, 1H), 1.98 (ddd, J=23.2, 9.7, 5.2 Hz, 1H), 1.81-1.71 (m, 1H), 1 .50 (dddt, J=22.1, 20.3, 11.7, 5.8 Hz, 2H). II-27 307.1 0.88 1H NMR (500 MHz, DMSO) δ 8.85 (dd, J=5.4, 0.6 Hz, 1H), 8.81 (s, 1H), 8.69 (d, J=0.9 Hz , 1H), 8.42 (d, J=9.5 Hz, 1H), 8.26 (dd, J=5.3, 1.5 Hz, 1H), 8.17 (dt, J=8, 4, 1.8 Hz, 2H), 7.63-7.56 (m, 3H), 7.56-7.49 (m, 1H). II-28 366.1 2.14 II-29 413 1.81 1H NMR (500MHz, chloroform-d) δ 8.80 (d, 1H), 8.72 (d, 1H), 8.29 (d, 2H), 8.26 (m, 1H), 7.97 ( d, 1H), 7.49-7.47 (d, 1H), 6.97-6.69 (t, 1H), 4.67 (m, 1H), 4.28 (m, 1H), 4 .22-4.04 (m, 3H), 3.83 (m, 1H), 3.71 (m, 1H), 3.25 (m, 1H), 2.80 (m, 1H). II-30 398.3 2.11 1H NMR (400 MHz, DMSO-d6) δ 9.21 (dd, J=3.8, 1.3 Hz, 1H), 8.76 (s, 1H), 8.66-8.48 (m, 2H), 7.75 (dd, J=9.5, 5.4 Hz, 1H), 7.39 (td, J=53.7, 15.3 Hz, 1H), 4.56 (d, J =12.2 Hz) and 4.32 (d, J=12.5 Hz, 1H), 4.23-4.02 (m, 2H), 3.91 (d, J=13.3 Hz) and 3.73 (d, J=13.2 Hz, 1H), 3.45 (dd, J=13.6, 10.8 Hz, 1H), 3.22-2.59 (m, 2H), 2 .12 (s, 1H), 2.00-1.75 (m, 2H), 1.75-1.43 (m, 1H). II-31 454.7 2.18 II-32 455 2.17 1H NMR (400 MHz, methanol-d4) δ 8.63 (s, 1H), 8.58 (s, 1H), 8.37 (d, 1H), 8.10 (s, 1H), 7.70 (d, 1H), 7.23-7.01 (t, 1H), 4.50 (m, 2H), 3.72 (m, 2H), 3.03 (s, 3H), 2.87 ( m, 1H), 2.77 (m, 1H), 1.31 (d, 3H). II-33 454.2 2.18 1H NMR (500 MHz, DMSO-d6) δ 8.76-8.63 (m, 2H), 8.56 (d, J=9.4 Hz, 1H), 8.01 (d, J=1, 1 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.45-7.16 (m, 2H), 4.60-4.30 (m, 2H), 3, 71-3.66 (m, 1H), 3.65-3.59 (m, 1H), 3.23-3.08 (m, 2H), 2.96 (s, 3H), 2.79 ( q, J=13.6 Hz, 2H), 1.23 (d, J=6.2 Hz, 3H). II-34 440.1 1.98 1H NMR (500 MHz, DMSO-d6) δ 8.73-8.65 (m, 2H), 8.56 (d, J=9.4 Hz, 1H), 7.99 (d, J=1, 1 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.45-7.18 (m, 2H), 4.58-4.42 (m, 1H), 4, 34-4.23 (m, 1H), 4.04 (ddd, J=11.6, 3.6, 1.5 Hz, 1H), 3.66-3.53 (m, 2H), 3, 25-3.10 (m, 3H), 3.00-2.85 (m, 4H). II-35 488.1 2.55 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=1.1 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.08 (s, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.6 Hz, 1H), 4.83 (s, 1H ), 4.51 (s, 1H), 3.45 (dd, J=13.4, 3.5 Hz, 1H), 2.99 (s, 4H), 2.89 (s, 2H), 2 .29-2.13 (m, 2H), 1.07 (d, J=6.7 Hz, 3H). II-36 488.2 2.55 1H NMR (500 MHz, DMSO-d6) δ 8.70-8.60 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.06 (d, J=1, 1 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.30 (d, J=16.1 Hz, 2H), 4.82 (s, 1H), 4.52 (s, 1H), 3.44 (dd, J=13.5, 3.5 Hz, 1H), 2.98 (s, 4H), 2.88 (q, J=15.6, 14.1 Hz, 2H), 2.30-2.09 (m, 2H), 1.06 (d, J=6.7 Hz, 3H). II-37 464.2 2.28 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.49 (d, J=9.4 Hz, 1H), 8.31 (d, J=5.4 Hz, 1H ), 7.76 (s, 1H), 7.68-7.64 (m, 2H), 7.29 (t, J=53.8 Hz, 1H), 4.60 (s, 2H), 3 .89-3.76 (m, 3H), 3.49 (s, 2H), 3.20-2.92 (m, 6H), 3.04 (s, 3H). II-38 386.2 1.98 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.49 (d, J=9.4 Hz, 1H), 8.27 (d, J=5.6 Hz, 1H ), 7.73 (s, 1H), 7.65 (d, J=9.4 Hz, 1H), 7.58 (d, J=5.0 Hz, 1H), 7.29 (t, J =53.9 Hz, 1H), 4.41-4.29 (m, 2H), 3.35 (d, J=12.0 Hz, 2H), 3.09-2.96 (m, 5H) , 2.83-2.76 (m, 1H), 2.56-2.33 (m, 3H). II-39 453.1 2.02 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.20 (d, J=5.3 Hz, 1H ), 7.67-7.59 (m, 2H), 7.41-7.03 (m, 3H), 4.68 (d, J=3.9 Hz, 1H), 4.15 (d, J=10.7 Hz, 1H), 3.89 (d, J=4.8 Hz, 1H), 3.77 (dd, J=13.2, 4.8 Hz, 1H), 3.18 ( d, J=5.2 Hz, 2H), 3.01-2.86 (m, 7H), 1.72 (d, J=12.9 Hz, 1H), 1.58-1.50 (m , 1H), 1.16 (s, 1H). II-40 453.1 1.98 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.23 (dd, J=5.3, 0, 7 Hz, 1H), 7.67-7.65 (m, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.41 (dd, J=5.3, 1.3 Hz, 1H), 7.37-7.13 (m, 1H), 7.12 (d, J=6.2 Hz, 1H), 4.97 (d, J=4.6 Hz, 1H), 4.48 (ddd, J=30.4, 12.8, 4.2 Hz, 2H), 3.51 (tq, J=9.6, 4.4 Hz, 1H), 2.99-2, 88 (m, 5H), 2.12-2.00 (m, 1H), 1.74 (th, J=10.8, 3.4 Hz, 1H), 1.09 (q, J=11, 9 Hz, 1H). II-41 439.3 2.1 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.63-8.41 (m, 2H), 8 .06 (s, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H), 7.40 (t, J=53, 7 Hz, 1H), 4.40 (d, J=93.6 Hz, 2H), 3.85 (s, 3H), 3.04 (s, 2H), 2.16 (d, J=12, 9 Hz, 1H), 2.04-1.77 (m, 2H), 1.70-1.51 (m, 1H), 1.27 (d, J=6.7 Hz, 1H). II-42 449.2 2.34 II-43 432 2.76 1H NMR (500 MHz, DMSO-d6) δ 8.62-8.53 (m, 2H), 8.46 (d, J=9.4 Hz, 1H), 7.93 (d, J=1, 2 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H), 7.24 (t, J=55.0 Hz, 1H), 4.80-3.72 (m, 4H) , 3.47 (s, 1H), 3.12 (dd, J=13.2, 8.3 Hz, 1H), 2.67 (d, J=10.8 Hz, 1H), 2.27 ( d, J=13.2 Hz, 1H), 1.28 (d, J=6.8 Hz, 3H), 1.08 (s, 9H). Note: the spectrum was taken at 350K II-44 463.2 2.41 1H NMR (500 MHz, methanol-d4) δ 8.68 (d, J=1.6 Hz, 1H), 8.60 (s, 1H), 8.40 (d, J=9.5 Hz, 1H ), 8.35 (d, J=1.6 Hz, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.03 (t, J=54.2 Hz, 1H), 5.61 (tt, J=3.3, 1.5 Hz, 1H), 3.71 (tq, J=2.6, 1.3 Hz, 2H), 3.60 (t, J=7, 0 Hz, 2H), 3.37 (d, J=5.7 Hz, 2H), 2.84 (d, J=5.1 Hz, 3H), 2.64 (s, 3H), 2.52 (t, J=6.9 Hz, 2H), 2.34 (td, J=5.6, 2.7 Hz, 2H). II-45 488.1 2.55 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=1.0 Hz, 1H), 8.68 (s, 1H), 8.56 (d, J=9.4 Hz, 1H ), 8.08 (s, 1H), 7.72 (d, J=9.4 Hz, 1H), 7.42-7.17 (m, 2H), 3.45 (ddd, J=13, 6, 5.6, 3.7 Hz, 1H), 2.99 (s, 4H), 2.91 (s, 2H), 2.23 (d, J=25.5 Hz, 2H), 1, 07 (d, J=6.7 Hz, 3H). II-46 387 1.77 1H NMR (500 MHz, DMSO-d6) δ 8.68-8.59 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.02 (d, J=1, 2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.38 (t, J=55.0 Hz, 1H), 6.59 (s, 1H), 4.55 (brs, 1H), 4.39 (brs, 1H), 3.81-3.64 (m, 2H), 3.44 (ddd, J=9.3, 8.2, 1.1 Hz, 1H ), 3.13-2.80 (m, 4H). II-47 388 1.92 1H NMR (500 MHz, DMSO-d6) δ 8.71-8.64 (m, 2H), 8.55 (d, J=9.4 Hz, 1H), 8.03 (d, J=1, 2 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.38 (t, J=55.0 Hz, 1H), 4.71 (brs, 1H), 4.47 -4.44 (m, 3H), 4.10 (dd, J=8.9, 5.3 Hz, 1H), 3.99-3.90 (m, 1H), 3.76-3.71 (m, 1H), 3.18-2.98 (m, 3H). II-48 437.3 2.09 1H NMR (400 MHz, DMSO-d6) δ 8.29 (t, J=1.2 Hz, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.55 (d , J=9.5 Hz, 1H), 6.88 (d, J=9.5 Hz, 1H), 6.26 (t, J=54.0 Hz, 1H), 2.90 (dd, J =7.6, 5.5 Hz, 5H), 2.48 (s, 3H), 2.29 (d, J=3.0 Hz, 4H), 1.51-1.29 (m, 1H) , 1.15 (d, J=8.8 Hz, 3H). II-49 451.2 2.43 1H NMR (500 MHz, methanol-d4) δ 9.08 (d, J=1.8 Hz, 1H), 8.68 (d, J=1.8 Hz, 1H), 8.57 (s, 1H ), 8.38 (d, J=9.5 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.03 (t, J=54.0 Hz, 1H), 3.51-3.45 (m, 1H), 3.30-3.27 (m, 1H), 3.13 (dd, J=13.2, 5.6 Hz, 1H), 3.07 ( dd, J=13.2, 8.3 Hz, 1H), 2.98-2.88 (m, 4H), 2.77-2.69 (m, 4H), 2.09-1.98 ( m, 1H), 1.98-1.90 (m, 2H), 1.88-1.77 (m, 1H), 1.38-1.31 (m, 1H). II-50 376 1.74 1H NMR (500 MHz, DMSO-d6) δ 8.73-8.66 (m, 2H), 8.55 (d, J=9.4 Hz, 1H), 8.05 (d, J=1, 2 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.49-7.20 (m, 3H), 4.59 (brs, 1H), 4.17 (brs, 1H), 4.09-3.95 (m, 2H), 3.70 (td, J=11.3, 2.9 Hz, 1H), 3.32 (ddd, J=13.9, 10, 8, 3.6 Hz, 1H), 3.17-3.14 (m, 1H). II-51 400 2.03 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=16.5 Hz, 2H), 8.57 (d, J=9.4 Hz, 1H), 8.02 (d, J =1.1 Hz, 1H), 7.79-7.68 (m, 2H), 7.34 (t, J=52.5 Hz, 1H), 3.35-3.13 (m, 6H) , 1.99-1.78 (m, 4H), 1.69-1.51 (m, 2H). II-52 386 1.93 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, J=1.7 Hz, 2H), 8.56 (d, J=9.4 Hz, 1H), 8.38 (s, 1H ), 8.03 (d, J=1.1 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.42 (t, J=52.5 Hz, 1H), 3.87-3.84 (m, 2H), 3.74-3.70 (m, 2H), 2.72 (s, 2H), 1.86 (ddd, J=11.8, 7.4 , 3.8 Hz, 2H), 1.76 (ddd, J=12.6, 7.4, 3.7 Hz, 2H). II-53 451.1 2.5 II-54 464 2.24 1H NMR (500 MHz, DMSO-d6) δ 8.68 (m, 2H), 8.58 (d, J=9.4 Hz, 1H), 7.81-7.70 (m, 2H), 7 .36 (t, J=52.5 Hz, 1H), 3.22-3.20 (m, 4H), 3.14- 3.10 (m, 2H), 2.91 (s, 3H), 2.07-1.91 (m, 2H), 1.77-1.70 (m, 4H), the water peak covers some signals. II-55 575.3 2.41 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.43 (d, J=9.4 Hz, 1H), 7.58 (d, J=9.4 Hz, 1H ), 7.22 (t, J=53.9 Hz, 1H), 7.06 (t, J=6.2 Hz, 1H), 6.90 (s, 1H), 6.55 (s, 1H ), 4.31 (s, 2H), 4.27-4.19 (m, 1H), 4.19-4.13 (m, 1H), 4.13-4.06 (m, 4H), 4.03 (s, 2H), 2.95-2.85 (m, 6H), 2.72-2.62 (m, 1H), 1.87-1.79 (m, 1H), 1. 76 (s, 3H), 1.74-1.64 (m, 2H), 1.52-1.41 (m, 1H), 1.29-1.21 (m, 1H). II-56 464 2.36 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.03 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.32 (t, J=52.5 Hz, 1H), 3.84-3.79 (m, 2H), 3.70-3.65 (m, 2H), 3.45-3.36 (m, 2H), 3.15 (d, J=9.8 Hz, 1H), 2.98 (d, J=9.8 Hz, 1H), 2.91 (s, 3H), 1.90-1.78 (m, 1H), 1.78-1.53 (m, 5H). II-57 488.1 2.75 II-58 488.1 2.77 1H NMR (500MHz, methanol-d4) δ 8.49 (s, 1H), 8.33-8.32 (d, 1H), 8.26-8.25 (d, 1H), 7.86 (s , 1H), 7.64 (d, 1H), 7.45 (m, 1H), 7.23-6.95 (t, 1H), 4.70 (m, 1H), 4.62 (m, 1H), 3.62 (m, 1H), 3.15 (m, 1H), 3.00-2.90 (m, 4H), 2.96 (m, 1H), 2.30-2.05 (m, 2H), 1.13 (d, 3H). II-59 438 2.17 1H NMR (500 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.71 (s, 1H), 7.48 (d, J=9.8 Hz, 1H), 7.06 (s , 1H), 6.83 (d, J=9.8 Hz, 1H), 6.29-6.01 (m, 1H), 3.60 (d, J=89.8 Hz, 1H), 2 .57 (d, J=11.7 Hz, 1H), 2.10 (qd, J=13.2, 12.7, 6.5 Hz, 2H), 1.96 (d, J=3.4 Hz, 3H), 1.04-0.88 (m, 3H), 0.70 (d, J=12.6 Hz, 1H), 0.55 (d, J=11.2 Hz, 1H), 0.31 (s, 1H), 0.13 - -0.23 (m, 1H). II-60 466.2 2.42 1H NMR (500 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.63 (s, 1H), 8.57 (d, J=9.4 Hz, 1H), 7.75 (d , J=9.5 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.28-6.93 (m, 2H), 5 .94 (d, J=2.3 Hz, 1H), 4.04 (dt, J=13.8, 6.9 Hz, 2H), 3.23 (t, J=12.3 Hz, 1H) , 3.04 (dd, J=13.3, 10.3 Hz, 1H), 2.98-2.62 (m, 8H), 1.87 (dt, J=12.6, 4.2 Hz , 1H), 1.78 (dq, J=12.9, 4.3 Hz, 2H), 1.58-1.47 (m, 1H), 1.43-1.29 (m, 1H). II-61 471.1 2.89 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 7.67-7.61 (m, 2H), 7 .45 (s, 1H), 7.27 (t, J=53.8 Hz, 1H), 7.11 (t, J=6.1 Hz, 1H), 4.34-4.27 (m, 1H), 4.20-4.14 (m, 1H), 2.99 (ddd, J=12.9, 11.5, 3.0 Hz, 1H), 2.95-2.86 (m, 5H), 2.74 (dd, J=13.1, 10.3 Hz, 1H), 1.90-1.80 (m, 1H), 1.79-1.65 (m, 2H), 1 .55-1.42 (m, 1H), 1.32-1.20 (m, 1H). II-62 345.1 1.94 II-63 505.1 3.09 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.50 (d, J=9.4 Hz, 1H), 7.98 (s, 1H), 7.80 (d , J=1.1 Hz, 1H), 7.66 (d, J=9.4 Hz, 1H), 7.26 (t, J=53.8 Hz, 1H), 7.11 (t, J =6.1 Hz, 1H), 4.34 (dd, J=13.1, 3.8 Hz, 1H), 4.30-4.21 (m, 1H), 3.12-3.01 ( m, 1H), 2.98-2.86 (m, 5H), 2.82 (dd, 1H), 1.91-1.81 (m, 1H), 1.82-1.67 (m, 2H), 1.57-1.44 (m, 1H), 1.36-1.18 (m, 1H). II-64 516 2.92 1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.42 (d, J=9.4 Hz, 1H), 7.57 (d, J=9.4 Hz, 1H ), 7.31-7.06 (m, 2H), 6.76 (s, 1H), 6.67 (d, J=1.0 Hz, 1H), 6.29 (q, J=4, 8 Hz, 1H), 3.83 (dd, J=13.5, 3.9 Hz, 1H), 3.76 (dd, J=13.3, 4.2 Hz, 1H), 3.62 ( dd, J=13.5, 6.7 Hz, 1H), 3.44 (dd, J=13.3, 7.1 Hz, 1H), 3.26-3.20 (m, 1H), 3 .01 (dd, J=13.0, 9.8 Hz, 1H), 2.91 (s, 3H), 2.82 (d, J=4.8 Hz, 3H), 2.35-2, 18 (m, 2H), 1.02 (d, J=6.8 Hz, 3H). II-65 517 2.87 1H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.43 (d, J=9.4 Hz, 1H), 7.58 (d, J=9.4 Hz, 1H ), 7.31-7.04 (m, 2H), 6.76 (s, 1H), 6.70 (s, 1H), 6.32 (q, J=4.7 Hz, 1H), 4 .78-4.64 (m, 1H), 4.44-4.32 (m, 1H), 3.43 (ddd, J=13.5, 5.5, 3.5 Hz, 1H), 2 .99-2.90 (m, 4H), 2.83 (d, J=4.8 Hz, 3H), 2.69 (dd, 2H), 2.23-2.00 (m, 2H), 1.03 (d, J=6.7 Hz, 3H). II-66 522.3 2.72 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.43 (d, J=9.4 Hz, 1H), 7.58 (d, J=9.4 Hz, 1H ), 7.23 (t, J=53.8 Hz, 1H), 7.07 (t, J=6.2 Hz, 1H), 7.00 (s, 1H), 6.87 (s, 1H ), 4.30-4.24 (m, 1H), 4.19-4.13 (m, 1H), 3.75-3.70 (m, 4H), 3.52-3.43 (m , 4H), 2.96-2.83 (m, 6H), 2.65 (dd, J=12.9, 10.1 Hz, 1H), 1.87-1.77 (m, 1H), 1.76-1.63 (m, 2H), 1.53-1.40 (m, 1H), 1.29-1.17 (m, 1H). II-67 533.1 2.42 II-68 466.2 2.62 1H NMR (500 MHz, DMSO-d6) δ 8.53-8.36 (m, 2H), 7.56 (d, J=9.4 Hz, 1H), 7.32-7.02 (m, 2H), 6.69 (s, 1H), 6.59 (s, 1H), 6.18 (s, 1H), 4.31-4.22 (m, 1H), 4.21-4.13 (m, 1H), 2.96-2.75 (m, 9H), 2.68-2.56 (m, 1H), 1.87-1.79 (m, 1H), 1.75-1 .64 (m, 2H), 1.53-1.41 (m, 1H), 1.29-1.14 (m, 1H). II-69 468.2 2.35 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.43 (d, J=9.4 Hz, 1H), 7.57 (d, J=9.4 Hz, 1H ), 7.33-6.96 (m, 3H), 6.76-6.67 (m, 2H), 4.27-4.18 (m, 1H), 4.13-4.03 (m , 1H), 4.01-3.93 (m, 1H), 3.66-3.53 (m, 2H), 3.12 (t, J=6.0 Hz, 2H), 2.94 ( s, 3H), 2.91-2.77 (m, 4H), 2.58 (dd, J=12.8, 10.5 Hz, 1H). II-70 450 2.26 1H NMR (500 MHz, DMSO-d6) δ 8.59-8.51 (m, 2H), 8.46 (d, J=9.4 Hz, 1H), 7.99 (s, 1H), 7 .62 (d, J=9.4 Hz, 1H), 7.28 (t, J=52.5 Hz, 1H), 4.82 (vbrs, 1H), 4.24 (vbrs, 1H), 3 .79 (t, J=7.9 Hz, 2H), 3.22-3.13 (m, 1H), 2.96 (s, 3H), 2.88-2.82 (m, 1H), 2.13 (d, J=12.3 Hz, 1H), 2.10-1.94 (m, 3H), 1.79-1.74 (m, 1H), 1.50-1.39 ( m, 1H). II-71 502.1 2.73 1H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.45 (d, J=9.4 Hz, 1H), 7.60 (d, J=9.4 Hz, 1H ), 7.33-7.06 (m, 2H), 6.83-6.71 (m, 2H), 4.46-4.35 (m, 1H), 4.30-4.18 (m , 1H), 3.39-3.34 (m, 2H), 3.25-3.15 (m, 1H), 3.01-2.92 (m, 5H), 2.85 (s, 3H ), 2.27-1.90 (m, 2H). II-72 547.2 2.42 1H NMR (500 MHz, DMSO-d6) δ 9.79-9.53 (m, 1H), 8.56 (s, 1H), 8.44 (d, J=9.4 Hz, 1H), 7 .58 (d, J=9.4 Hz, 1H), 7.21 (t, J=54.0 Hz, 1H), 7.06 (t, J=6.1 Hz, 1H), 6.92 (s, 1H), 6.54 (d, J=1.0 Hz, 1H), 4.48-4.38 (m, 2H), 4.29-4.13 (m, 6H), 4, 11 (s, 2H), 2.93-2.87 (m, 6H), 2.84 (d, J=5.0 Hz, 3H), 2.70-2.61 (m, 1H), 1 .88-1.78 (m, 1H), 1.75-1.63 (m, 2H), 1.53-1.40 (m, 1H), 1.30-1.18 (m, 1H) . II-73 466.2 2.17 1H NMR (500 MHz, DMSO-d6) δ 9.13 (d, J=1.8 Hz, 1H), 8.62 (s, 1H), 8.48 (d, J=9.4 Hz, 1H ), 8.34 (d, J=1.9 Hz, 1H), 8.29-8.20 (m, 2H), 7.62 (d, J=9.4 Hz, 1H), 7.23 (t, J=53.8 Hz, 1H), 7.07 (t, J=6.2 Hz, 1H), 4.31-4.21 (m, 2H), 3.22-3.14 ( m, 1H), 3.10-2.88 (m, 6H), 2.83-2.74 (m, 1H), 2.58-2.52 (m, 1H), 1.95-1, 78 (m, 3H), 1.74-1.60 (m, 1H), 1.30-1.13 (m, 1H). II-74 336 0.88 1H NMR (500 MHz, DMSO-d6) δ 8.66-8.54 (m, 2H), 8.46 (d, J=9.4 Hz, 1H), 7.61 (d, J=9, 4 Hz, 1H), 7.33-7.09 (m, 3H), 6.92 (d, J=0.9 Hz, 1H), 4.61-4.45 (m, 2H), 4, 35-4.24 (m, 1H), 4.24-4.14 (m, 1H), 3.03-2.95 (m, 1H), 2.95-2.88 (m, 5H), 2.74 (dd, J=13.0, 10.2 Hz, 1H), 2.65 (t, J=5.4 Hz, 2H), 2.07 (s, 3H), 1.89-1 .80 (m, 1H), 1.78-1.65 (m, 2H), 1.54-1.43 (m, 1H), 1.32-1.22 (m, 1H). II-75 487.2 2.57 1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.37 (d, J=5.9 Hz, 1H ), 8.17 (d, J=2.5 Hz, 1H), 7.61 (d, J=9.4 Hz, 1H), 7.40-7.12 (m, 2H), 6.93 (dd, J=6.0, 2.7 Hz, 1H), 4.30 (d, J=14.0 Hz, 1H), 4.07 (d, J=14.0 Hz, 1H), 3 .44 (ddd, J=13.4, 5.8, 3.5 Hz, 1H), 2.98 (s, 3H), 2.94-2.79 (m, 2H), 2.27-2 .13 (m, 2H), 1.24 (s, 1H), 1.06 (d, J=6.7 Hz, 3H). II-76 332.1 2.34 II-77 380 2.2 II-78 487 2.76 II-79 343.1 1.94 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.63 (s, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.17 (d , J=6.6 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.66-7.49 (m, 2H), 7.29 (t, J=53, 9 Hz, 1H), 4.34 (s, 4H), 4.22 (t, J=6.2 Hz, 4H). II-80 466.2 2.24 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.50 (d, J=9.4 Hz, 1H), 8.16 (s, 2H), 7.70 (s , 1H), 7.66 (d, J=9.4 Hz, 1H), 7.47 (s, 1H), 7.26 (t, J=53.8 Hz, 1H), 7.09 (t , J=6.1 Hz, 1H), 4.40-4.34 (m, 1H), 4.34-4.28 (m, 1H), 4.16-4.07 (m, 2H), 3.09-2.88 (m, 6H), 2.82 (dd, J=13.0, 10.0 Hz, 1H), 1.94-1.84 (m, 1H), 1.82- 1.67 (m, 2H), 1.57-1.44 (m, 1H), 1.38-1.22 (m, 1H). II-81 494 2.33 1H NMR (500MHZ, DMSO-d6) δ 8.85 (s, 1H), 8.78-8.76 (d, 1H), 8.19-8.17 (d, 1H), 8.15-8 .12 (m, 2H), 7.66 (d, 1H), 7.28-78.07 (t, 1H), 4.86-4.80 (m, 4H), 4.50 (m, 1H ), 4.24 (d, 1H), 4.08 (m, 1H), 4.79 (d, 1H), 4.75-4.70 (m, 1H), 3.30-3.25 ( masked, 3H), 3.20 (m, 1H), 3.11-3.7 (m, 1H), 2.95 (s, 3H). II-82 461.1 2.72 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.06 (d, J=1.6 Hz, 1H ), 7.92-7.82 (m, 2H), 7.63 (d, J=9.4 Hz, 1H), 7.24 (t, J=53.8 Hz, 1H), 7.07 (t, J=6.2 Hz, 1H), 3.57 (dd, J=42.3, 11.8 Hz, 2H), 3.29 (s, 1H), 3.07-2.83 ( m, 6H), 2.69 (dd, J=11.8, 9.6 Hz, 1H), 1.85 (d, J=11.6 Hz, 2H), 1.69 (d, J=11 .5 Hz, 1H), 1.21 (q, J=11.1, 10.1 Hz, 1H). II-83 534.2 2.61 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.44 (d, J=9.4 Hz, 1H), 7.59 (d, J=9.5 Hz, 1H ), 7.23 (t, J=53.8 Hz, 1H), 7.06 (t, J=6.1 Hz, 1H), 6.89 (s, 1H), 6.56 (s, 1H ), 4.74 (s, 4H), 4.24-4.11 (m, 6H), 2.98-2.82 (m, 6H), 2.68 (dd, J=12.9, 10 ,0 Hz, 1H), 1.88-1.78 (m, 1H), 1.76-1.63 (m, 2H), 1.54-1.40 (m, 1H), 1.30- 1.17 (m, 1H). II-84 508.2 2.43 1H NMR (500 MHz, DMSO-d6) δ 9.12-8.88 (m, 1H), 8.80-8.59 (m, 2H), 8.46 (d, J=9.4 Hz, 1H), 7.61 (d, J=9.4 Hz, 1H), 7.36-7.10 (m, 3H), 6.96 (d, J=0.9 Hz, 1H), 5, 39 (p, 1H), 4.52-4.37 (m, 2H), 4.30-4.19 (m, 1H), 4.18-4.03 (m, 3H), 3.04- 2.87 (m, 6H), 2.72 (dd, J=13.1, 10.2 Hz, 1H), 1.90-1.79 (m, 1H), 1.78-1.63 ( m, 2H), 1.56-1.41 (m, 1H), 1.35-1.21 (m, 1H). II-85 508.2 2.39 1H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.43 (d, J=9.4 Hz, 1H), 7.57 (d, J=9.4 Hz, 1H ), 7.22 (t, J=53.9 Hz, 1H), 7.06 (t, J=6.1 Hz, 1H), 6.87 (s, 1H), 6.52 (s, 1H ), 4.62-4.53 (m, 1H), 4.29-4.22 (m, 1H), 4.21-4.12 (m, 3H), 3.70 (dd, J=8 ,4, 4.6 Hz, 3H), 2.92-2.85 (m, 6H), 2.68-2.61 (m, 1H), 1.88-1.79 (m, 1H), 1.76-1.64 (m, 2H), 1.52-1.40 (m, 1H), 1.28-1.17 (m, 1H). II-86 534.2 2.7 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.44 (d, J=9.4 Hz, 1H), 7.59 (d, J=9.4 Hz, 1H ), 7.24 (t, J=53.8 Hz, 1H), 7.07 (t, J=6.2 Hz, 1H), 6.90 (s, 1H), 6.56 (s, 1H ), 4.46 (t, J=7.5 Hz, 2H), 4.26-4.20 (m, 3H), 4.18-4.12 (m, 1H), 4.07-4, 03 (m, 2H), 2.97-2.82 (m, 8H), 2.71-2.61 (m, 1H), 1.88-1.77 (m, 1H), 1.76- 1.63 (m, 2H), 1.54-1.41 (m, 1H), 1.30-1.16 (m, 1H). II-87 437.1 2.28 1H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J=1.6 Hz, 1H), 8.65 (s, 1H), 8.49 (d, J=9.4 Hz, 1H ), 8.40 (d, J=2.7 Hz, 1H), 8.37-8.29 (m, 1H), 7.64 (d, J=9.4 Hz, 1H), 7.37 -7.09 (m, 2H), 3.94-3.87 (m, 1H), 3.87-3.79 (m, 1H), 3.05-2.87 (m, 6H), 2 .78 (dd, J=12.7, 9.8 Hz, 1H), 1.90-1.73 (m, 3H), 1.65-1.53 (m, 1H), 1.34-1 .19 (m, 1H). II-88 387 2.22 II-89 510.2 2.65 1H NMR (500 MHz, DMSO-d6) δ 8.45-8.39 (m, 2H), 7.56 (d, J=9.4 Hz, 1H), 7.29-7.02 (m, 2H), 6.69-6.61 (m, 2H), 6.25 (t, J=5.5 Hz, 1H), 4.28-4.21 (m, 1H), 4.21-4 .14 (m, 1H), 3.54-3.47 (m, 2H), 3.47-3.41 (m, 2H), 3.29 (s, 3H), 2.95-2.82 (m, 6H), 2.66-2.58 (m, 1H), 1.87-1.79 (m, 1H), 1.75-1.63 (m, 2H), 1.53-1 .40 (m, 1H), 1.28-1.17 (m, 1H). II-90 438.1 1.99 II-91 496.2 2.33 II-92 533.2 2.39 1H NMR (500 MHz, DMSO-d6) δ 8.58-8.49 (m, 2H), 8.44 (d, J=9.4 Hz, 1H), 7.58 (d, J=9, 4 Hz, 1H), 7.22 (t, J=54.0 Hz, 1H), 7.06 (t, J=6.1 Hz, 1H), 6.92 (s, 1H), 6.55 (s, 1H), 4.27-4.22 (m, 1H), 4.21-4.14 (m, 5H), 4.12 (s, 4H), 2.95-2.84 (m , 6H), 2.71-2.61 (m, 1H), 1.88-1.78 (m, 1H), 1.74-1.62 (m, 2H), 1.53-1.40 (m, 1H), 1.30-1.18 (m, 1H). II-93 449.2 2.4 1H NMR (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.68 (d, J=9.5 Hz, 1H), 8.42 (d, J=7.2 Hz, 1H ), 7.89 (d, J=9.5 Hz, 1H), 7.56-7.19 (m, 2H), 7.10 (d, J=7.2 Hz, 1H), 3.37 (t, J=12.0 Hz, 1H), 3.20-3.11 (m, 1H), 3.04 (td, J=6.5, 3.0 Hz, 2H), 2.98 ( s, 3H), 1.91 (q, J=18.7, 16.9 Hz, 1H), 1.73-1.36 (m, 2H). II-94 453.1 2.25 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.62 (d, J=9.5 Hz, 1H), 8.40 (d, J=7.4 Hz, 1H ), 8.01 (d, J=2.8 Hz, 1H), 7.81 (d, J=9.5 Hz, 1H), 7.33 (t, J=53.7 Hz, 1H), 7.25-7.15 (m, 2H), 4.26 (d, J=13.9 Hz, 2H), 3.81-3.64 (m, 2H), 3.17 (td, J= 6.0, 3.9 Hz, 2H), 3.01 (dd, J=13.3, 10.7 Hz, 1H), 2.97 (s, 3H), 2.92 (dd, J=13 ,3, 10.7 Hz, 1H), 1.24 (d, J=6.1 Hz, 3H). II-95 464.1 2.18 1H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J=27.0 Hz, 2H), 8.58 (d, J=9.4 Hz, 1H), 7.82-7.65 (m, 2H), 7.37 (t, J=53.7 Hz, 1H), 7.20 (dd, J=13.2, 7.4 Hz, 1H), 3.85-3.56 ( m, 2H), 3.56-3.48 (m, 1H), 3.43 (q, J=10.5 Hz, 1H), 2.16-1.90 (m, 4H), 1.80 -1.69 (m, 1H), 1.69-1.51 (m, 2H), 1.39 (d, J=2.2 Hz, 2H). II-96 521.2 2.44 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.42 (d, J=9.4 Hz, 1H), 7.56 (d, J=9.4 Hz, 1H ), 7.22 (t, J=53.9 Hz, 1H), 7.07 (t, J=6.1 Hz, 1H), 6.93 (s, 1H), 6.84 (s, 1H ), 4.29-4.22 (m, 1H), 4.19-4.12 (m, 1H), 3.45-3.41 (m, 4H), 2.93-2.85 (m , 6H), 2.84-2.77 (m, 4H), 2.63 (dd, J=12.9, 10.2 Hz, 1H), 1.86-1.76 (m, 1H), 1.74-1.64 (m, 2H), 1.52-1.31 (m, 1H), 1.28-1.17 (m, 1H). II-97 375.2 2.02 II-98 452.2 2.15 1H NMR (500MHz, methanol-d4) δ 8.46 (s, 1H), 8.33-8.30 (d, 1H), 8.23 (m, 1H), 7.78 (d, 1H), 7.64-7.62 (d, 1H), 7.42 (m, 1H), 7.16-6.94 (t, 1H), 4.22-4.12 (m, 2H), 3. 42 (d, 1H), 3.25-3.15 (m, 2H), 3.08-2.96 (m, 5H), 2.60-2.38 (m, 5H). II-99 453.1 2.24 II-100 464 2.23 II-101 449.2 2.39 1H NMR (500 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.67 (s, 1H), 8.57-8.45 (m, 2H), 8.39 (s, 1H) , 7.64 (d, J=9.4 Hz, 1H), 7.26 (t, J=53.8 Hz, 1H), 3.72-3.63 (m, 4H), 3.47 ( s, 2H), 3.35-3.22 (m, 2H), 3.05 (s, 3H), 1.85-1.74 (m, 2H), 1.74-1.63 (m, 2H). II-102 437.2 2.02 1H NMR (500 MHz, methanol-d4) δ 8.72 (s, 1H), 8.42 (d, J=9.5 Hz, 1H), 8.31-8.27 (m, 1H), 8 .11 (d, J=6.5 Hz, 1H), 7.78 (dd, J=6.6, 1.5 Hz, 1H), 7.75 (d, J=9.5 Hz, 1H) , 7.09 (t, J=54.0 Hz, 1H), 4.27-4.15 (m, 2H), 4.08 (dt, J=13.1, 1.5 Hz, 1H), 3.90-3.79 (m, 2H), 3.61 (s, 6H), 3.57-3.45 (m, 2H), 3.43-3.36 (m, 1H), 3. 35 (s, 2H), 3.18 (dd, J=12.9, 10.6 Hz, 1H). II-103 473.1 2.38 II-104 435 2.21 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.46 (d, J=9.4 Hz, 1H), 8.23 (d, J=5.3 Hz, 1H ), 7.67 (d, J=1.3 Hz, 1H), 7.61 (d, J=9.4 Hz, 1H), 7.42 (dd, J=5.3, 1.3 Hz , 1H), 7.38 (s, 1H), 4.36-4.24 (m, 2H), 3.63-3.55 (m, 1H), 3.20-3.07 (m, 2H ), 2.97-2.91 (m, 1H), 2.90 (s, 3H), 2.69 (dd, J=12.9, 9.9 Hz, 1H), 1.88 (dd, J=13.1, 3.9 Hz, 1H), 1.80-1.56 (m, 4H), 1.49 (dtt, J=15.8, 12.3, 4.0 Hz, 1H) , 1.24 (tt, J=15.3, 7.7 Hz, 1H). II-105 453.1 2.22 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.61 (d, J=9.5 Hz, 1H), 8.40 (dd, J=7.3, 4, 9 Hz, 1H), 8.00 (dd, J=13.5, 2.8 Hz, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.31-7.07 ( m, 3H), 4.27-4.02 (m, 3H), 3.71-3.39 (m, 3H), 3.39-3.11 (m, 2H), 2.98 (d, J=13.6 Hz, 3H), 1.28-1.18 (m, 3H). II-106 453.1 2.37 1H NMR (500 MHz, DMSO-d6) δ 8.76 (d, J=10.8 Hz, 1H), 8.51 (dd, J=9.4, 2.5 Hz, 1H), 8.24 (t, J=5.6 Hz, 1H), 7.88 (d, J=24.0 Hz, 1H), 7.68 (dd, J=9.4, 3.7 Hz, 1H), 7 ,63-7.55 (m, 1H), 7.33 (t, J=53.7 Hz, 1H), 7.16 (dd, J=48.0, 8.4 Hz, 1H), 4, 36 (d, J=12.8 Hz, 1H), 4.23-4.15 (m, 1H), 4.15-4.02 (m, 2H), 3.67-3.59 (m, 2H), 3.59-3.33 (m, 1H), 3.05 (t, J=12.3 Hz, 1H), 2.97 (d, J=14.6 Hz, 3H), 2, 84 (dd, J=13.1, 10.2 Hz, 1H), 1.23 (dd, J=6.7, 2.6 Hz, 3H). II-107 398.7 2.19 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H ), 7.79 (br s, 1H), 7.72 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.57 (dd, J=5.4, 1 ,3 Hz, 1H), 7.56 (br s, 1H), 7.28 (t, J=53.9 Hz, 1H), 4.62-4.59 (m, 1H), 4.37 ( d, J=13.3 Hz, 1H), 4.20 (d, J=12.3 Hz, 1H), 4.05 (d, J=11.5 Hz, 1H), 3.74 (td, J=11.7, 3.2 Hz, 1H), 3.05-2.95 (m, 2H) II-108 398.6 2.19 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H ), 7.80 (br s, 1H), 7.72 (s, 1H), 7.62 (d, J=9.5 Hz, 1H), 7.57 (dd, J=5.5, 1 ,2 Hz, 1H), 7.56 (br s, 1H), 7.28 (t, J=53.9 Hz, 1H), 4.60 (dd, J=10.6, 2.5 Hz, 1H), 4.38 (d, J=11.9 Hz, 1H), 4.20 (d, J=12.5 Hz, 1H), 4.05 (d, J=9.1 Hz, 1H) , 3.77-3.72 (m, 1H), 3.05-2.95 (m, 2H). II-109 451.1 2.65 II-110 439.1 2.07 1H NMR (500 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.51 (d, J=9.4 Hz, 1H), 8.36 (d, J=6.1 Hz, 1H ), 8.12 (d, J=2.6 Hz, 1H), 7.65 (d, J=9.3 Hz, 1H), 7.41-7.14 (m, 2H), 6.94 (d, J=5.9 Hz, 1H), 4.05 (dd, J=11.3, 3.2 Hz, 1H), 3.99 (d, J=12.7 Hz, 1H), 3 .86 (s, 1H), 3.71-3.61 (m, 2H), 3.17 (t, J=6.0 Hz, 2H), 3.04 (s, 1H), 2.96 ( s, 3H), 2.80 (s, 1H). II-111 453.2 1.98 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.55 (s, 1H), 8.44 (d, J=9.4 Hz, 1H), 7.59 (d , J=9.4 Hz, 1H), 7.22 (t, J=53.8 Hz, 1H), 7.05 (t, J=6.1 Hz, 1H), 6.89 (s, 1H ), 6.72 (d, J=1.1 Hz, 1H), 4.29-3.93 (m, 2H), 2.98-2.82 (m, 6H), 2.70-2, 60 (m, 1H), 1.89-1.79 (m, 1H), 1.78-1.66 (m, 2H), 1.57-1.42 (m, 1H), 1.27- 1.17 (m, 1H). II-112 454.3 1.85 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=3.0 Hz, 1H), 8.59 (dd, J=5.8, 1.1 Hz, 1H), 8.53 (dd, J=9.4, 1.8 Hz, 1H), 8.01 (dd, J=4.4, 1.2 Hz, 1H), 7.69 (dd, J=9.4, 2 ,9 Hz, 1H), 7.31 (t, J=53.6 Hz, 1H), 4.37 (s, 3H), 3.97 (s, 1H), 3.56-3.36 (m , 1H), 3.23-3.02 (m, 2H), 3.00-2.81 (m, 4H), 1.76 (d, J=13.2 Hz, 1H), 1.55 ( d, J=11.4 Hz, 1H), 1.46-1.26 (m, 1H). II-113 357.1 1.94 1H NMR (500 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.65 (dd, J=5.3, 0.8 Hz, 1H), 8.51 (d, J=9, 4 Hz, 1H), 8.49-8.45 (m, 1H), 8.38 (s, 1H), 8.13 (s, 1H), 8.10 (dd, J=5.3, 1 ,7 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.36 (t, J=53.8 Hz, 1H), 5.03-4.89 (m, 1H ), 4.23 (t, J=5.6 Hz, 2H), 3.81 (t, J=5.6 Hz, 2H). II-114 465.2 2.68 II-115 451.2 2.63 II-116 466.1 2.61 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.47 (d, J=9.6 Hz, 1H), 7.63 (d, J=9.3 Hz, 1H ), 7.37-7.05 (m, 2H), 6.99-6.60 (m, 2H), 4.20-3.99 (m, 2H), 3.03 (s, 1H), 2.98-2.81 (m, 9H), 1.90-1.81 (m, 1H), 1.81-1.69 (m, 2H), 1.60-1.46 (m, 1H ), 1.34-1.20 (m, 1H). II-117 462.1 2.5 1H NMR (500 MHz, DMSO-d6) δ 9.05 (d, J=1.8 Hz, 1H), 8.75 (s, 1H), 8.51 (d, J=9.4 Hz, 1H ), 8.46 (d, J=1.8 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.26 (t, J=53.7 Hz, 1H), 7.08 (t, J=6.2 Hz, 1H), 3.69-3.56 (m, 2H), 3.06-2.92 (m, 3H), 2.90 (s, 3H) , 2.78 (dd, J=12.0, 9.5 Hz, 1H), 1.96-1.81 (m, 3H), 1.77-1.64 (m, 1H), 1.32 -1.16 (m, 1H). II-118 453.1 2.33 1H NMR (500 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.51 (d, J=9.4 Hz, 1H), 8.23 (d, J=5.7 Hz, 1H ), 7.85 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.60 (d, J=5.9 Hz, 1H), 7.28 (t, J =53.8 Hz, 1H), 7.15 (t, J=6.2 Hz, 1H), 4.12-4.06 (m, 1H), 4.00 (p, J=5.9 Hz , 1H), 3.87 (dd, J=12.8, 3.2 Hz, 1H), 3.68-3.61 (m, 2H), 3.28-3.15 (m, 3H), 2.93 (s, 3H), 1.21 (d, J=6.3 Hz, 3H). II-119 453.1 2.41 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.51 (d, J=9.4 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H ), 7.84 (s, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.60 (d, J=5.6 Hz, 1H), 7.28 (t, J =53.8 Hz, 1H), 7.22 (t, J=6.3 Hz, 1H), 4.33 (d, J=12.4 Hz, 1H), 4.21 (dt, J=13 ,1, 1.9 Hz, 1H), 3.75-3.64 (m, 2H), 3.19-3.11 (m, 2H), 2.97 (s, 3H), 2.69- 2.61 (m, 2H), 1.23 (d, J=6.2 Hz, 3H). II-120 467.8 2.8 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.45 (d, J=9.4 Hz, 1H), 7.60 (d, J=9.4 Hz, 1H ), 7.39-7.13 (m, 2H), 7.10 (t, J=6.2 Hz, 1H), 6.92 (s, 1H), 4.32 (dd, J=13, 1, 3.9 Hz, 1H), 4.21 (dt, J=13.1 Hz, 1H), 3.86 (s, 3H), 3.03-2.84 (m, 6H), 2, 72 (dd, J=13.0, 10.2 Hz, 1H), 1.91-1.81 (m, 1H), 1.80-1.65 (m, 2H), 1.58-1, 44 (m, 1H), 1.32-1.18 (m, 1H). II-121 439.1 2.22 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H ), 7.70 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.54 (dd, J=5.3, 1.3 Hz, 1H), 7.27 (t, J=53.7 Hz, 1H), 7.22 (t, J=6.3 Hz, 1H), 4.34 (d, J=12.4 Hz, 1H), 4.12 (d , J=12.2 Hz, 1H), 4.02 (dd, J=11.4, 3.0 Hz, 1H), 3.65-3.58 (m, 2H), 3.15 (t, J=6.1 Hz, 2H), 2.98-2.92 (m, 1H), 2.95 (s, 3H), 2.66-2.64 (m, 1H). II-122 455.1 2.74 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.49 (d, J=9.4 Hz, 1H), 7.65 (d, J=9.4 Hz, 1H ), 7.56 (s, 1H), 7.29 (t, J=53.7 Hz, 1H), 7.16-7.08 (m, 2H), 4.35-4.27 (m, 1H), 4.23-4.13 (m, 1H), 3.05-2.95 (m, 1H), 2.95-2.89 (m, 5H), 2.74 (dd, J= 13.1, 10.3 Hz, 1H), 1.90-1.81 (m, 1H), 1.80-1.65 (m, 2H), 1.57-1.43 (m, 1H) , 1.32-1.21 (m, 1H). II-123 423.1 2.23 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.19 (dd, J=5.3, 0, 7 Hz, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.38 (s, 1H), 7.32 (dd, J=5.3, 1.4 Hz, 1H) , 7.27 (t, J=54.0 Hz, 1H), 7.21-7.16 (m, 1H), 3.66 (dd, J=10.5, 7.3 Hz, 1H), 3.60 -3.55 (m, 1H), 3.46 (dt, J=10.3, 7.4 Hz, 1H), 3.25 (dd, J=10.5, 6.8 Hz, 1H), 3.07-3.05 (m, 2H), 2.93 (s, 3H), 2.53-2.47 (m, 1H), 2.17-2.10 (m, 1H) , 1.81 (dq, J=12.0, 7.9 Hz, 1H). II-124 439.1 2.51 1H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.77 (s, 1H), 8.52 (d, J=9.4 Hz, 1H), 8.20 (d , J=5.8 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.53 (s, 1H), 7.26 (t, J=53.8 Hz, 1H ), 4.07 (s, 2H), 3.67 (s, 4H), 2.97 (s, 3H), 1.98 (dt, J=11.6, 5.5 Hz, 1H), 1 .90-1.67 (m, 1H), 1.60 (s, 1H). II-125 437.1 2.3 1H NMR (500 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.46 (d, J=9.4 Hz, 1H), 8.28 (d, J=5.9 Hz, 1H ), 8.11 (d, J=2.6 Hz, 1H), 7.59 (d, J=9.4 Hz, 1H), 7.25 (t, J=53.9 Hz, 1H), 7.12 (t, J=6.1 Hz, 1H), 6.83 (dd, J=6.0, 2.6 Hz, 1H), 4.04-3.95 (m, 1H), 3 .95-3.86 (m, 1H), 3.06-2.86 (m, 6H), 2.76 (dd, J=13.1, 10.3 Hz, 1H), 1.90-1 .80 (m, 1H), 1.80-1.67 (m, 2H), 1.60-1.47 (m, 1H), 1.35-1.21 (m, 1H). II-126 451.1 2.39 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.30 (d, J=5.3 Hz, 1H ), 7.75 (s, 1H), 7.64 (d, J=9.4 Hz, 1H), 7.61 (dd, J=5.3, 1.3 Hz, 1H), 7.29 (t, J=53.7 Hz, 1H), 3.89 (d, J=9.1 Hz, 2H), 3.82 (d, J=9.2 Hz, 2H), 3.83-3 .77 (m, 2H), 3.77 (s, 2H), 3.54-3.52 (m, 2H), 3.07 (s, 3H). II-127 373.1 1.97 1H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.33 (d, J=5.9 Hz, 1H ), 8.14 (d, J=2.5 Hz, 1H), 7.61 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.7 Hz, 1H), 6.88 (dd, J=6.0, 2.6 Hz, 1H), 3.68-3.60 (m, 4H), 3.55-3.49 (m, 2H), 3.48- 3.41 (m, 2H), 2.08 (s, 3H). II-128 436.1 2.5 1H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.46 (d, J=9.4 Hz, 1H), 8.23 (dd, J=5.3, 0, 7 Hz, 1H), 7.70-7.65 (m, 1H), 7.61 (d, J=9.4 Hz, 1H), 7.42 (dd, J=5.3, 1.3 Hz, 1H), 7.38 (s, 1H), 4.29 (tt, J=8.9, 3.6 Hz, 2H), 3.27-3.19 (m, 2H), 2.98 (s, 3H), 2.93 (ddd, J=12.9, 11.5, 2.9 Hz, 1H), 2.71 (dd, J=13.0, 9.6 Hz, 1H), 1.94-1.86 (m, 1H), 1.79-1.69 (m, 2H), 1.70-1.59 (m, 2H), 1.49 (tdd, J=11.9 , 7.9, 3.9 Hz, 1H), 1.31-1.15 (m, 1H). II-129 451.1 2.69 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.52 (d, J=9.4 Hz, 1H), 7.86 (s, 1H), 7.70 (d , J=9.4 Hz, 1H), 7.46 (s, 1H), 7.28 (t, J=53.7 Hz, 1H), 7.12 (t, J=6.2 Hz, 1H ), 4.25-4.10 (m, 2H), 3.27-3.12 (m, 1H), 3.09-2.86 (m, 6H), 1.94-1.74 (m , 3H), 1.63-1.50 (m, 1H), 1.41-1.27 (m, 1H). II-130 462.2 2.71 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.50 (d, J=9.4 Hz, 1H), 8.04 (d, J=1.3 Hz, 1H ), 7.96 (d, J=1.1 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.29 (t, J=53.7 Hz, 1H), 7.12 (t, J=6.1 Hz, 1H), 4.39-4.32 (m, 1H), 4.26-4.16 (m, 1H), 3.05 (ddd, J= 13.5, 11.3, 3.0 Hz, 1H), 2.97-2.88 (m, 5H), 2.79 (dd, J=13.1, 10.2 Hz, 1H), 1 .90-1.81 (m, 1H), 1.81-1.66 (m, 2H), 1.56-1.43 (m, 1H), 1.34-1.20 (m, 1H) . II-131 489.2 1.9 1H NMR (500 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.24-9.18 (m, 1H), 8.82 (s, 1H), 8.68 (d, J= 5.2 Hz, 1H), 8.54 (d, J=9.4 Hz, 1H), 8.47 (dd, J=5.2, 1.6 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.27 (s, 1H), 4.51 (dd, J=13.3, 5.6 Hz, 1H), 4.37 (td, J=11.8 , 10.9, 2.9 Hz, 1H), 3.66 (dt, J=13.2, 6.8 Hz, 1H), 3.51 (d, J=13.7 Hz, 1H), 3 .38 (td, J=8.9, 4.7 Hz, 1H), 3.09-2.97 (m, 1H), 2.95 (s, 3H), 2.82 (d, J=8 ,9 Hz, 1H), 2.40-2.27 (m, 1H). II-132 489.9 1.96 1H NMR (500 MHz, DMSO-d6) δ 9.33 (d, J=1.6 Hz, 1H), 8.80 (s, 1H), 8.66 (d, J=5.2 Hz, 1H ), 8.53 (d, J=9.4 Hz, 1H), 8.43 (dd, J=5.2, 1.7 Hz, 1H), 7.71 (d, J=9.4 Hz , 1H), 7.39-7.15 (m, 2H), 4.28-4.15 (m, 1H), 4.11-3.93 (m, 1H), 3.47 (ddd, J =13.6, 5.9, 3.4 Hz, 1H), 3.25-3.18 (m, 1H), 3.10-2.96 (m, 2H), 2.92 (s, 3H ), 2.31 (t, J=12.6 Hz, 1H). II-133 451.2 2.58 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.23 (dd, J=5.4, 0, 6 Hz, 1H), 7.65-7.63 (m, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.39 (dd, J=5.3, 1.3 Hz, 1H), 7.37 (s, 1H), 7.07 (d, J=8.7 Hz, 1H), 4.56-4.46 (m, 1H), 4.34 (d, J =13.2 Hz, 1H), 3.27-3.20 (m, 1H), 2.94 (s, 3H), 2.80 (td, J=12.5, 2.8 Hz, 1H) , 2.63 (dd, J=13.1, 11.0 Hz, 1H), 1.87-1.70 (m, 2H), 1.49 (tddd, J=16.7, 12.7, 7.6, 3.7 Hz, 2H), 1.30 (qd, J=12.3, 3.8 Hz, 1H), 1.19 (d, J=6.7 Hz, 3H). II-134 451.2 2.52 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.23 (d, J=5.3 Hz, 1H ), 7.68 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.39 (dd, J=5.3, 1.3 Hz, 1H), 7.36 (s, 1H), 7.02 (d, J=8.6 Hz, 1H), 4.31 (t, J=15.4 Hz, 2H), 2.93 (s, 3H), 2.91 -2.74 (m, 2H), 1.90 (d, J=11.5 Hz, 1H), 1.77 (ddd, J=13.1, 5.5, 3.3 Hz, 1H), 1.57-1.40 (m, 2H), 1.34 (qd, J=12.1, 3.7 Hz, 1H), 1.21 (d, J=6.7 Hz, 3H). II-135 375.1 2.05 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.52 (d, J=9.4 Hz, 1H), 8.25 (d, J=5.7 Hz, 1H ), 7.95 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.64 (dd, J=5.8, 1.4 Hz, 1H), 7.48 -7.14 (m, 3H), 4.40 (dt, J=13.1, 1.9 Hz, 1H), 4.06 (ddd, J=10.3, 6.7, 2.8 Hz , 3H), 3.78-3.68 (m, 1H), 3.26-3.16 (m, 1H), 3.14-3.03 (m, 1H). II-136 449.2 2.56 1H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.50 (d, J=9.5 Hz, 1H), 8.24 (d, J=5.8 Hz, 1H ), 7.84 (s, 1H), 7.65 (d, J=10.0 Hz, 1H), 7.54 (s, 1H), 7.28 (t, J=53.6 Hz, 1H ), 3.81 (s, 2H), 3.67-3.61 (m, 4H), 3.55-3.52 (m, 2H), 3.04 (s, 3H), 1.84- 1.82 (m, 2H), 1.64 (br s, 2H). II-137 440.2 1.53 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.56-8.52 (m, 2H), 7.74-7.67 (m, 2H), 7.47- 7.14 (m, 2H), 5.24-5.15 (2×s, 1H), 3.82-3.78 (m, 0.4H), 3.63-3.51 (m, 3 ,6H), 3.21-3.17 (m, 2H), 2.98-2.96 (2×s, 3H), 2.15-2.11 (m, 0.2H), 1.98 -1.92 (m, 1.8H). II-138 421.2 2.12 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=1.9 Hz, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.23 (d, J =5.3 Hz, 1H), 7.73-7.69 (m, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.43 (dt, J=5.3, 1.2 Hz, 2H), 4.46-4.33 (m, 1H), 4.31-4.14 (m, 1H), 3.78 (d, J=16.6 Hz, 1H), 3.16-3.01 (m, 3H), 3.00-2.95 (m, 3H), 2.21 (d, J=7.3 Hz, 1H), 2.04-1.91 ( m, 1H), 1.71 (dq, J=12.2, 4.0 Hz, 1H), 1.54 (dd, J=16.9, 7.8 Hz, 1H), 1.44 (qd , J=11.1, 5.5 Hz, 1H). II-139 455.2 2.38 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.22 (d, J=5.4 Hz, 1H ), 7.74 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.46 (d, J=5.5 Hz, 1H), 7.43-7.35 (m, 1H), 7.27 (s, 1H), 4.37 (dd, J=14.0, 9.4 Hz, 1H), 4.14 (dt, J=13.1, 3.9 Hz, 1H), 3.28-3.13 (m, 4H), 1.98-1.61 (m, 4H). II-140 440.1 1.52 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.56-8.52 (m, 2H), 7.73-7.68 (m, 2H), 7.46- 7.18 (m, 1H), 7.11 (br s, 1H), 4.42 (s, 0.5H), 4.34 (s, 0.5H), 3.91-3.87 (m , 0.4H), 3.75 (d, J=12.4 Hz, 0.2H), 3.69-3.59 (m, 2H), 3.47 (d, J=10.8 Hz, 0.4H), 3.29 (q, J=11.7, 10.2 Hz, 1H), 3.20-3.10 (m, 1H), 2.96-2.94 (2×s, 3H), 242-2.38 (m, 2H). II-141 453.1 1.96 1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.44 (d, J=9.4 Hz, 1H), 7.59 (d, J=9.4 Hz, 1H ), 7.22 (t, J=53.8 Hz, 1H), 7.05 (t, J=6.1 Hz, 1H), 6.92 (s, 1H), 6.73 (d, J =1.1 Hz, 1H), 4.23-4.00 (m, 2H), 2.93-2.85 (m, 6H), 2.68-2.62 (m, 1H), 1, 90-1.79 (m, 1H), 1.78-1.65 (m, 2H), 1.54-1.43 (m, 1H), 1.28-1.17 (m, 1H). II-142 467.2 2.81 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.45 (d, J=9.4 Hz, 1H), 7.59 (d, J=9.4 Hz, 1H ), 7.39-7.12 (m, 2H), 7.09 (t, J=6.2 Hz, 1H), 6.91 (d, J=0.9 Hz, 1H), 4.31 (dd, J=13.0, 3.7 Hz, 1H), 4.25-4.18 (m, 1H), 3.85 (s, 3H), 3.02-2.87 (m, 6H ), 2.71 (dd, J=13.0, 10.1 Hz, 1H), 1.89-1.81 (m, 1H), 1.77-1.65 (m, 2H), 1, 55-1.43 (m, 1H), 1.32-1.20 (m, 1H). II-143 373.1 2.09 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.24 (d, J=5.3 Hz, 1H ), 7.71 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H), 7.34 (s, 1H ), 7.26 (t, J=53.9 Hz, 1H), 6.86 (s, 1H), 4.45 (d, J=12.1 Hz, 1H), 4.34 (d, J =12.4 Hz, 1H), 2.98-2.86 (m, 2H), 2.38-2.33 (m, 1H), 1.92 (d, J=9.0 Hz, 1H) , 1.75-1.62 (m, 2H), 1.52-1.47 (m, 1H). II-144 423.1 2.28 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.23 (d, J=5.3 Hz, 1H ), 7.71 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.42 (dd, J=5.3, 1.3 Hz, 1H), 7.29 (t, J=53.7 Hz, 1H), 6.89 (s, 2H), 4.38- 4.34 (m, 1H), 4.22 (dt, J=13.2, 4.1 Hz, 1H), 3.10-2.90 (m, 4H), 2.19-2.13 (m, 1H), 2.02-1.98 (m, 1H), 1.76-1, 70 (m, 1H), 1.57-1.50 (m, 1H), 1.45-1.38 (m, 1H). II-145 387.2 2.17 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H ), 7.70 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.40 (d, J=6.5 Hz, 1H), 7.33 (s, 1H ), 7.31 (t, J=53.8 Hz, 1H), 6.78 (s, 1H), 4.28 (d, J=10.9 Hz, 2H), 2.93 (td, J =13.0, 12.2, 2.9 Hz, 1H), 2.71-2.66 (m, 1H), 2.12-2.02 (m, 2H), 1.96-1.92 (m, 1H), 1.83-1.80 (m, 1H), 1.71 (dt, J=13.3, 3.6 Hz, 1H), 1.54-1.45 (m, 1H ), 1.24 (qd, J=12.0, 3.9 Hz, 1H). II-146 376.2 2.13 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H ), 7.71 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.52 (dd, J=5.3, 1.3 Hz, 1H), 7.28 (t, J=53.9 Hz, 1H), 4.50 (t, J=5.2 Hz, 1H), 4.24 (d, J=12.4 Hz, 1H), 4.14 (d , J=13.3 Hz, 1H), 3.97 (dd, J=11.1, 2.6 Hz, 1H), 3.65-3.55 (m, 4H), 2.90 (td, J=12.5, 3.5 Hz, 1H), 2.62 (dd, J=12.7, 10.6 Hz, 1H), 1.69-1.65 (m, 2H). II-147 398.1 2.18 1H NMR (500 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.51 (d, J=9.4 Hz, 1H), 8.26 (d, J=5.7 Hz, 1H ), 7.89 (s, 1H), 7.67 (dd, J=13.3, 4.0 Hz, 4H), 7.29 (t, J=53.9 Hz, 1H), 4.64 (dd, J=10.4, 2.7 Hz, 1H), 4.35 (d, J=13.5 Hz, 1H), 4.18 (d, J=13.8 Hz, 1H), 4 .09-4.06 (m, 1H), 3.77 (td, J=11.7, 2.8 Hz, 1H), 3.12 (dt, J=24.2, 11.1 Hz, 2H ). II-148 467.1 2.52 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.24 (d, J=5.4 Hz, 1H ), 7.69 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.49 (dd, J=5.3, 1.3 Hz, 1H), 7.26 (t, J=53.9 Hz, 1H), 7.14 (s, 1H), 4.45 (d, J=12.3 Hz, 1H), 4.14 (d, J=12.0 Hz , 1H), 3.87-3.82 (m, 1H), 3.08 (d, J=5.7 Hz, 2H), 2.96 (s, 3H), 2.75 (d, J= 12.8 Hz, 1H), 2.57-2.53 (m, 1H), 1.25 (s, 3H), 1.23 (s, 3H). II-149 439.1 2.2 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.28 (d, J=5.3 Hz, 1H ), 7.70 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.54 (dd, J=5.3, 1.3 Hz, 1H), 7.27 (t, J=53.7 Hz, 1H), 7.22 (t, J=6.3 Hz, 1H), 4.34 (d, J=12.2 Hz, 1H), 4.12 (d , J=12.7 Hz, 1H), 4.03-4.00 (m, 1H), 3.65-3.58 (m, 2H), 3.14 (t, J=6.1 Hz, 2H), 2.98-2.92 (m, 1H), 2.95 (s, 3H), 2.68-2.64 (m, 1H). II-150 372.2 2.38 1H NMR (500 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.43 (d, J=9.4 Hz, 1H), 7.76 (t, J=2.0 Hz, 1H ), 7.64-7.59 (m, 1H), 7.57 (d, J=9.4 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.24 (t, J=53.8 Hz, 1H), 7.05 (dd, J=8.3, 2.5 Hz, 1H), 3.68-3.57 (m, 4H), 3.24 ( dt, J=33.2, 5.2 Hz, 4H), 2.06 (s, 3H). II-151 406.1 2.19 1H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J=6.0 Hz, 1H), 8.54 (d, J=9.4 Hz, 1H), 8.17 (dd, J =6.1, 4.5 Hz, 1H), 8.06 (d, J=16.1 Hz, 1H), 7.72 (dd, J=9.4, 2.1 Hz, 1H), 7 ,60 (s, 1H), 7.36 (td, J=53.7, 21.8 Hz, 1H), 4.29 (dd, J=32.8, 13.2 Hz, 1H), 4, 14 (t, J=14.2 Hz, 1H), 3.20 (dd, J=45.0, 31.8 Hz, 1H), 2.90-2.65 (m, 2H), 2.61 (d, J=6.9 Hz, 3H), 2.18 (s, 1H), 2.05-1.90 (m, 1H), 1.82 (d, J=13.4 Hz, 1H) , 1.64 (t, J=12.1 Hz, 1H), 1.52 (q, J=11.3, 10.9 Hz, 1H). II-152 440.2 1.49 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.56 (d, J=1.2 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.74-7.68 (m, 2H), 7.47-7.15 (m, 2H), 4.22 (d, J=35.8 Hz, 1H), 3.74 (s, 2H), 3.50 (d, J=13.2 Hz, 1H), 3.07 (s, 1H), 2.95-2.90 (m, 2H), 2.91 (s, 3H), 2.47-2.40 (m, 1H). II-153 473.1 2.58 1H NMR (500 MHz, methanol-d4) δ 8.49 (s, 1H), 8.33 (d, J=9.4 Hz, 1H), 8.27 (d, J=5.4 Hz, 1H ), 7.86 (d, J=1.2 Hz, 1H), 7.64 (d, J=9.4 Hz, 1H), 7.48 (dd, J=5.5, 1.4 Hz , 1H), 7.06 (t, J=54.1 Hz, 1H), 4.40 (d, J=13.9 Hz, 1H), 4.33 (d, J=13.7 Hz, 1H ), 3.53 (dd, J=13.6, 3.9 Hz, 1H), 3.48-3.36 (m, 2H), 3.36-3.34 (m, 1H), 3, 22-3.12 (m, 2H), 2.99 (s, 3H), 2.31 (ddd, J=21.0, 9.5, 4.8 Hz, 1H). II-154 437.2 2.43 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.23 (d, J=5.3 Hz, 1H ), 7.68 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.41 (dd, J=5.3, 1.3 Hz, 1H), 7.26 (t, J=53.8 Hz, 1H), 7.11-7.08 (m, 1H), 4.39 (dd, J=12.2, 2.9 Hz, 1H), 4.24- 4.20 (m, 1H), 2.98-2.91 (m, 3H), 2.91 (s, 3H), 2.69 (dd, J=13.1, 10.3 Hz, 1H) , 1.88-1.84 (m, 1H), 1.77-1.68 (m, 2H), 1.53-1.46 (m, 1H), 1.29-1.22 (m, 1H). II-155 437.2 2.44 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.47 (d, J=9.5 Hz, 1H), 8.24 (d, J=5.4 Hz, 1H ), 7.68 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.41 (dd, J=5.3, 1.2 Hz, 1H), 7.26 (t, J=53.8 Hz, 1H), 7.10 (t, J=6.2 Hz, 1H), 4.39 (dd, J=13.4, 3.2 Hz, 1H), 4 .25-4.20 (m, 1H), 2.98-2.91 (m, 3H), 2.91 (s, 3H), 2.69 (dd, J=13.0, 10.3 Hz , 1H), 1.85 (dd, J=13.2, 4.1 Hz, 1H), 1.77-1.68 (m, 2H), 1.54-1.46 (m, 1H), 1.30-1.22 (m, 1H). II-156 399.1 2.06 1H NMR (300 MHz, DMSO-d6) 1.49-1.64 (m, 2H), 1.69-1.87 (m, 3H), 1.93-2.03 (m, 1H), 2 .77-2.94 (m, 2H), 3.11-3.28 (m, 2H), 4.29 (d, J=12.6 Hz, 1H), 4.42 (d, J=12 ,3 Hz, 1H), 7.06-7.48 (m, 2H), 7.62 (d, J=9.0 Hz, 1H), 7.66-7.76 (m, 2H), 8 .20 (d, J=5.0 Hz, 1H), 8.47 (d, J=9.5 Hz, 1H), 8.68 (s, 1H). II-157 437.1 2.16 1H NMR (300 MHz, DMSO-d6) 1.14-1.33 (m, 1H), 1.40-1.58 (m, 1H), 1.63-1.90 (m, 3H), 2 .66 (dd, J=12.8, 10.6 Hz, 1H), 2.84-3.00 (m, 6H), 4.22 (br. d, J=12.8 Hz, 1H), 4.40 (br. d, J=10.9 Hz, 1H), 7.05-7.47 (m, 3H), 7.61 (d, J=9.0 Hz, 1H), 7.67 (s, 1H), 8.22 (d, J=5.1 Hz, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.64 (s, 1H). II-158 454.3 1.91 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58-8.50 (m, 2H), 8.00 (d, J=1.2 Hz, 1H), 7 .70 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.6 Hz, 1H), 7.02 (t, J=6.7 Hz, 1H), 4.71 (s, 1H), 3.91 (s, 1H), 3.30 (d, J=18.1 Hz, 3H), 3.00 (d, J=6.6 Hz, 2H), 2.92 (s, 3H), 1.85-1.68 (m, 2H), 1.60 (dd, J=19.0, 9.2 Hz, 2H). II-159 454.3 2.15 1H NMR (500 MHz, DMSO-d6) δ 8.67-8.61 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.01 (d, J=1, 2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.46-7.01 (m, 2H), 4.28 (s, 3H), 4.09-4, 04 (m, 1H), 3.62-3.49 (m, 2H), 3.43 (ddd, J=10.7, 5.0, 2.5 Hz, 1H), 3.11 (d, J=12.3 Hz, 1H), 2.96 (s, 3H), 1.22 (d, J=6.9 Hz, 3H). II-160 371.2 2.18 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.28 (s, 1H), 8.25 (dd , J=5.4, 0.7 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J=9.4 Hz, 1H), 7.57 (d, J=5, 5 Hz, 1H), 7.28 (t, J=53.9 Hz, 1H), 4.22 (s, 2H), 3.75 (s, 2H), 0.85 n- 0.83 (m , 2H), 0.80-0.78 (m, 2H). II-161 399.3 2.29 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.50 (d, J=9.4 Hz, 1H), 8.31 (s, 2H), 8.21 (d , J=5.6 Hz, 1H), 7.83 (s, 1H), 7.66 (d, J=9.5 Hz, 1H), 7.49 (s, 1H), 7.28 (t , J=53.8 Hz, 1H), 3.66-3.63 (m, 4H), 3.10 (s, 4H), 1.67 (t, J=5.9 Hz, 4H), 1 .61 (t, J=5.7 Hz, 4H). II-162 360.2 2.36 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.21 (d, J=5.0 Hz, 1H ), 7.73 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.36 (dd, J=5.3, 1.3 Hz, 1H), 7.20 (t, J=53.9 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H), 4.41-4.37 (m, 1H), 4.31-4.27 ( m, 1H), 3.44-3.33 (m, 2H), 2.94-2.89 (m, 1H), 2.68 (dd, J=13.0, 10.4 Hz, 1H) , 1.80-1.77 (m, 1H), 1.74-1.62 (m, 2H), 1.53-1.44 (m, 1H), 1.23 (qd, J=12, 1, 3.9 Hz, 1H). II-163 387.3 2.16 1H NMR (400 MHz, 380 K, DMSO-d6) δ 8.51 (s, 1H), 8.39 (d, J=9.6 Hz, 1H), 8.21 (d, J=6.0 Hz, 1H), 7.59 (s, 1H), 7.55 (d, J=9.4 Hz, 1H), 7.27 (dd, J=5.3, 1.4 Hz, 1H), 7.17 (t, J=54.1 Hz, 1H), 3.88-3.76 (m, 4H), 3.71-3.68 (m, 2H), 3.48-3.45 ( m, 2H), 2.00-1.88 (m, 5H). II-164 359.2 1.97 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.26 (dd, J=5.3, 0, 7 Hz, 1H), 7.69 (s, 1H), 7.64-7.61 (m, 2H), 7.43 (dd, J=5.3, 1.3 Hz, 1H), 7, 29 (t, J=53.9 Hz, 1H), 3.89-3.85 (m, 4H), 3.25-3.23 (m, 2H), 2.57-2.55 (m, 2H). II-165 343.2 2.01 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.46 (d, J=9.3 Hz, 1H), 8.17 (d, J=5.3 Hz, 1H ), 7.61 (d, J=9.4 Hz, 1H), 7.38-7.16 (m, 3H), 4.73 (s, 1H), 3.68 (s, 1H), 3 .53 (dd, J=9.3, 2.1 Hz, 1H), 3.26 (d, J=8.4 Hz, 1H), 2.93 (dd, J=9.5, 1.9 Hz, 1H), 2.84 (d, J=9.5 Hz, 1H), 1.80 (d, J=8.5 Hz, 1H), 1.69 (d, J=9.3 Hz, 1H). II-166 345.2 2.11 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.46 (d, J=9.4 Hz, 1H), 8.18 (d, J=5.3 Hz, 1H ), 7.60 (d, J=9.4 Hz, 1H), 7.58 (s, 1H), 7.35-7.14 (m, 2H), 3.76 (t, J=6, 2 Hz, 2H), 3.71 (t, J=5.3 Hz, 2H), 2.89 (d, J=5.2 Hz, 2H), 2.68 (t, J=5.9 Hz , 2H), 1.85-1.81 (m, 2H). II-167 385.2 2.19 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.27 (d, J=5.3 Hz, 1H ), 7.75 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.54-7.53 (m, 1H), 7.30 (t, J=53, 8 Hz, 1H), 4.63-4.59 (m, 1H), 4.49-4.45 (m, 1H), 3.90 (d, J=10.9 Hz, 2H), 3, 66-3.60 (m, 1H), 2.90-2.80 (m, 1H), 2.69-2.66 (m, 1H), 2.31-2.28 (m, 1H), 2.21-2.15 (m, 1H), 1.69-1.63 (m, 1H), 1.21 (d, J=7.1 Hz, 1H). II-168 374.2 2.38 1H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.46 (d, J=9.7 Hz, 1H), 8.22 (d, J=5.3 Hz, 1H ), 7.68 (s, 1H), 7.61 (d, J=9.6 Hz, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.28 (t, J =53.8 Hz, -1H), 4.39-4.37 (m, 3H), 3.50-3.47 (m, 2H), 2.86 (t, J=12.0 Hz, 2H ), 1.76 (d, J=13.0 Hz, 2H), 1.72-1.65 (m, 1H), 1.40 (q, J=6.6 Hz, 2H), 1.21 -1.12 (m, 2H). II-169 361.2 1.88 1H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.24 (d, J=5.3 Hz, 1H ), 7.69 (s, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.45 (dd, J=5.4, 1.3 Hz, 1H), 7.26 (t, J=53.9 Hz, 1H), 4.77-4.75 (m, 1H), 4.31 (d, J=12.1 Hz, 1H), 4.19 (d, J= 12.4 Hz, 1H), 3.45-3.41 (m, 2H), 3.05 (d, J=11.5 Hz, 1H), 2.90-2.85 (m, 1H), 2.79-2.75 (m, 2H), 2.56-2.52 (m, 1H). II-170 403.2 2.16 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.27 (d, J=5.4 Hz, 1H ), 7.72 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.52 (dd, J=5.3, 1.3 Hz, 1H), 7.30 (t, J=53.7 Hz, 1H), 4.16 (s, 2H), 3.65-3.56 (m, 8H), 3.32 (s, 3H). II-171 373.2 1.96 1H NMR (500 MHz, DMSO-d6) δ 8.83 (d, J=1.7 Hz, 1H), 8.56 (s, 1H), 8.46 (d, J=9.4 Hz, 1H ), 8.39 (d, J=2.8 Hz, 1H), 8.09 (t, J=2.3 Hz, 1H), 7.59 (d, J=9.4 Hz, 1H), 7.27 (t, J=53.7 Hz, 1H), 3.64 (dt, J=6.4, 2.8 Hz, 4H), 3.37 (t, J=5.4 Hz, 2H ), 3.30 (m, 2H - hidden under DMSO), 2.07 (s, 3H). II-172 386.2 2.06 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H ), 7.72 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.52 (dd, J=5.3, 1.3 Hz, 1H), 7.29 (t, J=53.9 Hz, 1H), 6.51 (s, 1H), 4.48 (dd, J=13.0, 4.3 Hz, 1H), 4.35 (d, J= 11.4 Hz, 1H), 3.74-3.67 (m, 2H), 3.44 (t, J=8.8 Hz, 1H), 3.01 (dd, J=9.2, 4 ,6 Hz, 1H), 2.91 (td, J=12.4, 3.3 Hz, 1H), 2.85-2.76 (m, 2H). II-173 386.2 2.07 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.26 (d, J=5.3 Hz, 1H ), 7.71 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.52 (dd, J=5.4, 1.2 Hz, 1H), 7.29 (t, J=53.9 Hz, 1H), 6.51 (s, 1H), 4.49-4.46 (m, 1H), 4.35 (d, J=11.4 Hz, 1H) , 3.74-3.67 (m, 2H), 3.44 (t, J=8.8 Hz, 1H), 3.01 (dd, J=9.2, 4.8 Hz, 1H), 2.91 (td, J=12.4, 3.2 Hz, 1H), 2.85-2.76 (m, 2H). II-174 369.2 1.94 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.50-8.48 (m, 2H), 8.33 (d, J=5.3 Hz, 1H), 7 .81 (s, 1H), 7.66-7.63 (m, 2H), 7.31 (t, J=53.8 Hz, 1H), 4.99 (s, 2H), 4.22- 4.20 (m, 2H), 4.16-4.14 (m, 2H). II-175 386.2 2.06 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H ), 7.72 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.52 (dd, J=5.3, 1.3 Hz, 1H), 7.29 (t, J=53.8 Hz, 1H), 6.51 (s, 1H), 4.48 (dd, J=12.8, 3.7 Hz, 1H), 4.35 (d, J= 13.0 Hz, 1H), 3.75-3.67 (m, 2H), 3.44 (t, J=8.8 Hz, 1H), 3.01 (dd, J=9.2, 4 ,8 Hz, 1H), 2.91 (td, J=12.6, 3.4 Hz, 1H), 2.85-2.76 (m, 2H). II-176 373.1 2.16 1H NMR (500 MHz, DMSO) δ 8.68 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 8.27 (d, J=5.1 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.51 (dd, J=5.3, 1.3 Hz, 1H), 7.30 (t , J=53.8 Hz, 1H), 3.68-3.66 (m, 2H), 3.61-3.58 (m, 6H), 2.07 (s, 3H). II-177 454.3 2.18 1H NMR (500 MHz, DMSO-d6) δ 8.69-8.61 (m, 2H), 8.55 (d, J=9.4 Hz, 1H), 7.98 (d, J=1, 2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.4 Hz, 1H), 4.42 (d, J=117.6 Hz , 2H), 4.06 (dd, J=11.4, 3.4 Hz, 1H), 3.57 (td, J=11.7, 2.8 Hz, 1H), 3.40 (dd, J=12.8, 5.6 Hz, 1H), 3.28 (ddd, J=10.2, 7.4, 2.6 Hz, 1H), 3.09 (d, J=13.1 Hz , 1H), 3.01 (s, 3H), 2.87 (d, J=11.9 Hz, 1H), 1.24 (d, J=6.6 Hz, 3H). II-178 418.8 1.85 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.56 (dd, J=5.4, 4, 0 Hz, 2H), 7.74 (d, J=9.5 Hz, 1H), 7.41 (t, J=53.6 Hz, 1H), 6.53 (t, J=5.5 Hz , 1H), 4.59 (t, J=5.5 Hz, 1H), 4.25-4.14 (m, 1H), 3.99 (d, J=14.7 Hz, 1H), 3 .39 (q, J=6.1 Hz, 2H), 3.16-3.07 (m, 2H), 3.06-3.00 (m, 1H), 2.99-2.85 (m , 1H), 2.79 (td, J=12.6, 2.8 Hz, 1H), 2.04 (d, J=3.7 Hz, 1H), 1.90-1.65 (m, 2H), 1.62-1.43 (m, 1H). II-179 416.2 2.14 1H NMR (500 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.35 (s, 1H), 8.06 (d, J=6.6 Hz, 1H), 7.93 (d , J=9.7 Hz, 1H), 7.67-7.53 (m, 2H), 7.09 (t, J=6.1 Hz, 1H), 4.13 (d, J=13, 3 Hz, 1H), 4.05 (d, J=13.3 Hz, 1H), 3.26 (t, J=12.0 Hz, 1H), 3.08 (t, J=11.7 Hz , 1H), 2.99-2.85 (m, 8H), 1.94-1.76 (m, 3H), 1.59 (q, J=12.3 Hz, 1H), 1.38 ( t, J=10.7 Hz, 1H). II-180 387.1 2.07 1H NMR (400 MHz, methanol-d4) δ 9.13 (d, J=1.3 Hz, 1H), 8.78 (s, 1H), 8.68 (d, J=1.3 Hz, 1H ), 8.42 (d, J=9.5 Hz, 1H), 7.74 (d, J=9.5 Hz, 1H), 7.14 (t, J=54.1 Hz, 1H), 4.82-4.65 (m, 4H), 4.01-3.53 (m, 1H), 3.20 (s, 2H), 2.99 (s, 1H), 2.59-2, 33 (m, 1H), 2.26-2.08 (m, 2H), 2.06-1.68 (m, 3H). II-181 436 2.02 II-182 389.1 2.21 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.41 (d, J=9.7 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H ), 7.82 (t, J=71.3 Hz, 1H), 7.77 (s, 1H), 7.47 (d, J=5.6 Hz, 1H), 7.31 (d, J =9.6 Hz, 1H), 3.72-3.70 (m, 2H), 3.62 (s, 6H), 2.08 (s, 3H). II-183 401.1 2.33 1H NMR (500 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.19 (d, J=5.3 Hz, 1H), 8.14 (d, J=9.3 Hz, 1H ), 7.74 (s, 1H), 7.39 (dd, J=5.3, 1.3 Hz, 1H), 7.27 (d, J=9.3 Hz, 1H), 7.09 (t, J=6.2 Hz, 1H), 4.37 (d, J=13.5 Hz, 1H), 4.24 (d, J=13.0 Hz, 1H), 2.98-2 .84 (m, 6H), 2.64 (s, 4H), 1.91-1.80 (m, 1H), 1.73 (ddd, J=18.1, 8.9, 4.9 Hz , 2H), 1.58-1.37 (m, 1H), 1.25 (tt, J=11.9, 5.8 Hz, 1H). II-184 422.9 2.2 II-185 353.2 1.65 1H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.30 (d, J=9.4 Hz, 1H), 8.19 (d, J=5.9 Hz, 1H ), 8.05 (s, 1H), 7.64 (d, J=5.9 Hz, 1H), 7.49 (d, J=9.4 Hz, 1H), 4.76 (s, 2H ), 3.74-3.72 (m, 2H), 3.67-3.65 (m, 6H), 2.08 (s, 3H). II-186 374 1.85 II-187 343.1 1.95 1H NMR (500 MHz, DMSO) δ 8.62 (s, 1H), 8.38 (d, J=9.5 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 7.67-7.65 (m, 2H), 7.55 (d, J=9.5 Hz, 1H), 7.47 (d, J=5.2 Hz, 1H), 3.90-3 .85 (m, 4H), 3.28 (t, J=6.6 Hz, 2H), 2.61-2.59 (m, 2H). II-188 355.1 2.02 1H NMR (500 MHz, DMSO) δ 8.68 (s, 2H), 8.56 (s, 1H), 8.37 (d, J=9.4 Hz, 1H), 8.23 (d, J =5.6 Hz, 1H), 7.56-7.52 (m, 2H), 7.41 (s, 1H), 3.94-3.90 (m, 2H), 3.69-3, 66 (m, 2H), 3.36-3.28 (m, 2H), 3.11-3.07 (m, 2H), 2.92-2.85 (m, 2H), 1.86- 1.81 (m, 1H), 1.62-1.55 (m, 1H). II-189 357.1 2.09 1H NMR (500 MHz, DMSO) δ 8.55 (s, 1H), 8.34 (d, J=9.5 Hz, 1H), 8.24 (d, J=5.5 Hz, 1H), 7.57 (s, 1H), 7.49 (d, J=9.5 Hz, 1H), 7.36 (dd, J=5.2, 1.2 Hz, 2H), 6.84 (s , 1H), 4.45-4.42 (m, 1H), 4.33 (d, J=13.4 Hz, 1H), 2.94 (dd, J=13.1, 11.1 Hz, 1H), 2.87 (td, J=12.9, 3.2 Hz, 1H), 2.37-2.32 (m, 1H), 1.91 (d, J=11.4 Hz, 1H ), 1.76-1.70 (m, 1H), 1.69-1.60 (m, 1H), 1.53-1.44 (m, 1H). II-190 388 1.97 II-191 418 1.81 II-192 396 1.71 II-193 337 2.03 1H NMR (500 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.23 (dd, J=5.4, 0.7 Hz, 1H), 8.15 (d, J=9, 3 Hz, 1H), 7.75 (brs, 1H), 7.53 (dd, J=5.3, 1.3 Hz, 1H), 7.29 (d, J=9.3 Hz, 1H) , 3.75-3.52 (m, 8H), 2.65 (s, 3H), 2.07 (s, 3H). II-194 316.1 2.29 II-195 329.1 2.23 II-196 418.4 2.04 1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J=1.0 Hz, 1H), 8.56 (s, 1H), 8.27 (d, J=9.4 Hz, 1H ), 8.11 (d, J=1.1 Hz, 1H), 7.46 (d, J=9.4 Hz, 1H), 7.25 (t, J=6.2 Hz, 1H), 4.47 (s, 1H), 4.28 (s, 1H), 4.05 (ddd, J=11.6, 3.7, 1.5 Hz, 1H), 3.62 (tt, J= 7.7, 2.7 Hz, 2H), 3.28-3.19 (m, 1H), 3.14 (q, J=6.1 Hz, 2H), 3.05 (q, J=7 ,5 Hz, 2H), 3.01-2.96 (m, 1H), 2.95 (s, 3H), 1.39 (t, J=7.5 Hz, 3H). II-197 454.1 2.11 1H NMR (500MHz, DMSO-d6) δ 8.65 (s, 2H), 8.54 (d, 1H), 7.99 (s, 1H), 7.71 (d, 1H), 7.29 ( m, 2H), 3.87 (d, 1H), 3.75-3.73 (m, 1H), 3.55 (m, 1H), 3.35 (masked, 3H), 3.22 (m , 2H), 3.00 (s, 3H), 1.26 (m, 3H). II-198 467 2.05 1H NMR (500MHz, methanol-d4) δ 8.75 (s, 1H), 8.71 (s, 1H), 8.48 (d, 1H), 8.14 (s, 1H), 7.80 ( d, 1H), 7.15 (t, 1H), 4.43 (s, 1H), 3.85 (s, 1H), 3.65-3.50 (m, 3H), 3.45 (s , 3H), 3.20-3.10 (m, 2H), 2.94 (s, 3H), 2.30 (m, 1H), 2.03 (m, 1H), 1.51 (m, 1H). II-199 410 1.85 II-200 386 1.86 II-201 390 2.01 II-202 439 2 II-203 383 1.83 II-204 353 2.09 1H NMR (500MHz, methanol-d4) δ 8.49 (s, 1H), 8.33 (d, 1H), 8.06-8.11 (m, 2H), 7.83 (dd, 1H), 7.17-7.19 (d, 1H), 4.20 (s, 3H), 3.86-3.89 (m, 8H), 2.20 (s, 3H). II-205 440 1.95 II-206 521 2.12 II-207 383 2.31 1H NMR (500MHz, methanol-d4) δ 8.63 (s, 1H), 8.25-8.27 (d, 1H), 8.19 (s, 1H), 8.11-8.13 (m , 1H), 7.63 (d, 1H), 7.56-7.58 (d, 1H), 4.55 (d, 1H), 4.22-4.25 (d, 2H), 3, 78-3.82 (m, 1H), 3.40-3.50 (m, 1H), 3.12-3.22 (m, 2H), 2.45-2.50 (m, 2H), 2.13-2.15 (m, 1H), 1.95-1.99 (m, 1H), 1.80-1.88 (m, 1H), 1.73-1.78 (m, 1H ). II-208 357 2.12 1H NMR (500MHz, DMSO-d6) δ 8.66 (s, 1H), 8.38-8.40 (d, 1H), 8.25-8.26 (d, 1H), 7.72 (s , 1H), 7.55-7.57 (m, 2H), 3.70-3.71 (m, 2H), 3.64 (m, 6H), 2.08 (s, 3H). II-209 446 2.27 II-210 390 1.67 II-211 414 1.99 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.01 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.47-7.26 (m, 2H), 3.74 (br s, 4H), 3.11-2.96 (m, 2H), 2.19 (t, J=7.0 Hz, 2H), 1.79-1.64 (m, 2H), 1 .56 (t, J=5.6 Hz, 4H). II-212 402 1.98 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.47-7.26 (m, 2H), 6.74 (s, 1H), 4.47 (br s, 2H), 2.98 (t, J=12.6 Hz, 2H), 2.16-2.03 (m, 2H), 1.86-1 .75 (m, 2H), 1.58 (ddp, J=10.8, 7.0, 4.2, 3.3 Hz, 1H), 1.47 (q, J=7.3 Hz, 2H ), 1.11 (qd, J=12.6, 4.3 Hz, 2H). II-213 452.3 2.3 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.71 (d, J=11.9 Hz, 1H), 8.59 (d, J=9.4 Hz, 1H ), 7.78 (d, J=9.3 Hz, 1H), 7.72 (d, J=31.8 Hz, 1H), 7.48-7.26 (m, 1H), 7.16 -7.11 (m, 1H), 4.04-3.99(m, 1H), 3.87-3.83 (m, 1H), 3.70 (d, J=12.3 Hz, 1H ), 3.49-3.45 (m, 1H), 3.40-3.36 (m, 1H), 3.24-3.19 (m, 1H), 2.96 (d, J=11 ,8 Hz, 3H), 2.23 (d, J=40.9 Hz, 1H), 1.21 (d, J=18.1 Hz, 3H), 1.01 (d, J=14.2 Hz, 3H). II-214 402 2.06 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.46-7.25 (m, 2H), 6.71 (s, 1H), 4.32 (br s, 2H), 3.09 (t, J=12.5 Hz, 1H), 2.81 (t, J=11.2 Hz, 1H), 2, 24-2.08 (m, 2H), 1.96-1.83 (m, 1H), 1.83-1.70 (m, 1H), 1.62-1.34 (m, 4H), 1.33-1.15 (m, 1H). II-215 403 1.9 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.35 (t, J=55.0 Hz, 1H), 6.10 (t, J=5.9 Hz, 1H), 5.41 (d, J=4.1 Hz, 2H), 4.68-4.07 (m, 2H), 3.10 (td , J=12.3, 11.1, 2.8 Hz, 1H), 2.97 (t, J=6.3 Hz, 2H), 2.81 (t, J=11.7 Hz, 1H) , 1.88-1.74 (m, 2H), 1.63 (ddd, J=11.3, 7.2, 4.1 Hz, 1H), 1.46 (q, J=12.4, 11.8 Hz, 1H), 1.37-1.20 (m, 1H). II-216 415 1.91 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.74-7.67 (m, 2H), 7.34 (t, J=55.0 Hz, 1H), 6.17 (br s, 1H), 6.05 (s, 1H), 4.38-4.25 (m, 1H), 3.73-3.45 (m, 4H), 2.46-2.41 (m, 1H), 2.25-2.09 (m, 1H ), 2.01-1.87 (m, 1H), 0.56 (td, J=6.8, 4.7 Hz, 2H), 0.38-0.26 (m, 2H). II-217 411 2.36 1H NMR (500 MHz, DMSO-d6) δ 12.49-12.42 (m, 1H), 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8 .52 (d, J=9.4 Hz, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.61 -7.24 (m, 2H), 6.05 (s, 1H), 4.46 (s, 2H), 2.99 (t, J=12.7 Hz, 2H), 2.56 (s, 2H), 2.06-1.86 (m, 1H), 1.80-1.73 (m, 2H), 1.18 (qd, J=12.5, 4.2 Hz, 2H). II-218 436 2.2 1H NMR (500 MHz, DMSO-d6) δ 9.43 (s, 1H), 8.72-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8 .06 (d, J=1.3 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.52-7.29 (m, 2H), 7.22 (t, J=7.7 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 4.89 (s, 2H), 3.92 (s, 2H), 2.86 (t, J=6.0 Hz, 2H), 2.07 (s, 3H). II-219 424 2.04 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.02 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.36 (t, J=55.0 Hz, 1H), 6.93 (s, 2H), 4.52-4.42 (m, 2H), 3.15-2.95 (m, 4H), 2.17-2.15 (m, 1H), 1. 97 (br d, J=11.4 Hz, 1H), 1.79-1.76 (m, 1H), 1.49 (tdd, J=21.4, 11.4, 7.9 Hz, 2H ). II-220 317.1 0.62 II-221 452.3 2.36 1H NMR (500MHz, CD3OD) δ 8.75 (s, 1H), 8.72 (s, 1H), 8.50 (d, 1H), 8.08 (m, 1H), 7.85 (d, 1H), 7.28-7.04 (t, 1H), 5.30 (br m, 1H), 4.80-4.30 (br m, 2H), 2.95 (m, 5H), 1 .90 (m, 2H), 1.70 (m, 1H), 1.47 (m, 2H), 1.35 (m, 3H). II-222 373.1 2.05 1H NMR (400 MHz, DMSO-d6) δ 9.20 (dd, J=5.6, 1.3 Hz, 1H), 8.76 (d, J=0.8 Hz, 1H), 8.61 -8.53 (m, 2H), 7.75 (dd, J=9.5, 3.1 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.57 ( d, J=11.2 Hz) and 4.35 (d, J=13.0 Hz, 1H), 4.15-3.98 (m) and 3.86 (d, J=13.5 Hz, 1H), 3.42 (dd, J=13.3, 10.7 Hz, 1H), 3.23-2.62 (m, 2H), 2.06 (s, 4H), 2.01-1 .73 (m, 2H), 1.55 (dd, J=46.2, 12.7 Hz, 1H). NB 2 rotary isomers, ratio approximately 1:1. II-223 391.1 2.34 1H NMR (500 MHz, DMSO) δ 8.77 (s, 1H), 8.58 (d, J=9.2 Hz, 1H), 8.30 (d, J=5.5 Hz, 1H), 7.81 (d, J=9.5 Hz, 1H), 7.71 (s, 1H), 7.48 (dd, J=5.3, 1.3 Hz, 1H), 3.67-3 .65 (m, 2H), 3.60-3.59 (m, 6H), 2.07 (s, 3H). II-224 457.1 2.39 II-225 416.1 2.36 II-226 431.1 2.67 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.61-8.56 (m, 1H), 8.30 (dd, J=5.3, 0.7 Hz, 1H), 7.82 (d, J=9.5 Hz, 1H), 7.76-7.72 (m, 1H), 7.50 (dd, J=5.3, 1.3 Hz, 1H ), 4.57-4.47 (m, 1H), 4.43-4.32 (m, 1H), 3.86 (dd, J=11.1, 3.9 Hz, 1H), 3, 83-3.73 (m, 1H), 3.23-3.11 (m, 1H), 3.00-2.87 (m, 2H), 1.19-0.96 (m, 3H), 0.89 (ddd, J=10.2, 7.1, 4.8 Hz, 1H). II-227 440.1 1.95 1H NMR (300 MHz, DMSO-d6) δ 1.36-1.62 (m, 2H), 1.65-1.77 (m, 1H), 2.00 (d, J=11.7 Hz, 1H), 2.10-2.24 (m, 1H), 2.86-2.97 (m, 1H), 2.99-3.23 (m, 6H), 4.09 (d, J= 13.2 Hz, 1H), 4.43 (d, J=13.2 Hz, 1H), 7.41 (d, J=5.6 Hz, 1H), 7.66 (s, 1H), 7 .80 (d, J=9.4 Hz, 1H), 8.26 (d, J=4.6 Hz, 1H), 8.58 (d, J=9.4 Hz, 1H), 8.71 (s, 1H). II-228 426.1 2.04 1H NMR (300 MHz, DMSO-d6) δ 1.51-1.68 (m, 1H), 1.69-1.93 (m, 2H), 2.15-2.26 (m, 1H), 2.93-3.14 (m, 5H), 3.21-3.31 (m, 1H), 4.25 (d, J=13.8 Hz, 1H), 4.91 (d, J= 12.3 Hz, 1H), 7.42-7.50 (m, 1H), 7.76 (s, 1H), 7.82 (d, J=9.4 Hz, 1H), 8.30 ( d, J=5.0 Hz, 1H), 8.59 (d, J=9.4 Hz, 1H), 8.77 (s, 1H). II-229 416.1 2.34 1H NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.78 (s, 1H), 8.57 (d, J=9.5 Hz, 1H), 8.30 (d , J=5.3 Hz, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.77 (d, J=4.2 Hz, 1H), 7.75 (s, 1H ), 7.54 (s, 1H), 7.50 (dd, J=5.4, 1.3 Hz, 1H), 4.60 (dd, J=10.5, 2.7 Hz, 1H) , 4.36-4.28 (m, 1H), 4.21 (d, J=12.8 Hz, 1H), 4.09-4.00 (m, 1H), 3.73 (td, J =11.7, 2.8 Hz, 1H), 3.07-2.93 (m, 2H). II-230 416.3 2.34 1H NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.78 (s, 1H), 8.57 (d, J=9.5 Hz, 1H), 8.30 (d , J=5.3 Hz, 1H), 7.80 (d, J=9.5 Hz, 1H), 7.77 (d, J=4.2 Hz, 1H), 7.75 (s, 1H ), 7.54 (s, 1H), 7.50 (dd, J=5.4, 1.3 Hz, 1H), 4.60 (dd, J=10.5, 2.7 Hz, 1H) , 4.36-4.28 (m, 1H), 4.21 (d, J=12.8 Hz, 1H), 4.09-4.00 (m, 1H), 3.73 (td, J =11.7, 2.8 Hz, 1H), 3.07-2.93 (m, 2H). II-231 441.1 1.9 1H NMR (300 MHz, DMSO-d6) δ 1.39-1.63 (m, 2H), 1.70-1.84 (m, 1H), 1.92-2.05 (m, 1H), 2.77-2.88 (m, 1H), 2.95 (s, 4H), 3.19-3.31 (m, 1H), 4.10 (d, J=13.2 Hz, 1H) , 4.41 (d, J=9.7 Hz, 1H), 7.26 (d, J=7.6 Hz, 1H), 7.40 (d, J=4.7 Hz, 1H), 7 .70 (s, 1H), 7.80 (d, J=9.5 Hz, 1H), 8.25 (d, J=4.7 Hz, 1H), 8.57 (d, J=9, 5 Hz, 1H), 8.72 (s, 1H). II-232 471.1 1.85 1H NMR (300 MHz, DMSO-d6) δ 2.20-2.34 (m, 1H), 2.86-3.02 (m, 4H), 3.29-3.39 (m, 2H), 3.41-3.59 (m, 2H), 3.60-3.90 (m, 3H), 4.02-4.24 (m, 2H), 7.11 (t, J=5.6 Hz, 1H), 7.34 (dd, J=5.3, 1.2 Hz, 1H), 7.59 (s, 1H), 7.81 (d, J=9.4 Hz, 1H), 8.23 (d, J=5.3 Hz, 1H), 8.58 (d, J=9.4 Hz, 1H), 8.73 (s, 1H). II-233 467 2.08 1H NMR (500MHz, methanol-d4) δ 8.75 (s, 1H), 8.71 (s, 1H), 8.48 (d, 1H), 8.14 (s, 1H), 7.80 ( d, 1H), 7.15 (t, 1H), 4.43 (s, 1H), 3.85 (s, 1H), 3.65-3.50 (m, 3H), 3.45 (s , 3H), 3.20-3.10 (m, 2H), 2.94 (s, 3H), 2.30 (m, 1H), 2.03 (m, 1H), 1.51 (m, 1H). II-234 454.1 2.11 1H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 2H), 8.54 (d, 1H), 7.99 (s, 1H), 7.71 (d, 1H), 7.29 (m, 2H), 3.87 (d, 1H), 3.75-3.73 (m, 1H), 3.55 (m, 1H), 3.35 (masked, 3H), 3.22 ( m, 2H), 3.00 (s, 3H), 1.26 (m, 3H). II-235 468.1 1.94 1H NMR (500 MHz, DMSO-d6) δ 8.72 (m, 2H), 8.55 (d, 1H), 7.99 (s, 1H), 7.76 (d, 1H), 7.36 -7.15 (t, 1H), 3.51 (m, 1H), 4.40-4.10 (br s, 3H), 3.15 (m, 1H), 2.98-2.91 ( m, 4H), 2.82-2.73 (m, 4H), 2.08-1.92 (m, 2H), 1.20-1.15 (m, 1H). II-236 438.3 2.31 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.64 (d, J=1.0 Hz, 1H), 8.55 (d, J=9.4 Hz, 1H ), 8.09-8.01 (m, 1H), 7.73 (d, J=9.5 Hz, 1H), 7.48-7.23 (m, 1H), 7.03 (d, J=5.3 Hz, 1H), 4.54 (t, J=52.6 Hz, 4H), 3.16-3.00 (m, 4H), 2.61 (d, J=4.9 Hz, 2H), 2.12-2.04 (m, 1H), 1.96 (dd, J=34.3, 12.7 Hz, 1H), 1.83-1.72 (m, 1H) , 1.50 (q, J=12.8 Hz, 1H). II-237 438.1 2.14 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.71 (s, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.46-7.25 (m, 1H), 7.19 (s, 1H), 3 .91 (br s, 1H), 3.72 (br s, 1H), 3.35-3.33 (m, 1H), 3.23-3.18 (m, 1H), 3.10 (br s, 1H), 2.99 (br s, 1H), 2.94 (s, 3H), 2.22-2.03 (m, 2H), 1.13 (s, 3H). II-238 438.1 2.14 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.71 (s, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.46-7.24 (m, 1H), 7.20 (s, 1H), 3 .90 (br s, 1H), 3.74 (br s, 1H), 3.35-3.33 (m, 1H), 3.21-3.17 (m, 1H), 3.11 (br s, 1H), 3.01 (br s, 1H), 2.94 (s, 3H), 2.20-2.04 (m, 2H), 1.13 (s, 3H). II-239 468.3 1.95 1H NMR (500 MHz, DMSO-d6) δ 8.77-8.68 (m, 2H), 8.57 (d, J=9.4 Hz, 1H), 8.01 (d, J=1, 1 Hz, 1H), 7.76 (d, J=9.4 Hz, 1H), 7.44-7.15 (m, 1H), 7.03 (dd, J=7.8, 4.5 Hz, 1H), 4.11 (s, 3H), 3.53 (s, 2H), 3.30 (dt, J=12.6, 4.0 Hz, 2H), 2.90 (s, 3H ), 2.71 (ddd, J=12.5, 10.8, 7.7 Hz, 1H), 1.80-1.64 (m, 1H), 1.60 (ddd, J=13.5 , 9.6, 4.2 Hz, 1H), 1.18 (s, 3H). II-240 468.3 1.97 1H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J=6.4 Hz, 2H), 8.57 (d, J=9.4 Hz, 1H), 7.98 (d, J =1.1 Hz, 1H), 7.75 (d, J=9.5 Hz, 1H), 7.30 (t, J=53.5 Hz, 1H), 7.04 (dd, J=7 .5, 5.0 Hz, 1H), 3.42-3.29 (m, 2H), 3.07 (s, 1H), 2.94 (s, 4H), 1.63 (dt, J= 33.4, 12.4 Hz, 3H), 1.23 (s, 3H). II-241 387.1 2.07 II-242 387.2 2.07 II-243 438.3 2.13 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.82 (s, 0.3H), 7.68 (d, J=9.4 Hz, 1H), 7.66 (br s, 0.7H), 7.46-7.18 (m , 1H), 7.14 (t, J=5.5 Hz, 1H), 4.52 (br s, 0.7H), 4.16 (br s, 0.3H), 3.62 (br s , 1H), 3.42 (br s, 1H), 3.14-3.09 (m, 2H), 2.95 (s, 3H), 2.42 (br s, 1H), 2.16 ( br s, 1H), 1.87 (br s, 1H), 1.13 (s, 3H). II-244 438.3 2.16 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.74 (br s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.36 (br d, 1H), 7.21 (s, 1H), 4.09 (br d, 1H), 3.61-3.56 (m, 1H), 3.60 (br s, 1H), 2.99-2.95 (m, 1H), 2.92-2.87 (m, 1H), 2.89 (s, 3H), 2.16 (br s, 2H), 1.90 (br s, 1H), 1.29 (s, 3H). II-245 452.1 2.37 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.56 (d, 1H), 8.51 (d, 1H), 8.00 (d, 1H), 7.66 (d, 1H), 7.32 (t, 1H), 7.05 (s, 1H), 4.60 (s, 1H), 4.27 (s, 1H), 3.02-2.89 ( m, 2H), 2.85 (s, 3H), 2.65 (masked, 1H), 2.05 (m, 2H), 1.87 (m, 2H), 1.60-1.50 (m , 1H), 1.24 (d, 3H). II-246 452.3 2.37 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.56 (d, 1H), 8.51 (d, 1H), 8.00 (d, 1H), 7.66 (d, 1H), 7.32 (t, 1H), 7.05 (s, 1H), 4.60 (s, 1H), 4.27 (s, 1H), 3.02-2.89 ( m, 2H), 2.85 (s, 3H), 2.65 (masked, 1H), 2.05 (m, 2H), 1.87 (m, 2H), 1.60-1.50 (m , 1H), 1.24 (d, 3H). II-247 452.1 2.35 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.59 (s, 1H), 8.51 (d, 1H), 8.00 (d, 1H), 7.69 -7.67 (d, 1H), 7.39-7.21 (t, 1H), 7.18 (s, 1H), 4.60- 4.27 (broad s, 2H), 3.02- 2.89 (m, 5H), 2.70 (m, 1H), 1.75-1.62 (m, 4H), 1.40-1.35 (m, 1H), 1.24 (d, 3H). II-248 452.3 2.35 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.59 (s, 1H), 8.51 (d, 1H), 8.00 (d, 1H), 7.69 -7.67 (d, 1H), 7.39-7.21 (t, 1H), 7.18 (s, 1H), 4.60- 4.27 (broad s, 2H), 3.02- 2.89 (m, 5H), 2.70 (m, 1H), 1.75-1.62 (m, 4H), 1.40-1.35 (m, 1H), 1.24 (d, 3H). II-249 430.3 2.1 1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J=0.9 Hz, 1H), 8.53 (s, 1H), 8.23 (d, J=9.4 Hz, 1H ), 8.03 (s, 1H), 7.37 (d, J=9.5 Hz, 1H), 7.27 (t, J=6.3 Hz, 1H), 4.48 (s, 1H ), 4.30 (s, 1H), 4.06 (ddd, J=11.6, 3.7, 1.5 Hz, 1H), 3.63 (ddd, J=11.4, 8.9 , 3.0 Hz, 2H), 3.26 (d, J=12.6 Hz, 1H), 3.19-3.14 (m, 2H), 3.01 (d, J=11.9 Hz , 1H), 2.95 (s, 3H), 2.41 (tt, J=8.2, 4.9 Hz, 1H), 1.22 (ddd, J=8.5, 5.0, 2 ,1 Hz, 2H), 1.13 (tt, J=4.5, 2.3 Hz, 2H). II-250 395 2.06 1H NMR (400 MHz, DMSO-d6) δ 9.22 (d, J=1.3 Hz, 1H), 8.77 (s, 1H), 8.61 (d, J=1.3 Hz, 1H ), 8.57 (d, J=9.4 Hz, 1H), 7.76 (d, J=9.5 Hz, 1H), 7.38 (s, 1H), 3.81-3.73 (m, 2H), 3.59-3.37 (m, 3H), 2.99 (s, 3H), 2.49-2.39 (m, 1H), 2.28-2.14 (m , 1H). II-251 333.3 2.14 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.63 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.98 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.37 (t, J=53.6 Hz, 1H), 3.79-3.64 (m, 8H). II-252 345.3 1.92 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.55 (d, J=1.2 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.69 (d, J=9.4 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H), 7.35 (t, J=53.7 Hz, 1H), 4.77 (s, 4H), 4.32 (s, 4H). II-253 359.3 1.88 1H NMR (400 MHz, DMSO-d6) δ 9.21 (dd, J=2.8, 1.3 Hz, 1H), 8.77 (s, 1H), 8.62-8.51 (m, 2H), 7.75 (dd, J=9.4, 1.3 Hz, 1H), 7.38 (td, J=53.7, 2.3 Hz, 1H), 4.02-3.37 (m, 5H), 2.47-2.04 (m, 2H), 2.00 (d, J=4.8 Hz, 3H). II-254 404.1 1.65 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=1.3 Hz, 1H), 8.76 (s, 1H), 8.57 (dd, J=5.4, 4, 0 Hz, 2H), 7.75 (d, J=9.5 Hz, 1H), 7.38 (t, J=53.6 Hz, 1H), 6.17 (t, J=5.6 Hz , 1H), 4.63 (t, J=5.5 Hz, 1H), 3.77 (dd, J=9.7, 7.4 Hz, 1H), 3.68 (t, J=7, 3 Hz, 1H), 3.58-3.44 (m, 2H), 3.40 (d, J=5.8 Hz, 3H), 3.12 (qd, J=6.3, 1.9 Hz, 2H), 2.36 (ddd, J=13.7, 7.0, 3.3 Hz, 1H), 2.26-2.10 (m, 1H). II-255 423.2 1.98 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.62-8.47 (m, 2H), 7 .74 (d, J=9.4 Hz, 1H), 7.37 (t, J=53.7 Hz, 1H), 3.62 (s, 1H), 3.29 (d, J=3, 5 Hz, 2H), 3.11 (t, J=8.5 Hz, 1H), 3.02 (s, 3H), 2.95-2.62 (m, 4H), 2.60-2, 51 (m, 1H), 2.39-2.21 (m, 1H), 2.12 (d, J=7.8 Hz, 1H). II-256 464.3 2.37 II-257 468.3 2.31 1H NMR (500MHz, methanol-d4) δ 8.80 (s, 1H), 8.77 (s, 1H), 8.51 (d, 1H), 8.05 (s, 1H), 7.85 ( d, 1H), 7.27-7.05 (t, 1H), 4.03 (m, 1H), 3.35-3.10 (6H), 3.02 (s, 3H), 1.38 (s, 3H), 1.30 (s, 3H). II-258 474.3 2.3 1H NMR (500 MHz, DMSO-d6) δ 8.68-8.63 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.07 (d, J=1, 2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.44-7.17 (m, 2H), 4.71 (s, 1H), 4.55-4, 31 (m, 1H), 3.57 (dd, J=29.9, 13.8 Hz, 1H), 3.09-2.99 (m, 3H), 2.94 (s, 3H), 2 .30 (d, J=10.8 Hz, 1H), 1.96 (dtd, J=43.6, 12.3, 11.7, 5.1 Hz, 2H). II-259 517.4 2.31 1H NMR (500 MHz, DMSO-d6) δ 8.70-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.11-8.04 (m, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.40-7.08 (m, 2H), 4.68 (s, 2H), 3.41 (ddd, J=13 ,5, 5.5, 3.5 Hz, 1H), 3.03-2.87 (m, 6H), 2.48 (s, 6H), 2.17 (s, 1H), 1.24- 1.17 (m, 1H). II-260 517.3 2.36 1H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J=1.4 Hz, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.12 (d, J =1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.43-7.10 (m, 2H), 4.00 (s, 2H), 3.74 (dd, J=13.7, 6.9 Hz, 1H), 3.27 (d, J=12.9 Hz, 1H), 2.91 (s, 5H), 2.42 (s, 6H) . II-261 402.3 2.09 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.07-7.85 (m, 2H), 7.68 (d, J=9.4 Hz, 1H), 7.37 (t, J=53.7 Hz, 1H), 4.30 (s, 2H), 3.17-2.99 (m, 3H), 2.88-2.76 (m, 1H), 1.83 (s, 5H), 1.67 (ddd, J=10 ,7, 6.9, 3.9 Hz, 1H), 1.46 (d, J=12.4 Hz, 1H), 1.29 (qd, J=13.8, 4.2 Hz, 1H) . II-262 463.9 2.41 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.0 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.47-7.12 (m, 2H), 4.67 -4.13 (m, 2H), 3.15-3.04 (m, 1H), 2.98 (p, J=6.7 Hz, 2H), 2.84 (t, J=11.8 Hz, 1H), 2.65-2.52 (m, 1H), 1.94-1.63 (m, 3H), 1.48 (q, J=12.0 Hz, 1H), 1.33 (dd, J=11.9, 3.5 Hz, 1H), 1.02-0.83 (m, 4H). II-263 452.1 2.34 II-264 452.1 2.34 II-265 452.1 2.33 II-266 452.1 2.33 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.60 (d, 1H), 8.00 (s, 1H), 7.69 (d, 1H), 7.25 (t, 1H), 7.13 (m, 1H), 4.70-4.20 (br m, 2H), 2.94 (m, 5H), 1.90 (m, 2H), 1.77 (m, 1H), 1.41 (m, 2H), 1.22 (m, 1H), 1.10 (m, 3H). II-267 468 2.29 1H NMR (500MHz, methanol-d4) δ 8.75 (m, 2H), 8.45 (dd, 1H), 8.09 (s, 1H), 7.79 (s, 1H), 7.27 ( t, 1H), 4.84 (masked 3H), 4.12 (m, 2H), 3.79 (m, 1H), 3.70 (m, 1H), 3.02 (s, 3H), 1 .97 (m, 2H), 1.01 (m, 4H). II-268 466 2.46 II-269 468 2.25 II-270 505.3 2.77 1H NMR (500 MHz, DMSO-d6) δ 8.50 (m, 3H), 8.26 (d, J=7.8 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H ), 7.28 (t, J=53.7 Hz, 1H), 4.17 (d, J=11.6 Hz, 1H), 3.82 (d, J=12.6 Hz, 1H), 3.43 (dd, J=13.5, 3.4 Hz, 1H), 2.95 (m, 4H), 2.93 (s, 3H), 2.37 (m, 2H) 1.05 ( d, J=6.7 Hz, 3H). II-271 469.3 2.67 1H NMR (500 MHz, methanol-d4) δ 8.46 (s, 1H), 8.33 (d, J=9.4 Hz, 1H), 8.24 (m, 2H), 7.63 (d , J=9.5 Hz, 1H), 7.07 (t, J=54.0 Hz, 1H), 4.41-4.31 (m, 1H), 3.77 (dd, J=12, 9, 4.3 Hz, 1H), 3.14-3.02 (m, 3H), 2.98 (s, 3H), 2.08-1.88 (m, 3H), 1.80-1 .73 (m, 2H), 1.59-1.52 (m, 1H) 1.27 (d, J=6.8 Hz, 3H). II-272 479.3 2.11 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.63-8.55 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 7 .99 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.52-7.12 (m, 2H), 4.64-4, 37 (m, 1H), 4.40-4.16 (m, 1H), 4.09 (d, J=15.5 Hz, 1H), 3.88-3.59 (m, 4H), 3 .07 (d, J=11.6 Hz, 1H), 2.96 (dq, J=11.3, 6.8, 6.3 Hz, 2H), 2.82 (t, J=11.9 Hz, 1H), 1.79 (d, J=17.7 Hz, 2H), 1.66 (s, 1H), 1.47 (d, J=12.3 Hz, 1H), 1.39- 1.20 (m, 1H). II-273 452.3 2.17 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=1.1 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.04 (d, J=1.2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.6 Hz, 1H), 3.95 (s, 2H), 3.91-3.76 (m, 6H), 3.68 (t, J=4.8 Hz, 2H), 3.07 (s, 3H). II-274 379 2.66 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.93 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.37 (t, J=55.0 Hz, 1H), 4.12 (s, 1H), 3.93 (d, J=14.2 Hz, 1H), 3.75 (s, 1H), 2.12-2.04 (m, 3H), 1.75 (s, 1H), the water peak covers one signal. II-275 423 2.21 1H NMR (500 MHz, DMSO-d6) δ 9.17 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.66-8.45 (m, 2H), 7 .74 (d, J=9.5 Hz, 1H), 7.38 (t, J=55.0 Hz, 1H), 3.64-3.53 (m, 1H), 3.47 (dt, J=13.3, 4.5 Hz, 1H), 3.41-3.34 (m, 1H), 3.07 (tt, J=10.7, 3.3 Hz, 1H), 2.93 (s, 3H), 2.12 (dq, J=13.6, 4.3 Hz, 1H), 2.03-1.96 (m, 3H), 1.93-1.85 (dq, J =10.9, 5.9, 5.3 Hz, 1H), 1.83-1.69 (m, 1H), the water peak covers some signals. II-276 423 2.21 1H NMR (500 MHz, DMSO-d6) δ 9.17 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.66-8.45 (m, 2H), 7 .74 (d, J=9.5 Hz, 1H), 7.38 (t, J=55.0 Hz, 1H), 3.64-3.53 (m, 1H), 3.47 (dt, J=13.3, 4.5 Hz, 1H), 3.41-3.34 (m, 1H), 3.07 (tt, J=10.7, 3.3 Hz, 1H), 2.93 (s, 3H), 2.12 (dq, J=13.6, 4.3 Hz, 1H), 2.03-1.96 (m, 3H), 1.93-1.85 (dq, J =10.9, 5.9, 5.3 Hz, 1H), 1.83-1.69 (m, 1H), the water peak covers some signals. II-277 439 2.04 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.3 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.30 (t, J=55.0 Hz, 1H), 6.66 (t, J=6.3 Hz, 1H), 6.52 (s, 2H), 4.45 (brs, 1H), 4.32 (brs, 1H), 3.17-3.03 (m, 1H), 2.91-2.80 (m, 3H), 1.96-1.63 (m, 3H), 1.58-1.41 (m, 1H), 1.40-1 .25 (m, 1H). II-278 439 2.03 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.30 (t, J=55.0 Hz, 1H), 6.66 (s, 1H), 6.52 (s, 2H), 4.44 (brs, 1H), 4.31 (brs, 1H), 3.09 (t, J=12.4 Hz, 1H ), 2.86-2.82 (m, 3H), 1.92-1.67 (m, 3H), 1.46 (t, J=12.9 Hz, 1H), 1.39-1, 25 (m, 1H). II-279 450 2.2 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.56 (d, J=1.2 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.69 (d, J=9.4 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.35 (t, J=55.0 Hz, 1H), 3.86 (s, 4H), 3.20-3.04 (m, 4H), 2.90 (s, 3H), 1.82-1.79 (m, 2H), 1.67-1, 64 (m, 2H). II-280 452 2.05 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.70 (d, J=9.4 Hz, 1H), 7.63 (d, J=1.2 Hz, 1H), 7.37 (t, J=55.0 Hz, 1H), 4.10 (d, J=9.6 Hz, 2H), 4.05 (d, J=9.6 Hz, 2H), 3.80 (t, J=4.8 Hz, 2H), 3, 37 (s, 2H), 3.21-3.11 (m, 2H), 2.96 (s, 3H). II-281 450 2.27 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.05 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.39 (d, J=55.0 Hz, 1H), 3.95 (s, 2H), 3.71-3.58 (m, 6H), 3.03 (s, 3H), 1.87 (dd, J=7.4, 4.6 Hz, 2H) , 1.73-1.53 (m, 2H). II-282 436 2.1 1H NMR (500 MHz, DMSO-d6) δ 8.64-8.61 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 7.80-7.69 (m, 2H), 7.34 (t, J=55.0 Hz, 1H), 4.62 (brs, 1H), 3.78-3.71 (m, 2H), 3.62 (brs, 1H), 3.47 (brs, 1H), 3.25-3.01 (m, 3H), 2.93 (s, 3H), 2.23 (brs, 1H), 1.98 (brs, 1H). II-283 438 2.24 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.35 (t, J=55.0 Hz, 1H), 6.78 (s, 2H), 4.90 (vbrs, 1H), 4.37 (vbrs, 1H), 3.04 (ddd, J=13.8, 11.5, 5.1 Hz, 2H) , 2.86 (ddd, J=13.7, 11.5, 4.4 Hz, 1H), 2.36-2.19 (m, 1H), 2.15-1.96 (m, 1H) , 1.88-1.57 (m, 5H), 1.56-1.35 (m, 1H). II-284 451 2.03 II-285 453 1.9 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.66 (d, J=1.1 Hz, 1H), 8.56 (d, J=9.4 Hz, 1H ), 7.74 (d, J=9.4 Hz, 1H), 7.63 (d, J=1.1 Hz, 1H), 7.32 (d, J=55.0 Hz, 1H), 6.99 (s, 2H), 4.24-4.04 (m, 4H), 3.80 (t, J=4.9 Hz, 2H), 3.20 (s, 2H), 2.99 (s, 2H). II-286 437 1.93 II-287 480.3 2.23 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.36 (t, J=53.8 Hz, 1H), 3.84-3.77 (m, 2H), 3.78-3.71 (m, 2H), 3.68 (s, 2H), 3.38-3.27 (m, 2H), 2. 97 (dd, J=11.8, 2.7 Hz, 2H), 2.88 (s, 3H), 1.94 (d, J=13.9 Hz, 2H), 1.62 (ddd, J =13.8, 11.6, 4.5 Hz, 2H). II-288 480.3 2.23 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.02 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.8 Hz, 1H), 3.93 (d, J=13.5 Hz, 2H), 3.86-3.75 (m, 2H), 3.54 (ddd, J=13.6, 8.1, 5.2 Hz, 2H), 3.28-3.18 (m, 1H), 3.16-3.04 (m, 3H), 2.85 (s, 3H), 1.87-1.74 (m, 1H) , 1.74-1.56 (m, 3H). II-289 480.1 2.21 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.53 (s, 1H), 7.32 (t, J =53.7 Hz, 1H), 4.87-4.75 (m, 2H), 4.73-4.58 (m, 3H), 4.56-4.16 (m, 2H), 3, 08 (t, J=11.5 Hz, 1H), 2.95 (d, J=6.3 Hz, 2H), 2.82 (t, J=11.7 Hz, 1H), 1.81 ( t, J=16.5 Hz, 2H), 1.66 (s, 1H), 1.48 (d, J=12.5 Hz, 1H), 1.32 (t, J=12.4 Hz, 1H). II-290 454.3 2.2 1H NMR (500 MHz, DMSO-d6) δ 8.68-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.01 (d, J=1, 2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.5 Hz, 1H), 4.47-4.32 (m, 1H) , 4.32-4.16 (m, 1H), 4.05 (ddd, J=11.7, 3.6, 1.5 Hz, 1H), 3.75 (dtd, J=10.9, 5.8, 2.6 Hz, 1H), 3.62 (td, J=11.6, 2.8 Hz, 1H), 3.39-3.33 (m, 2H), 3.28 (dd , J=5.9, 2.8 Hz, 1H), 3.21-3.09 (m, 1H), 2.95 (s, 3H), 2.88 (s, 3H). II-291 456 2.37 1H NMR (500 MHz, methanol-d4) δ 8.69 (s, 1H), 8.57 (s, 1H), 8.46 (d, J=9.4 Hz, 1H), 8.14 (s , 1H), 7.78 (d, J=9.5 Hz, 1H), 4.54 (s, 1H), 4.25 (s, 1H), 3.31-3.27 (m, 1H) , 3.07 (s, 2H), 2.96 (s, 3H), 2.02 (s, 1H), 1.86 (s, 2H), 1.64 (s, 1H), 1.50 ( d, J=12.1 Hz, 1H), 1.35 (d, J=5.8 Hz, 2H). II-292 458 2.1 1H NMR (500 MHz, methanol-d4) δ 8.72 (s, 1H), 8.62 (d, J=1.2 Hz, 1H), 8.47 (d, J=9.5 Hz, 1H ), 8.13 (d, J=1.1 Hz, 1H), 7.79 (d, J=9.5 Hz, 1H), 4.52 (s, 1H), 4.27 (s, 1H ), 4.12 (d, J=11.5 Hz, 1H), 3.70 m, 2H), 3.26 (m, 4H), 3.01 (m, 4H). II-293 506 2.71 1H NMR (500 MHz, methanol-d4) δ 8.75 (s, 1H), 8.74 (d, J=0.9 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.21 (s, 1H), 7.87 (d, J=9.5 Hz, 1H), 5.19 (s, 1H), 4.45 (s, 1H), 3.61 (dd , J=13.9, 3.9 Hz, 1H), 3.20 (m, 1H) 3.15 (m, 3H), 3.00 (s, 3H), 2.30 (s, 2H), 1.18 (d, J=6.7 Hz, 3H). II-294 506 2.71 1H NMR (500 MHz, methanol-d4) δ 8.70 (s, 1H), 8.63 (d, J=1.1 Hz, 1H), 8.46 (d, J=9.5 Hz, 1H ), 8.26 (d, J=1.1 Hz, 1H), 7.79 (d, J=9.5 Hz, 1H), 4.20-4.02 (m, 3H), 3.51 (d, J=8.2 Hz, 1H), 3.38 (d, J=4.2 Hz, 2H), 3.07 (dd, J=13.3, 10.2 Hz, 1H), 2 .92 (s, 3H), 2.35 (s, 2H), 1.14 (d, J=6.9 Hz, 3H). II-295 381.2 1.91 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=1.1 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.09 (d, J=1.2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.35 (t, J=53.6 Hz, 1H), 4.25-4.18 (m, 4H), 3.29-3.24 (m, 4H). II-296 365.2 1.65 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=1.1 Hz, 1H), 8.64 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.08 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.36 (t, J=53.6 Hz, 1H), 4.45-4.30 (m, 2H), 4.01 (ddd, J=13.5, 11.3, 1.9 Hz, 2H), 2.97 (ddd, J=14.4, 11 ,5, 3.4 Hz, 2H), 2.82 (ddd, J=12.1, 4.3, 2.3 Hz, 2H). II-297 431.2 2.27 1H NMR (500 MHz, DMSO-d6) δ 8.65-8.64 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.05 (s, 1H), 7 .70 (d, J=9.4 Hz, 1H), 7.26 (t, J=53.9 Hz, 1H), 4.96 (t, J=5.6 Hz, 1H), 4.66 -4.59 (m, 1H), 4.09-4.01 (m, 4H), 3.61-3.52 (m, 3H). II-298 431.2 2.38 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, J=1.1 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.10 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.28 (t, J=54.0 Hz, 1H), 5.03 (t, J=5.7 Hz, 1H), 4.59 (br s, 1H), 4.49-4.43 (m, 2H), 3.79-3.74 (m, 1H ), 3.64-3.54 (m, 2H), 3.13 (t, J=11.9 Hz, 1H), 2.97 (t, J=12.1 Hz, 1H). II-299 370.3 2.42 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.01 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.7 Hz, 1H), 4.56-4.39 (m, 1H), 4.39-4.22 (m, 1H), 3.15-3.03 (m, 1H), 2.94 (dd, J=13.2 , 10.3 Hz, 1H), 2.62 (dd, J=6.8, 1.4 Hz, 2H), 1.99-1.86 (m, 2H), 1.80 (dp, J= 10.3, 3.3 Hz, 1H), 1.62-1.35 (m, 2H). II-300 438.3 2.19 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.7 Hz, 1H), 7.18-7.13 (m, 1H), 4.69-4.19 (m, 2H), 3.14-3.04 (m, 1H), 3.00-2.89 (m, 5H ), 2.89-2.80 (m, 1H), 1.91-1.83 (m, 1H), 1.78 (dt, J=13.5, 3.6 Hz, 1H), 1, 75-1.65 (m, 1H), 1.54-1.42 (m, 1H), 1.33 (qd, J=11.7, 3.8 Hz, 1H). II-301 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.65 (s, 1H), 8.54 (d, J=9.4 Hz, 1H), 8.27 (s , 1H), 7.69 (d, J=9.4 Hz, 1H), 7.41-7.16 (m, 1H), 3.99-3.91 (m, 1H), 3.91- 3.83 (m, 1H), 3.80 (td, J=11.4, 10.6, 3.6 Hz, 1H), 3.76-3.60 (m, 1H), 3.43- 3.33 (m, 1H), 2.94-2.74 (m, 1H), 1.21-1.07 (m, 1H), 0.70-0.58 (m, 1H). II-302 488 2.52 1H NMR (500MHz, methanol-d4) δ 8.52-8.50 (m, 2H), 8.26 (d, 1H), 8.11 (s, 1H), 7.58 (d, 1H), 7.12-6.91 (t. 1H), 5.02 (m, 1H), 3.22 (masked, 3H), 2.95 (m, 1H), 2.79 (s, 3H), 2 .25 (m, 1H), 2.12-1.94 (m, 2H), 1.31 (s, 3H). 1 CH proton is not observed. II-303 488 2.5 II-304 488 2.51 II-305 488.1 2.55 1H NMR (500MHz, methanol-d4) δ 8.52-8.50 (m, 2H), 8.26 (d, 1H), 8.11 (s, 1H), 7.58 (d, 1H), 7.12-6.91 (t. 1H), 5.02 (m, 1H), 4.59 (m, 1H), 3.44 (m, 1H), 3.22 (m, 1H), 3 .02 (m, 1H), 2.79 (s, 3H), 2.40 (m, 1H), 2.32-2.18 (m, 1H), 2.04 (m, 1H), 1, 24 (s, 3H). II-306 508.3 2.51 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.67 (s, 1H), 8.55 (d, J=9.4 Hz, 1H), 8.10 (s , 1H), 7.71 (d, J=9.4 Hz, 1H), 7.40 (s, 1H), 7.28 (t, J=53.8 Hz, 1H), 4.62-4 .45 (m, 4H), 3.85-3.80 (m, 1H), 3.29-3.12 (m, 2H), 2.99-2.94 (m, 1H), 2.97 (s, 3H). II-307 508.3 2.4 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.66 (d, J=4.6 Hz, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.05 (s, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.31 (t, J=6.2 Hz, 1H), 7.27 (t, J =53.8 Hz, 1H), 4.71-4.65 (m, 1H), 4.12-4.00 (m, 5H), 3.55 (dd, J=13.4, 7.8 Hz, 1H), 3.30-3.19 (m, 1H), 2.95 (s, 3H). II-308 331 2.68 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.35 (t, J=55.0 Hz, 1H), 3.74-3.72 (m, 4H), 1.72-1.67 (m, 2H), 1.64-1.55 (m, 4H). II-309 432 1.78 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.20-8.02 (m, 2H), 7.69 (d, J=9.4 Hz, 1H), 7.30 (t, J=55.0 Hz, 1H), 4.12 (br d, J=15.0 Hz, 1H), 3.96 (d, J=16.3 Hz, 2H), 3.86-3.83 (m, 4H), 3.71-3.66 (m, 2H), 3.29-3.27 (m, 2H), 3.16 (d, J=13.0 Hz, 1H). II-310 452 2.43 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=1.1 Hz, 1H), 8.59 (d, J=1.2 Hz, 1H), 8.53 (d, J =9.4 Hz, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.69 (dd, J=9.4, 1.1 Hz, 1H), 7.28 (t , J=55.0 Hz, 1H), 4.54-4.22 (m, 2H), 3.17-3.05 (m, 2H), 2.94 (dd, J=13.4, 6 ,2 Hz, 1H), 2.91-2.82 (m, 4H), 2.80 (s, 3H), 1.96-1.70 (m, 3H), 1.51 (d, J= 12.4 Hz, 1H), 1.32 (d, J=11.3 Hz, 1H). II-311 453 2.24 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.58 (s, 1H), 8.48 (d, J=9.4 Hz, 1H), 7.93 (d , J=1.1 Hz, 1H), 7.65 (d, J=9.4 Hz, 1H), 7.20 (t, J - 55.0 Hz, 1H), 6.66 (s, 2H ), 4.58-4.07 (m, 2H), 3.15 (t, J=11.7 Hz, 1H), 2.90-2.84 (m, 2H), 2.73 (dd, J=13.3, 6.0 Hz, 1H), 2.60 (s, 3H), 1.90-1.65 (m, 3H), 1.46-1.41 (m, 1H), 1 .34-1.18 (m, 1H). II-312 467.4 2.01 1H NMR (500MHz, DMSO-d6) δ 8.63 (m, 2H), 8.54 (d, 1H), 7.97 (s, 1H), 7.70 (d, 1H), 7.20 ( m, 2H), 4.80 (broad m, 1H), 4.30 (broad m, 1H), 3.35 (m, 1H), 2.99 (s, 3H), 2.80-2.65 (m, 2H), 2.25 (m, 6H), 1.15 (m, 3H). II-313 453.4 1.83 II-314 431.3 2.28 1H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J=1.1 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.06 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.27 (t, J=53.9 Hz, 1H), 4.96 (t, J=5.6 Hz, 1H), 4.67-4.60 (m, 1H), 4.10-4.01 (m, 4H), 3.61-3.52 ( m, 3H). II-315 431.3 2.38 1H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J=1.1 Hz, 1H), 8.66 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.11 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.28 (t, J=54.0 Hz, 1H), 5.03 (t, J=5.7 Hz, 1H), 4.60 (br s, 1H), 4.50-4.43 (m, 2H), 3.79-3.74 (m, 1H ), 3.64-3.54 (m, 2H), 3.13 (t, J=11.9 Hz, 1H), 2.97 (t, J=12.1 Hz, 1H). II-316 489 2.37 1H NMR (500 MHz, DMSO-d6) δ 8.76-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.08 (d, J=1, 2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.29 (t, J=55.0 Hz, 1H), 6.82 (dd, J=8.0, 5.1 Hz, 1H), 6.68 (s, 2H), 4.84 (br s, 1H), 4.55 (brs, 1H), 3.48-3.36 (m, 1H), 2 .99-2.73 (m, 3H), 2.32-2.12 (m, 2H), 1.07 (d, J=6.7 Hz, 3H). II-317 438 2.12 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.32 (t, J=55.0 Hz, 1H), 6.77 (s, 2H), 4.32 (vbrs, 2H), 3.20-2.99 (m, 3H), 2.91 (dd, J=13.2, 9.2 Hz, 1H) , 1.96-1.82 (m, 1H), 1.83-1.59 (m, 4H), 1.48 (d, J=12.9 Hz, 1H), 1.31 (d, J =11.6 Hz, 1H). II-318 440 1.89 1H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J=1.3 Hz, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.01 (d, J =1.2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.36 (t, J=55.0 Hz, 1H), 6.85 (s, 2H), 4.40 (brs, 1H), 4.25 (brs, 1H), 4.07-3.96 (m, 1H), 3.66-3.55 (m, 2H), 3.21-3, 01 (m, 3H), 2.87 (t, J=11.8 Hz, 1H), 2.10-1.85 (m, 2H). II-319 452 2.13 II-320 450 2.36 1H NMR (500 MHz, DMSO-d6) δ 8.72-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.04 (d, J=1, 2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.33 (t, J=55.0 Hz, 1H), 5.17 (brs, 1H), 4.28 (brs, 1H), 3.27 (t, J=9.8 Hz, 2H), 3.19 (d, J=12.3 Hz, 2H), 3.09 (q, J=12.2, 10.0 Hz, 1H), 2.99 (s, 3H), 2.37 (d, J=17.6 Hz, 1H), 1.98-1.73 (m, 2H), 1.53 ( dd, J=11.0, 7.7 Hz, 2H). II-321 502 2.67 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=1.1 Hz, 1H), 8.64 (s, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.08 (s, 1H), 7.75 (d, J=9.5 Hz, 1H), 7.25 (s, 1H), 5.04 (s, 1H), 4.27 (s , 1H), 3.44 (ddd, J=13.4, 5.2, 3.6 Hz, 1H), 3.06-2.92 (m, 5H), 2.92-2.76 (m , 1H), 2.35-2.12 (m, 5H), 1.05 (d, J=6.7 Hz, 3H). II-322 454.1 2.1 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=1.0 Hz, 1H), 8.65 (s, 1H), 8.54 (d, J=9.5 Hz, 1H ), 7.98 (d, J=1.1 Hz, 1H), 7.76 (d, J=9.5 Hz, 1H), 7.22 (t, J=6.2 Hz, 1H), 4.45 (bs, 1H), 4.23 (bs, 1H), 4.04 (ddd, J=11.6, 3.6, 1.5 Hz, 1H), 3.61 (ddq, J= 11.0, 8.4, 2.8 Hz, 2H), 3.25-3.16 (m, 1H), 3.16-3.07 (m, 2H), 2.95 (s, 4H) , 2.26 (t, J=19.3 Hz, 3H). II-323 345.3 2.85 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.98 (d, J=1.2 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.9 Hz, 1H), 4.86-4.68 (m, 1H), 4.45-4.27 (m, 1H), 3.03 (td, J=13.2, 3.1 Hz, 1H), 1.84- 1.76 (m, 1H), 1.76-1.56 (m, 4H), 1.45 (tq, J=11.9, 7.0, 5.9 Hz, 1H), 1.22 ( d, J=6.8 Hz, 3H). II-324 347.3 2.26 1H NMR (500 MHz, DMSO-d6) δ 8.65-8.62 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 7.97 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.7 Hz, 1H), 4.51-4.42 (m, 1H) , 4.11 (d, J=13.3 Hz, 1H), 4.00 (dd, J=11.5, 3.9 Hz, 1H), 3.79 (dt, J=11.4, 1 ,1 Hz, 1H), 3.71-3.64 (m, 1H), 3.56-3.48 (m, 1H), 3.28-3.19 (m, 1H), 1.26 ( d, J=6.7 Hz, 3H). II-325 347.3 2.26 1H NMR (500 MHz, DMSO-d6) δ 8.65-8.62 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 7.97 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.7 Hz, 1H), 4.54-4.42 (m, 1H) , 4.11 (d, J=13.1 Hz, 1H), 4.00 (dd, J=11.5, 3.9 Hz, 1H), 3.79 (dt, J=11.5, 1 ,1 Hz, 1H), 3.71-3.63 (m, 1H), 3.52 (ddd, J=12.2, 11.4, 3.1 Hz, 1H), 3.29-3, 20 (m, 1H), 1.26 (d, J=6.7 Hz, 3H). II-326 414.3 1.94 1H NMR (500 MHz, DMSO-d6) δ 8.67-8.62 (m, 2H), 8.57-8.51 (m, 2H), 8.04-7.98 (m, 2H), 7.71 (d, J=9.4 Hz, 1H), 7.35 (t, J=53.6 Hz, 1H), 4.55-4.37 (m, 3H), 4.27-4 .09 (m, 1H), 4.01 (ddd, J=11.6, 3.6, 1.7 Hz, 1H), 3.94 (ddq, J=10.8, 7.1, 4, 2, 3.5 Hz, 1H), 3.58 (td, J=11.6, 2.9 Hz, 1H), 3.14 (td, J=12.3, 3.6 Hz, 1H), 2.93 (dd, J=13.2, 10.4 Hz, 1H). II-327 412.4 2.18 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.51 (d, J=9.4 Hz, 1H ), 8.18 (d, J=1.0 Hz, 1H), 7.92 (d, J=1.2 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.7 Hz, 1H), 4.45 (dd, J=13.8, 7.2 Hz, 1H ), 4.38 (dd, J=13.8, 7.0 Hz, 1H), 4.35-4.10 (m, 2H), 3.23-3.11 (m, 1H), 3, 01 (dd, J=13.1, 10.1 Hz, 1H), 2.15 (ddq, J=10.2, 7.0, 3.5 Hz, 1H), 1.80 (dq, J= 11.7, 3.8 Hz, 1H), 1.71 (dq, J=12.5, 4.1 Hz, 1H), 1.57-1.42 (m, 1H), 1.41-1 .28 (m, 1H). II-328 404.3 1.8 1H NMR (500 MHz, DMSO-d6) δ 8.60 (d, J=1.1 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=9.3 Hz, 1H ), 8.10 (d, J=1.2 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 7.26 (t, J=6.3 Hz, 1H), 4.49-4.34 (m, 1H), 4.31-4.15 (m, 1H), 4.03 (ddd, J=11.6, 3.8, 1.5 Hz, 1H), 3.65-3.53 (m, 2H), 3.21-3.07 (m, 3H), 2.96 (s, 3H), 2.86 (dd, J=13.3, 10.3 Hz, 1H), 2.68 (s, 3H). II-329 488.1 2.4 1H NMR (500 MHz, methanol-d4) δ 8.76 (s, 2H), 8.48 (d, 1H), 8.18 (s, 1H0, 7.81 (dd, 1H), 7.25- 7.04 (t, 1H), 5.40 (br m, 1H), 3.50 (br s, 1H), 3.13 (m, 2H), 3.02 (s, 3H), 2.38 (m, 1H), 2.27 (m, 1H), 2.18-2.02 (m, 1H), 1.37 (d, 3H). II-330 508.3 2.42 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=1.1 Hz, 1H), 8.66 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.05 (s, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.31 (s, 1H), 7.27 (t, J=53.8 Hz, 1H ), 4.72-4.65 (m, 1H), 4.15-4.00 (m, 4H), 3.55 (dd, J=13.5, 7.9 Hz, 1H), 3, 24-3.21 (m, 2H), 2.95 (s, 3H). II-331 508.3 2.52 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=1.1 Hz, 1H), 8.67 (s, 1H), 8.55 (d, J=9.4 Hz, 1H ), 8.10 (d, J=1.2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.40 (br s, 1H), 7.28 (t, J=53.8 Hz, 1H), 4.64-4.49 (m, 4H), 3.85-3.80 (m, 1H), 3.26-3.13 (m, 2H), 2 .99-2.94 (m, 1H), 2.98 (s, 3H) II-332 453 1.92 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=1.1 Hz, 1H), 8.57 (s, 1H), 8.47 (d, J=9.4 Hz, 1H ), 7.93 (d, J=1.2 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.22 (t, J=55.0 Hz, 1H), 6.81 (s, 2H), 4.82 (vbrs, 1H), 4.13 (t, J=4.1 Hz, 1H), 3.99 (dd, J=11.8, 3.7 Hz , 1H), 3.89 (vbrs, 1H), 3.57 (td, J=12.0, 2.9 Hz, 1H), 3.52-3.40 (m, 2H), 3.08 ( t, J=9.8 Hz, 1H), the water peak covers some signals. II-333 451 2.1 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.04 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.32 (t, J=55.0 Hz, 1H), 6.92 (s, 2H), 3.92 (s, 2H), 3.63 (s, 2H), 3.48 (d, J=1.3 Hz, 4H), 1.84 (t, J =5.8 Hz, 2H), 1.61 (s, 2H). II-334 453 1.93 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=1.0 Hz, 1H), 8.59 (s, 1H), 8.47 (d, J=9.4 Hz, 1H ), 7.95 (d, J=1.2 Hz, 1H), 7.65 (d, J=9.4 Hz, 1H), 7.25 (t, J=55.0 Hz, 1H), 6.98 (s, 2H), 3.89 (s, 2H), 3.69 (dd, J=6.1, 3.8 Hz, 2H), 3.62 (t, J=8.6 Hz , 4H), 3.59-3.53 (m, 2H). II-335 451 2.19 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J=1.1 Hz, 1H), 8.55 (s, 1H), 8.46 (d, J=9.4 Hz, 1H ), 7.95 (d, J=1.2 Hz, 1H), 7.62 (d, J=9.4 Hz, 1H), 7.22 (t, J=55.0 Hz, 1H), 6.78 (s, 2H), 5.05 (vbrs, 1H), 4.14 (vbrs, 1H), 3.43 (t, J=9.2 Hz, 1H), 3.30 (dt, J =8.8, 4.4 Hz, 1H), 3.09-2.86 (m, 3H), 2.25 (dd, J=11.5, 5.8 Hz, 1H), 1.86- 1.68 (m, 2H), 1.52-1.41 (m, 2H). II-336 453.1 1.78 1H NMR (500 MHz, DMSO-d6) δ 8.61 (m, 2H), 8.52 (d, 1H), 8.02 (s, 1H), 7.70 (d, 1H), 7.45 -7.25 (t, 1H), 7.05 (br s, 1H), 4.80 (br s, 1H), 3.60 (m, 1H), 3.30- 3.12 (masked, 5H ), 2.87 (m, 5H), 1.21 (m, 3H). II-337 482.1 2.16 1H NMR (500 MHz, DMSO-d6) δ 8.69 (d, J=1.0 Hz, 1H), 8.52 (d, J=1.9 Hz, 1H), 8.31 (d, J =9.4 Hz, 1H), 8.21 (d, J=8.9 Hz, 1H), 7.57 (dd, J=9.4, 3.3 Hz, 1H), 7.27 (t , J=6.4 Hz, 1H), 5.02 (dq, J=11.1, 6.5 Hz, 1H), 4.35 (s, 1H), 3.44 (ddd, J=13, 4, 5.4, 3.6 Hz, 1H), 3.03-2.94 (m, 5H), 2.91-2.81 (m, 1H), 2.24 (s, 2H), 1 .58 (dd, J=6.5, 2.7 Hz, 3H), 1.07 (dd, J=6.8, 2.4 Hz, 3H). 1× CH not observed II-338 434.1 1.65 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=0.9 Hz, 1H), 8.58 (s, 1H), 8.34 (d, J=9.5 Hz, 1H ), 8.09 (d, J=1.0 Hz, 1H), 7.61 (dd, J=9.5, 0.7 Hz, 1H), 7.25 (t, J=6.3 Hz , 1H), 5.06-4.97 (m, 1H), 4.50 (s, 3H), 4.23 (s, 15H), 4.06 (ddd, J=11.6, 3.7 , 1.5 Hz, 1H), 3.61 (dddd, J=15.9, 8.5, 5.2, 3.0 Hz, 2H), 3.29-3.18 (m, 1H), 3.15 (tt, J=6.4, 1.8 Hz, 2H), 2.96 (s, 4H), 1.56 (d, J=6.5 Hz, 3H). II-339 412.4 2.13 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.57-8.54 (m, 2H), 8.51 (d, J=9.4 Hz, 1H), 7 .98 (s, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.30 (t, J=53, 8 Hz, 1H), 4.37-4.21 (m, 2H), 4.22-4.07 (m, 2H), 3.20 (ddd, J=13.6, 10.8, 3, 1 Hz, 1H), 3.02 (dd, J=13.2, 9.8 Hz, 1H), 2.20-2.09 (m, 1H), 1.79 (dq, J=12.2 , 4.1 Hz, 1H), 1.70 (dq, J=12.8, 4.2 Hz, 1H), 1.57-1.43 (m, 1H), 1.32 (dtd, J= 12.8, 10.6, 3.8 Hz, 1H). II-340 481.4 2.49 II-341 377.3 1.88 1H NMR (400 MHz, DMSO-d6) δ 8.72-8.57 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 7.98 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 4.79 (t, J=3.5 Hz , 1H), 4.48 (d, J=7.1 Hz, 1H), 4.15 (d, J=13.3 Hz, 1H), 3.77 (dd, J=10.1, 4, 0 Hz, 2H), 3.67-3.53 (m, 3H), 1.30 (d, J=6.7 Hz, 3H). II-342 377.1 1.94 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.00 (s, 1H), 7.69 (d , J=9.4 Hz, 1H), 7.52-7.06 (m, 1H), 4.86 (t, J=5.5 Hz, 1H), 4.09 (q, J=5, 2 Hz, 1H), 4.06-3.99 (m, 1H), 3.68-3.46 (m, 3H), 3.40 (d, J=10.4 Hz, 1H), 3, 30 (s, 1H), 1.12 (d, J=25.8 Hz, 3H). II-343 405.3 1.73 1H NMR (500 MHz, methanol-d4) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.39 (d, J=9.5 Hz, 1H ), 8.12 (s, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.09 (t, J=54.1 Hz, 1H), 4.00-3.98 (m, 2H), 3.91 (s, 2H), 3.73 (dd, J=11.6, 2.7 Hz, 1H), 3.55 (br s, 1H), 3.49 (s , 2H). One×CH2 and one×CH are not observed. II-344 451 2.14 II-345 454.1 2.11 II-346 454.4 2.04 1H NMR (400 MHz, methanol-d4) δ 8.66-8.53 (m, 2H), 8.38 (d, J=9.4 Hz, 1H), 8.11 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.12 (t, J=54.1 Hz, 1H), 4.70-4.53 (m, 1H) , 4.33 (dd, J=14.0, 3.9 Hz, 1H), 3.96 (td, J=11.8, 4.0 Hz, 1H), 3.91-3.78 (m , 2H), 3.53-3.35 (m, 3H), 2.97 (s, 3H), 1.43 (d, J=6.7 Hz, 3H). II-347 441 1.82 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.46 (d, J=9.4 Hz, 1H ), 7.92 (d, J=1.2 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.24 (t, J=55.0 Hz, 1H), 6.66 (t, J=6.4 Hz, 1H), 6.54 (s, 2H), 4.43 (brs, 1H), 4.16 (brs, 1H), 3.99-3.88 (m, 1H), 3.55-3.48 (m, 2H), 3.07-3.01 (m, 2H), 2.93 (dt, J=13.6, 7.0 Hz, 1H ), 2.74 (t, J=11.8 Hz, 1H). II-348 467 2.47 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.45-7.19 (m, 2H), 4.60 -4.21 (m, 2H), 3.12-3.03 (m, 1H), 2.95-2.80 (m, 3H), 2.68 (s, 6H), 1.90-1 .74 (m, 2H), 1.73-1.65 (m, 1H), 1.52-1.41 (m, 1H), 1.38-1.29 (m, 1H). II-349 469 2.23 1H NMR (500 MHz, DMSO-d6) δ 8.69-8.60 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.00 (d, J=1, 2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.45-7.02 (m, 2H), 4.47 (brs, 1H), 4.24 (brs, 1H), 4.08-3.95 (m, 1H), 3.67-3.45 (m, 2H), 3.18-3.02 (m, 3H), 2.84 (dd, J= 13.2, 10.3 Hz, 1H), 2.70 (s, 6H). II-350 471.5 2.34 1H NMR (500 MHz, DMSO-d6) δ 8.65-8.60 (m, 2H), 8.53 (dd, J=9.4, 1.7 Hz, 1H), 8.06 -
7.95 (m, 1H), 7.70 (dt, J=9.4, 1.8 Hz, 1H), 7.44-7.12 (m, 2H), 4.14 (s, 1H) , 3.83 (s, 1H), 3.71(d, J=6.1 Hz, 1H), 3.38-3.32 (m, 2H), 2.99-2.80 (m, 4H ), 2.21 (d, J=8.1 Hz, 1H), 1.79 (s, 1H), 1.44 (d, J=21.3 Hz, 1H). II-351 444 2.14 II-352 402 1.85 II-353 429 1.87 II-354 345.3 2.84 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.98 (d, J=1.2 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.9 Hz, 1H), 4.84-4.71 (m, 1H), 4.43-4.30 (m, 1H), 3.03 (td, J=13.2, 3.1 Hz, 1H), 1.84- 1.76 (m, 1H), 1.76-1.58 (m, 4H), 1.53-1.38 (m, 1H), 1.22 (d, J=6.8 Hz, 3H) . II-355 379.3 1.77 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=1.1 Hz, 1H), 8.64 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.06 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.35 (t, J=53.7 Hz, 1H), 5.16-5.02 (m, 1H), 4.67-4.54 (m, 1H), 4.03 (t, J=13.3 Hz, 1H), 3.10 (dt, J= 14.6, 2.5 Hz, 1H), 3.07-2.91 (m, 2H), 2.81 (dd, J=14.7, 5.7 Hz, 1H), 1.63 (d , J=7.1 Hz, 3H). II-356 379.3 1.82 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=1.0 Hz, 1H), 8.64 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.05 (d, J=1.2 Hz, 1H), 7.70 (dd, J=9.4, 0.7 Hz, 1H), 7.35 (t, J=53.8 Hz , 1H), 5.11-4.97 (m, 1H), 4.84-4.69 (m, 1H), 3.56-3.37 (m, 3H), 2.94 (dd, J =12.8, 4.6 Hz, 1H), 2.71-2.59 (m, 1H), 1.38 (d, J=6.9 Hz, 3H). II-357 330.3 2.24 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=1.3 Hz, 1H), 8.77 (s, 1H), 8.72 (d, J=1.4 Hz, 1H ), 8.57 (d, J=9.4 Hz, 1H), 7.75 (d, J=9.4 Hz, 1H), 7.53-7.27 (m, 1H), 7.23 -7.18 (m, 1H), 4.38 (q, J=2.9 Hz, 2H), 3.90 (t, J=5.4 Hz, 2H), 2.69-2.59 ( m, 2H). II-358 332.3 2.1 1H NMR (500 MHz, DMSO-d6) δ 9.19 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.58-8.53 (m, 2H), 7 .74 (d, J=9.4 Hz, 1H), 7.39 (t, J=53.7 Hz, 1H), 4.01 (ddd, J=11.4, 4.3, 1.9 Hz, 2H), 3.52 (td, J=11.6, 2.4 Hz, 2H), 3.08 (tt, J=11.5, 4.1 Hz, 1H), 1.96-1 .76 (m, 4H). II-359 389.3 2.05 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.99 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.9 Hz, 1H), 4.86 (br s, 1H), 4.49 (br s, 1H), 3.83 (br s, 1H), 3.69-3.64 (m, 1H), 3.59 (d, J=13.1 Hz, 1H ), 3.52-3.44 (m, 2H), 3.04-2.99 (m, 1H), 0.91-0.86 (m, 1H), 0.83-0.78 (m , 1H), 0.66-0.62 (m, 1H), 0.57-0.53 (m, 1H). II-360 488.4 2.39 1H NMR (500 MHz, methanol-d4) δ 8.64 (m, 2H), 8.39 (d, 1H), 8.18 (s, 1H), 7.71 (dd, 1H), 7.22 -7.01 (t, 1H), 3.35 (masked, 2H), 3.13 (m, 2H), 3.02 (s, 3H), 2.38 (m, 1H), 2.27 ( m, 1H), 2.18-2.02 (m, 2H), 1.32 (d, 3H). II-361 488 2.39 II-362 424.1 2.09 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.0 Hz, 1H), 8.52 (d, J=9.5 Hz, 1H ), 8.01 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.46-7.13 (m, 2H), 4.51 -4.06 (m, 2H), 3.39 (d, J=5.9 Hz, 1H), 3.11 (ddt, J=22.5, 13.0, 6.5 Hz, 2H), 2.99 (s, 3H), 2.00 (dd, J=8.7, 4.9 Hz, 1H), 1.86-1.75 (m, 1H), 1.55 (tt, J= 11.6, 6.2 Hz, 2H). II-363 467.1 2.01 II-364 467.1 2.01 1H NMR (500 MHz, methanol-d4) δ 8.58 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.34 (d, J=9.4 Hz, 1H ), 8.03-7.99 (m, 1H), 7.66 (d, J=9.4 Hz, 1H), 7.09 (t, J=53.7 Hz, 1H), 3.53 (dd, J=13.0, 5.0 Hz, 1H), 3.35 (s, 1H), 3.27 (m, 2H), 3.03 (m, 4H), 2.97 (m, 1H), 2.36 (s, 4H), 2.30 (td, J=12.1, 3.6 Hz, 1H), 1.28 (d, J=6.7 Hz, 3H). II-365 482.4 1.99 II-366 480.3 2.01 II-367 482.3 2.07 II-368 388.3 2 1H NMR (500 MHz, DMSO-d6) δ 8.75 (m, 2H), 8.55 (d, 1H), 7.96 (s, 1H), 7.77 (d, 1H), 7.46 -7.24 (t, 1H), 4.80 (br s, 1H), 4.32-4.18 (m, 2H), 3.91-3.83 (m, 1H), 3.45 ( m, 1H), 3.37 (m, 1H), 3.16-2.99 (m, 1H), 2.11 (m, 3H), 1.26-1.18 (dd, 3H). II-369 466.3 2.2 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=1.1 Hz, 1H), 8.64 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 7.94 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.9 Hz, 1H), 4.34-4.25 (m, 1H), 4.11 (td, J=10.1, 4.3 Hz, 1H), 4.08-4.02 (m, 1H), 4.01- 3.88 (m, 2H), 3.80-3.65 (m, 3H), 3.06-2.93 (m, 4H), 2.84 (dd, J=11.2, 10.2 Hz, 1H), 2.61-2.53 (m, 1H), 1.70-1.58 (m, 1H). II-370 422.3 1.89 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.01 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.42 (t, J=53.7 Hz, 1H), 4.52 (s, 1H), 4.37 (s, 1H), 3.80 (s, 1H), 3.16-3.02 (m, 4H), 2.97 (s, 3H), 2 .22 (d, J=9.9 Hz, 1H), 2.00 (d, J=11.9 Hz, 1H), 1.76 (d, J=12.1 Hz, 1H), 1.50 (tt, J=20.7, 10.3 Hz, 2H). II-371 454.3 2.11 II-372 454.1 2.12 II-373 375 2.27 1H NMR (500 MHz, DMSO-d6) δ 8.64-8.54 (m, 2H), 8.52 (d, J=9.4 Hz, 1H), 8.04 (br s, 1H), 7.27 (t, J=55.0 Hz, 1H), 4.63 (br s, 2H), 3.35 (ddd, J=12.0, 7.6, 3.9 Hz, 2H), 3.02 (v br s, 1H), 1.90-1.75 (m, 2H), 1.58 (d, J=11.2 Hz, 1H), 1.53-1.14 (m, 3H), 1.09 (br s, 3H). II-374 438.3 2.26 1H NMR (500 MHz, DMSO-d6) δ 8.68 (s, 2H), 8.56 (d, J=9.5 Hz, 1H), 8.02 (d, J=1.1 Hz, 1H ), 7.74 (d, J=9.5 Hz, 1H), 7.46-7.16 (m, 2H), 3.10 (s, 1H), 2.97 (s, 3H), 2 .03 (ddt, J=13.3, 7.7, 4.2 Hz, 1H), 1.87 (s, 1H), 1.66 (dd, J=33.7, 13.8 Hz, 2H ), 1.28 (dd, J=7.0, 1.7 Hz, 3H). II-375 466.3 2.23 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.62 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.98 (s, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.29 (t, J=53.6 Hz, 1H), 7.21 (t, J =6.2 Hz, 1H), 4.50 (br s, 2H), 3.76-3.70 (m, 1H), 3.61-3.57 (m, 1H), 3.14 (t , J=6.3 Hz, 2H), 3.01-2.95 (m, 1H), 2.94 (s, 3H), 0.94-0.90 (m, 1H), 0.88- 0.81 (m, 1H), 0.71-0.66 (m, 1H), 0.60-0.55 (m, 1H). II-376 410.3 1.94 1H NMR (500 MHz, DMSO-d6) δ 8.74-8.66 (m, 2H), 8.57 (d, J=9.4 Hz, 1H), 8.12-7.96 (m, 1H), 7.75 (d, J=9.5 Hz, 1H), 7.30 (t, J=53.7 Hz, 1H), 7.03 (s, 2H), 4.93 (d, J=27.3 Hz, 1H), 4.38 (s, 1H), 3.32-3.01 (m, 3H), 2.23 (dt, J=13.5, 4.0 Hz, 1H ), 2.00-1.89 (m, 1H), 1.89-1.74 (m, 1H), 1.66-1.49 (m, 1H). II-377 438.3 2.19 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=9.1 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.02 (s, 1H ), 7.69 (d, J=9.4 Hz, 1H), 7.36 (d, J=19.2 Hz, 2H), 3.47 (d, J=9.9 Hz, 2H), 3.29 (s, 2H), 2.99 (s, 4H), 1.87-1.66 (m, 3H), 1.69-1.48 (m, 1H), 1.22-1, 12 (m, 3H). II-378 374.1 1.85 1H NMR (400 MHz, DMSO-d6) δ 8.68-8.57 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.03 (d, J=1, 2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.49-7.14 (m, 2H), 6.94 (s, 1H), 4.82-4, 08 (m, 2H), 3.07 (t, J=11.9 Hz, 2H), 2.42-2.26 (m, 1H), 1.94 (d, J=14.0 Hz, 1H ), 1.84-1.61 (m, 2H), 1.53-1.36 (m, 1H). II-379 492.1 2.45 1H NMR (500 MHz, DMSO-d6) δ 9.54 (t, J=5.6 Hz, 1H), 8.72 (s, 2H), 8.58 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.0 Hz, 1H), 7.76 (d, J=9.5 Hz, 1H), 7.31 (t, J=53.7 Hz, 1H), 4.40-4.25 (m, 1H), 3.19 (qd, J=13.9, 5.1 Hz, 3H), 3.12-2.93 (m, 1H), 1.98- 1.73 (m, 3H), 1.60-1.45 (m, 1H), 1.45-1.32 (m, 1H). 1 C-H missing II-380 399.3 2.63 II-381 488.4 2.43 1H NMR (500 MHz, DMSO-d6) δ 8.72-8.65 (m, 2H), 8.55 (d, J=9.4 Hz, 1H), 8.06 (d, J=1, 2
Hz, 1H), 7.72 (d, J=9.5 Hz, 1H), 7.41-7.15 (m, 2H), 3.10 (t, J=6.1 Hz, 2H), 2.96 (s, 4H),
2.22-2.12 (m, 1H), 2.06-1.99 (m, 1H), 1.33 (d, J=6.9 Hz, 3H). II-382 488.3 2.41 1H NMR (500 MHz, methanol-d4) δ 8.67-8.59 (m, 2H), 8.37 (d, J=9.5 Hz, 1H), 8.27 (d, J=1, 1 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.15 (t, J=54.3 Hz, 1H), 5.36-5.22 (m, 1H) , 4.57 (s, 1H), 4.41 (d, J=14.4 Hz, 1H), 3.55-3.45 (m, 1H), 3.18 (ddd, J=13.1 , 10.1, 3.1 Hz, 1H), 3.09-3.02 (m, 1H), 2.88 (s, 3H), 2.42-2.33 (m, 1H), 2, 17 (s, 1H), 1.40 (dd, J=7.0, 1.9 Hz, 3H). II-383 466.1 2.24 1H NMR (500 MHz, methanol-d4) δ 8.63 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.38 (d, J=9.4 Hz, 1H ), 8.09 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.11 (t, J=54.0 Hz, 1H), 4.52 (br s, 1H), 4.02 (br s, 1H), 3.86 (dtd, J=10.9, 5.7, 2.7 Hz, 1H), 3.63 (d, J=13.4 Hz, 1H), 3.28 (dd, J=5.7, 2.1 Hz, 2H), 3.11 (dd, J=13.0, 10.9 Hz, 1H), 3.00 (s, 3H), 1.03-0.99 (m, 1H), 0.86-0.75 (m, 2H), 0.70-0.65 (m, 1H). II-384 466.1 2.23 1H NMR (500 MHz, methanol-d4) δ 8.63 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.38 (d, J=9.4 Hz, 1H ), 8.10-8.00 (m, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.11 (t, J=53.9 Hz, 1H), 4.51 (br s, 1H), 4.01 (br s, 1H), 3.88-3.83 (m, 1H), 3.63 (d, J=13.3 Hz, 1H), 3.28 ( dd, J=5.7, 2.1 Hz, 2H), 3.11 (dd, J=13.3, 10.7 Hz, 1H), 3.00 (s, 3H), 1.03-0 .99 (m, 1H), 0.86-0.75 (m, 2H), 0.69-0.65 (m, 1H). II-385 453 2.2 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.30 (t, J=55.0 Hz, 1H), 6.99 (t, J=6.2 Hz, 1H), 6.70 (q, J=5.1 Hz, 1H), 4.47 (v brs, 1H), 4.31 (v brs, 1H ), 3.16-3.06 (m, 1H), 2.92-2.70 (m, 3H), 2.46 (d, J=5.2 Hz, 3H), 1.88-1, 82 (m, 1H), 1.81-1.69 (m, 2H), 1.52-1.343 (m, 1H), 1.36-1.28 (m, 1H). II-386 455 1.98 1H NMR (500 MHz, DMSO-d6) δ 8.61-8.51 (m, 2H), 8.46 (d, J=9.4 Hz, 1H), 7.92 (d, J=1, 2 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.24 (t, J=55.0 Hz, 1H), 7.04 (t, J=6.2 Hz , 1H), 6.69 (q, J=5.1 Hz, 1H), 4.42 (br s, 1H), 4.15 (br s, 1H), 3.99-3.89 (m, 1H), 3.51 (tt, J=11.6, 3.2 Hz, 2H), 3.06 (br t, J=12.1 Hz, 1H), 2.96 (dt, J=13, 5, 5.8 Hz, 1H), 2.88 (dt, J=13.4, 6.6 Hz, 1H), 2.74 (t, J=11.7 Hz, 1H), 2.41 ( d, J=5.2 Hz, 3H). II-387 453 2.08 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.56-8.45 (m, 2H), 7.77 (d, J=1.2 Hz, 2H), 7 .68 (d, J=9.4 Hz, 1H), 7.20 (t, J=55.0 Hz, 1H), 6.63 (s, 2H), 4.03 (dt, J=11, 5, 5.7 Hz, 1H), 3.46-3.37 (m, 1H), 2.82 (td, J=12.8, 2.9 Hz, 1H), 2.15-2.05 (m, 1H), 1.71-1.64 (m, 1H), 1.62-1.53 (m, 1H), 1.50-1.40 (m, 1H), 1.39-1 .21 (m, 2H), 1.12 (d, J=6.8 Hz, 3H), the water peak covers some signals. II-388 470.1 2.36 1H NMR (500 MHz, methanol-d4) δ 8.63 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.37 (d, J=9.4 Hz, 1H ), 8.19 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.16 (t, J=54.0 Hz, 1H), 4.05 (d, J=13.8 Hz, 1H), 3.95 (s, 2H), 3.85 (dd, J=13.7, 6.4 Hz, 1H), 3.28 (dd , J=12.9, 3.7 Hz, 1H), 2.97 (dd, J=13.0, 11.0 Hz, 1H), 2.94 (s, 3H), 2.13 (s, 1H), 1.95-1.86 (m, 2H), 1.49 (d, J=22.8 Hz, 3H). II-389 470.1 2.38 1H NMR (500 MHz, methanol-d4) δ 8.63 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.37 (d, J=9.4 Hz, 1H ), 8.19 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.15 (t, J=54.0 Hz, 1H), 4.05 (d, J=14.2 Hz, 1H), 3.95 (d, J=5.8 Hz, 2H), 3.84 (dd, J=13.8, 6.5 Hz, 1H ), 3.31-3.26 (m, 1H), 2.94 (s, 4H), 2.14 (dtd, J=10.7, 6.8, 3.3 Hz, 1H), 2, 00-1.87 (m, 2H), 1.49 (d, J=22.8 Hz, 3H). II-390 468.3 2.21 II-391 466.3 2.48 1H NMR (500 MHz, methanol-d4) δ 8.69-8.62 (m, 2H0, 3.38 (d, 1H), 8.10-7.90 (d, 1H), 7.73 (d , 1H), 7.20-6.90 (dt, 1H), 3.25 (m, 3H), 3.10-2.90 (m, 2H), 2.86 (m, 2H), 2, 10-1.85 (m, 4H), 1.72-1.50 (m, 4H), 0.80-0.70 (m, 3H). II-392 377.3 1.96 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=1.3 Hz, 2H), 8.52 (d, J=9.4 Hz, 1H), 7.97 (s, 1H ), 7.68 (d, J=9.4 Hz, 1H), 7.29 (t, J=56.1 Hz, 1H), 4.89 (s, 2H), 4.02 (dd, J =11.4, 3.8 Hz, 1H), 3.69-3.43 (m, 3H), 3.45-3.37 (m, 1H), 3.32 (s, 1H), 1, 09 (d, J=6.5 Hz, 3H). II-393 377.3 1.94 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J=1.2 Hz, 2H), 8.53 (dd, J=9.4, 1.2 Hz, 1H), 8.00 (s, 1H), 7.69 (dd, J=9.5, 1.1 Hz, 1H), 7.20-7.50 (m, 1H), 4.78-5.05 (m, 2H ), 4.03 (d, J=10.7 Hz, 1H), 3.72-3.45 (m, 3H), 3.45-3.35 (m, 1H), 3.30 (s, 1H), 1.12 (d, J=25.0 Hz, 3H). II-394 424 1.97 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.72 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.44-7.19 (m, 2H), 3.86 -3.42 (m, 4H), 3.07 (s, 2H), 2.93 (s, 3H), 2.53-2.45 (m, 1H) 2.28-2.05 (m, 1H), 1.92-1.75 (m, 1H). II-395 395 1.85 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.77 (d, J=0.9 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.35 (t, J=53.8 Hz, 1H), 4.15 (br s, 1H), 4.08-3.87 (m, 2H), 3.69 (br d, J=24.6 Hz, 2H), 3.12 (s, 3H), 2 .49-2.46 (m, 2H). II-396 409 1.92 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.57 (s, 1H), 8.53 (d, J=9.3 Hz, 1H), 7.74 (s , 1H), 7.69 (d, J=9.4 Hz, 1H), 7.51-7.17 (m, 1H), 4.00 (br s, 1H), 3.81 (br s, 1H), 3.63 (br s, 1H), 3.53-3.37 (m, 3H), 3.06 (s, 3H), 2.82 (s, 1H), 2.43-2, 18 (m, 1H), 2.01-1.76 (m, 1H). II-397 452.3 2.4 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=5.5 Hz, 2H), 8.57 (d, J=9.3 Hz, 1H), 8.04 (s, 1H ), 7.75 (dd, J=9.6, 2.4 Hz, 1H), 7.43-7.11 (m, 2H), 2.93 (s, 5H), 2.68 (s, 2H), 1.93-1.85 (m, 1H), 1.68 (d, J=37.4 Hz, 2H), 0.99 (d, J=6.5 Hz, 4H). II-398 452.3 2.38 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=17.1 Hz, 2H), 8.56 (d, J=9.4 Hz, 1H), 8.04 (d, J =1.1 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.32 (s, 1H), 7.08 (t, J=6.0 Hz, 1H), 3.65 (s, 2H), 3.40 (d, J=7.5 Hz, 1H), 2.91 (td, J=6.7, 3.8 Hz, 2H), 2.86 (s , 3H), 2.01 (s, 2H), 1.73-1.60 (m, 1H), 1.52 (ddd, J=12.8, 8.0, 4.6 Hz, 1H), 0.95 (d, J=6.7 Hz, 3H). II-399 360 1.67 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.56 (d, J=1.2 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.72 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.53 (br s, 1H), 7.34 (t, J=53.6 Hz, 1H), 7.00 (br s, 1H), 3.87-3.46 (m, 4H), 3.09 (s, 1H), 2.46 (s, 1H), 2.30-2, 16 (m, 1H). II-400 357 2.89 II-401 359 2.27 II-402 361 2.49 1H NMR (500 MHz, DMSO-d6) δ 8.68 (d, J=1.1 Hz, 1H), 8.64 (s, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.19 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.30 (t, J=55.0 Hz, 1H), 3.88 (dd, J=6.0, 4.8 Hz, 2H), 3.74 (dd, J=6.0, 4.8 Hz, 2H), 3.51 (s, 2H), 1 .53 (s, 6H). II-403 468.3 2.27 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.01 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.41-7.22 (m, 1H), 7.20 (d, J=5.5 Hz, 1H), 4.48 (br s, 1H), 4.20 (br s, 1H), 3.84-3.78 (m, 1H), 3.12- 3.08 (m, 2H), 2.98-2.95 (m, 1H), 2.97 (s, 3H), 2.81-2.74 (m, 1H), 1.27 (s, 3H), 1.18 (s, 3H). II-404 424.3 2.1 II-405 424.3 2.1 II-406 456.3 1.93 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.65-8.63 (m, 2H), 7.96 (d, J=1.2 Hz, 1H), 7 .88 (d, J=9.5 Hz, 1H), 4.43 (br s, 1H), 4.20 (br s, 1H), 4.01 (dd, J=11.6, 3.4 Hz, 1H), 3.58 (td, J=11.6, 2.9 Hz, 1H), 3.53-3.48 (m, 1H), 3.20 (dd, J=12.3, 5.0 Hz, 1H), 3.12-2.99 (m, 2H), 2.06 (s, 6H), 2.84 (t, J=11.7 Hz, 1H). II-407 440 2.08 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.63 (d, J=9.5 Hz, 1H), 8.59 (d, J=1.0 Hz, 1H ), 7.97 (s, 1H), 7.86 (d, J=9.5 Hz, 1H), 4.16 (br s, 1H), 3.30-3.21 (m, 2H), 3.13-3.04 (m, 1H), 3.01 (s, 3H), 3.00 (s, 3H), 2.94-2.77 (m, 1H), 1.95-1, 89 (m, 1H), 1.83-1.71 (m, 1H), 1.58-1.43 (m, 2H). II-408 422 1.94 II-409 346 1.77 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.54 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.71 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.7 Hz, 1H), 3.84-3.42 (m, 3H), 3.23-3.15 (m, 1H), 2.72-2.57 (m, 2H), 2.47-2.23 (m, 1H), 2.23-1 .99 (m, 1H), 1.92-1.67 (m, 1H). II-410 453.3 1.93 II-411 453.3 1.9 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.60 (s, 1H), 8.54-8.52 (d, 1H), 8.01 (s, 1H) , 7.70-7.68 (d, 1H), 7.30 (t, 1H), 7.20 (s, 1H), 4.40 (br s, 2H), 3.30 (masked, 2H) , 3.04 (m, 2H), 2.96 (s, 3H), 2.75 (m, 2H), 1.08 (d, 3H). II-412 438.1 2.26 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.05 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.8 Hz, 1H), 7.05 (s, 1H), 3.98 (d, J=13.9 Hz, 2H), 3.66 (d, J=13.3 Hz, 1H), 3.49 (t, J=10 .7 Hz, 1H), 3.00 (s, 3H), 2.00-1.49 (m, 4H), 1.36 (s, 3H). II-413 377.1 1.91 II-414 377.1 1.91 II-415 425 1.84 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.71 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.48-7.17 (t, J=50 Hz, 1H), 6.76 (br s, 1H), 6.55 (s, 2H), 3.88-3.41 (m, 4H), 2.99 (br s, 2H), 2.26-2.00 (m, 2H), 1.96-1.73 (m, 1H). II-416 466.1 2.48 II-417 466.1 2.48 II-418 467.1 2.09 1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, 1H), 8.67 (s, 1H), 8.57-8.55 (d, 1H), 8.08 (s, 1H) , 7.74-7.72 (d, 1H), 7.43 (s, 1H), 7.43-7.22 (t, 1H), 4.80-4.50 (br d, 1H), 3.50 (masked, 4H), 3.30 (m, 2H), 3.07 (s, 3H), 2.90 (s, 3H), 2.80 (m, 1H), 1.50-1 .25 (m, 4H). II-419 466.1 2.11 II-420 464.1 2.47 II-421 438.3 2.25 II-422 439.3 2.12 II-423 467.3 2.18 1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.67 (s, 1H), 8.57-8.54 (d, 1H), 8.04 (s, 1H) , 7.74-7.72 (d, 1H), 7.55 (m, 1H), 7.30 (t, 1H), 4.90 (br s, 2H), 3.30 (masked, 6H) , 2.98-2.90 (m, 6H), 1.08 (d, 3H). II-424 438 2.2 II-425 438.1 1.88 1H NMR (500 MHz, DMSO-d6) δ 8.69-8.59 (m, 2H), 8.57-8.47 (m, 1H), 8.00 (s, 1H), 7.76- 7.67 (m, 1H), 7.35 (t, J=53.7 Hz, 1H), 4.08 (s, 2H), 3.70 (d, J=59.8 Hz, 2H), 3.31 (m, 2H hidden), 2.99 (s, 3H), 1.16 (m, 3H+2H). II-426 439.1 2.16 1H NMR (500 MHz, DMSO-d6) δ 8.74-8.59 (m, 2H), 8.55 (d, J=9.4 Hz, 1H), 8.00 (s, 1H), 7 .73 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.5 Hz, 1H), 4.19-4.01 (m, 2H), 3.67 (m, J=11.7 Hz, 6H, partially hidden), 3.05 (s, 3H), 1.25-1.05 (m, 3H). II-427 467.3 2.02 1H NMR (500 MHz, methanol-d4) δ 8.74 (d, 1H), 8.71 (s, 1H), 8.44 (d, 1H), 8.18 (s, 1H), 7.76 -7.74 (d, 1H), 7.24-7.03 (t, 1H), 5.20 (brs,2H), 3.69 (m, 1H), 3.52-3.40 (m , 3H), 3.23 (m, 1H), 3.09 (s, 3H), 1.54-1.53 (d, 3H), 1.41-1.40 (d, 3H). II-428 511 2.14 1H NMR (500 MHz, DMSO-d6) δ 8.62-8.50 (m, 2H), 8.45 (d, J=9.4 Hz, 1H), 7.86 (s, 1H), 7 .61 (d, J=9.4 Hz, 1H), 7.36-7.13 (m, 2H), 4.57-4.41 (m, 1H), 4.00 (v brs s, 2H ), 3.20-2.96 (m, 4H), 2.94-2.75 (m, 5H), 2.68 (ddd, J=24.1, 13.8, 3.7 Hz, 1H ), 2.48 (br s, 1H), 1.86 (dt, J=10.4, 5.2 Hz, 1H), 1.69 (d, J=10.8 Hz, 1H), water peak blocks some signals. II-429 511 2.11 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=1.9 Hz, 1H), 8.57-8.41 (m, 2H), 7.97 (s, 1H), 7 .68 (dd, J=9.4, 1.8 Hz, 1H), 7.42 (br t, J=55.0 Hz, 1H), 7.10 (br t, J=7.2 Hz, 1H), 5.04 (br d, J=58.1 Hz, 1H), 4.30 (v br s, 2H), 3.62-5.52 (m, 2H), 3.25-2, 99 (m, 3H), 2.99-2.68 (m, 6H), 1.95 (br s, 1H), 1.72 (br d, J=13.6 Hz, 1H), 1.42 (br t, J=12.0 Hz, 1H), the water peak covers some signals. II-430 423.3 2.2 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.5 Hz, 1H ), 8.01 (d, J=1.0 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.6 Hz, 1H), 4.53 (br s, 1H), 4.39 (br s, 1H), 3.23-3.22 (m, 2H), 3.11-3.03 (m, 2H), 3.05 ( s, 3H), 2.20 (br s, 1H), 1.96 (d, J=10.0 Hz, 1H), 1.79-1.76 (m, 1H), 1.58-1, 45 (m, 2H). II-431 488.1 2.5 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J=12.2 Hz, 2H), 8.55 (d, J=9.4 Hz, 1H), 8.06 (s, 1H ), 7.71 (d, J=9.4 Hz, 1H), 7.29 (s, 1H), 3.47 (dd, J=13.1, 4.1 Hz, 1H), 3.29 (s, 1H), 3.22 (s, 1H), 3.10 (t, J=12.1 Hz, 1H), 3.01 (s, 3H), 2.46 (s, 1H), 2 .40 (s, 1H), 2.25 (d, J=14.0 Hz, 1H), 2.16 (s, 1H), 2.09 (s, 1H), 1.26-1.14 ( m, 3H). II-432 488.1 2.51 1H NMR (500 MHz, DMSO-d6) δ 8.70-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.06 (d, J=1, 2 Hz, 1H), 7.71 (d, J=9.5 Hz, 1H), 7.29 (s, 1H), 3.51-3.43 (m, 1H), 3.29 (s, 4H), 3.10 (t, J=12.2 Hz, 1H), 3.01 (s, 3H), 2.41 (s, 1H), 2.32-2.22 (m, 2H), 2.17 (s, 1H), 2.09 (s, 1H), 1.21 (d, J=6.9 Hz, 4H). II-433 488.1 2.51 1H NMR (500 MHz, DMSO-d6) δ 8.70-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.04 (d, J=1, 2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.5 Hz, 1H), 5.00 (d, J=19.8 Hz , 1H), 4.85 (s, 1H), 3.48-3.41 (m, 1H), 3.27 (s, 1H), 3.05-2.92 (m, 5H), 2, 37-2.14 (m, 3H), 1.29-1.23 (m, 3H). II-434 488.1 2.51 1H NMR (500 MHz, DMSO-d6) δ 8.70-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.03 (d, J=1, 3 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.5 Hz, 1H), 5.02-4.95 (m, 1H) , 4.83 (s, 1H), 3.45 (dd, J=13.4, 3.5 Hz, 1H), 2.99 (s, 5H), 2.38-2.14 (m, 3H ), 1.29-1.22 (m, 3H). II-435 465.1 1.95 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 2H), 8.69-8.58 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8 .03 (d, J=1.2 Hz, 1H), 7.96 (dd, J=7.4, 4.5 Hz, 1H), 7.70 (d, J=9.5 Hz, 1H) , 7.30 (t, J=53.7 Hz, 1H), 4.50 (t, J=7.8 Hz, 1H), 4.28 (m, 2H), 4.09 (m, 2H) , 3.20 (m, some protons obscured, should be 4H), 1.96 (s, 1H), 1.83 (s, 1H), 1.55 (d, J=8.8 Hz, 2H), 1.33-1.08 (m, 1H). II-436 452.1 2.14 1H NMR (500 MHz, methanol-d4) δ 8.48 (s, 1H), 8.40 (s, 1H), 8.24 (d, J=9.4 Hz, 1H), 7.91 (s , 1H), 7.57 (d, J=9.5 Hz, 1H), 7.00 (t, J=53.9 Hz, 1H), 4.53 (s, 2H), 2.99 (dd , J=13.1, 5.3 Hz, 1H), 2.96-2.89 (m, 1H), 2.56 (t, J=12.4 Hz, 1H), 2.43 (t, J=12.4 Hz, 1H), 1.85 (d, J=13.4 Hz, 1H), 1.78-1.64 (m, 1H), 1.59 (dq, J=10.3 , 6.0, 5.0 Hz, 1H), 0.97-0.81 (m, 4H). II-437 452.1 2.41 1H NMR (500 MHz, methanol-d4) δ 8.56 (s, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.33 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.3 Hz, 1H), 7.65 (d, J=9.4 Hz, 1H), 7.10 (t, J=54.0 Hz, 1H), 4.61 (s, 2H), 3.10 (dd, J=13.1, 5.4 Hz, 1H), 3.05-3.01 (m, 1H), 2.63 (t, J= 12.4 Hz, 1H), 2.54-2.45 (m, 1H), 2.00-1.91 (m, 1H), 1.80 (dh, J=11.9, 3.9 Hz , 1H), 1.69 (td, J=11.4, 9.6, 5.6 Hz, 1H), 1.07-0.96 (m, 4H). II-438 359 1.99 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.58-8.47 (m, 2H), 7.68 (d, J=9.4 Hz, 2H), 7 .35 (t, J=52.5 Hz, 1H), 4.76 (br s, 1H), 4.01-3.52 (m, 6H), 1.66-1.62 (m, 1H) , 0.89 (dd, J=8.0, 4.7 Hz, 1H), 0.43 (t, J=4.5 Hz, 1H). II-439 450 2.17 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58-8.46 (m, 2H), 7.69-7.65 (m, 3H), 7.48- 7.08 (m, 1H), 3.84 (br s, 1H), 3.62 (br s, 1H), 3.43 (td, J=10.2, 6.9 Hz, 1H), 3 ,19 (br t, J=10.7 Hz, 1H), 2.93 (s, 3H), 2.76-2.54 (m, 1H), 2.05 (br s, 1H), 1, 91-1.61 (m, 1H), 1.02-0.66 (m, 4H). II-440 480.3 2.29 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.62 (d, J=1.1 Hz, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.05 (s, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.31 (t, J=53.8 Hz, 1H), 7.18 (s, 1H ), 4.04-4.01 (m, 2H), 3.85 (br s, 1H), 3.70 (dd, J=13.0, 6.1 Hz, 1H), 3.49 (dd , J=13.3, 7.1 Hz, 1H), 3.18-3.08 (m, 3H), 2.93 (s, 3H), 1.15-1.03 (m, 1H), 0.52-0.48 (m, 2H), 0.41-0.32 (m, 2H). II-441 480.3 2.29 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.62 (d, J=1.1 Hz, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.05 (s, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.8 Hz, 1H), 7.18 (s, 1H ), 4.05-4.00 (m, 2H), 3.85 (br s, 1H), 3.70 (dd, J=13.6, 6.0 Hz, 1H), 3.49 (dd , J=13.4, 7.1 Hz, 1H), 3.18-3.08 (m, 3H), 2.93 (s, 3H), 1.11-1.04 (m, 1H), 0.52-0.47 (m, 2H), 0.41-0.32 (m, 2H). II-442 450.3 2.32 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=3.8 Hz, 2H), 8.57 (d, J=9.4 Hz, 1H), 8.02 (d, J =1.1 Hz, 1H), 7.75 (d, J=9.4 Hz, 1H), 7.52-7.13 (m, 2H), 4.34 (d, J=100.4 Hz , 2H), 3.48-3.08 (m, 3H), 2.72-2.59 (m, 1H), 2.05 (dd, J=12.8, 6.2 Hz, 1H), 1.92-1.77 (m, 1H), 1.72-1.44 (m, 2H), 1.03-0.83 (m, 4H). II-443 480.1 2.39 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.63 (d, J=0.9 Hz, 1H), 8.54 (d, J=9.5 Hz, 1H ), 8.05 (s, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.30 (t, J=54.0 Hz, 1H), 7.27 (br s, 1H), 4.44 (br s, 2H), 3.57-3.51 (m, 1H), 3.22-3.11 (m, 2H), 2.97 (s, 3H), 2, 94-2.89 (m, 2H), 2.80-2.74 (m, 1H), 0.98-0.93 (m, 1H), 0.56-0.51 (m, 2H), 0.41-0.35 (m, 2H). II-444 480.1 2.38 1H NMR (500 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.63 (d, J=1.1 Hz, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.05 (s, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.9 Hz, 1H), 7.28 (br s, 1H), 4.42 (br s, 2H), 3.57-3.51 (m, 1H), 3.22-3.12 (m, 2H), 2.98 (s, 3H), 2, 96-2.89 (m, 2H), 2.77 (br s, 1H), 0.99-0.92 (m, 1H), 0.56-0.51 (m, 2H), 0.40 -0.38 (m, 2H). II-445 438.1 2.26 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.05 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.7 Hz, 1H), 7.05 (s, 1H), 4.03 (d, J=47.3 Hz, 2H), 3.66 (d, J=13.2 Hz, 1H), 3.49 (dd, J=12 ,7, 8.5 Hz, 1H), 3.00 (s, 3H), 1.94-1.53 (m, 4H), 1.36 (s, 3H). II-446 438.1 2.26 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.53 (d, J=9.5 Hz, 1H ), 8.05 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.7 Hz, 1H), 7.06 (s, 1H), 4.15-3.88 (m, 2H), 3.65 (d, J=13.3 Hz, 1H), 3.48 (td, J=9.8, 8.8, 5.0 Hz, 1H), 2.99 (s, 3H), 1.97-1.54 (m, 4H), 1.36 (s, 3H). II-447 436 2.1 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58-8.48 (m, 2H), 7.70-7.68 (m, 2H), 7.47- 7.18 (m, 2H), 4.01-3.50 (m, 4H), 3.24 (br s, 2H), 2.95 (br s, 3H), 1.78-1.65 ( m, 1H), 0.95 (dd, J=7.9, 4.9 Hz, 1H), 0.50 (t, J=4.6 Hz, 1H). II-448 481.4 2.19 1H NMR (500 MHz, methanol-d4) δ 8.65 (s, 1H), 8.58 (s, 1H), 8.39-8.37 (d, 1H), 8.11 (s, 1H) , 7.70-7.68 (d, 1H), 7.28-7.04 (t, 1H), 4.80-4.60 (m, 2H), 3.56 (m, 1H), 3 .08-3.04 (m, 4H), 2.85 (m, 1H), 2.52 (m, 1H), 2.36 (s, 3H), 2.28 (m, 1H), 1, 31-1.25 (m, 6H). II-449 438.1 2.3 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.05 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.47-7.10 (m, 2H), 4.95 -3.98 (m, 2H), 3.34-3.20 (m, 2H), 2.99 (s, 3H), 2.80-2.64 (m, 1H), 2.04 (d , J=12.3 Hz, 1H), 1.69 (s, 1H), 1.20 (q, J=12.2 Hz, 1H), 0.97 (d, J=6.5 Hz, 3H ). II-450 439.3 1.75 1H NMR (500 MHz, DMSO-d6) δ 8.62-8.59 (m, 2H), 8.53-8.51 (d, 1H0, 7.97 (s, 1H), 7.70-7 .68 (d, 1H), 7.42-7.20 (m, 2H), 4.40 (br s, 1H), 4.20 (br s, 1H), 3.07 (m, 4H), 2.95 (s, 3H), 2.70 (m, 3H). II-451 345 1.96 1H NMR (400 MHz, DMSO-d6) δ 8.72-8.61 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 7.91 (d, J=1, 2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.35 (t, J=53.6 Hz, 1H), 4.78 (s, 2H), 4.05 -3.60 (m, 4H), 3.20 (dt, J=8.9, 6.6 Hz, 1H), 1.93 (d, J=9.0 Hz, 1H). II-452 465 2.02 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J=1.1 Hz, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.04 (d, J =1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.34 (t, J=52.5 Hz, 1H), 4.12 (d, J=8 ,9 Hz, 2H), 3.94 (s, 2H), 3.67 (s, 2H), 3.51 (d, J=8.8 Hz, 2H), 3.07 (s, 3H), 2.59 (dd, J=6.2, 4.4 Hz, 2H), 2.44 (s, 3H). II-453 389 1.75 1H NMR (500 MHz, DMSO-d6) δ 8.68-8.57 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.03 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.50-7.17 (m, 3H), 4.40 (br s, 1H), 4.24 (brs , 1H), 3.21 (t, J=11.6 Hz, 1H), 2.98 (d, J=11.6 Hz, 1H), 2.65-2.60 (m, 1H), 2 ,23-2.28 (m, 4H), the peak of water covers some signals. II-454 388 1.82 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.01 (d, J=1.1 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.30 (t, J=52.5 Hz, 1H), 5.29 (s, 1H), 4.53 (brs, 1H), 4.35 (br s, 1H), 3.10-3.00 (m, 1H), 2.91-2.87 (m , 2H), 2.74-2.59 (m, 1H), 2.39 (dd, J=10.8, 3.1 Hz, 1H), 2.22 (s, 1H), 0.68- 0.45 (m, 4H). II-455 438.05 2.29 1H NMR (400 MHz, chloroform-d) δ 9.00 (s, 1H), 8.85 (s, 1H), 8.44 (d, J=9.4 Hz, 1H), 8.10 (s , 1H), 7.70 (d, J=9.4 Hz, 1H), 7.08 (s, 1H), 5.19 (s, 1H), 4.41 (s, 1H), 3.83 (ddt, J=11.7, 8.1, 3.8 Hz, 1H), 3.33 (s, 1H), 3.02 (s, 1H), 2.96 (d, J=16.0 Hz, 6H), 2.17-2.11 (m, 1H), 2.11 (s, 1H), 1.97 (qd, J=11.7, 3.6 Hz, 1H), 1.77 (t, J=13.6 Hz, 1H). II-456 523.4 2.52 1H NMR (500 MHz, DMSO-d6) δ 9.74 (s, 1H), 8.71-8.61 (m, 2H), 8.55 (d, J=9.4 Hz, 1H), 8 .00 (d, J=1.1 Hz, 1H), 7.72 (d, J=9.4 Hz, 1H), 7.38 (d, J=53.8 Hz, 1H), 4.59 (s, 2H), 3.76-3.64 (m, 2H), 3.56 (s, 3H), 3.17 (t, J=11.2 Hz, 1H), 2.91 (s, 1H), 2.87 (s, 6H), 1.97 (ddp, J=10.4, 6.8, 3.4 Hz, 1H), 1.93-1.80 (m, 2H), 1 .55-1.44 (m, 1H), 1.39 (ddt, J=13.8, 11.3, 5.7 Hz, 1H). 2 CH is not observed. II-457 468.3 2.3 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.66 (s, 1H), 8.55 (d, J=9.4 Hz, 1H), 8.19 (d , J=1.2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.38-7.12 (m, 2H), 4.31 (dd, J=13, 8, 3.7 Hz, 1H), 3.92-3.86 (m, 1H), 3.76 (d, J=11.8 Hz, 1H), 3.50 (d, J=11.9 Hz, 1H), 3.32 (dd, J=13.8, 10.0 Hz, 1H), 3.20-3.10 (m, 2H), 2.95 (s, 3H), 1.61 (s, 3H), 1.47 (s, 3H). II-458 482.1 2.41 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=2.7 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.01 (s, 1H ), 7.69 (d, J=9.5 Hz, 1H), 7.54-7.04 (m, 2H), 5.05 (s, 1H), 4.51 (s, 1H), 4 .19 (s, 1H), 3.95 (s, 1H), 3.02 (d, J=6.4 Hz, 2H), 2.96 (s, 3H), 1.30 (s, 3H) , 1.22 (s, 3H), 1.17-1.07 (m, 3H). II-459 402 2.11 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.60 (s, 1H), 8.53 (d, J=9.4 Hz, 1H), 8.03 (s , 1H), 7.69 (d, J=9.4 Hz, 1H), 7.33 (t, J=55.0 Hz, 1H), 5.02 (s, 1H), 4.37 (vbrs , 2H), 3.27-3.20 (m, 1H), 3.08 (br t, J=15.0 Hz, 1H), 2.94 (br d, J=11.6 Hz, 1H) , 2.39 (s, 3H), 2.16 (br t, J=15.0 Hz, 1H), 1.28 (d, J=10.7 Hz, 1H), 0.85-0.79 (m, 1H), 0.69-0.48 (m, 2H), 0.38 (br s, 1H). II-460 452.3 1.53 1H NMR (500 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.68 (d, J=2.5 Hz, 2H), 8.56 (d, J=9.4 Hz, 1H ), 8.04 (d, J=1.2 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.8 Hz, 1H), 4.47 (s, 1H), 4.23 (d, J=16.2 Hz, 1H), 3.40 (t, J=11.6 Hz, 1H), 3.36-3.27 (m , 1H), 3.25 (s, 3H), 2.64-2.54 (m, 1H), 2.07-1.97 (m, 1H), 1.81 (dddd, J=37.9 , 14.2, 9.7, 4.0 Hz, 2H), 1.50 (q, J=11.7, 11.3 Hz, 1H). II-461 502.3 2.72 II-462 502.4 2.7 1H NMR (500 MHz, DMSO-d6) δ 8.67-8.63 (m, 2H), 8.55-8.52 (m, 1H), 8.09 (s, 1H), 7.71- 7.68 (m, 1H), 7.29 m, 2H), 4.80 (brs, 1H), 3.62 (m, 1H), 3.30 (masked, 1H), 3.01 (s, 3H), 2.97 (s, 2H), 2.60-2.30 (m, 1H), 2.15 (m, 1H), 1.30-1.22 (m, 3H), 1.07 (m, 3H). II-463 493.4 2.54 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=9.4 Hz, 1H), 7.96 (s , 1H), 7.69 (d, J=9.5 Hz, 1H), 7.49-7.02 (m, 2H), 3.83-3.66 (m, 1H), 3.10 ( d, J=11.2 Hz, 1H), 2.98 (s, 3H), 2.94-2.80 (m, 1H), 2.66-2.57 (m, 1H), 2.54 (s, 3H), 2.41-2.25 (m, 1H), 1.66-1.54 (m, 1H), 1.14-1.01 (m, 2H), 0.74-0 .61 (m, 1H), 0.57-0.42 (m, 2H), 0.34 (d, J=4.1 Hz, 1H). II-464 439 1.82 II-465 453 1.83 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=3.2 Hz, 1H), 8.59 (t, J=1.3 Hz, 1H), 8.56-8.49 (m, 1H), 7.97 (dd, J=19.0, 1.2 Hz, 1H), 7.69 (dd, J=9.4, 2.2 Hz, 1H), 7.42- 7.04 (m, 2H), 4.68-4.06 (vbr s, 2H), 3.51-3.33 (m, 1H), 3.18-2.87 (m, 5H), 2 .87-2.53 (m, 3H), 1.24 (dd, J=6.8, 1.4 Hz, 3H). II-466 471.3 1.98 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 9.15 (s, 1H), 8.80-8.70 (m, 2H), 8.67 (d, J= 9.5 Hz, 1H), 7.99 (d, J=1.2 Hz, 1H), 7.91 (d, J=9.5 Hz, 1H), 7.61-7.46 (m, 1H), 3.51 (d, J=11.3 Hz, 2H), 3.23 (dt, J=14.3, 6.7 Hz, 5H), 3.04 (s, 3H), 2, 50 (s, 2H), 1.28 (d, J=7.0 Hz, 3H). Some peaks are masked by solvent peaks. II-467 502.4 2.62 II-468 502.4 2.62 II-469 502.1 2.71 II-470 502.1 2.7 II-471 502.1 2.68 1H NMR (500 MHz, chloroform-d) δ 8.89-8.64 (m, 2H), 8.26 (d, 1H), 7.49 (d, 1H), 7.01 (d, 1H) , 4.53 (s, 1H), 3.68 (d, 1H), 3.38 (d,1H), 3.05 (s, 3H), 2.95 (m, 1H), 2.45 ( d, 1H), 2.27-1.97 (m, 2H), 1.42-1.10 (m, 6H). II-472 502.1 2.68 1H NMR (400 MHz, DMSO-d6) δ 8.67-8.64 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.08 (s, 1H), 7 .70 (d, J=9.4 Hz, 1H), 7.38-7.11 (m, 2H), 5.75-3.98 (m, 2H), 3.49-3.45 (m , 1H), 3.14-3.06 (m, 1H), 3.00 (s, 3H), 2.54-2.49 (masked signal, 1H), 2.29-2.19 (m, 1H), 1.26-1.11 (m, 3H), 1.07 (d, J=6.6 Hz, 3H). II-473 467 2.05 1H NMR (500 MHz, DMSO-d6) δ 8.65-8.34 (m, 3H), 7.87 (s, 1H), 7.62 (d, J=9.3 Hz, 1H), 7 .36-7.04 (m, 2H), 4.42 (vbrs, 1H), 4.22 (vbrs, 1H), 3.77-3.69 (m, 1H), 3.10-2.70 (m, 6H), 2.19 (s, 3H), 2.06-2.01 (m, 1H), 1.35-1.02 (m, 4H). II-474 467 2.13 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.61 (s, 1H), 8.54 (d, J=9.4 Hz, 1H), 7.99 (s , 1H), 7.70 (d, J=9.4 Hz, 1H), 7.32 (t, J=52.5 Hz, 1H), 6.96 (d, J=7.9 Hz, 1H ), 4.24 (vbrs, 2H), 3.88-3.70 (m, 1H), 3.16 (t, J=13.1 Hz, 1H), 3.12-3.02 (m, 4H), 2.97 (d, J=12.1 Hz, 1H), 2.36-2.28 (m, 4H), 2.07 (dt, J=10.5, 3.6 Hz, 1H ), 1.27 (d, J=6.8 Hz, 3H). II-475 502.1 2.54 II-476 502.1 2.54 II-477 389 1.72 1H NMR (500 MHz, methanol-d4) δ 8.61 (d, J=1.1 Hz, 1H), 8.56 (s, 1H), 8.29 (d, J=9.4 Hz, 1H ), 8.10 (d, J=1.3 Hz, 1H), 7.60 (d, J=9.4 Hz, 1H), 6.99 (t, J=55.0 Hz, 1H), 5.37 (vbrs, 1H), 4.49 (vbrs, 2H), 4.13 (d, J=4.5 Hz, 1H), 3.47 (ddd, J=12.6, 3.1, 1.6 Hz, 1H), 3.39-3.31 (m, 1H), 3.19-3.16 (m, 1H), 1.25 (d, J=7.0 Hz, 3H), solvent peaks mask some signals. II-478 493.1 2.54 1H NMR (500 MHz, methanol-d4) δ 8.62 (s, 1H), 8.55 (d, J=1.0 Hz, 1H), 8.36 (d, J=9.4 Hz, 1H ), 8.06 (s, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.11 (t, J=53.6 Hz, 1H), 4.68-4.26 (m, 2H), 3.92 (dd, J=12.9, 4.7 Hz, 1H), 3.18 (d, J=10.4 Hz, 1H), 3.10-3.04 ( m, 1H), 3.02 (s, 3H), 2.71 (dt, J=11.0, 4.1 Hz, 1H), 2.46-2.35 (m, 1H), 1.72 -1.58 (m, 1H), 1.23 (d, J=6.7 Hz, 3H), 0.72 (dd, J=7.2, 4.7 Hz, 1H), 0.62- 0.51 (m, 2H), 0.48-0.39 (m, 1H). II-479 493.1 2.54 1H NMR (500 MHz, methanol-d4) δ 8.62 (s, 1H), 8.55 (d, J=1.0 Hz, 1H), 8.36 (d, J=9.4 Hz, 1H ), 8.06 (s, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.11 (t, J=53.6 Hz, 1H), 4.68-4.26 (m, 2H), 3.92 (dd, J=12.9, 4.7 Hz, 1H), 3.18 (d, J=10.4 Hz, 1H), 3.10-3.04 ( m, 1H), 3.02 (s, 3H), 2.71 (dt, J=11.0, 4.1 Hz, 1H), 2.46-2.35 (m, 1H), 1.72 -1.58 (m, 1H), 1.23 (d, J=6.7 Hz, 3H), 0.72 (dd, J=7.2, 4.7 Hz, 1H), 0.62- 0.51 (m, 2H), 0.48-0.39 (m, 1H). II-480 424.1 2.17 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J=1.7 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.03 (s, 1H ), 7.70 (d, J=9.4 Hz, 1H), 7.52-7.11 (m, 2H), 4.88 (s, 1H), 4.50-4.15 (m, 1H), 3.31-3.21 (m, 1H), 3.17-3.00 (m, 2H), 2.64 (d, J=4.8 Hz, 3H), 2.15 (d , J=12.8 Hz, 1H), 1.94-1.73 (m, 2H), 1.65-1.47 (m, 1H). II-481 454.1 1.95 1H NMR (500 MHz, DMSO-d6) δ 8.58 (d, J=9.7 Hz, 2H), 8.50 (d, J=9.4 Hz, 1H), 7.88 (s, 1H ), 7.66 (d, J=9.5 Hz, 1H), 7.45-6.94 (m, 2H), 4.31 (s, 1H), 4.06-3.35 (m, 7H), 2.91 (s, 5H), 2.25 (q, J=19.4, 17.4 Hz, 1H). II-482 481.4 2.25 II-483 389 1.54 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.45 (brs, 1H), 7.40 (t, J =55.0 Hz, 1H), 6.85 (brs, 1H), 4.40 (vbrs, 1H), 4.28 (vbrs, 1H), 3.10-2.88 (m, 3H), 2 .82-2.54 (m, 3H), 2.24 (d, J=6.7 Hz, 2H). II-484 482.3 2.49 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.61 (s, 1H), 8.53 (d, J=9.3 Hz, 1H), 8.02 (s , 1H), 7.69 (d, J=9.4 Hz, 1H), 7.41-7.20 (m, 1H), 3.70-3.66 (m, 1H), 3.46- 3.43 (m, 1H), 3.00-2.93 (m, 5H), 1.27 (s, 3H), 1.20-1.16 (m, 6H). One×CH2 is not observed. II-485 436.1 2.04 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 8.43 (d, J=1.1 Hz, 1H), 8.25 (d, J=9.5 Hz, 1H ), 8.01 (s, 1H), 7.57 (d, J=9.4 Hz, 1H), 7.13 (t, J=53.7 Hz, 1H), 4.75 (s, 2H ), 3.32 (dd, J=13.9, 9.1 Hz, 1H), 3.02 (s, 5H), 2.51 (s, 1H), 1.86-1.47 (m, 4H), 1.21 (d, J=6.9 Hz, 3H). II-486 436.1 2.04 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 8.42 (d, J=1.1 Hz, 1H), 8.25 (d, J=9.4 Hz, 1H ), 8.10-7.93 (m, 1H), 7.57 (d, J=9.5 Hz, 1H), 7.13 (t, J=53.6 Hz, 1H), 5.27 -4.30 (m, 2H), 3.32 (dd, J=13.9, 9.1 Hz, 1H), 3.02 (s, 6H), 2.51 (s, 1H), 1, 90-1.44 (m, 4H), 1.21 (d, J=6.8 Hz, 3H). II-487 436.3 2.04 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 1H), 8.44 (d, J=1.1 Hz, 1H), 8.26 (d, J=9.5 Hz, 1H ), 8.06-7.95 (m, 1H), 7.57 (d, J=9.5 Hz, 1H), 7.10 (t, J=53.8 Hz, 1H), 5.22 -4.17 (m, 2H), 3.15 (td, J=14.8, 6.8 Hz, 2H), 3.00 (s, 4H), 2.40 (s, 1H), 1, 89-1.49 (m, 4H), 1.20 (d, J=6.7 Hz, 3H). II-488 436.3 2.04 1H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 8.43 (d, J=1.1 Hz, 1H), 8.25 (d, J=9.5 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.57 (d, J=9.5 Hz, 1H), 7.10 (t, J=53.9 Hz, 1H), 5.01 (s, 1H), 4.72-4.29 (m, 1H), 3.19-3.10 (m, 2H), 3.00 (s, 4H), 2.39 (d, J=10.6 Hz, 1H), 1.93-1.47 (m, 4H), 1.20 (d, J=6.8 Hz, 3H). II-489 482.3 2.42 1H NMR (500 MHz, DMSO-d6) δ 8.63-8.62 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.01 (s, 1H), 7 .69 (d, J=9.4 Hz, 1H), 7.39-7.16 (m, 2H), 5.08 (br s, 1H), 4.53 (br s, 1H), 4, 15 (br s, 1H), 3.95 (s, 1H), 3.58 (br s, 1H), 3.06-3.00 (m, 1H), 2.96 (s, 3H), 1 .30 (s, 3H), 1.22 (s, 3H), 1.17-1.11 (m, 3H). II-490 482.3 2.42 1H NMR (500 MHz, DMSO-d6) δ 8.55-8.54 (m, 2H), 8.46 (d, J=9.4 Hz, 1H), 7.94 (s, 1H), 7 .62 (d, J=9.4 Hz, 1H), 7.32-7.11 (m, 2H), 4.98 (br s, 1H), 4.44 (br s, 1H), 4, 08 (br s, 1H), 3.87 (s, 1H), 3.51 (br s, 1H), 2.99-2.93 (m, 1H), 2.89 (s, 3H), 1 .22 (s, 3H), 1.14 (s, 3H), 1.078-1.02 (m, 3H). II-491 482 2.62 1H NMR (500 MHz, DMSO-d6) δ 8.66 (m,2 H), 8.54-8.51 (d, 1H), 8.01 (m, 1H), 7.70-7.67 (m,1H), 7.39 (m, 1H), 7.37-7.16 (m. 1H), 5.10-4.70 (m, 2H), 4.08-4.05 (m , 1H), 3.53 (m, 1H), 3.05-2.95 (m, 4H), 2.80 (m, 1H), 1.37 (d, 3H), 1.12 (d, 3H). II-492 403 1.71 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.01 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.54-7.32 (m, 2H), 6.84 (s, 1H), 4.22 (brs, 1H), 4.21 (brs,1H), 3.36 (ddd, J=12.9, 10.0, 3.2 Hz, 1H), 3, 18-2.97 (m, 1H), 2.82 (d, J=11.9 Hz, 1H), 2.60-2.52 (m, 1H), 2.31-2.24 (m, 4H), 2.14-2.06 (m, 1H), water and solvent peaks cover some signals. II-493 437 2.26 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.60-8.55 (m, 1H), 8.52 (d, J=9.4 Hz, 1H), 8 .00 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.34 (t, J=55.0 Hz, 1H), 4.33 (br s, 2H), 3.29-3.15 (m, 2H), 3.11 (t, J=12.8 Hz, 1H), 2.97 (s, 3H), 2.95-2 .77 (m, 1H), 1.99-1.84 (m, 1H), 1.84-1.59 (m, 4H), 1.55-1.21 (m, 2H). II-494 511.3 2.26 1H NMR (500 MHz, methanol-d4) δ 8.76 (d, J=1.0 Hz, 2H), 8.74 (s, 1H), 8.46 (d, J=9.5 Hz, 1H ), 8.11 (d, J=1.1 Hz, 1H), 7.78 (d, J=9.5 Hz, 1H), 7.16 (t, J=53.8 Hz, 1H), 5.22 (s, 1H), 4.71 (d, J=14.7 Hz, 1H), 3.82 (td, J=4.7, 4.2, 2.0 Hz, 2H), 3 ,81-3.75 (m, 1H), 3.75 (d, J=5.0 Hz, 1H), 3.66 (m, 2H), 3.50-3.35 (m, 6H), 3.09 (s, 3H), 2.68 (s, 3H), 1.48 (d, J=7.1 Hz, 3H). II-495 507.4 2.52 1H NMR (500 MHz, methanol-d4) δ 8.62 (s, 1H), 8.54 (d, J=1.1 Hz, 1H), 8.31 (d, J=9.4 Hz, 1H ), 8.04 (d, J=1.2 Hz, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.06 (t, J=53.7 Hz, 1H), 4.51-4.35 (m, 2H), 3.53 (dd, J=13.0, 4.9 Hz, 1H), 3.30-3.22 (m, 2H), 3.02 ( dd, J=13.0, 9.7 Hz, 1H), 3.01 (s, 3H), 2.74-2.70 (m, 1H), 2.70-2.60 (m, 1H) , 2.50 (td, J=12.9, 12.4, 3.5 Hz, 1H), 2.35 (dd, J=13.3, 6.4 Hz, 1H), 1.30 (d , J=6.7 Hz, 3H), 0.92 (dddd, J=12.9, 6.5, 4.1, 1.5 Hz, 1H), 0.63-0.49 (m, 2H ), 0.24-0.10 (m, 2H). II-496 376 1.64 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.34 (t, J=52.5 Hz, 1H), 4.55 (brs, 1H), 4.31 (vbrs, 2H), 3.58 (s, 2H), 3.09-2.87 (m, 2H), 2.81-2.61 (m, 3H), 2.40 (brs, 1H), 1.64-1.47 (m, 2H). II-497 375.2 2.28 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.51 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.9 Hz, 1H), 4.47 (t, J=5.2 Hz, 1H), 4.34 (s, 2H), 3.52 (tq, J=9.8, 4.6 Hz, 2H), 3.06 (td , J=12.3, 11.5, 2.9 Hz, 1H), 2.82 (dd, J=13.2, 10.3 Hz, 1H), 1.92-1.83 (m, 1H ), 1.80-1.58 (m, 2H), 1.52-1.17 (m, 4H). II-498 377.2 1.94 1H NMR (400 MHz, DMSO-d6) δ 8.66-8.58 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.00 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.7 Hz, 1H), 4.55 (t, J=5.2 Hz , 1H), 4.29 (d, J=40.6 Hz, 2H), 4.04-3.94 (m, 1H), 3.67-3.49 (m, 4H), 3.16- 3.00 (m, 1H), 2.81 (t, J=11.8 Hz, 1H), 1.68 (q, J=6.4 Hz, 2H). II-499 393.3 2.45 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.62 (d, J=9.5 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H ), 7.96 (d, J=1.2 Hz, 1H), 7.86 (d, J=9.5 Hz, 1H), 4.42 (t, J=5.1 Hz, 1H), 4.27 (s, 2H), 3.50 (td, J=6.6, 5.1 Hz, 2H), 3.06 (t, J=12.1 Hz, 1H), 2.83 (dd , J=13.1, 10.4 Hz, 1H), 1.94-1.82 (m, 1H), 1.75 (dt, J=13.2, 3.7 Hz, 1H), 1, 65 (ddd, J=10.6, 7.0, 3.8 Hz, 1H), 1.54-1.19 (m, 4H). II-500 395 2.05 1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.66-8.58 (m, 2H), 7.95 (d, J=1.2 Hz, 1H), 7 .88 (d, J=9.5 Hz, 1H), 4.52 (t, J=5.2 Hz, 1H), 4.20 (s, 2H), 4.07-3.94 (m, 1H), 3.67-3.47 (m, 4H), 3.15-3.02 (m, 1H), 2.84 (dd, J=13.0, 10.5 Hz, 1H), 1 .75-1.50 (m, 2H). II-501 388.3 2.61 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.67-8.62 (m, 1H), 8.62 (t, J=1.2 Hz, 1H), 7 .99 (d, J=1.3 Hz, 1H), 7.88 (d, J=9.5 Hz, 1H), 4.50 (s, 1H), 4.16 (s, 1H), 3 .20-3.04 (m, 1H), 3.01-2.84 (m, 1H), 2.59 (dd, J=6.6, 2.0 Hz, 2H), 1.99-1 .71 (m, 2H), 1.66-1.33 (m, 2H), 1.26 (q, J=7.3, 6.7 Hz, 1H). II-502 422 1.95 1H NMR (500 MHz, methanol-d4) δ 8.47 (s, 1H), 8.38 (s, 1H), 8.23 (d, J=9.4 Hz, 1H), 7.94 (s , 1H), 7.55 (d, J=9.4 Hz, 1H), 7.06 (t, J=53.5 Hz, 1H), 4.35 (d, J=71.4 Hz, 2H ), 3.28 (s, 1H), 3.05 (s, 6H), 2.99-2.80 (m, 2H), 1.95 (s, 1H), 1.77 (s, 1H) , 1.52 (s, 2H). II-503 422 1.95 1H NMR (500 MHz, methanol-d4) δ 8.47 (s, 1H), 8.38 (s, 1H), 8.23 (d, J=9.4 Hz, 1H), 7.94 (s , 1H), 7.55 (d, J=9.4 Hz, 1H), 7.06 (t, J=53.5 Hz, 1H), 4.35 (d, J=71.4 Hz, 2H ), 3.28 (s, 1H), 3.05 (s, 6H), 2.99-2.80 (m, 2H), 1.95 (s, 1H), 1.77 (s, 1H) , 1.52 (s, 2H). II-504 393.2 1.54 1H NMR (400 MHz, DMSO-d6) δ 8.77-8.62 (m, 3H), 8.14-8.00 (m, 1H), 7.92 (d, J=9.5 Hz, 1H), 4.30 (d, J=96.9 Hz, 2H), 3.53-3.28 (m, 2H), 2.62-2.54 (m, 1H), 2.15-1 .91 (m, 1H), 1.89-1.66 (m, 2H), 1.56 (t, J=12.6 Hz, 1H). II-505 375 1.45 1H NMR (400 MHz, DMSO-d6) δ 8.77-8.66 (m, 2H), 8.57 (d, J=9.4 Hz, 1H), 8.06 (s, 1H), 7 .75 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 4.47 (s, 1H), 4.15 (s, 1H), 3 .58-3.35 (m, 2H), 2.66-2.54 (m, 1H), 2.13-1.91 (m, 1H), 1.80 (dq, J=13.7, 8.6, 7.5 Hz, 2H), 1.65-1.45 (m, 1H). II-506 393.2 1.54 1H NMR (400 MHz, DMSO-d6) δ 8.79-8.61 (m, 3H), 8.05 (d, J=1.1 Hz, 1H), 7.92 (d, J=9, 5 Hz, 1H), 4.35 (d, J=139.8 Hz, 2H), 3.36 (dd, J=26.7, 13.4 Hz, 2H), 2.61-2.53 ( m, 1H), 2.04 (d, J=13.1 Hz, 1H), 1.90-1.66 (m, 2H), 1.55 (s, 1H). II-507 495.3 2.6 1H NMR (500 MHz, methanol-d4) δ 8.73 (d, J=1.0 Hz, 1H), 8.71 (s, 1H), 8.43 (d, J=9.5 Hz, 1H ), 8.15 (d, J=1.1 Hz, 1H), 7.75 (d, J=9.4 Hz, 1H), 7.15 (t, J=53.8 Hz, 1H), 5.28 (s, 1H), 4.82-4.72 (m, 1H), 4.13 (p, J=6.8 Hz, 1H), 3.86-3.77 (m, 2H) , 3.74-3.67 (m, 1H), 3.56 (t, J=13.7 Hz, 1H), 3.39 (dd, J=11.6, 4.7 Hz, 1H), 3.26 (d, J=12.9 Hz, 1H), 3.12 (s, 3H), 1.52 (d, J=6.5 Hz, 3H), 1.47 (d, J=7 ,0 Hz, 3H), 1.40 (d, J=6.6 Hz, 3H). II-508 375.2 1.41 1H NMR (400 MHz, DMSO-d6) δ 8.72-8.63 (m, 2H), 8.56 (d, J=9.5 Hz, 1H), 8.06 (s, 1H), 7 .74 (d, J=9.5 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 4.46 (s, 1H), 4.13 (s, 1H), 3 .58-3.28 (m, 2H), 2.63-2.53 (m, 1H), 2.02 (dd, J=9.9, 5.8 Hz, 1H), 1.79 (q , J=9.4, 8.7 Hz, 2H), 1.55 (d, J=12.5 Hz, 1H). II-509 454.1 2.13 1H NMR (500 MHz, DMSO-d6) δ 8.70-8.58 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 7.98 (d, J=1, 3 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.45-7.17 (m, 2H), 4.52 (s, 1H), 4.30 (s, 1H), 4.06 (dd, J=11.6, 3.2 Hz, 1H), 3.58 (td, J=11.6, 2.8 Hz, 1H), 3.41 (dt, J =14.3, 7.1 Hz, 1H), 3.29 (s, 3H), 3.09 (t, J=12.3 Hz, 1H), 2.87 (t, J=11.8 Hz , 1H), 1.24 (d, J=6.6 Hz, 3H). II-510 454 2.13 II-511 466.3 2.56 1H NMR (500 MHz, DMSO-d6) δ 8.64 (t, J=3.3 Hz, 2H), 8.46 (dd, J=9.6, 3.5 Hz, 1H), 8.01 (d, J=3.9 Hz, 1H), 7.64 (dd, J=9.6, 3.1 Hz, 1H), 7.35-7.08 (t, 1H), 7.07- 6.37 (bs, 2H), 4.95 (s, 1H), 4.32 (d, J=12.5 Hz, 1H), 2.98 (dd, J=17.5, 10.0 Hz , 2H), 2.94 (d, J=3.4 Hz, 3H), 2.78-2.67 (m, 1H), 1.98 (dq, J=13.3, 7.6, 6 ,0 Hz, 1H), 1.79-1.62 (m, 2H), 1.21 (d, J=12.4 Hz, 1H), 1.15 (t, J=6.4 Hz, 3H ), 1.04 (d, J=6.3 Hz, 3H). II-512 372.2 2.2 1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H ), 7.71 (d, J=9.4 Hz, 1H), 7.56-7.16 (m, 1H), 4.48 (s, 1H), 4.20 (s, 1H), 4 ,12-3.95 (m, 1H), 3.92-3.77 (m, 1H), 3.67 (td, J=11.7, 2.8 Hz, 1H), 3.14 (td , J=12.3, 3.6 Hz, 1H), 2.99 (dd, J=17.0, 4.5 Hz, 1H), 2.93-2.82 (m, 2H). II-513 390.2 2.36 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.58 (m, 3H), 7.96 (d, J=1.2 Hz, 1H), 7.89 (d, J=9, 5 Hz, 1H), 4.49 (s, 1H), 4.08 (dt, J=11.7, 5.9 Hz, 2H), 3.89-3.73 (m, 1H), 3, 67 (td, J=11.7, 2.8 Hz, 1H), 3.19 (td, J=12.4, 11.7, 3.8 Hz, 1H), 3.01-2.79 ( m, 3H). II-514 390 1.89 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.33 (t, J=55.0 Hz, 1H), 4.55 (brs, 1H), 4.18 (vbrs, 2H), 3.57 (t, J=6.5 Hz, 2H), 3.29-3.24 (m, 1H), 3.07 (dd, J=13.1, 9.4 Hz, 1H), 2.85 (dt, J=11.9, 3.4 Hz, 1H), 2.25-2.21 (m, 5H), 1.84 (dtd, J=14.0, 6.9, 3.2 Hz, 1H), 1.50 (ddt, J=14.3, 8.2, 6.2 Hz, 1H). II-515 495.3 1.95 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=1.7 Hz, 2H), 8.54 (d, J=9.4 Hz, 1H), 7.90 (d, J =1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.7 Hz, 1H), 5.02-4.94 (m , 1H), 4.29 (q, J=7.3 Hz, 1H), 4.18 (s, 1H), 3.90-3.69 (m, 2H), 3.48-3.33 ( m, 3H), 2.97 (s, 3H), 2.10 (s, 3H), 1.33 (d, J=6.9 Hz, 3H). II-516 379.2 2.32 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.63 (d, J=9.5 Hz, 1H), 8.58 (d, J=1.1 Hz, 1H ), 7.98 (d, J=1.2 Hz, 1H), 7.87 (d, J=9.5 Hz, 1H), 4.59 (t, J=5.1 Hz, 1H), 4.31 (s, 2H), 3.43-3.34 (m, 1H), 3.30 (d, J=2.8 Hz, 1H), 3.08 (t, J=11.5 Hz , 1H), 2.86 (t, J=11.8 Hz, 1H), 1.86-1.70 (m, 2H), 1.70-1.54 (m, 1H), 1.56- 1.21 (m, 2H). II-517 379.2 2.32 1H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.63 (d, J=9.5 Hz, 1H), 8.59 (d, J=1.0 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.87 (d, J=9.5 Hz, 1H), 4.46 (d, J=100.1 Hz, 3H), 3.44-3.36 (m, 2H), 3.16-3.02 (m, 1H), 2.86 (t, J=11.8 Hz, 1H), 1.86-1.71 ( m, 2H), 1.64 (s, 1H), 1.56-1.29 (m, 2H). II-518 381.2 1.97 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.67-8.59 (m, 2H), 7.97 (d, J=1.2 Hz, 1H), 7 .88 (d, J=9.5 Hz, 1H), 4.87 (t, J=5.5 Hz, 1H), 4.27 (d, J=69.2 Hz, 2H), 4.01 (dd, J=12.1, 3.3 Hz, 1H), 3.60-3.38 (m, 4H), 3.19-3.05 (m, 1H), 2.96-2.76 (m, 1H). II-519 361.3 2.15 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.04 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.8 Hz, 1H), 4.69 (t, J=5.1 Hz, 1H), 4.39 (s, 2H), 3.40 (dt, J=10.3, 5.0 Hz, 1H), 3.30-3 .24 (m, 1H), 3.18-3.03 (m, 1H), 2.85 (t, J=11.8 Hz, 1H), 1.83-1.54 (m, 3H), 1.53-1.18 (m, 2H). II-520 361.3 2.14 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.04 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.8 Hz, 1H), 4.69 (t, J=5.1 Hz, 1H), 4.54-4.17 (m, 2H), 3.40 (dt, J=10.3, 5.1 Hz, 1H), 3 ,32-3.27 (m, 1H), 3.08 (td, J=12.3, 11.4, 2.8 Hz, 1H), 2.85 (t, J=11.8 Hz, 1H ), 1.86-1.57 (m, 3H), 1.54-1.20 (m, 2H). II-521 363.2 1.82 1H NMR (400 MHz, DMSO-d6) δ 8.65-8.57 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.00 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.7 Hz, 1H), 4.88 (t, J=5.5 Hz , 1H), 4.44 (s, 1H), 4.22 (s, 1H), 4.05-3.93 (m, 1H), 3.65-3.40 (m, 4H), 3, 12 (td, J=12.5, 3.6 Hz, 1H), 2.92-2.74 (m, 1H). II-522 408.2 1.8 1H NMR (500 MHz, DMSO-d6) δ 8.63 (dd, J=1.9, 0.9 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.08 (dd, J=6.0, 1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.34 (td, J=53.7, 11.3 Hz, 1H), 4.87 (s, 1H), 4.47 (s, 1H), 3.31-3.15 (m, 2H), 3.03 (t, J=12.9 Hz, 1H), 2.97 (d, J=1.7 Hz, 3H), 2.32-2.17 (m, 1H), 1.87 (dtt, J=36.5, 12.4, 5.7 Hz, 2H), 1.54 (qd, J=10.2, 7.7, 5.0 Hz, 1H). II-523 470.4 2.03 1H NMR (500 MHz, methanol-d4) δ 8.64 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.38 (d, J=9.5 Hz, 1H ), 8.08 (s, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.13 (t, J=53.7 Hz, 1H), 4.52 (br s, 1H), 3.56 (dd, J=13.2, 5.1 Hz, 1H), 3.34-3.32 (m, 2H), 3.12-3.05 (m, 2H), 3 .05 (s, 3H), 2.47 (d, J=43.5 Hz, 2H), 1.32 (d, J=6.7 Hz, 3H). II-524 440.3 2.21 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.7 Hz, 1H), 7.12 (s, 1H), 4.39 (br d, J=65.8 Hz, 2H), 3.12-3.06 (m, 1H), 2.92 (s, 3H), 2, 87-2.82 (m, 1H), 1.87 -1.84 (m, 1H), 1.80-1.76 (m, 1H), 1.72-1.66 (m, 1H), 1.52-1.44 (m, 1H), 1.37-1.29 (m, 1H) II-525 466.3 2.13 1H NMR (500 MHz, DMSO-d6) δ 8.72 (m, 2H), 8.56-8.54 (d, 1H), 8.02 (s, 1H), 7.73-7.71 ( d, 1H), 7.30-7.20 (t, 1H), 7.18 (m, 1H), 4.30 (br s, 2H), 3.78 (m, 1H), 3.65 ( m, 1H), 3.38 (m, 1H), 3.15 (m, 1H), 2.90 (m, 5H), 1.08 (d, 3H). II-526 466.3 2.18 1H NMR (500 MHz, DMSO-d6) δ 8.74 (d, 1H), 8.70 (s, 1H), 8.57-8.55 (d, 1H), 8.17 (s, 1H) , 7.74-7.72 (d, 1H), 7.42-7.20 (t, 1H), 7.10 (m, 1H), 4.80 (br s, 1H), 4.60 ( br s, 1H), 3.40 (m, 1H), 3.30-3.05 (m, 2H), 3.05 (m, 1H), 2.99 (s, 3H), 2.82- 2.72 (m, 2H), 1.02 (d, 3H). II-527 510.3 2.39 II-528 500.3 2.59 1H NMR (500 MHz, DMSO-d6, 380K) δ 8.68-8.56 (m, 2H), 8.46 (dd, J=9.5, 2.4 Hz, 1H), 8.03 ( d, J=2.0 Hz, 1H), 7.64 (dt, J=9.5, 2.0 Hz, 1H), 7.23 (td, J=53.9, 2.3 Hz, 1H ), 6.95 (d, J=9.3 Hz, 1H), 4.58 (d, J=13.9 Hz, 1H), 3.94-3.86 (m, 1H), 3.70 (d, J=14.2 Hz, 1H), 3.55-3.45 (m, 1H), 3.40 (dd, J=13.7, 5.3 Hz, 1H), 3.11 ( ddt, J=20.9, 13.8, 6.3 Hz, 1H), 2.95 (t, J=1.7 Hz, 3H), 2.41 (d, J=36.9 Hz, 1H ), 1.10-0.97 (m, 1H), 0.78 (q, J=11.5, 10.7 Hz, 3H). II-529 409 2.06 1H NMR (500 MHz, DMSO-d6) δ 8.67-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.08 (s, 1H), 7 .71 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.7 Hz, 1H), 4.85 (s, 1H), 4.36 (s, 1H), 3 .38 (d, J=5.1 Hz, 1H), 3.29 (s, 1H), 3.20-3.10 (m, 1H), 3.05 (s, 3H), 2.23 ( d, J=11.8 Hz, 1H), 1.97-1.76 (m, 2H), 1.62-1.48 (m, 1H). II-530 409 2.06 1H NMR (500 MHz, DMSO-d6) δ 8.67-8.61 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.08 (s, 1H), 7 .71 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.7 Hz, 1H), 4.85 (s, 1H), 4.36 (s, 1H), 3 .40-3.32 (m, 1H), 3.19-3.10 (m, 1H), 3.05 (s, 3H), 2.23 (d, J=12.7 Hz, 1H), 1.97-1.81 (m, 2H), 1.56 (d, J=15.5 Hz, 1H). II-531 358 2.2 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=1.1 Hz, 1H), 8.66 (s, 1H), 8.55 (d, J=9.5 Hz, 1H ), 8.06 (d, J=1.2 Hz, 1H), 7.72 (d, J=9.4 Hz, 1H), 7.37 (t, J=53.6 Hz, 1H), 5.20 (t, J=3.5 Hz, 1H), 4.42 (d, J=14.0 Hz, 1H), 4.11 (d, J=13.5 Hz, 1H), 3, 98 (dt, J=12.0, 3.5 Hz, 1H), 3.94-3.84 (m, 1H), 3.69 (dd, J=13.9, 3.7 Hz, 1H) , 3.46 (ddd, J=13.4, 9.5, 3.7 Hz, 1H). II-532 356 2.24 1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J=1.7 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.05 (d, J =1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.37 (t, J=53.8 Hz, 1H), 4.19 (dd, J=13 ,5, 6.2 Hz, 1H), 3.87 (dd, J=13.5, 3.5 Hz, 2H), 3.58 (ddd, J=12.9, 8.0, 3.8 Hz, 1H), 3.18 (tt, J=6.3, 3.7 Hz, 1H), 2.07-1.89 (m, 2H), 1.71 (ddddd, J=16.4, 13.6, 10.4, 7.1, 3.8 Hz, 2H). II-533 376.2 2.4 1H NMR (400 MHz, DMSO-d6) δ 8.74-8.70 (m, 2H), 8.65 (d, J=9.5 Hz, 1H), 8.01 (d, J=1, 2 Hz, 1H), 7.90 (d, J=9.5 Hz, 1H), 5.23 (t, J=3.6 Hz, 1H), 4.34 (d, J=13.7 Hz , 1H), 4.09-3.94 (m, 2H), 3.94-3.84 (m, 1H), 3.73 (dd, J=13.9, 3.7 Hz, 1H), 3.49 (ddd, J=13.8, 9.3, 3.8 Hz, 1H). II-534 374.2 2.48 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.69-8.55 (m, 2H), 8.04 (d, J=1.2 Hz, 1H), 7 .89 (d, J=9.5 Hz, 1H), 4.13 (dd, J=13.5, 6.6 Hz, 1H), 3.90 (dd, J=13.4, 3.5 Hz, 1H), 3.79 (dd, J=16.7, 3.6 Hz, 1H), 3.70-3.57 (m, 1H), 3.19 (tt, J=7.0, 3.8 Hz, 1H), 2.00 (dqd, J=20.5, 7.7, 6.7, 4.3 Hz, 2H), 1.72 (dddd, J=23.9, 14, 7, 9.5, 5.5 Hz, 2H). II-535 466 1.81 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=1.0 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.03 (d, J =1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.32 (t, J=55.0 Hz, 1H), 7.03 (s, 2H), 4.03-3.84 (m, 4H), 3.66 (br s, 2H), 3.36 (d, J=8.6 Hz, 2H), 2.57 (br t, J=5, 0 Hz, 2H), 2.42 (s, 3H). II-536 404 1.89 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.98 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.31 (t, J=55.0 Hz, 1H), 5.30-3.60 (v brs, 3H), 3.57 (br s, 2H), 3.19 (br s, 1H), 2.91 (d, J=11.1 Hz, 1H), 2.21-2.13 (m, 5H), 1.92 (dq, J=12.7, 6.6 Hz, 1H), 1.43 (ddd, J=13.7, 9.3, 6.6 Hz, 1H), 1.15 (br s, 3H). II-537 468.3 2.44 1H NMR (500 MHz, methanol-d4) δ 8.64 (m,2H), 8.39-8.37 (d, 1H), 8.00 (s, 1H), 7.73-7.71 ( d, 1H), 7.09 (t, 1H), 4.45 (m, 1H), 4.32 (m, 1H), 4.05 (m, 2H), 3.82 (m, 2H), 2.90 (s, 3H), 2.72 (m, 1H), 1.12 (d, 3H). II-538 468.3 2.47 1H NMR (500 MHz, methanol-d4) δ 8.62 (s, 1H), 8.60 (d, 1H), 8.37-8.35 (d, 1H), 8.22 (s, 1H) , 7.69-7.67 (d, 1H), 7.24-7.03 (t, 1H), 4.45 (m, 2H), 3.95 (m, 1H), 3.70 (m , 1H), 3.35 (masked, 1H), 3.06 (m, 1H), 2.93 (s, 3H), 2.78 (m, 1H), 1.79 (d, 3H). II-539 373 1.92 1H NMR (500 MHz, DMSO-d6) δ 9.18 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.56 (d, J=9.4 Hz, 1H ), 8.54 (d, J=1.3 Hz, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.39 (t, J=52.5 Hz, 1H), 4.54 (ddt, J=13.1, 4.4, 2.2 Hz, 1H), 4.04-3.92 (m, 1H), 3.22 (ddd, J=13.6, 12 ,4, 2.7 Hz, 1H), 3.09 (tt, J=11.7, 3.7 Hz, 1H), 2.71 (td, J=12.8, 2.8 Hz, 1H) , 2.06 (s, 3H), 2.04-1.93 (m, 2H), 1.76 (qd, J=12.4, 4.2 Hz, 1H), 1.61 (qd, J =12.4, 4.3 Hz, 1H). II-540 436 2.13 II-541 436 2.13 1H NMR (500 MHz, methanol-d4) δ 8.59 (s, 1H), 8.50 (s, 1H), 8.35 (d, J=9.4 Hz, 1H), 8.07 (s , 1H), 7.67 (d, J=9.4 Hz, 1H), 7.17 (t, J=53.8 Hz, 1H), 4.64-4.49 (br m, 1H), 3.41-3.31 (m, 2H), 3.18 (d, J=7.3 Hz, 6H), 2.82-2.71 (m, 1H), 2.48 (t, J= 12.6 Hz, 1H), 2.09-2.05 (m, 1H), 1.82-1.72 (m, 1H), 1.29 (q, J=12.0 Hz, 1H), 1.04 (d, J=6.6 Hz, 3H). II-542 481.1 2.21 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.62 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.97 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.24 (d, J=26.4 Hz, 2H), 3.39 (dd, J=12.8, 4.3 Hz, 2H), 3.30 (d, J=7.8 Hz, 1H), 3.16 (s, 2H), 2.99 (s , 3H), 2.97 (d, J=12.1 Hz, 1H), 2.90-2.79 (m, 2H), 2.48 (d, J=7.0 Hz, 1H), 2 .35-2.26 (m, 1H), 1.18-1.12 (m, 3H), 1.00 (t, J=7.0 Hz, 3H). II-543 481.1 2.21 1H NMR (500 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.62 (s, 1H), 8.53 (d, J=9.4 Hz, 1H), 7.97 (s , 1H), 7.70 (d, J=9.4 Hz, 1H), 7.25 (d, J=26.1 Hz, 2H), 3.39 (dd, J=12.8, 4, 8 Hz, 1H), 3.28 (d, J=14.9 Hz, 1H), 3.14 (d, J=18.7 Hz, 1H), 2.99 (s, 3H), 2.96 (s, 1H), 2.90-2.76 (m, 2H), 2.35-2.26 (m, 1H), 1.15 (d, J=6.6 Hz, 3H), 1, 00 (t, J=7.0 Hz, 3H). II-544 466.3 2.59 1H NMR (500 MHz, DMSO-d6) δ 8.73 (m,2H), 8.58 (d, 1H), 8.15-7.98 (m, 1H), 7.76 (d, 1H) , 7.43-7.15 (m, 2H), 5.30-5.00 (m, 1H), 4.30 (masked, 2H), 3.05-2.90 (m, 5H), 1 .95 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.28 (m, 1H), 1.15 (m, 3H), 0.98 (m, 3H). II-545 466.1 2.59 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=12.2 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.05 (s, 1H ), 7.68 (d, J=9.4 Hz, 1H), 7.52-7.19 (m, 1H), 7.19-7.03 (m, 1H), 5.08 (d, J=269.3 Hz, 1H), 4.51-3.70 (m, 1H), 2.92 (d, J=23.7 Hz, 6H), 1.92 (s, 1H), 1, 70-1.51 (m, 2H), 1.36-0.90 (m, 7H). II-546 466.1 2.59 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=12.6 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.05 (s, 1H ), 7.68 (d, J=9.5 Hz, 1H), 7.46-7.18 (m, 1H), 7.14 (s, 1H), 5.47-4.69 (m, 1H), 4.55-3.66 (m, 1H), 3.08-2.69 (m, 6H), 1.89 (s, 1H), 1.74-1.54 (m, 2H) , 1.29-0.90 (m, 7H). II-547 402 2.11 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=1.1 Hz, 1H), 8.64 (s, 1H), 8.54 (d, J=9.4 Hz, 1H ), 8.02 (d, J=1.2 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.36 (t, J=52.5 Hz, 1H), 5.00 (vbrs, 1H), 4.44-4.31 (m, 1H), 4.22 (dd, J=9.4, 5.1 Hz, 1H), 4.08 (dt, J= 9.0, 4.7 Hz, 1H), 3.84-3.65 (m, 1H), 3.30-3.21 (m, 2H), 3.16 (td, J=12.3, 4.1 Hz, 1H), 1.20 (d, J=6.8 Hz, 3H). II-548 360.3 2.15 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.96 (d, J=1.2 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.8 Hz, 1H), 4.24-4.18 (m, 1H), 3.12-3.06 (m, 1H), 3.01-2.91 (m, 3H), 2.76 (dd, J=13.1 , 3.3 Hz, 1H), 1.28 (d, J=6.7 Hz, 3H), 1.15 (d, J=6.7 Hz, 3H). II-549 512.1 2.07 II-550 512.1 2.1 II-551 438.1 2.22 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.59 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.03 (s, 1H), 7 .70 (d, J=9.5 Hz, 1H), 7.46-7.04 (m, 2H), 4.68 (d, J=58.5 Hz, 2H), 3.32-3, 23 (m, 1H), 3.02 (s, 3H), 2.85 (m, 1H), 1.93-1.59 (m, 4H), 1.20 (d, J=6.8 Hz , 3H). II-552 438 2.27 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.0 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.03 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.46-7.14 (m, 2H), 4.78 (s, 1H), 4 .43 (d, J=14.1 Hz, 1H), 3.73 (s, 1H), 3.45-3.35 (m, 1H), 2.97 (s, 3H), 2.19- 1.93 (m, 2H), 1.63 (d, J=12.1 Hz, 1H), 1.44 (s, 1H), 1.23-1.15 (m, 3H). II-553 463.3 2.22 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, 1H), 8.67 (s, 1H), 8.56 (d, 1H), 8.04 (d, 1H), 7.74 (d, 1H), 7.29-7.19 (m, 2H), 4.70-4.30 (m, 1H), 4.10 (masked, 1H), 3.27 (m, 1H), 3.03 (m, 1H), 2.98 (m, 2H), 2.95 (s, 3H), 2.87 (m, 1H), 2.21 (m, 1H), 1.76 (m , 1H), 1.65 (m, 1H). II-554 375.1 2.36 1H NMR (400 MHz, methanol-d4) δ 8.58 (s, 1H), 8.52 (d, J=1.1 Hz, 1H), 8.36 (d, J=9.5 Hz, 1H ), 8.10 (s, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.03 (t, J=54.2 Hz, 1H), 4.80 (d, J =5.8 Hz, 2H), 3.53 (qd, J=10.9, 7.6 Hz, 2H), 3.10 (s, 1H), 2.08-1.94 (m, 1H) , 1.94-1.83 (m, 1H), 1.72-1.41 (m, 3H), 1.22 (d, J=6.9 Hz, 3H). II-555 375.1 2.36 1H NMR (400 MHz, ) δ 8.58 (s, 1H), 8.52 (d, J=1.1 Hz, 1H), 8.36 (d, J=9.5 Hz, 1H), 8 ,10 (s, 1H), 7.67 (d, J=9.5 Hz, 1H), 7.03 (t, J=54.2 Hz, 1H), 4.95 (br s, 2H), 3.53 (qd, J=10.9, 7.6 Hz, 2H), 3.10 (s, 1H), 1.99 (s, 1H), 1.89 (d, J=12.6 Hz , 1H), 1.74-1.41 (m, 3H), 1.22 (d, J=6.9 Hz, 3H). The peak at 4.95 is quite broad. II-556 432 2.54 1H NMR (500 MHz, DMSO-d6) δ 8.85 (brs, 1H), 8.72 (d, J=1.1 Hz, 1H), 8.67 (s, 1H), 8.57 (d , J=9.4 Hz, 1H), 8.00 (d, J=1.2 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.30 (t, J =55.0 Hz, 1H), 4.88-4.86 (m, 1H), 4.30-4.22 (m, 1H), 3.89 (dt, J=12.9, 6.3 Hz, 3H), 3.66-3.55 (m, 3H), 1.48-1.45 (m, 12H), the water peak covers some signals. II-557 463.3 2.17 II-558 463.3 2.17 II-559 509 2.58 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.60 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.85 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.30 (t, J=52.5 Hz, 1H), 7.04 (dd, J=7.5, 4.2 Hz, 1H), 5.10-5.06 (m, 1H), 3.90-3.86 (m, 1H), 3.43- 3.37 (m, 1H), 3.26-2.99 (m, 5H), 2.96 (s, 3H), 1.30 (d, J=7.0 Hz, 3H), 1.06 (s, 9H). II-560 479.1 2.21 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.61 (s, 1H), 8.53 (d, J=9.4 Hz, 1H), 8.01 (s , 1H), 7.69 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.5 Hz, 1H), 7.20 (s, 1H), 4.58 (m , 2H), 3.28 (m, 2H), 2.98-3.01 (m, 4H), 2.74 (dt, J=25.4, 11.6 Hz, 2H), 2.28 ( dd, J=11.4, 6.5 Hz, 1H), 2.12-2.00 (m, 2H), 1.85-1.90 (m, 1H), 1.79-1.68 ( m, 2H), 1.48-1.35 (m, 1H). II-561 470.1 2.04 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=5.9 Hz, 2H), 8.53 (d, J=9.4 Hz, 1H), 7.97 (s, 1H ), 7.70 (d, J=9.4 Hz, 1H), 7.35 (d, J=57.9 Hz, 1H), 7.20 (s, 1H), 3.46-3.34 (m, 1H), 2.99 (s, 3H), 2.87 (dt, J=30.2, 11.3 Hz, 2H), 2.20 (d, J=28.2 Hz, 2H) , 1.34-1.04 (m, 3H). 3 CH absent/not observed. II-562 470.1 2.04 1H NMR (500 MHz, DMSO-d6) δ 8.67-8.58 (m, 2H), 8.53 (d, J=9.5 Hz, 1H), 7.97 (s, 1H), 7 .70 (d, J=9.4 Hz, 1H), 7.27 (m, 1H), 7.20 (t, J=6.4 Hz, 1H), 3.44-3.33 (m, 1H), 2.99 (s, 3H), 2.95-2.76 (m, 2H), 2.28-2.08 (m, 2H), 1.23-1.13 (m, 3H) . 3 CH is not observed. II-563 449.3 2.37 1H NMR (500 MHz, DMSO-d6) δ 8.73-8.65 (m, 2H), 8.57 (d, J=9.4 Hz, 1H), 8.01 (d, J=1, 1 Hz, 1H), 7.74 (d, J=9.4 Hz, 1H), 7.35 (t, J=53.8 Hz, 1H), 4.43-4.15 (m, 2H) , 3.30 (dd, J=13.2, 9.5 Hz, 2H), 3.26-3.13 (m, 1H), 3.08-2.95 (m, 2H), 2.49 -2.41 (m, 1H), 2.11 (tp, J=8.7, 2.9 Hz, 2H), 2.05-1.89 (m, 2H), 1.89-1.75 (m, 2H), 1.65 (dtd, J=13.3, 10.1, 3.7 Hz, 1H), 1.61-1.49 (m, 1H). II-564 372.2 2.29 II-565 372 2.25 II-566 464.3 2.52 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.5 Hz, 1H ), 8.07 (d, J=1.3 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.29 (t, J=53.9 Hz, 1H), 6.91 (t, J=5.9 Hz, 1H), 4.55-4.20 (m, 2H), 3.40 (dd, J=13.3, 3.3 Hz, 1H), 3 .20 (t, J=12.0 Hz, 1H), 3.02-2.90 (m, 2H), 2.82 (s, 3H), 1.93-1.74 (m, 1H), 1.40-1.21 (m, 1H), 0.99 (d, J=13.6 Hz, 1H), 0.63-0.46 (m, 2H), 0.46-0.37 ( m, 2H). II-567 467 1.97 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.02 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 7.16 (t, J=5.7 Hz, 1H), 3.29 (s, 1H), 2.97-3.00 (m, 3H), 2.95 (s, 6H), 2.76 (s, 1H), 2.55 (s, 1H), 2.12 (s, 1H), 1.14 (s, 3H), 1.04 (s, 3H). II-568 497 2.11 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.62 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.01 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.29 (t, J=53.5 Hz, 1H), 7.25 (s, 1H), 5.36-5.16 (m, 1H), 4.62-4.58 (m, 2H), 3.48 (dd, J=22.7, 11.3 Hz, 1H), 3.32-3.27 (m, 1H), 3.04-2.97 (m, 1H), 2.99 (s, 3H), 2.88-2.81 (m, 2H), 2.50-2.41 (m, 1H), 2.28 (dtd, J=24.6, 11.4, 5.2 Hz, 2H), 2.17-2.09 (m, 1H), 1.61 (dddd, J=36.9, 13.6, 10.7, 3.0 Hz, 1H). II-569 467.1 1.97 II-570 467.1 1.96 II-571 468 2.31 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 2H), 8.56 (d, J=9.5 Hz, 1H), 8.01 (NH), 7.74 (d, J =9.4 Hz, 1H), 7.31 (t, J=53.6 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 4.08 (dd, J=11 ,2, 3.5 Hz, 2H), 3.6 (m, 2H not observed), 3.34 (t, J=4.6 Hz, 2H), 3.11 (dd, J=51.5, 12.4 Hz, 1H), 2.97 (s, 3H), 2.53 (m, 1H) not observed, 1.76-1.63 (m, 1H), 1.50 (ddd, J=13 ,6, 8.5, 6.9 Hz, 1H), 0.96 (t, J=7.3 Hz, 3H). II-572 468.1 2.35 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 2H), 8.56 (d, J=9.4 Hz, 1H), 7.97 (s, NH), 7.74 (d , J=9.4 Hz, 1H), 7.48-7.15 (m, 2H), 4.06 (dd, J=11.7, 3.4 Hz, 3H), 3.66-3, 52 (m, 1H), 3.49-3.29 (m, 2H), 3.16 (d, J=12.7 Hz, 1H), 3.02 (s, 3H), 1.71 (dq , J=11.4, 3.8 Hz, 1H), 1.49 (td, J=19.1, 17.0, 9.6 Hz, 1H), 1.19 (d, J=6.3 Hz, 1H), 0.96 (t, J=7.3 Hz, 3H). II-573 436 2.05 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.32 (t, J=53.8 Hz, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.10-3.02 (m, 1H), 3.01-2.97 (m, 6H), 2.97-2, 85 (m, 2H), 2.87-2.79 (m, 1H), 1.87 (dd, J=12.8, 3.9 Hz, 1H), 1.81-1.73 (m, 1H), 1.66-1.60 (m, 1H), 1.46 (t, J=12.6 Hz, 1H), 1.40-1.28 (m, 1H). II-574 436 2.05 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.99 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.32 (t, J=53.8 Hz, 1H), 4.45 (s, 1H), 4.34 (s, 1H), 3.10-3.02 (m, 1H), 3.01-2.97 (m, 6H), 2.97-2, 85 (m, 2H), 2.87-2.79 (m, 1H), 1.87 (dd, J=12.8, 3.9 Hz, 1H), 1.81-1.73 (m, 1H), 1.66-1.60 (m, 1H), 1.46 (t, J=12.6 Hz, 1H), 1.40-1.28 (m, 1H). II-575 445.3 2.26 1H NMR (500 MHz, DMSO-d6) δ 9.35 (d, J=1.4 Hz, 1H), 8.83 (s, 1H), 8.70 (d, J=1.4 Hz, 1H ), 8.58 (d, J=9.4 Hz, 1H), 7.73 (d, J=9.5 Hz, 1H), 7.55 (dd, J=7.7, 1.4 Hz , 1H), 7.53-7.46 (m, 2H), 7.43-7.40 (m, 1H), 7.39-7.18 (m, 1H), 4.29 (d, J =6.1 Hz, 2H), 2.97 (s, 3H), 2.41 (s, 3H). II-576 431.2 2.3 1H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J=1.3 Hz, 1H), 9.13 (d, J=1.4 Hz, 1H), 8.82 (s, 1H ), 8.59 (d, J=9.4 Hz, 1H), 8.29 (q, J=1.4, 1.0 Hz, 1H), 8.18 (dt, J=7.3, 1.8 Hz, 1H), 7.78 (d, J=9.4 Hz, 1H), 7.72 (t, J=6.3 Hz, 1H), 7.66-7.56 (m, 2H), 7.43 (t, J=53.6 Hz, 1H), 4.33 (d, J=6.3 Hz, 2H), 2.95 (s, 3H). II-577 389.1 2.49 II-578 436 2.02 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (s, 1H), 8.52 (d, J=9.4 Hz, 1H), 8.00 (s , 1H), 7.68 (d, J=9.5 Hz, 1H), 7.28 (1H, hidden), 3.40 (2H hidden), 3.06 (d, J=3.7 Hz, 6H), 2.55 (2H, hidden), 1.78-1.52 (m, 4H), 1.17 (d, J=18.7 Hz, 3H). II-579 436 2.08 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.51 (d, J=9.4 Hz, 1H ), 7.97 (d, J=1.2 Hz, 1H), 7.66 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 4.42 (s, 2H), 3.52 (d, J=3.0 Hz, 2H), 2.98 (s, 6H), 2.08-1.87 (m, 2H), 1.52 (d, J=10.0 Hz, 2H), 1.23 (d, J=6.9 Hz, 3H). II-580 401 1.89 1H NMR (500 MHz, DMSO-d6) δ 9.40 (d, J=1.3 Hz, 1H), 9.22 (d, J=1.4 Hz, 1H), 8.85 (s, 2H ), 8.61 (d, J=9.4 Hz, 1H), 8.55 (ddd, J=7.9, 1.8, 1.0 Hz, 1H), 8.21 (ddd, J= 7.8, 1.9, 1.0 Hz, 1H), 7.91 (t, J=7.8 Hz, 1H), 7.79 (d, J=9.4 Hz, 1H), 7, 42 (t, J=53.7 Hz, 1H), 3.30 (s, 3H). II-581 436 2.01 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.51 (d, J=9.4 Hz, 1H ), 7.97 (d, J=1.1 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 4.42 (s, 2H), 2.98 (s, 6H), 2.53 (d, J=1.9 Hz, 2H, not observed), 2.07-1.83 (m, 2H), 1.52 (d, J=10.2 Hz, 2H), 1.23 (d, J=7.0 Hz, 3H). II-582 436 2.01 1H NMR (500 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.57-8.46 (m, 2H), 7.97 (d, J=1.2 Hz, 1H), 7 .67 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 4.52-4.33 (m, 2H), 3.52 (d, J=3.0 Hz, 2H), 2.98 (s, 6H), 2.08-1.87 (m, 2H), 1.52 (d, J=10.1 Hz, 2H), 1, 23 (d, J=7.0 Hz, 3H). II-583 450 2.04 1H NMR (500 MHz, methanol-d4) δ 8.60 (s, 1H), 8.52 (d, J=1.1 Hz, 1H), 8.37 (d, J=9.4 Hz, 1H ), 8.10 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.11 (t, J=54.1 Hz, 1H), 4.81 (s, 1H), 4.51 (s, 1H), 3.21 (dd, J=12.2, 8.5 Hz, 1H), 3.18-3.09 (m, 2H) , 3.07-3.03 (m, 1H), 3.04-3.02 (m, 3H), 2.98 (d, J=1.0 Hz, 7H), 2.09-1.97 (m, 1H), 1.93-1.85 (m, 1H), 1.84-1.71 (m, 2H), 1.72-1.63 (m, 1H), 1.39 (d , J=6.9 Hz, 3H). II-584 450.1 2.07 1H NMR (500 MHz, methanol-d4) δ 8.57 (s, 1H), 8.52 (dd, J=5.7, 1.5 Hz, 1H), 8.39-8.32 (m, 1H), 8.07-8.01 (m, 1H), 7.70-7.63 (m, 1H), 7.10 (dd, J=55.0, 53.1 Hz, 1H), 4 .73 (br s, 2H), 3.14 (s, 6H), 3.04 (d, J=7.6 Hz, 3H), 2.01-1.87 (m, 2H), 1.77 (dd, J=12.9, 3.8 Hz, 1H), 1.56 (dqd, J=41.1, 12.9, 4.1 Hz, 2H), 1.21 (d, J=7 ,0 Hz, 3H). II-585 389.1 2.38 1H NMR (400 MHz, methanol-d4) δ 8.61 (s, 1H), 8.54 (d, J=1.1 Hz, 1H), 8.37 (d, J=9.4 Hz, 1H ), 8.12 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.05 (t, J=54.2 Hz, 1H), 5.70-5.34 (m, 1H), 4.59 (s, 1H), 3.90 (s, 1H), 3.50 (t, J=9.7 Hz, 2H), 2.75 (d, J=111, 4 Hz, 1H), 2.00 (d, J=33.9 Hz, 1H), 1.68 (s, 2H), 1.42-0.83 (m, 6H). II-586 389.1 2.38 1H NMR (400 MHz, methanol-d4) δ 8.46 (s, 1H), 8.39 (d, J=1.1 Hz, 1H), 8.23 (d, J=9.5 Hz, 1H ), 8.00 (s, 1H), 7.55 (d, J=9.5 Hz, 1H), 6.91 (t, J=54.3 Hz, 1H), 5.33 (s, 1H ), 4.44 (s, 1H), 3.74 (s, 1H), 3.38 (t, J=9.6 Hz, 2H), 2.60 (d, J=104.0 Hz, 1H ), 1.88 (d, J=30.9 Hz, 1H), 1.55 (s, 2H), 1.24-0.71 (m, 6H). II-587 451 2.42 II-588 451 2.32 1H NMR (400 MHz, methanol-d4) δ 8.64 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.38 (d, J=9.4 Hz, 1H ), 8.16 (d, J=1.1 Hz, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.23 (t, J=53.7 Hz, 1H), 4.96 (s, 1H), 4.65-4.05 (m, 1H), 3.31-3.26 (m, 1H), 3.16 (dd, J=14.1, 4.8 Hz, 1H), 3.08 (s, 3H), 2.83 (s, 1H), 2.22 (s, 1H), 2.13-1.88 (m, 1H), 1.61 (d , J=11.3 Hz, 1H), 1.39-1.29 (m, 4H), 1.12 (d, J=7.1 Hz, 3H). II-589 460 2.09 1H NMR (400 MHz, DMSO-d6) δ 8.74-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.10 (d, J=1, 2 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.71 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.7 Hz , 1H), 4.39-4.02 (m, 2H), 3.88 (s, 1H), 3.59-3.39 (m, 2H), 3.02 (s, 3H), 2, 43-1.97 (m, 2H). II-590 358.1 1.79 1H NMR (500 MHz, methanol-d4) δ 8.60 (d, J=1.1 Hz, 1H), 8.54 (s, 1H), 8.22 (d, J=9.5 Hz, 1H ), 8.01 (d, J=1.2 Hz, 1H), 7.51 (d, J=9.5 Hz, 1H), 3.97-3.89 (m, 2H), 3.89 -3.82 (m, 2H), 3.82-3.72 (m, 4H), 2.20 (s, 3H). II-591 466 2.41 II-592 466 2.41 II-593 436 1.92 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.00 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.6 Hz, 1H), 3.43 (d, J =5.3 Hz, 2H), 3.06 (d, J=3.7 Hz, 6H), 1.82-1.59 (m, 4H), 1.55 (m, 2H), 1.19 (s, 3H). II-594 436 1.91 1H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.2 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.00 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.5 Hz, 1H), 3.42 (m, 2H ), 3.06 (d, J=3.7 Hz, 6H), 2.51 (m, 2H) partially hidden, 1.75 (t, J=9.9 Hz, 1H), 1.72-1 .49 (m, 3H), 1.17 (d, J=18.5 Hz, 3H). II-595 429.2 2.1 1H NMR (500 MHz, DMSO-d6) δ 9.35 (d, J=1.3 Hz, 1H), 9.12 (d, J=1.3 Hz, 1H), 8.83 (s, 1H ), 8.60 (d, J=9.4 Hz, 1H), 8.32 (d, J=1.9 Hz, 1H), 8.20 (dt, J=7.0, 1.9 Hz , 1H), 7.78 (d, J=9.4 Hz, 1H), 7.69-7.61 (m, 2H), 7.44 (t, J=53.7 Hz, 1H), 4 .58 (s, 2H), 3.63 (s, 6H). II-596 460 2.14 1H NMR (400 MHz, DMSO-d6) δ 8.69-8.62 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.10 (d, J=1, 2 Hz, 1H), 7.97 (s, 1H), 7.71 (d, J=9.5 Hz, 1H), 7.32 (t, J=53.7 Hz, 1H), 4.25 (s, 2H), 3.88 (d, J=19.1 Hz, 1H), 3.62-3.40 (m, 2H), 3.02 (s, 3H), 2.42-2, 00 (m, 2H). II-597 460 2.13 1H NMR (400 MHz, DMSO-d6) δ 8.76-8.61 (m, 2H), 8.54 (d, J=9.4 Hz, 1H), 8.10 (d, J=1, 2 Hz, 1H), 7.97 (s, 1H), 7.71 (d, J=9.5 Hz, 1H), 7.32 (t, J=53.7 Hz, 1H), 4.25 (s, 2H), 3.88 (s, 1H), 3.48 (td, J=15.6, 14.4, 9.9 Hz, 2H), 3.02 (s, 3H), 2, 40-1.96 (m, 2H). II-598 415.2 1.94 1H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J=1.3 Hz, 1H), 9.13 (d, J=1.4 Hz, 1H), 8.83 (s, 1H ), 8.60 (d, J=9.4 Hz, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.23 (dt, J=7.6, 1.6 Hz , 1H), 7.78 (d, J=9.4 Hz, 1H), 7.73-7.61 (m, 2H), 7.43 (t, J=53.5 Hz, 1H), 4 .63-4.50 (m, 2H), 3.78-3.71 (m, 1H), 2.85 (d, J=0.9 Hz, 3H). II-599 415.2 2.17 1H NMR (500 MHz, DMSO-d6) δ 9.30 (d, J=1.3 Hz, 1H), 9.08 (d, J=1.3 Hz, 1H), 8.81 (s, 1H ), 8.59 (d, J=9.4 Hz, 1H), 7.90 (t, J=2.0 Hz, 1H), 7.83-7.72 (m, 2H), 7.44 (t, J=7.8 Hz, 1H), 7.38 (t, J=53.6 Hz, 1H), 7.13 (ddd, J=8.0, 2.3, 1.0 Hz, 1H), 3.30 (s, 6H). II-600 438.2 2.26 1H NMR (400 MHz, methanol-d4) δ 8.48 (s, 1H), 8.42 (d, J=1.1 Hz, 1H), 8.25 (d, J=9.4 Hz, 1H ), 8.03 (d, J=1.2 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.02 (t, J=54.0 Hz, 1H), 4.92-4.70 (m, 1H), 4.49 (s, 1H), 3.59-3.50 (m, 1H), 3.01 (td, J=13.5, 3.7 Hz, 1H), 2.90 (s, 3H), 2.07 (tt, J=13.6, 4.5 Hz, 1H), 1.88-1.52 (m, 3H), 1.24 (d, J=7.0 Hz, 3H). II-601 438.2 2.26 1H NMR (400 MHz, methanol-d4) δ 8.48 (s, 1H), 8.42 (d, J=1.1 Hz, 1H), 8.25 (d, J=9.4 Hz, 1H ), 8.03 (d, J=1.1 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.02 (t, J=54.0 Hz, 1H), 4.78 (s, 1H), 4.49 (s, 1H), 3.56 (dd, J=3.8, 2.3 Hz, 1H), 3.11-2.94 (m, 1H) , 2.90 (s, 3H), 2.17-1.98 (m, 1H), 1.91-1.52 (m, 3H), 1.24 (d, J=7.0 Hz, 3H ). II-602 438 2.14 1H NMR (400 MHz, methanol-d4) δ 8.64 (s, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.39 (d, J=9.5 Hz, 1H ), 8.17 (d, J=1.1 Hz, 1H), 7.71 (d, J=9.5 Hz, 1H), 7.17 (t, J=53.8 Hz, 1H), 4.96 (s, 1H), 4.63 (s, 1H), 3.58 (dt, J=10.7, 5.2 Hz, 1H), 3.04 (s, 4H), 2.10 -1.57 (m, 4H), 1.33 (d, J=6.9 Hz, 3H). II-603 438 2.13 1H NMR (400 MHz, methanol-d4) δ 8.63 (s, 1H), 8.56 (d, J=1.1 Hz, 1H), 8.38 (d, J=9.5 Hz, 1H ), 8.16 (d, J=1.2 Hz, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.16 (t, J=53.8 Hz, 1H), 4.96 (s, 1H), 4.63 (s, 1H), 3.57 (dt, J=10.7, 5.3 Hz, 1H), 3.04 (s, 4H), 1.99 -1.57 (m, 4H), 1.33 (d, J=6.9 Hz, 3H). II-604 450 2.16 II-605 450 2.18 II-606 450 2.16 II-607 450.1 2.17 1H NMR (500 MHz, methanol-d4) δ 8.49 (s, 1H), 8.42 (s, 1H), 8.24 (d, J=9.5 Hz, 1H), 8.01 (s , 1H), 7.56 (d, J=9.4 Hz, 1H), 7.36-6.94 (m, 1H), 3.32 (s, 1H), 3.06-2.98 ( m, 4H), 2.57 (s, 1H), 2.50-2.40 (m, 1H), 1.70-1.66 (m, 2H), 1.33 (q, J=12, 6 Hz, 1H), 1.21-1.17 (m, 5H), 0.96 (d, J=6.3 Hz, 3H). II-608 389 2.42 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.54 (d, J=1.0 Hz, 1H), 8.51 (d, J=9.4 Hz, 1H ), 7.98 (d, J=1.3 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.24 (t, J=53.8 Hz, 1H), 4.57 (s, 2H), 3.03-2.67 (m, 2H), 1.98-1.71 (m, 2H), 1.40 (h, J=8.6 Hz, 3H) , 1.14 (d, J=6.9 Hz, 6H). II-609 445.2 2.47 II-610 443.2 2.34 1H NMR (500 MHz, DMSO-d6) δ 9.33 (d, J=1.3 Hz, 1H), 9.12 (d, J=1.3 Hz, 1H), 8.82 (s, 1H ), 8.60 (d, J=9.4 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.00 (d, J=2.1 Hz, 1H), 7.79 (s, 1H), 7.48 (d, J=2.0 Hz, 1H), 7.37 (t, J=53.7 Hz, 1H), 4.54 (s, 2H), 3.65(s, 6H), 2.48(s, 3H). II-611 457.2 2.48 1H NMR (500 MHz, DMSO-d6) δ 9.35 (d, J=1.3 Hz, 1H), 9.16 (d, J=1.4 Hz, 1H), 8.83 (s, 1H ), 8.72 (dq, J=1.7, 0.8 Hz, 1H), 8.59 (d, J=9.4 Hz, 1H), 8.22 (dq, J=1.8, 1.0 Hz, 1H), 8.03 (td, J=1.6, 0.8 Hz, 1H), 7.77 (d, J=9.4 Hz, 1H), 7.40 (t, J=53.9 Hz, 1H), 3.52 (s, 6H), 2.52 (s, 3H). II-612 445.2 2.53 1H NMR (500 MHz, DMSO-d6) δ 9.37 (d, J=1.3 Hz, 1H), 9.17 (d, J=1.3 Hz, 1H), 8.86 (s, 1H ), 8.64 (d, J=9.4 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 8.03 (q, J=1.4 Hz, 1H), 7.82 (d, J=9.4 Hz, 1H), 7.78-7.68 (m, 1H), 7.60-7.33 (m, 2H), 4.33 (d, J= 6.2 Hz, 2H), 3.00 (s, 3H), 2.52 (s, 3H). II-613 389.1 2.42 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58-8.48 (m, 2H), 8.01 (d, J=1.2 Hz, 1H), 7 .69 (d, J=9.4 Hz, 1H), 7.26 (t, J=53.8 Hz, 1H), 4.58 (s, 2H), 4.43 (s, 1H), 2 .82 (s, 2H), 1.89 (s, 1H), 1.79 (s, 1H), 1.51-1.28 (m, 3H), 1.14 (d, J=6.7 Hz, 6H). II-614 389 2.42 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58-8.41 (m, 2H), 8.02 (d, J=1.2 Hz, 1H), 7 .69 (d, J=9.4 Hz, 1H), 7.26 (t, J=53.8 Hz, 1H), 4.58 (s, 2H), 4.43 (s, 1H), 2 .82 (s, 2H), 1.89 (s, 1H), 1.79 (s, 1H), 1.53-1.30 (m, 3H), 1.14 (d, J=6.7 Hz, 6H). II-615 377.2 1.95 1H NMR (400 MHz, DMSO-d6) δ 8.71-8.58 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 7.99 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 4.82 (dd, J=6.1, 5.0 Hz, 1H), 4.04 (s, 1H), 3.96-3.73 (m, 3H), 3.63-3.37 (m, 4H), 1.17 (d, J =6.3 Hz, 3H). II-616 377.2 2.02 1H NMR (400 MHz, DMSO-d6) δ 8.69-8.56 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.00 (d, J=1, 2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.8 Hz, 1H), 4.71-4.09 (m, 2H) , 3.72-3.40 (m, 4H), 2.72 (dt, J=22.7, 12.0 Hz, 2H), 1.21 (d, J=6.2 Hz, 3H). II-617 496 2.21 II-618 496 2.21 1H NMR (500 MHz, DMSO-d6) δ 8.62 (m, 1H), 8.58 (m, 1H), 8.54-8.52 (m, 1H), 8.12-7.98 ( m, 1H), 7.78 (m, 1H), 7.32-7.15 (m, 1H), 7.04 (m, 1H), 5.30-4.60 (m, 1H), 4 .38 (s, 1H), 3.65-3.3 (masked, 2H), 3.21-3.12 (m, 1H), 2.99-2.85 (m, 4H), 1.85 -1.65 (m, 1H), 1.54 (m, 1H), 1.37-1.17 (m, 3H), 1.17 (s, 3H), 0.97 (m, 3H). II-619 452.3 2.33 1H NMR (500 MHz, DMSO-d6) δ 8.65-8.56 (m, 2H), 8.53 (d, J=9.4 Hz, 1H), 8.00 (d, J=1, 3 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.8 Hz, 1H), 7.04 (d, J=8.6 Hz , 1H), 4.61-4.18 (m, 1H), 3.41-3.25 (m, 2H), 3.11-2.96 (m, 1H), 2.98-2.87 (m, 4H), 1.97-1.88 (m, 1H), 1.88-1.77 (m, 1H), 1.50 (tq, J=8.8, 5.7, 4, 6 Hz, 1H), 1.41 (qd, J=12.2, 11.5, 3.6 Hz, 2H), 1.23 (d, J=6.7 Hz, 3H). II-620 452.2 2.37 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 7.96 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.6 Hz, 1H), 7.10 (s, 1H), 4.83-4.35 (m, 1H), 3.29-3.16 (m, 1H), 3.01-2.83 (m, 4H), 2. 80-2.68 (m, 1H), 1.89-1.76 (m, 2H), 1.55-1.29 (m, 4H), 1.21 (d, J=6.7 Hz, 3H). II-621 417.1 2.7 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58-8.44 (m, 2H), 7.98 (d, J=1.3 Hz, 1H), 7 .68 (d, J=9.4 Hz, 1H), 7.29 (t, J=53.9 Hz, 1H), 4.54 (s, 2H), 2.84 (s, 2H), 2 .04-1.69 (m, 3H), 1.66-1.26 (m, 3H), 1.05 (s, 3H), 0.88 (d, J=6.7 Hz, 3H), 0.80 (d, J=6.7 Hz, 3H). II-622 417.1 2.87 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58-8.47 (m, 2H), 8.01 (d, J=1.2 Hz, 1H), 7 .70 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.7 Hz, 1H), 4.59 (s, 2H), 2.86 (s, 2H), 1 .96-1.69 (m, 3H), 1.59 (s, 1H), 1.45 (d, J=10.2 Hz, 2H), 0.98 (s, 3H), 0.87 ( dd, J=6.7, 3.9 Hz, 6H). II-623 411 2.48 1H NMR (400 MHz, methanol-d4) δ 8.59 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.36 (d, J=9.4 Hz, 1H ), 8.16 (d, J=1.3 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.07 (t, J=54.0 Hz, 1H), 4.73 (d, J=35.2 Hz, 2H), 4.07 (dd, J=11.0, 3.7 Hz, 1H), 3.63 (dd, J=11.0, 9, 5 Hz, 1H), 3.40-3.25 (m, 1H), 3.12-2.97 (m, 1H), 2.89 (t, J=12.8 Hz, 1H), 2, 33-1.95 (m, 2H), 1.12 (d, J=6.7 Hz, 3H). II-624 411 2.47 1H NMR (400 MHz, methanol-d4) δ 8.63-8.51 (m, 2H), 8.32 (d, J=9.5 Hz, 1H), 8.08 (d, J=1, 0 Hz, 1H), 7.65 (d, J=9.5 Hz, 1H), 6.99 (t, J=54.0 Hz, 1H), 4.78-4.39 (m, 2H) , 3.96 (dd, J=11.0, 3.7 Hz, 1H), 3.53 (dd, J=11.0, 9.4 Hz, 1H), 3.21 (p, J=1 ,6 Hz, 1H), 3.04 (t, J=13.0 Hz, 1H), 2.90 (t, J=12.9 Hz, 1H), 2.26-1.94 (m, 2H ), 1.03 (d, J=6.7 Hz, 3H). II-625 451 2.5 II-626 451 2.5 II-627 464.3 2.44 1H NMR (500 MHz, chloroform-d) δ 8.72 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.16 (d, J=9.4 Hz, 1H ), 7.98 (d, J=1.2 Hz, 1H), 7.41 (d, J=9.4 Hz, 1H), 7.18-6.93 (m, 1H), 4.69 (s, 1H), 4.34 (s, 1H), 3.23 (tt, J=10.9, 4.5 Hz, 1H), 3.04 (ddddd, J=21.6, 19.7 , 12.5, 8.8, 6.2 Hz, 4H), 2.75 (dd, J=13.2, 10.7 Hz, 1H), 2.36 (t, J=12.3 Hz, 1H), 1.98 (ddq, J=10.0, 3.8, 2.1, 1.6 Hz, 1H), 1.67 (qt, J=10.4, 3.4 Hz, 1H) , 1.36 (t, J=7.5 Hz, 3H), 1.33-1.23 (m, 4H), 0.95 (d, J=6.6 Hz, 3H). II-628 402.3 1.96 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=1.1 Hz, 1H), 8.66 (s, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.03 (s, 1H), 7.72 (d, J=9.5 Hz, 1H), 7.32 (t, J=53.9 Hz, 1H), 5.25-4.00 (m, 2H), 4.02-3.88 (m, 1H), 3.68-3.56 (m, 1H), 3.48-3.00 (m, 3H), 1.87-1 .68 (m, 3H), 1.68-1.53 (m, 1H), 1.43 (q, J=13.9, 12.8 Hz, 2H). II-629 436.3 2.24 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.54-8.49 (m, 2H), 8.05-7.98 (m, 1H), 7.67 ( d, J=9.4 Hz, 1H), 7.33 (t, J=53.7 Hz, 1H), 4.58-4.26 (m, 1H), 4.04-3.85 (m , 1H), 3.52-3.33 (m, 2H), 3.28-3.11 (m, 1H), 2.92 (s, 6H), 1.88 (ddt, J=10.1 , 6.9, 3.6 Hz, 1H), 1.67-1.53 (m, 1H), 1.53-1.40 (m, 1H), 0.92 (d, J=6.7 Hz, 3H). II-630 450.1 2.25 1H NMR (500 MHz, chloroform-d) δ 8.65 (s, 1H), 8.58 (s, 1H), 8.14 (d, J=9.4 Hz, 1H), 7.97 (s , 1H), 7.39 (d, J=9.4 Hz, 1H), 6.98 (d, J=51.6 Hz, 1H), 4.74 (s, 1H), 4.32 (s , 1H), 3.48-3.39 (m, 1H), 3.03 (d, J=1.0 Hz, 3H), 2.98 (d, J=1.0 Hz, 3H), 2 .45 (s, 1H), 1.75-1.65 (m, 1H), 1.46 (q, J=12.5 Hz, 1H), 1.22 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.1 Hz, 1H), 0.96 (d, J=6.4 Hz, 3H). II-631 450.1 2.25 1H NMR (500 MHz, chloroform-d) δ 8.65 (s, 1H), 8.58 (s, 1H), 8.14 (d, J=9.4 Hz, 1H), 7.97 (s , 1H), 7.39 (d, J=9.4 Hz, 1H), 6.98 (d, J=51.6 Hz, 1H), 4.74 (s, 1H), 4.32 (s , 1H), 3.48-3.39 (m, 1H), 3.03 (d, J=1.0 Hz, 3H), 2.98 (d, J=1.0 Hz, 3H), 2 .45 (s, 1H), 1.75-1.65 (m, 1H), 1.46 (q, J=12.5 Hz, 1H), 1.22 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.1 Hz, 1H), 0.96 (d, J=6.4 Hz, 3H). II-632 436.1 2.22 1H NMR (500 MHz, chloroform-d) δ 8.85-8.72 (m, 1H), 8.65 (d, J=1.1 Hz, 1H), 8.23 (d, J=9, 4 Hz, 1H), 8.07 (s, 1H), 7.48 (d, J=9.4 Hz, 1H), 7.07 (t, 1H), 4.44 (s, 1H), 4 ,13 (s, 1H), 3.54 (dt, J=5.4, 3.0 Hz, 1H), 3.43 (dd, J=13.2, 2.5 Hz, 1H), 3, 27 (ddd, J=13.6, 10.3, 3.4 Hz, 1H), 2.95 (s, 6H), 2.04-1.87 (m, 1H), 1.82-1, 70 (m, 1H), 1.62-1.50 (m, 1H), 1.02 (d, J=6.8 Hz, 3H). II-633 436.1 2.22 1H NMR (500 MHz, chloroform-d) δ 8.85-8.72 (m, 1H), 8.65 (d, J=1.1 Hz, 1H), 8.23 (d, J=9, 4 Hz, 1H), 8.07 (s, 1H), 7.48 (d, J=9.4 Hz, 1H), 7.07 (t, 1H), 4.44 (s, 1H), 4 ,13 (s, 1H), 3.54 (dt, J=5.4, 3.0 Hz, 1H), 3.43 (dd, J=13.2, 2.5 Hz, 1H), 3, 27 (ddd, J=13.6, 10.3, 3.4 Hz, 1H), 2.95 (s, 6H), 2.04-1.87 (m, 1H), 1.82-1, 70 (m, 1H), 1.62-1.50 (m, 1H), 1.02 (d, J=6.8 Hz, 3H). II-634 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=5.9 Hz, 1H), 8.57 (d, J=1.0 Hz, 1H), 8.53 (dd, J =9.4, 4.3 Hz, 1H), 8.07-7.76 (m, 1H), 7.68 (dd, J=9.4, 5.9 Hz, 1H), 7.30 ( td, J=53.8, 6.6 Hz, 1H), 3.31-3.23 (m, 3H, partially hidden), 3.02 (d, J=12.4 Hz, 3H), 2, 76-2.56 (m, 2H), 1.95 (dd, J=28.1, 12.7 Hz, 1H), 1.65 (d, J=3.7 Hz, 1H), 1.28 -1.13 (m, 2H), 1.12-0.96 (m, 2H), 0.95 (dd, J=6.6, 1.2 Hz, 3H), 0.93-0.80 (m, 2H). II-635 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=0.8 Hz, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.55-8.48 (m, 1H), 8.03 (dd, J=5.0, 1.2 Hz, 1H), 7.68 (dd, J=9.4, 1.1 Hz, 1H), 7.33 ( td, J=53.8, 4.4 Hz, 1H), 3.31 (s, 3H) not observed, 3.26-3.10 (m, 2H), 2.94 (d, J=3, 5 Hz, 3H), 2.52 (d, J=1.8 Hz, 2H), 1.98-1.87 (m, 1H), 1.72-1.60 (m, 1H), 1, 32-1.11 (m, 4H), 0.95 (d, J=6.6 Hz, 3H). II-636 422 1.9 II-637 422 1.9 II-638 422 1.91 II-639 422 1.91 II-640 450.1 2.27 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.04 (d, J=1.2 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.8 Hz, 1H), 3.27 (d, J=13.3 Hz, 2H), 3.15 (d, J=7.4 Hz, 2H), 2.94 (s, 3H), 2.51 (d, J=1 ,9 Hz, 2H), 1.94 (d, J=12.6 Hz, 2H), 1.70-1.61 (m, 2H), 1.27 (t, J=7.4 Hz, 3H ), 0.95 (d, J=6.6 Hz, 3H). II-641 450.1 2.26 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.3 Hz, 1H ), 8.03 (d, J=1.3 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.8 Hz, 1H), 3.17 (ddd, J=32.8, 14.5, 7.1 Hz, 2H), 2.95 (s, 3H), 2.68 (s, 2H), 2.55-2.51 ( m, 2H), 1.94 (d, J=12.8 Hz, 2H), 1.67-1.63 (m, 2H), 1.27-1.13 (m, 3H), 0.95 (d, J=6.6 Hz, 3H). II-642 450.1 2.26 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.03 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.34 (t, J=53.8 Hz, 1H), 3.17 (ddd, J=32.9, 14.4, 7.1 Hz, 2H), 2.95 (s, 3H), 2.70-2.66 (m, 2H), 2.51 ( p, J=1.8 Hz, 2H), 1.94 (d, J=12.7 Hz, 2H), 1.67-1.63 (m, 2H), 1.26-1.13 (m , 3H), 0.95 (d, J=6.6 Hz, 3H). II-643 450.1 2.27 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.5 Hz, 1H ), 8.04 (d, J=1.3 Hz, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.33 (t, J=53.7 Hz, 1H), 3.26 (s, 2H), 3.15 (q, J=7.4 Hz, 2H), 2.94 (s, 3H), 2.51 (d, J=1.9 Hz, 2H), 1.94 (d, J=12.9 Hz, 2H), 1.66 (s, 2H), 1.27 (t, J=7.4 Hz, 3H), 0.95 (d, J=6 ,5 Hz, 3H). II-644 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.01 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.29 (t, J=53.7 Hz, 1H), 3.03 (s, 3H ), 2.65 (s, 2H), 2.53 (d, J=1.9 Hz, 1H), 1.98 (d, J=12.7 Hz, 2H), 1.64 (s, 2H ), 1.26-1.14 (m, 2H), 1.13-1.05 (m, 1H), 0.99 (dq, J=7.9, 3.6 Hz, 1H), 0, 95 (d, J=6.6 Hz, 3H), 0.87 (dtd, J=17.4, 10.2, 8.7, 5.6 Hz, 2H). II-645 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.03 (s, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.8 Hz, 1H), 3.29-3.20 (m, 2H), 3.01 (s, 3H), 2.50-2.42 (m, 3H), 1.92 (d, J=12.6 Hz, 1H), 1.71-1, 57 (m, 1H), 1.32-1.15 (m, 3H), 1.10-0.99 (m, 1H), 1.02-0.79 (m, 5H). II-646 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.03 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.31 (t, J=53.8 Hz, 1H), 3.27 (dd, J=7.0, 5.2 Hz, 3H), 3.01 (s, 3H), 2.73-2.62 (m, 2H), 1.92 (d, J= 12.8 Hz, 1H), 1.69-1.58 (m, 1H), 1.29-1.10 (m, 2H), 1.10-0.97 (m, 2H), 0.94 (dd, J=8.2, 5.7 Hz, 5H). II-647 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.01 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.29 (t, J=53.7 Hz, 1H), 3.31-3.25 (m, 3H), 3.03 (s, 3H), 2.64 (p, J=1.9 Hz, 2H), 1.97 (d, J=12.9 Hz, 1H), 1.73 -1.56 (m, 1H), 1.30-1.13 (m, 2H), 1.08 (dd, J=10.6, 5.1 Hz, 1H), 1.04-0.96 (m, 1H), 0.95 (d, J=6.5 Hz, 3H), 0.87 (dddd, J=21.0, 14.9, 9.3, 4.8 Hz, 2H). II-648 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.02 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 3.27-3.20 (m, 2H), 3.05 (d, J=6.6 Hz, 6H), 1.98 (d, J=13.0 Hz, 2H), 1.50-1 .41 (m, 2H), 1.38-1.31 (m, 1H), 1.29-1.23 (m, 1H), 1.19-1.09 (m, 2H), 0.95 (t, J=7.5 Hz, 3H). II-649 462.2 2.26 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.03 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.9 Hz, 1H), 3.25-3.08 (m, 4H), 2.98 (ddt, J=41.4, 13.1, 7.0 Hz, 4H), 2.19-2.00 (m, 4H), 1.97 (d, J=13.0 Hz, 1H), 1.66 (m, 2H), 1.20 (dt, J=23.8, 12.0 Hz, 1H), 0.95 (d , J=6.6 Hz, 3H). II-650 450.1 2.24 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.02 (d, J=1.1 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 3.23 (d, J=11.8 Hz, 2H), 3.13-3.01 (m, 6H), 2.68 (m, 2H), 1.98 (d, J=12.7 Hz , 2H), 1.46 (d, J=3.5 Hz, 1H), 1.31 (dtd, J=37.8, 13.6, 6.7 Hz, 2H), 1.15 (q, J=11.9 Hz, 1H), 0.95 (t, J=7.4 Hz, 3H). II-651 450.2 2.24 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.53 (d, J=9.4 Hz, 1H ), 8.02 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.8 Hz, 1H), 3.26 (m, 2H), 3.06 (d, J=6.7 Hz, 6H), 2.53 (m, 2H), 1.99 (d, J=12.8 Hz, 2H), 1.47 (t, J=3.9 Hz, 1H), 1.45-1.21 (m, 2H), 1.16 (dd, J=13.3, 10.4 Hz, 1H), 0 .95 (t, J=7.5 Hz, 3H). II-652 426.4 2.01 1H NMR (500 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.61 (d, J=5.8 Hz, 2H), 8.52 (d, J=9.4 Hz, 1H ), 8.07 (s, 1H), 7.74-7.08 (m, 4H), 4.86 (d, J=187.6 Hz, 1H), 4.30-3.61 (m, 2H), 2.77 (d, J=101.3 Hz, 2H), 1.17 (d, J=6.0 Hz, 3H), 0.98 (s, 3H). II-653 426.4 2.01 1H NMR (500 MHz, DMSO-d6) δ 12.95-12.36 (m, 1H), 8.61 (d, J=5.6 Hz, 2H), 8.52 (d, J=9, 4 Hz, 1H), 8.07 (s, 1H), 7.77-7.10 (m, 4H), 4.87 (d, J=185.9 Hz, 1H), 4.26-3, 60 (m, 2H), 2.96-2.57 (m, 2H), 1.17 (d, J=5.8 Hz, 3H), 0.98 (d, J=6.2 Hz, 3H ). II-654 490.1 2.35 1H NMR (500 MHz, methanol-d4) δ 8.72 (s, 1H), 8.65 (d, J=1.0 Hz, 1H), 8.32 (d, J=9.4 Hz, 1H ), 8.14 (s, 1H), 7.63 (d, J=9.4 Hz, 1H), 7.04 (t, J=53.7 Hz, 1H), 5.04 (s, 1H ), 3.45-3.35 (m, 1H), 3.17 (s, 3H), 3.13 (s, 3H), 3.00-2.88 (m, 2H), 2.51 ( dtt, J=12.0, 8.2, 4.5 Hz, 1H), 2.32-2.21 (m, 1H), 1.71 (q, J=12.4 Hz, 1H). II-655 368.2 0.75* ------------------- II-656 368.2 0.75* ------------------- II-657 377.3 ------------------- II-658 317.3 1H NMR (400 MHz, DMSO-d6) δ 9.16 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.61-8.51 (m, 3H), 7 ,81-7.70 (m, 1H), 7.37 (t, J=53.8 Hz, 1H), 3.48-3.37 (m, 1H), 3.30-3.23 (m , 1H), 3.09-2.85 (m, 3H), 2.25-2.10 (m, 1H), 1.99 (dq, J=12.6, 7.3 Hz, 1H) II-659 331.0 0.64* 1H NMR (400 MHz, ) δ 9.18 (dd, J=3.6, 1.3 Hz, 1H), 8.80 (d, J=1.5 Hz, 1H), 8.69 (dd, J=4.8, 1.3 Hz, 1H), 8.44 (d, J=9.5 Hz, 1H), 7.76 (d, J=9.5 Hz, 1H), 7.38- 6.92 (m, 1H), 3.65 (dd, J=12.5, 4.0 Hz, 1H), 3.59-3.48 (m, 1H), 3.48-3.36 ( m, 2H), 3.29-3.02 (m, 1H), 2.41-1.69 (m, 4H) II-660 372.1 0.62* ------------------- II-661 346.1 0.63* 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.57 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 7.98 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.35 (t, J=53.7 Hz, 1H), 4.27 (d, J=51.8 Hz, 2H), 3.16-2.98 (m, 1H), 2.90-2.60 (m, 2H), 2.00-1.85 ( m, 1H), 1.79 (dt, J=12.8, 3.9 Hz, 1H), 1.60-1.24 (m, 2H). II-662 388.3 0.60* ------------------- II-663 360.1 0.62* ------------------- II-664 374.1 0.58* ------------------- II-665 358.1 0.59* ------------------- II-666 374.1 0.66* ------------------- II-667 374.1 0.59* ------------------- II-668 372.1 0.63* ------------------- II-669 374.3 0.61* ------------------- II-670 372.1 0.65* ------------------- II-671 360.2 0.66* ------------------- II-672 362.1 0.58* ------------------- II-673 386.1 0.64* ------------------- II-674 372.1 0.67* ------------------- II-675 386.1 0.71* ------------------- II-676 380.2 1.63 1H NMR (500 MHz, methanol-d4) δ 8.75 (d, J=21.2 Hz, 2H), 8.45 (d, J=9.4 Hz, 1H), 8.21 (s, 1H ), 7.78 (dd, J=10.9, 3.6 Hz, 1H), 7.16 (t, J=54.0 Hz, 1H), 4.72 (dd, J=12.4, 8.0 Hz, 2H), 4.30-4.10 (m, 2H), 3.60 (dd, J=8.2, 3.9 Hz, 4H). II-677 358.1 0.62* ------------------- II-678 360.3 0.65* ------------------- II-679 372.1 0.66* ------------------- II-680 374.2 0.63* ------------------- II-681 346.3 0.56* ------------------- II-682 382.0 0.65* ------------------- II-683 402.1 0.62* ------------------- II-684 411.3 0.74* ------------------- II-685 391.3 0.58* ------------------- II-686 390.1 0.59* ------------------- II-687 453.3 0.65* ------------------- II-688 362.3 0.52* ------------------- II-689 403.3 0.70* ------------------- II-690 435.1 0.64* ------------------- II-691 433.3 2.31 1H NMR (500 MHz, chloroform-d) δ 8.35 (s, 1H), 8.24-8.13 (m, 2H), 8.03 (s, 1H), 7.46 (d, J= 9.4 Hz, 1H), 7.13 (dd, J=6.1, 1.5 Hz, 1H), 6.89 (t, J=54.1 Hz, 1H), 4.51 (s, 1H), 4.42 (d, J=13.5 Hz, 1H), 3.35 (ddd, J=10.9, 6.5, 4.6 Hz, 1H), 3.12 (s, 3H ), 3.03 (d, J=5.4 Hz, 1H), 3.00-2.99 (m, 3H), 2.91-2.80 (m, 1H), 2.61 (ddd, J=12.6, 9.8, 6.8 Hz, 1H), 2.06-1.99 (m, 1H), 1.34-1.22 (m, 1H), 1.01 (d, J=6.5 Hz, 3H). II-692 413.2 2.03 1H NMR (500 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.65-8.53 (m, 2H), 7.92 (d, J=9.4 Hz, 1H), 7 .80 (d, J=1.2 Hz, 1H), 7.10 (t, J=6.2 Hz, 1H), 4.13 (s, 1H), 3.19 (ddd, J=13, 8, 11.3, 3.0 Hz, 1H), 2.91 (d, J=9.0 Hz, 7H), 1.96-1.84 (m, 1H), 1.85-1.76 (m, 1H), 1.70 (dd, J=7.1, 3.5 Hz, 1H), 1.56-1.42 (m, 1H), 1.43-1.29 (m, 1H ). II-693 401.3 1.88 1H NMR (500 MHz, DMSO-d6) δ 8.83-8.53 (m, 3H), 8.03-7.82 (m, 2H), 7.73-7.49 (m, 2H), 5.26-4.55 (m, 1H), 4.13 (m, 1H), 3.03-2.75 (m, 1H), 1.24 (s, 1H), 1.17 (d, J=6.0 Hz, 3H), 0.93 (m, 4H). II-694 490.1 2.34 1H NMR (500 MHz, methanol-d4) δ 8.65 (s, 1H), 8.61 (d, J=1.3 Hz, 1H), 8.38 (d, J=9.4 Hz, 1H ), 8.19 (d, J=1.1 Hz, 1H), 7.70 (d, J=9.5 Hz, 1H), 7.17 (t, J=53.8 Hz, 1H), 5.08 (s, 1H), 4.50 (s, 1H), 3.53-3.43 (m, 1H), 3.22-3.16 (m, 6H), 2.97-2, 86 (m, 2H), 2.63 (dtd, J=12.1, 8.2, 4.0 Hz, 1H), 2.27 (d, J=12.7 Hz, 1H), 1.67 (td, J=12.6, 11.1 Hz, 1H). II-695 490.1 2.34 1H NMR (500 MHz, methanol-d4) δ 8.65 (s, 1H), 8.61 (d, J=1.1 Hz, 1H), 8.38 (d, J=9.4 Hz, 1H ), 8.19 (d, J=1.3 Hz, 1H), 7.70 (d, J=9.4 Hz, 1H), 7.17 (t, J=53.8 Hz, 1H), 5.08 (s, 1H), 4.50 (s, 1H), 3.53-3.43 (m, 1H), 3.19 (dd, J=7.1, 0.8 Hz, 6H) , 2.91 (q, J=13.1 Hz, 2H), 2.63 (dtd, J=11.9, 8.1, 3.8 Hz, 1H), 2.27 (d, J=12 .5 Hz, 1H), 1.67 (td, J=12.6, 11.1 Hz, 1H). II-696 436.1 2.03 1H NMR (500 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.52 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.3 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.30 (t, J=53.7 Hz, 1H), 3.31 (m, 4H) partially hidden, 3.07 (s, 6H), 1.86-1.51 (m, 4H), 1.20 (s, 3H). II-697 436.1 2.13 1H NMR (500 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.53 (d, J=1.1 Hz, 1H), 8.51 (d, J=9.4 Hz, 1H ), 8.00 (d, J=1.2 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.32 (t, J=53.8 Hz, 1H), 4.84 (s, 1H), 4.11 (d, J=13.9 Hz, 1H), 3.73 (m, 1H), 3.29 (m, 1H), 3.05-2.91 (m, 8H), 2.28-2.15 (m, 1H), 2.04-1.86 (m, 1H), 1.49 (d, J=13.0 Hz, 1H), 1, 42-1.33 (m, 1H), 1.20 (d, J=6.8 Hz, 3H). II-698 444.4 2.15 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.63 (d, J=10.3 Hz, 2H), 8.06 (d, J=1.2 Hz, 1H ), 7.87 (d, J=9.5 Hz, 1H), 7.54 (d, J=26.5 Hz, 2H), 4.10 (s, 1H), 2.89 (d, J =19.9 Hz, 1H), 2.67-2.55 (m, 2H), 1.16 (d, J=5.9 Hz, 3H), 0.99 (s, 3H). II-699 375.3 1.89 1H NMR (500 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.65 (d, J=1.1 Hz, 1H), 8.59 (d, J=9.4 Hz, 1H ), 7.93 (d, J=9.4 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H), 4.50 (dt, J=13.2, 3.1 Hz , 1H), 4.40 (d, J=11.5 Hz, 2H), 3.52 (dtd, J=12.3, 7.2, 5.3, 3.1 Hz, 1H), 3, 15-3.05 (m, 1H), 2.97-2.87 (m, 1H), 2.82-2.72 (m, 1H), 2.29 (dd, J=8.1, 4 ,8 Hz, 2H), 2.03 (dtd, J=10.8, 5.2, 2.9 Hz, 1H), 1.90-1.77 (m, 1H), 1.68 (dddd, J=15.9, 11.1, 8.1, 2.9 Hz, 1H), 1.55 (tdd, J=12.4, 9.4, 3.2 Hz, 1H). II-700 472.1 2.2 1H NMR (500 MHz, methanol-d4) δ 8.64 (s, 1H), 8.59 (d, J=1.1 Hz, 1H), 8.38 (d, J=9.5 Hz, 1H ), 8.19 (s, 1H), 7.69 (d, J=9.5 Hz, 1H), 7.13 (t, J=53.9 Hz, 1H), 6.80-6.45 (m, 1H), 3.74 (s, 1H), 3.24-3.19 (m, 6H), 2.04-1.86 (m, 4H), 1.80-1.65 (m , 2H), 1.33-1.29 (m, 1H). II-701 472 2.2 1H NMR (500 MHz, methanol-d4) δ 8.52 (s, 1H), 8.47 (d, J=1.1 Hz, 1H), 8.26 (d, J=9.5 Hz, 1H ), 8.07 (s, 1H), 7.57 (d, J=9.5 Hz, 1H), 7.01 (t, J=53.8 Hz, 1H), 6.68-6.34 (m, 1H), 3.63 (s, 2H), 3.12-3.07 (m, 6H), 1.93-1.74 (m, 3H), 1.61 (d, J=13 ,9 Hz, 2H), 1.22-1.17 (m, 1H). II-702 411.4 1.94 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.61-8.55 (m, 2H), 7.91 (d, J=9.4 Hz, 1H), 7 .85 (d, J=1.2 Hz, 1H), 4.10 (q, J=5.2 Hz, 1H), 3.24 (ddt, J=15.3, 9.3, 6.0 Hz, 1H), 3.18 (d, J=4.7 Hz, 2H), 3.06 (d, J=1.0 Hz, 3H), 3.02 (m, J=1.0 Hz, 4H), 2.00-1.91 (m, 1H), 1.73-1.62 (m, 1H), 1.25-1.13 (m, 1H), 0.96 (d, J= 6.6 Hz, 3H). II-703 411.4 1.94 1H NMR (500 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.61-8.55 (m, 2H), 7.91 (d, J=9.4 Hz, 1H), 7 .85 (d, J=1.2 Hz, 1H), 4.10 (q, J=5.2 Hz, 1H), 3.24 (ddt, J=15.3, 9.3, 6.0 Hz, 1H), 3.18 (d, J=4.7 Hz, 2H), 3.06 (d, J=1.0 Hz, 3H), 3.02 (m, J=1.0 Hz, 4H), 2.00-1.91 (m, 1H), 1.73-1.62 (m, 1H), 1.25-1.13 (m, 1H), 0.96 (d, J= 6.6 Hz, 3H). II-704 444.4 2.17 1H NMR (500 MHz, methanol-d4) δ 8.60 (s, 1H), 8.48 (d, J=1.1 Hz, 1H), 8.35 (d, J=9.5 Hz, 1H ), 8.09 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.5 Hz, 1H), 7.57 (s, 2H), 5.10 (s, 1H ), 4.16 (s, 1H), 3.73 (s, 1H), 3.05-2.78 (m, 1H), 2.60 (s, 1H), 1.19 (d, J= 6.0 Hz, 3H), 1.00 (d, J=6.9 Hz, 3H). II-705 444.4 2.16 1H NMR (500 MHz, methanol-d4) δ 8.58 (s, 1H), 8.47 (d, J=6.5 Hz, 1H), 8.33 (d, J=9.4 Hz, 1H ), 8.05 (s, 1H), 7.66 (d, J=9.5 Hz, 1H), 7.57 (s, 2H), 5.08 (s, 1H), 4.15 (s , 1H), 3.71 (d, J=19.1 Hz, 1H), 2.90 (s, 1H), 2.57 (d, J=14.1 Hz, 1H), 1.18 (d , J=5.9 Hz, 3H), 1.07-0.89 (m, 3H). II-706 430.4 1.97 1H NMR (500 MHz, DMSO-d6) δ 12.72 (s, 1H), 8.71 (s, 1H), 8.65-8.59 (m, 2H), 8.03 (s, 1H) , 7.87 (d, J=9.5 Hz, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 4.03-3.96 (m, 1H), 3, 17-3.09 (m, 1H), 2.88-2.75 (m, 1H), 2.73 (s, 1H), 2.64 (p, J=1.9 Hz, 1H), 2 .37 (p, J=1.9 Hz, 1H), 0.99 (d, J=6.7 Hz, 3H). II-707 430.4 2.05 1H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.76-8.50 (m, 4H), 8.23 (s, 1H), 7.85 (m, 2H) , 3.24-3.15 (m, 1H), 2.97 (s, 1H), 2.90-2.77 (m, 1H), 2.69-2.63 (m, 1H), 2 .37 (p, J=1.9 Hz, 1H), 1.24 (s, 1H), 1.04 (d, J=6.1 Hz, 1H), 0.86 (d, J=6, 4 Hz, 3H). II-708 416.1 2.36 1H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.83 (s, 1H), 8.74 (s, 1H), 8.68 (d, J=9.3 Hz , 1H), 8.52 (s, 1H), 8.10 (s, 1H), 7.94 (d, J=9.4 Hz, 1H), 4.57 (d, J=8.8 Hz , 1H), 4.00 (d, J=11.3 Hz, 2H), 3.51 (t, J=10.9 Hz, 2H), 2.16-1.88 (m, 4H). II-709 398.1 2.2 1H NMR (400 MHz, DMSO-d6) δ 9.14 (d, J=1.4 Hz, 1H), 8.82-8.71 (m, 2H), 8.66-8.53 (m, 2H), 8.30 (s, 1H), 7.76 (d, J=9.5 Hz, 1H), 7.51 (t, J=53.5 Hz, 1H), 4.56 (ddd, J=15.7, 9.2, 7.1 Hz, 1H), 4.01 (dt, J=11.5, 3.4 Hz, 2H), 3.51 (ddd, J=11.6, 7.7, 5.3 Hz, 2H), 2.05 (h, J=4.4 Hz, 4H). II-710 421.4 1.97 1H NMR (500 MHz, methanol-d4) δ 8.60 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.37 (d, J=9.4 Hz, 1H ), 8.11 (d, J=1.2 Hz, 1H), 7.68 (d, J=9.4 Hz, 1H), 7.12 (t, J=54.2 Hz, 1H), 4.67-4.49 (m, 1H), 3.92 (s, 1H), 3.66-3.53 (m, 2H), 2.40-2.25 (m, 2H), 2. 19-2.04 (m, 1H), 1.90-1.78 (m, 1H), 1.65 (d, J=12.8 Hz, 3H), 1.60 (d, J=12, 8 Hz, 3H), 1.07 (d, J=7.0 Hz, 3H). II-711 421.4 2.01 1H NMR (500 MHz, methanol-d4) δ 8.59 (s, 1H), 8.55 (d, J=1.1 Hz, 1H), 8.35 (d, J=9.4 Hz, 1H ), 8.09 (d, J=1.2 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.12 (t, J=54.2 Hz, 1H), 4.91 (d, J=21.7 Hz, 1H), 4.48 (s, 1H), 3.04 (td, J=12.5, 3.4 Hz, 1H), 2.78-2 .57 (m, 1H), 2.21-2.08 (m, 2H), 1.77 (dtd, J=11.2, 7.0, 3.3 Hz, 1H), 1.65 (d , J=12.8 Hz, 3H), 1.61 (d, J=12.9 Hz, 3H), 1.53-1.36 (m, 1H), 1.10 (d, J=6, 5 Hz, 3H). II-712 439.1 2.05 1H NMR (500 MHz, methanol-d4) δ 8.68 (d, J=3.2 Hz, 1H), 8.56 (t, J=2.1 Hz, 1H), 8.45 (ddd, J =9.8, 1.6, 0.9 Hz, 1H), 8.12-8.04 (m, 1H), 7.78 (dd, J=9.5, 0.8 Hz, 1H), 4.58 (s, 1H), 3.76 (s, 1H), 3.73-3.56 (m, 2H), 2.41-2.22 (m, 2H), 2.16 (dddd, J=13.3, 9.9, 8.5, 4.5 Hz, 1H), 1.85 (tt, J=12.5, 4.9 Hz, 1H), 1.68-1.62 ( m, 3H), 1.60 (dd, J=12.8, 0.7 Hz, 3H), 1.08 (d, J=6.9 Hz, 3H). II-713 439.1 2.09 1H NMR (500 MHz, methanol-d4) δ 8.60-8.52 (m, 1H), 8.49-8.40 (m, 1H), 8.33 (dd, J=9.7, 3 ,8 Hz, 1H), 8.05-7.91 (m, 1H), 7.67 (dd, J=9.5, 2.3 Hz, 1H), 4.93 (d, J=16, 8 Hz, 1H), 4.18 (s, 1H), 2.88 (t, J=12.4 Hz, 1H), 2.63 (t, J=12.7 Hz, 1H), 2.00 (ddt, J=26.1, 10.7, 4.0 Hz, 2H), 1.67 (ddt, J=18.5, 11.4, 5.7 Hz, 1H), 1.53 (d , J=12.8 Hz, 3H), 1.49 (d, J=12.8 Hz, 3H), 1.44-1.26 (m, 1H), 0.99 (d, J=6, 6 Hz, 3H). II-714 397.3 2.14 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.61 (s, 1H), 8.59 (d, J=1.0 Hz, 1H), 8.52 (d , J=9.4 Hz, 1H), 8.10 (s, 1H), 7.69 (d, J=9.4 Hz, 1H), 7.62-7.22 (m, 2H), 6 .90 (s, 1H), 4.54 (d, J=73.6 Hz, 2H), 3.08 (dt, J=22.6, 12.4 Hz, 2H), 2.90-2, 63 (m, 1H), 2.19-2.03 (m, 1H), 1.79 (ddd, J=24.0, 12.8, 8.8 Hz, 2H), 1.69-1, 47 (m, 1H). II-715 415.3 2.29 II-716 433.3 2.31 1H NMR (500 MHz, chloroform-d) δ 8.32 (s, 1H), 8.17 (dd, J=9.4, 7.8 Hz, 2H), 7.98-7.91 (m, 1H), 7.45 (d, J=9.4 Hz, 1H), 7.11 (dd, J=6.2, 1.5 Hz, 1H), 6.87 (t, J=54.0 Hz, 1H), 4.49 (d, J=13.5 Hz, 1H), 4.40 (d, J=13.4 Hz, 1H), 3.39-3.30 (m, 1H), 3.10 (s, 3H), 3.03-3.01 (m, 1H), 2.99 (d, J=1.0 Hz, 3H), 2.86-2.77 (m, 1H) , 2.60-2.52 (m, 1H), 2.01 (dt, J=13.0, 4.1 Hz, 1H), 1.32-1.21 (m, 1H), 0.99 (d, J=6.5 Hz, 3H). II-717 420.2 2.32 1H NMR (500 MHz, methanol-d4) δ 8.69 (s, 1H), 8.58 (s, 1H), 8.46 (d, J=9.5 Hz, 1H), 8.19 (s , 1H), 7.79 (d, J=9.5 Hz, 1H), 5.74 (s, 1H), 3.97-3.65 (m, 1H), 2.97-2.82 ( m, 1H), 2.76 (d, J=12.0 Hz, 1H), 1.90-1.78 (m, 1H), 1.72 (h, J=11.5, 10.5 Hz , 2H), 1.36-1.16 (m, 4H), 1.11 (d, J=5.5 Hz, 3H). II-718 420.2 2.32 1H NMR (500 MHz, methanol-d4) δ 8.58 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=9.4 Hz, 1H), 8.07 (s , 1H), 7.67 (d, J=9.5 Hz, 1H), 5.49 (s, 1H), 3.94-3.61 (m, 1H), 2.62 (dd, J= 16.7, 9.4 Hz, 1H), 1.75-1.66 (m, 1H), 1.60 (t, J=9.4 Hz, 2H), 1.24-1.14 (m , 1H), 1.14-1.05 (m, 3H), 0.99 (d, J=5.4 Hz, 3H). II-719 420.1 2.26 1H NMR (400 MHz,) δ 5.10 (s, 1H), 3.99 (s, 1H), 3.30 (dd, J=13.8, 3.2 Hz, 1H), 2.87 ( dt, J=13.1, 4.6 Hz, 1H), 2.24-2.08 (m, 2H), 1.52-1.39 (m, 1H), 1.15 (d, J= 6.9 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H). II-720 420.2 2.33 II-721 421.2 1.79 1H NMR (400 MHz, chloroform-d) δ 8.66 (s, 1H), 8.38 (d, J=9.1 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H ), 5.31 (s, 1H), 4.28 (d, J=13.6 Hz, 1H), 2.88 (d, J=12.8 Hz, 2H), 1.97 (t, J =14.8 Hz, 1H), 1.81 (s, 1H), 1.61 (q, J=12.8 Hz, 1H), 1.48 (dd, J=12.5, 7.0 Hz , 1H), 1.37 (dd, J=6.6, 3.7 Hz, 2H), 1.33 (d, J=6.6 Hz, 3H), 1.28-1.14 (m, 1H), 1.03 (d, J=6.2 Hz, 3H), 0.77 (d, J=7.6 Hz, 1H). II-722 453.3 2.54 II-723 453.3 2.54 II-724 435.1 2.12 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.27 (d, J=5.9 Hz, 1H ), 8.15 (d, J=2.6 Hz, 1H), 7.60 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.9 Hz, 1H), 6.79 (dd, J=6.0, 2.6 Hz, 1H), 3.96 (dddd, J=23.7, 14.7, 4.2, 2.0 Hz, 2H), 3, 05 (d, J=0.9 Hz, 3H), 3.03 (d, J=0.9 Hz, 3H), 2.65 (dd, J=12.9, 10.7 Hz, 1H), 2.49-2.45 (m, 1H), 2.02-1.89 (m, 1H), 1.78-1.66 (m, 1H), 1.21-1.09 (m, 1H ), 0.95 (d, J=6.5 Hz, 3H). II-725 435.2 2.12 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.47 (d, J=9.4 Hz, 1H), 8.27 (d, J=5.9 Hz, 1H ), 8.15 (d, J=2.6 Hz, 1H), 7.60 (d, J=9.4 Hz, 1H), 7.28 (t, J=53.9 Hz, 1H), 6.79 (dd, J=6.0, 2.6 Hz, 1H), 3.96 (dd, J=20.9, 13.7 Hz, 2H), 3.05 (s, 3H), 3 .03 (s, 3H), 2.70-2.59 (m, 2H), 2.37 (p, J=1.9 Hz, 1H), 1.93 (d, J=12.7 Hz, 1H), 1.80-1.67 (m, 1H), 1.14 (q, J=11.8 Hz, 1H), 0.95 (d, J=6.6 Hz, 3H). II-726 429.4 1.64 1H NMR (500 MHz, DMSO-d6) δ 8.63-8.54 (m, 2H), 8.41 (d, J=9.4 Hz, 1H), 8.26 (s, 1H), 8 .09 (s, 2H), 7.79 (d, J=9.4 Hz, 1H), 3.21 (tt, J=11.3, 4.7 Hz, 1H), 3.07-3, 01 (m, 6H), 3.07-2.91 (m, 1H), 1.94 (d, J=12.9 Hz, 1H), 1.69 (s, 1H), 1.16 (q , J=12.0 Hz, 1H), 0.94 (d, J=6.6 Hz, 3H). II-727 393.3 1.6 1H NMR (500 MHz, DMSO-d6) δ 8.61 (d, J=3.1 Hz, 2H), 8.42 (d, J=9.4 Hz, 1H), 8.40 (s, 1H ), 8.17 (d, J=1.3 Hz, 1H), 8.07 (s, 1H), 7.81 (d, J=9.4 Hz, 1H), 4.52 (s, 1H ), 4.49 (dt, J=13.5, 3.0 Hz, 1H), 3.52 (q, J=8.4, 7.5 Hz, 1H), 3.03 (td, J= 12.8, 12.4, 3.4 Hz, 1H), 2.88 (t, J=12.0 Hz, 1H), 2.76 (td, J=12.9, 12.3, 3, 2 Hz, 1H), 2.29 (dd, J=8.1, 4.8 Hz, 2H), 2.05 (dq, J=13.2, 4.1 Hz, 1H), 1.87- 1.77 (m, 1H), 1.68 (ddd, J=16.0, 7.6, 3.4 Hz, 1H), 1.61-1.44 (m, 1H). II-728 419.4 1.6 II-729 455.1 2.6 1H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J=9.4 Hz, 1H), 8.37 (d, J=2.7 Hz, 1H), 8.28 (d, J =2.2 Hz, 1H), 7.77 (d, J=4.7 Hz, 1H), 7.67 (d, J=9.4 Hz, 1H), 7.21 (t, J=53 ,8 Hz, 1H), 7.06 (t, J=6.2 Hz, 1H), 4.32-4.24 (m, 1H), 4.13-4.05 (m, 1H), 3 .00-2.84 (m, 6H), 2.67 (dd, J=12.9, 10.3 Hz, 1H), 1.88-1.78 (m, 1H), 1.79-1 .65 (m, 2H), 1.58-1.44 (m, 1H), 1.29-1.18 (m, 1H). II-730 471.2 2.72 1H NMR (500 MHz, DMSO-d6) δ 8.47 (d, J=9.4 Hz, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 7.62 (d , J=9.4 Hz, 1H), 7.29-7.01 (m, 3H), 4.36-4.27 (m, 1H), 4.18-4.09 (m, 1H), 2.97-2.85 (m, 6H), 2.71-2.62 (m, 1H), 1.87-1.79 (m, 1H), 1.75-1.60 (m, 2H ), 1.51-1.40 (m, 1H), 1.28-1.19 (m, 1H). II-764 458.90 1.477 1H NMR (400 MHz, chloroform-d) d 8.65 (d, J=1.1 Hz, 1H), 8.47 (s, 1H), 8.19 (s, 1H), 7.86 (d , J=9.6 Hz, 1H), 6.52 (d, J=9.6 Hz, 1H), 5.53 (dddd, J=56.7, 9.4, 6.1, 3.4 Hz, 1H), 4.64-4.27 (m, 4H), 3.43-3.29 (m, 1H), 3.11-3.04 (m, 6H), 2.76 (t, J=11.7 Hz, 2H), 2.44 (t, J=12.3 Hz, 2H), 2.08 (d, J=12.9 Hz, 2H), 1.31 (q, J= 12.0 Hz, 1H), 1.03 (d, J=6.6 Hz, 3H). Spectra

Table 6: Analysis data for compounds of formula III

[001474] The purity and retention time of the compounds of the present invention were determined using HPLC.

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, pH9). Duration of the study is 5 minutes.

III- LCMS_Plus LCMS_RT NMR III-1 374.1 1.96 1H NMR (500 MHz, DMSO-d6) δ 9.54 (d, J=7.2 Hz, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.80 (d , J=1.1 Hz, 1H), 7.55 (d, J=7.2 Hz, 1H), 7.35-7.07 (m, 1H), 3.90-3.61 (m, 8H), 2.08 (s, 3H). III-2 438.2 2.28 1H NMR (500 MHz, DMSO-d6) δ 9.56 (d, J=7.2 Hz, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 7.80 (d , J=1.1 Hz, 1H), 7.58 (d, J=7.2 Hz, 1H), 7.35-7.00 (m, 2H), 4.67-4.25 (m, 2H), 3.21 (t, J=12.3 Hz, 1H), 3.06-2.81 (m, 6H), 1.96-1.79 (m, 2H), 1.75 (dh , J=10.1, 5.8, 5.3 Hz, 1H), 1.61-1.44 (m, 1H), 1.43-1.28 (m, 1H). III-3 378.1 1.91 1H NMR (500 MHz, DMSO) δ 9.62 (d, J=7.1 Hz, 1H), 9.01 (s, 1H), 8.60 (d, J=1.0 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 7.68-7.66 (m, 2H), 3.88-3.85 (m, 4H), 3.31-3.27 ( m, 2H), 2.60-2.58 (m, 2H). III-4 440.2 2.06 1H NMR (500 MHz, DMSO-d6) δ 9.58 (d, J=7.2 Hz, 1H), 9.08 (s, 1H), 8.79 (d, J=0.9 Hz, 1H ), 7.81 (d, J=1.0 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.32 (t, J=6.3 Hz, 1H), 7.17 (t, J=54.0 Hz, 1H), 4.54 (s, 1H), 4.33 (s, 2H), 4.07 (ddd, J=11.6, 3.5, 1.5 Hz, 1H), 3.68-3.55 (m, 2H), 3.34-3.24 (m, 1H), 3.22-3.09 (m, 2H), 3.07 -2.97 (m, 1H), 2.97 (s, 3H). III-5 458.1 2.14 1H NMR (500 MHz, DMSO-d6) δ 10.03 (d, J=5.8 Hz, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.77 (d , J=1.1 Hz, 1H), 7.32 (t, J=52.5 Hz, 1H), 7.30 (t, J=6.3 Hz, 1H), 4.61-4.37 (m, 1H), 4.26 (s, 1H), 4.09-4.03 (m, 1H), 3.65-3.55 (m, 2H), 3.16 (m, 3H), 2.96 (s, 3H), 2.95-2.87 (m, 1H). III-6 439.1 2.29 1H NMR (500 MHz, DMSO-d6) δ 9.43 (d, J=7.2 Hz, 1H), 9.09 (s, 1H), 8.23-8.18 (m, 1H), 7 .61 (s, 1H), 7.56 (d, J=5.3 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.26-7.01 (m, 2H), 4.38-4.26 (m, 1H), 4.18-4.07 (m, 1H), 4.02 (ddd, J=11.5, 3.5, 1.6 Hz, 1H), 3.69-3.55 (m, 2H), 3.14 (td, J=6.1, 2.2 Hz, 2H), 3.02-2.88 (m, 4H), 2 .72-2.59 (m, 1H). III-7 487.2 2.86 1H NMR (500 MHz, DMSO-d6) δ 9.43 (d, J=7.2 Hz, 1H), 9.07 (s, 1H), 8.25-8.19 (m, 1H), 7 .67 (s, 1H), 7.52 (dd, J=5.3, 1.2 Hz, 1H), 7.42 (d, J=7.2 Hz, 1H), 7.28 (t, J=6.3 Hz, 1H), 7.13 (t, J=54.2 Hz, 1H), 4.79 (d, J=13.8 Hz, 1H), 4.43 (d, J= 13.5 Hz, 1H), 3.52-3.40 (m, 1H), 2.98 (s, 3H), 2.75 (td, J=12.8, 5.4 Hz, 2H), 2.26-2.04 (m, 3H), 1.19-0.92 (m, 3H). III-8 373.1 2.24 1H NMR (500 MHz, DMSO-d6) δ 9.42 (d, J=7.1 Hz, 1H), 9.10 (s, 1H), 8.19 (dd, J=5.3, 0, 7 Hz, 1H), 7.61 (s, 1H), 7.58-7.51 (m, 1H), 7.41 (d, J=7.2 Hz, 1H), 7.15 (t, J=54.2 Hz, 1H), 3.69-3.63 (m, 2H), 3.63-3.52 (m, 6H), 2.07 (s, 3H). III-9 391.1 2.45 1H NMR (500 MHz, DMSO) δ 9.55 (d, J=7.2 Hz, 1H), 9.18 (s, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.61 (d, J=7.3 Hz, 1H), 7.58 (s, 1H), 7.51 (dd, J=5.2, 1.3 Hz, 1H), 3.66-3 .64 (m, 2H), 3.60-3.55 (m, 6H), 2.07 (s, 3H). III-10 458 2.14 1H NMR (500 MHz, DMSO-d6) δ 10.01 (d, J=5.9 Hz, 1H), 9.00 (s, 1H), 8.71-8.62 (m, 1H), 7 .77 (d, J=1.1 Hz, 1H), 7.37 (d, J=52.5 Hz, 1H), 7.29 (t, J=6.3 Hz, 1H), 4.46 (s, 1H), 4.24 (s, 1H), 4.08-4.00 (m, 1H), 3.59 (dtt, J=15.2, 5.9, 2.7 Hz, 2H ), 3.22-3.08 (m, 3H), 2.96 (s, 3H), 2.95-2.84 (m, 1H). III-11 506.3 2.73 1H NMR (500 MHz, methanol-d4) δ 9.65 (d, J=5.3 Hz, 1H), 8.98 (s, 1H), 8.72 (d, J=0.9 Hz, 1H ), 7.97 (d, J=1.0 Hz, 1H), 7.17 (t, J=52.5 Hz, 1H), 3.62 (dd, J=14.0, 3.8 Hz , 1H), 3.36-3.30 (m, 1H), 3.26-3.19 (m, 2H), 3.18-3.05 (m, 1H), 3.03 (s, 3H ), 2.45-2.17 (m, 2H), 1.18 (d, J=6.7 Hz, 3H). III-12 488.3 2.62 1H NMR (500 MHz, DMSO-d6) δ 9.54 (d, J=7.2 Hz, 1H), 9.02 (s, 1H), 8.73 (s, 1H), 7.87 (s , 1H), 7.55 (d, J=7.2 Hz, 1H), 7.34 (dd, J=7.5, 5.4 Hz, 1H), 7.16 (t, J=54, 0 Hz, 1H), 5.03-4.69 (m, 1H), 4.69-4.38 (m, 1H), 3.05-2.87 (m, 7H), 2.34-2 .15 (m, 2H), 1.06 (d, J=6.7 Hz, 3H). III-13 502.4 2.78 1H NMR (500 MHz, DMSO-d6) δ 9.49 (d, J=7.2 Hz, 1H), 8.94 (s, 1H), 8.62 (d, J=1.1 Hz, 1H ), 7.87 (d, J=1.2 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.30 (dd, J=8.4, 4.2 Hz , 1H), 7.12 (s, 0H), 3.63 (dd, J=10.3, 6.2 Hz, 1H), 3.48 (d, J=13.2 Hz, 1H), 3 ,20-3.06 (m, 1H), 3.01 (s, 3H), 2.64 (p, J=1.8 Hz, 1H), 2.37 (p, J=1.8 Hz, 1H), 1.27 (t, J=6.9 Hz, 4H), 1.19 (d, J=6.9 Hz, 3H), 1.08 (d, J=6.7 Hz, 3H) . III-14 436.4 1.68 1H NMR (500 MHz, methanol-d4) δ 9.40 (d, J=7.2 Hz, 1H), 9.02 (s, 1H), 8.70 (d, J=0.8 Hz, 1H ), 7.93 (s, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.03 (t, J=54.3 Hz, 1H), 3.56 (tt, J =10.1, 4.5 Hz, 1H), 3.30 (s, 3H), 3.00 (s, 1H), 2.78 (s, 1H), 2.15 (dd, J=12, 9, 4.2 Hz, 1H), 1.88 (d, J=7.9 Hz, 1H), 1.46-1.34 (m, 1H), 1.31 (s, 1H), 1, 10 (d, J=6.6 Hz, 3H).

Example 75: N-(2-Hydroxyethyl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide, IV- 479

[001475] 3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (20 mg, 0.07 mmol), N-(2-hydroxyethyl)piperidine-3- carboxamide (11.5 mg, 0.07 mmol) and DIPEA (58 μl, 0.33 mmol) were mixed in NMP (1 ml). The reaction mixture was stirred at 85°C overnight, then diluted in DMSO and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give N-(2-hydroxyethyl) -1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide (28 mg, 95%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34-10.14 (m, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.69 (s, 1H) , 8.37 (d, J=6.3 Hz, 1H), 7.94 (t, J=5.6 Hz, 1H), 6.89 (d, J=6.4 Hz, 1H), 4 .65 (t, J=5.5 Hz, 1H), 4.42 (s, 2H), 3.40 (p, J=5.9 Hz, 2H), 3.23-2.97 (m, 4H), 2.45-2.31 (m, 1H), 1.90 (d, J=12.3 Hz, 1H), 1.76 (dtd, J=24.0, 12.2, 10, 9, 3.9 Hz, 2H), 1.48 (d, J=12.9 Hz, 1H); ES+ [M+H]= 436.4.

[001476] The following intermediates were prepared using a methodology similar to that described in Example 75:

Methyl 1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxylate;

6-(Difluoromethyl)-3-(4-(2,5-dimethyl-3-((methylsulfinyl)methyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine;

3-(4-Chloro-6-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine;

[001477] The following compounds were prepared using a methodology similar to that described in Example 75:

1-(4-(6-(Imidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one IV-2;

2-(1H-Pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-3;

4-(2-(6-Cyclopropylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)morpholine IV-4;

N-((1-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide IV-5;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)morpholine IV-6;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 10;

Trans-2-Methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-11;

Cis-2-Methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-12;

N-(((3S,5S)-4,4-Difluoro-5-methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl )piperidin-3-yl)methyl)methanesulfonamide IV-17;

3-(4-(2-(1H-Pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV-18;

4-(2-(6-Bromimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)morpholine IV-19;

4-(2-(6-Methylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)morpholine IV-20;

N-(((3S,5S)-1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5- methylpiperidin-3-yl)methyl)methanesulfonamide IV-21;

1-(4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-22;

(S)-N-((4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide IV- 23;

N-((1-(2-(6-Bromimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)methanesulfonamide IV-27;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)morpholine IV-28;

(S)-N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide IV- 29;

Imino(methyl)((1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-λ6-sulfanone IV -34;

1-(4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-35;

3-(4-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-36;

3-(4-(2-(1H-Pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-38;

4-(2-(Imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-(1H-pyrazol-4-yl)morpholine IV-39;

2-(1H-Pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV-40;

1-((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)urea IV-41;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-42;

N-(2-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethyl)methanesulfonamide IV-43;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-N-methylpiperidin-3-carboxamide IV-44;

3-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)propanamide IV-45;

N-((1-(4-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)-4,4-difluoro-5-methylpiperidin-3-yl) methyl)methanesulfonamide IV-46;

(S)-N-((4-(2-(6-Methylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methyl)methanesulfonamide IV-47;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide IV-48;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,4-diazepan-5-one IV-49;

(S)-1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-50;

3-(4-(3-(2H-Tetrazol-5-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-51;

6-(Difluoromethyl)-3-(4-(3-(pyridin-3-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-52;

3-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-53;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-carboxamide IV-54;

1-(6-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)piperidin-3-carboxamide IV-55;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-sulfonamide IV-56;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methylpiperidin-3-carboxamide IV-57;

3-(4-(3-(1H-Pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-58;

3-(4-(3-(1H-Pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-59;

(S)-1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-60;

N-(1-(4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide IV-61;

N-(1-(4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)ethyl)methanesulfonamide IV-62;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-carboxamide IV-63;

3-(4-(3-(1H-Pyrazol-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-64;

6-(Difluoromethyl)-3-(4-(3-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 65;

N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)methanesulfonamide IV-66;

3-(4-(3-(1H-Imidazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-67;

6-(Difluoromethyl)-3-(4-(3-(pyridin-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-68;

7-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-1-one IV-69;

N-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanesulfonamide IV-70;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-N-methylpyrrolidin-3-sulfonamide IV-71;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol IV-72;

6-(Difluoromethyl)-3-(4-(3-(oxetan-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-73;

6-(Difluoromethyl)-3-[4-[3-[(sulfamoylamino)methyl]-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyrazine IV-74;

3-[4-(6-Azaspiro[3,4]octan-6-yl)pyrimidin-2-yl]-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-75;

6-(Difluoromethyl)-3-(4-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-76;

6-(Difluoromethyl)-3-(4-(3-(pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-77;

1-(4-(2-(6-(1,1-Difluoroethyl))imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV -78;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)thiomorpholine-1-oxide IV-80;

(S)-4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methylmorpholine IV-81;

2-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetonitrile IV-82;

7-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo [4,3-a]pyrazin-3(2H)-one IV-83;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)thiomorpholine 1,1-dioxide IV-84;

(S)-6-(Difluoromethyl)-3-(4-(2-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-85;

8-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)- he IV-86;

8-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1-oxa-3,8-diazaspiro[4.6]undecan-2-one IV -87;

(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)azepan-3-yl)methanol IV-88;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-carboxamide IV-89;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-4-methylazepan-4-ol IV-90;

3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane IV-91;

2-(3-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-pyrazol-5- yl)ethan-1-ol IV-92;

(3-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-pyrazol-5-yl) methanol IV-93;

3-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-pyrazol-5-carboxamide IV- 94;

3-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-N-methyl-1H-pyrazol-5 -carboxamide IV-95;

6-(Difluoromethyl)-3-(4-(5-(3-methyl-1H-pyrazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)pyrimidin-2-yl)imidazo[1 ,2-a]pyrazine IV-96;

6-(Difluoromethyl)-3-(4-(3-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 97;

2-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one IV-98 ;

2-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydro-6H-pyrido[1,2-a]pyrazin-6-one IV- 99;

7-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydro-3H-oxazolo[3,4-a]pyrazin-3-one IV- 100;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,4-diazepan-1-sulfonamide IV-101;

6-(Difluoromethyl)-3-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-102;

6-(Difluoromethyl)-3-(4-(piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-103;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-104;

3-(4-(Azepan-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-105;

Cis-1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-6-methylpiperidin-3-carboxamide IV-106;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-4-methylpiperidin-3-carboxamide IV-108;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-carboxamide IV-109;

Cis-1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methylpiperidine-3-carboxylic acid IV-110;

(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol IV- 111;

6-(Difluoromethyl)-3-(4-(3-(5-methyl-1H-pyrazol-3-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 112;

3-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1-methyl-1H-pyrazol-5 -ol IV-113;

(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide IV-114;

2-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,2,3,4-tetrahydroisoquinoline IV-115;

2-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydro-1H-isoindol-5-ol IV-116;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,4-oxazepane-6-carboxamide IV-117;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,6-dimethylmorpholine IV-119;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-ol IV-120;

(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol IV-121;

6-(Difluoromethyl)-3-(4-((2S,6R)-2,6-dimethylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-122;

(R)-6-(Difluoromethyl)-3-(4-(3-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-129;

6-(Difluoromethyl)-3-(4-(octahydro-1H-cyclopenta[b]pyridin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-130;

3-(4-(Azepan-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-131;

tert-Butyl-6-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydro-1H-pyrrolo[2,3-c]pyridin-1 -carboxylate IV-132;

tert-Butyl-2-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate IV -133;

6-(Difluoromethyl)-3-(4-(2,3-dimethylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-134;

3-(4-(2-Azabicyclo[4.1.0]heptan-2-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-135;

(R)-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol IV-136;

(S)-6-(Difluoromethyl)-3-(4-(3-methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-137;

(R)-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol IV-138;

((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)dimethyl-λ6-sulfanone IV-141;

(S)-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol IV-142;

N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide IV-152;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-N-methylpiperidin-3-sulfonamide IV-164;

6-(Difluoromethyl)-3-(4-(3-(methylsulfonyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-165;

N-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-N-methylmethanesulfonamide IV-168;

N-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanesulfonamide IV-169;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-N,N-dimethylpiperidine-3-sulfonamide IV-170;

N-Cyclopentyl-1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-sulfonamide IV-171;

4-((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)sulfonyl)morpholine IV-172;

4-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)thiazole IV-174;

3-(6-(4-Acetylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-184;

3-(4-(3-Methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-187;

3-(4-(3-Methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 189;

3-(4-(4-Acetyl-1,4-diazepan-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-190;

3-(4-(2-Methyl-6-(1H-pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV-191;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine IV-192;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine IV-193;

3-(4-(2-Methyl-6-(1H-pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV-194;

1-(4-(2-(6-(1H-Pyrazol-3-yl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethane-1- he IV-203;

3-(6-(Piperidin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-204;

3-(6-(3-Methylpiperidin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-205;

Cis-6-Chloro-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 206;

Cis-3-(4-(2-Methyl-3-(1H-pyrazol-3-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-207;

Cis-3-(4-(3-Methyl-2-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-208;

3-(6-(6-Oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-210;

3-(4-(3-(1H-Pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-211;

3-(6-(4-Methylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-212;

Cis-3-Methyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-215;

Trans-3-Methyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-218;

3-(6-(4-Hydroxypiperidin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-219;

3-(6-(3-(Hydroxymethyl)piperidin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-220;

3-(6-(4-(Hydroxymethyl)piperidin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-221;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-222;

3-(6-(4-(2-Hydroxypropan-2-yl)piperidin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-226;

3-(6-(3-Oxohexahydroimidazo[1,5-a]pyrazin-7(1H)-yl)pyridin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-227;

(S)-3-(6-(6-Oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyridin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV -228;

Cis-4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-235 ;

Trans-4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-236 ;

3-(4-(4-Methylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-239;

3-(4-(2-(Hydroxymethyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-241;

3-(4-(3-(Hydroxymethyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-242;

3-(4-(4-(Hydroxymethyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-243;

3-(4-(4-Acetamidopiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-248;

3-(4-(3-Acetamidopiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-249;

3-(4-(3-(Methylsulfonamido)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-250;

3-(4-(3-(N-Methylsulfamoyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-251;

3-(4-(4-(N-Methylsulfamoyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-252;

3-(4-(3-Cyano-4-oxopiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-253;

3-(4-(4-Cyanopiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-254;

3-(4-(3-(1H-Imidazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-255;

3-(4-(6-Oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-257;

3-(4-(2-Cyanopiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-258;

1-(4-(6-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one IV-259;

3-(6-(4-Acetylpiperazin-1-yl)pyridin-2-yl)-N-methylimidazo[1,2-a]pyrazin-6-carboxamide IV-260;

3-(4-(2-Methylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-261;

3-(4-(5-Oxohexahydro-1H-pyrrolo[1,2-a][1,4]diazepin-2(3H)-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin- 6-carboxamide IV-262;

3-(4-(4-Oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-263;

3-(4-(2,3-Dimethylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-264;

3-(4-(Octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-265;

3-(4-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-266;

3-(4-(3-(N-Methylacetamido)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-267;

3-(4-(4-Oxahexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-268;

3-(4-(1-Oxa-8-azaspiro[4.5]decan-8-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-269;

3-(4-(6-Oxa-2-azaspiro[3,4]octan-2-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-270;

3-(4-(2,5-Dimethylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-271;

3-(4-(4-Acetyl-2-methylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-272;

3-(6-(4-Acetylpiperazin-1-yl)pyridin-2-yl)-N,N-dimethylimidazo[1,2-a]pyrazin-6-carboxamide IV-276;

3-(4-(4-(Cyclopropanecarbonyl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-277;

6-Chloro-3-(4-(2,5-dimethyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine (all-syn diastereoisomer) IV-278;

6-Bromo-3-(4-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine (completely syn-diastereoisomer) IV-279;

Cis-3-(4-(3-Methyl-2-(1H-pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carbonitrile IV-280;

Trans-3-(4-(3-Methyl-2-(1H-pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV-281;

3-(6-(4-(Cyclopropanecarbonyl)piperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-284;

1-(4-(2-(6-(Pyridin-4-yl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV -285;

2-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydro-6H-pyrido[1,2-a]pyrazin-6-one IV-286;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (fully syn-diastereoisomer) IV-304;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile (completely syn-diastereoisomer) IV-305;

Cis-4-(2-(6-Bromimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-306 ;

Trans-4-(2-(6-Bromimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-312 ;

5-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)isoxazole IV-317;

3-(4-(3-(1H-Imidazol-1-yl)-4-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-319 ;

3-(4-(3-(1H-Imidazol-1-yl)-4-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-320 ;

3-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1,2,4-oxadiazole IV- 321;

5-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1,2,4-oxadiazole IV- 322;

6-(Trifluoromethyl)-3-(4-(2,3,6-trimethyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-323;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-5-fluoropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine IV-324;

3-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-325;

3-(4-(3-(4H-1,2,4-Triazol-3-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-326;

3-(4-(3,3-Dimethyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-327;

3-(4-(5-Isopropyl-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyrazine (fully syn-diastereoisomer) IV-330;

3-(4-(3-(2H-Tetrazol-5-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-331;

N-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)formamide IV-332;

3-(4-(2-Methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 333;

4-(5-Fluoro-2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl) )morpholine IV-334;

4-(5-Fluoro-2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl) )morpholine IV-335;

3-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-340;

3-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV-341;

Cis-6-Bromo-3-(4-(3-methyl-2-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 342;

Cis-6-Bromo-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 343;

Cis-6-Bromo-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 344;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-345;

3-(4-(3-(1H-Pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-346;

3-(4-(3-(1H-Imidazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-chloroimidazo[1,2-a]pyrazine IV-347;

3-(4-(3-(1H-Imidazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-348;

3-(4-(3-(1H-Imidazol-4-yl)-2,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-chlorimidazo[1,2-a]pyrazine IV-349;

3-(4-(3-(1H-Imidazol-4-yl)-2,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV -352;

6-Chloro-3-(4-(3,3-dimethyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 353;

6-Bromo-3-(4-(3,3-dimethyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 354;

6-Bromo-3-(4-(3-(2-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-355;

6-Bromo-3-(4-(5-(2-methyl-1H-imidazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)pyrimidin-2-yl)imidazo[1,2 -a]pyrazine IV-356;

(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl) methanol IV-359;

3-(4-(3-(1H-Pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-371;

3-(4-(2-(1H-Imidazol-4-yl)-3,6-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine (fully syn- diastereoisomer) IV-372;

3-(4-(3-(1H-Imidazol-4-yl)-2,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine (fully syn- diastereoisomer) IV-373;

3-(4-(3-(2H-1,2,3-Triazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-378;

Cis-3-(4-(3-(1H-Imidazol-4-yl)-5-methylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV -379;

Cis-2-(1H-Imidazol-4-yl)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-380;

Trans-2-(1H-Imidazol-4-yl)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-381;

6-Chloro-3-(2-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyrazine IV- 382;

6-Bromo-3-(2-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyrazine IV- 383;

6-Bromo-3-(4-(3-(2-isopropyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-384;

6-Bromo-3-(4-(5-(2-isopropyl-1H-imidazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)pyrimidin-2-yl)imidazo[1,2 -a]pyrazine IV-385;

3-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-ol IV- 386;

Cis-6-Bromo-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 387;

3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 388;

3-(4-(3-(1H-Imidazol-4-yl)-2-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-389 ;

Trans-((5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3 -yl)imino)dimethyl-λ6-sulfanone IV-394;

Cis-((5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3 -yl)imino)dimethyl-λ6-sulfanone IV-395;

3-(4-(3-Methoxy-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 396;

3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-397;

6-Methyl-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-398;

3-(4-(3-(2-Chloro-1H-imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 409;

6-(1H-Pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-2-one IV- 410;

Cis-6-Cyclopropyl-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 411;

Cis-6-Cyclopropyl-3-(4-(3-methyl-2-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 412;

3,6-Dimethyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-415;

3,6-Dimethyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-416;

3-Methyl-2-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV- 417;

3-Methyl-2-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV- 418;

3-(2-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-5-fluoropyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine (fully syn-diastereoisomer) IV-421;

3-(5-Fluoro-2-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyrazine (all-syn diastereoisomer) IV-422;

3-(4-(Piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-423;

3-(4-(3-Methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-424;

4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,4-oxazepane-6-carboxamide IV-425;

4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-426;

4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,4-oxazepane IV-427;

3-(4-(Pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-428;

3-(4-(Azepan-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-429;

3-(4-(5-(3-Fluoro-1H-pyrazol-4-yl)-3,6-dihydropyridin-1(2H)-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyrazine IV-430;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)acetamide IV-432;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-ol IV-433;

(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methanol IV-434;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)ethan-1-ol IV-435;

(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-2-yl)methanol IV-436;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-ol IV-437;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-2-yl)ethan-1-ol IV-438;

(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanol IV-439;

(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-2-yl)methanol IV-440;

v

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-ol IV-441;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-yl)ethan-1-ol IV-442;

(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methanol IV-443;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethan-1-ol IV-444;

(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)azepan-3-yl)methanol IV-445;

(4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methanol IV-446;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)azepan-4-ol IV-447;

3-(4-(3-(5-Methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 452;

Cis-2-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-453;

6-(Difluoromethyl)-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 454;

6-(Difluoromethyl)-3-(4-(3-methyl-2-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 455;

3-(4-(3-(1H-Imidazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-456;

3-(4-(3-(1H-Pyrazol-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-457;

2,5-Dimethyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-464;

3-(4-(3-(Difluoromethoxy)-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-466;

3-(4-(3-(Difluoromethoxy)-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-472;

3-(4-(3-(5-Fluoro-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 473;

1-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine IV- 478;

7-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydroimidazo[1,5-a]pyrazin-3(2H)-one IV-480 ;

2,5-Dimethyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-481;

3-(4-(3-((Methylsulfonyl)methyl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-482;

3-(4-(3-(Methylsulfonyl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-483;

3-(2-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-484;

3-(2-(2-Methyl-3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 485;

4-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)piperazin-2-one IV-490;

3-(4-(3-(1H-1,2,3-Triazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-493;

3-(4-(3-(1H-Pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-494;

3-(4-(3-(Methoxymethyl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-495;

7-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-oxa-7-azaspiro[4.5]decane IV-496;

5-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydro-2H-furo[2,3-c]pyrrole IV-497;

2,2,2-Trifluoro-1-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethane- 1-amine IV-502;

2,2,2-Trifluoro-1-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)ethane- 1-amine IV-503;

8-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydropyrazino[2,1-c][1,4]oxazine IV-504;

2-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-9-oxa-2-azaspiro[5.5]undecane IV-505;

1-(tert-Butyl)-7-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydro-3H-oxazolo[3,4-a ]pyrazine IV-506;

3-(4-(3-(Tetrahydro-2H-pyran-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-507;

3-(4-(3-(Oxetan-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-508;

3-(4-(3-(Methoxymethyl)azepan-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-509;

4-((1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-yl)methyl)morpholine IV-510;

7-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-oxa-7-azaspiro[3.5]nonane IV-511;

3-(4-(4-(Methoxymethyl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-512;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-carbonitrile IV-513;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetonitrile IV-514;

(3aR,7aR)-5-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydro-3H-pyrrolo[3,4-c]pyridine -3-on IV-515;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carbonitrile IV-516;

3-(4-(4-Methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-517;

3-(4-(2-Methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-518;

3-(4-(2,3-Dimethylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-519;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)propan-2-ol IV-520;

(R)-1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-carbonitrile IV-521;

2-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-8-oxa-2-azaspiro[4.5]decane IV-522;

6-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-oxa-6-azaspiro[3.5]nonane IV-523;

3-(4-(3-(3-Fluoro-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 524;

2-(1H-Imidazol-4-yl)-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine (fully syn-diastereoisomer) IV-525;

N-((1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)acetamide IV-526;

1-((1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)urea IV-527;

N-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)acetamide IV-528;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide IV-529;

N-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)acetamide IV-530;

2,2-Dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-531;

3,3-Dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-532;

7-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-1-one IV-533;

7-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one IV-534;

4-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,2,5,6-tetrahydropyridin-3-yl)isothiazole IV-535;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-sulfonamide IV-536;

N-((1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)acetamide IV-537;

3-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-539;

7-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-1-one IV-542;

3-(4-(3-(1H-1,2,4-Triazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-547;

4-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,2,5,6-tetrahydropyridin-3-yl)- 1H-pyrazole-3-carbonitrile IV-548;

3-(4-(3-(Pyridin-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-550;

(4aS,7aS)-4-Methyl-6-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydropyrrolo[3,4-b][ 1,4]oxazin-3(2H)-one IV-551;

3-(4-(3-(Pyridin-2-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-552;

4-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine IV-553;

7-Methyl-2-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[4.5]decan-6-one IV -554;

3-(4-(3,4-Dimethylpyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-555;

3-(4-(3-Phenylpyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-556;

1-((1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)pyrrolidin-2-one IV- 557;

3-(4-(3-(1H-Pyrazol-4-yl)-5-(trifluoromethyl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-558;

3-(4-(3-(Phenoxymethyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-559;

7-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,3,7-triazaspiro[4.4]nonane-2,4-dione IV -560;

3-(4-(2-Benzylpyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-561;

3-(4-(3-(1H-Imidazol-1-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-564;

9-Methyl-2-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-6-oxa-2,9-diazaspiro[4.5]decane- 8-on IV-565;

2-(4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,4-diazepan-1-yl)acetamide IV-566;

3-(4-Chloro-6-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine (fully syn-diastereoisomer) IV-567;

8-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydro-2H-pyrazino[1,2-a]pyrazin-1(6H)- he IV-568;

5-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)hexahydro-2H-thieno[2,3-c]pyrrole 1,1-dioxide IV -570;

2-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydro-4H-pyrido[1,2-a]pyrazin-4-one IV- 571;

6-(Trifluoromethyl)-3-(4-(3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-572;

(4-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)-1H-pyrazol-3-yl) methanol IV-573;

3-(4-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-574;

3-(4-(3-(3-Methyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 575;

3-(4-(3-(3-Cyclopropyl-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 576;

3-(6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrazin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (fully syn-diastereoisomer) IV-577;

6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-N-methyl-2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3 -yl)pyrimidin-4-amine IV-578;

3-Methyl-7-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1-oxa-3,7-diazaspiro[4.4]nonan- 2-on IV-579;

3-(4-(3-(Tetrahydrofuran-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-580;

3-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-carboxamide IV-581;

5,5-Difluoro-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-582;

3-(6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyridin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (fully syn-diastereoisomer) IV-583;

1-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imidazolidin-2-one IV-584;

3-(4-(4-Methylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-585;

2-(Methoxymethyl)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-586;

2-(Methoxymethyl)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-587;

2-(Methoxymethyl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-588;

3-(4-(3-(1H-Pyrazol-3-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-589;

(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl) dimethylphosphine oxide IV-590;

(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl) dimethylphosphine oxide IV-591;

(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl) dimethylphosphine oxide IV-592;

3-(4-(3-((Methylthio)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-594;

4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide IV-595;

1-Methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-2-carboxamide IV-596;

(S)-3-(4-(2-Methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-597;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-carboxamide IV-598;

4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine-2-carboxamide IV-599;

4-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)piperazin-2-one IV-602;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-yl)acetamide IV-605;

N-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)-1H-pyrazol-4-amine IV- 606;

3-(4-(3-(Tetrahydrofuran-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-608;

3-(4-(3-(Tetrahydrofuran-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-609;

6-(Trifluoromethyl)-3-(4-(2,2,4-trimethylpyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-610;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-carboxamide IV-611;

4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-carboxamide IV-612;

(5-Methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholin-2-yl)methanol IV-613;

3-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)propan-1-ol IV-616;

2-(4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol IV-617;

2-Hydroxy-1-(4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV -618;

2-Methyl-1-(4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propan-2-ol IV -619;

3-(4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)propanenitrile IV-620;

N-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-carboxamide IV-625;

1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-626;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-6-methylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine IV-627;

3-(4-(3-(3-(1-Methylcyclopropyl))-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyrazine IV-630;

6-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-631;

3-(4-(Azetidin-1-yl)-6-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl )imidazo[1,2-a]pyrazine (fully syn-diastereoisomer) IV-637;

3-(4-(3-(5-Methyl-1H-1,2,4-triazol-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-641;

3-(4-(3-(4H-1,2,4-Triazol-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-642;

6-(Trifluoromethyl)-3-(4-(2,3,5-trimethylpiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-643;

3-(4-(3-Cyclopentylpyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-644;

1-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)piperidin-4-ol IV-645;

3-(4-(3-(Pyridin-3-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-646;

1-Methyl-3-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)-1H-pyrazol-5 -ol IV-647;

6-(Trifluoromethyl)-3-(4-(3-(5-(trifluoromethyl)-1H-pyrazol-3-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-653;

3-(4-(3-(1-Methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-654;

3-(4-(3-(1-Methyl-1H-pyrazol-5-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 655;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1,3,4-oxadiazole IV- 656;

2-(4-Methyl-1H-pyrazol-3-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 657;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)isothiazolidine 1,1-dioxide IV-658;

3-(4-(3-(5-Cyclohexyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-659;

5-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1,2-dihydro-3H-1 ,2,4-triazol-3-one IV-660;

2-(5-Methyl-1H-1,2,4-triazol-3-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4 -yl)morpholine IV-661;

2-(1-Methyl-3-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H- pyrazol-5-yl)ethan-1-ol IV-662;

4-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)pyrrolidin-2-one IV-663;

6-(Trifluoromethyl)-3-(4-(3-(3-(trifluoromethyl)-1H-pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-664;

3-(4-(3-(1H-Pyrazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-665;

3-(4-(2,5-Dimethyl-3-(2-(trifluoromethyl)-1H-imidazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyrazine (all syn-diastereoisomer) IV-666;

Cis-3-(4-(3-Methyl-5-(1-methyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-667;

3-(4-(3-(1H-Pyrazol-4-yl)pyrrolidin-1-yl)-6-methylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-668 ;

Cis-3-(4-(3-Methyl-5-(1-methyl-1H-imidazol-5-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-672;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)thiazole IV-675;

5-(3,6-Dimethyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)pyridin-2( 1H)-one (fully syn-diastereoisomer) IV-676;

5-(3,6-Dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-2-yl)pyridin-2( 1H)-one (fully syn-diastereoisomer) IV-677;

5-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)oxazole IV-678;

3-(4-((8aS)-4-(1H-Pyrazol-4-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2-yl)-6-(trifluoromethyl) imidazo[1,2-a]pyrazine IV-679;

3-(4-(4-(1H-Pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-680;

3-(4-(3-(Azetidin-1-ylmethyl)-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-681;

2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)oxazole IV-686;

3-(4-(2,5-Dimethyl-3-(1-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine (fully syn-diastereoisomer) IV-687;

3-(6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-4-fluoropyridin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine (fully syn-diastereoisomer) IV-690;

5-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)thiazole IV-691;

Dimethyl(6-methyl-5-(1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidine -3-yl)phosphine oxide IV-693;

4-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)oxazole IV-694;

Dimethyl(6-methyl-5-(1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidine -3-yl)phosphine oxide IV-697;

3-(4-(4-Acetyl-3,3-dimethylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-699.

The following compounds were prepared using a methodology similar to that described in Example 1 and were further purified using chiral SFC:

2-(1H-Pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-7;

2-(1H-Pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-8;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-9;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 13;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 14;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 15;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 16;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1,4-oxazepane-6-carboxamide IV-128;

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-sulfonamide IV-177;

2-(1H-Pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV-185;

2-(1H-Pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV-186;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV- 199;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV- 200;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV- 201;

2-Methyl-6-(1H-pyrazol-4-yl)-4-(4-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-2-yl)morpholine IV- 202;

6-Chloro-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-213;

6-Chloro-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-214;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine IV-216;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methyl-6-(1H-pyrazol-4-yl)morpholine IV-217;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-223;

3-(4-((2S,3R,5S)-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo [1,2-a]pyrazine IV-224;

6-Chloro-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-229;

6-Chloro-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-230;

3-(4-(3-(1H-Pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-231;

3-(4-(3-(1H-Pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-232;

3-(4-(3-(1H-Pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-chloroimidazo[1,2-a]pyrazine IV-237;

3-(4-(3-(1H-Pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-chloroimidazo[1,2-a]pyrazine IV-238;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-244;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-245;

6-Chloro-3-(4-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 246;

6-Chloro-3-(4-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 247;

3-(4-(6-Oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-273;

3-(4-(6-Oxooctahydro-2H-pyrido[1,2-a]pyrazin-2-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide IV-274;

6-Chloro-3-(4-(2,5-dimethyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-282;

6-Chloro-3-(4-(2,5-dimethyl-3-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-283;

6-Bromo-3-(4-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 287;

6-Bromo-3-(4-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 288;

3-(4-(3-Methyl-2-(1H-pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV-290;

3-(4-(3-Methyl-2-(1H-pyrazol-4-yl)morpholino)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV-291;

2-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydro-6H-pyrido[1,2-a]pyrazin-6-one IV-293;

2-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)octahydro-6H-pyrido[1,2-a]pyrazin-6-one IV-294;

3-(4-(4-Ethyl-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-295;

3-(4-(4-Ethyl-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-296;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV- 313;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-carbonitrile IV- 314;

3-Methyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 315;

4-(2-(6-Chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-316;

3-Methyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 318;

4-(2-(6-Bromimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-328;

4-(2-(6-Bromimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3-methyl-2-(1H-pyrazol-4-yl)morpholine IV-329;

6-(Trifluoromethyl)-3-(4-(2,3,6-trimethyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-336;

6-(Trifluoromethyl)-3-(4-(2,3,6-trimethyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-337;

((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone IV-338;

((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino)(methyl)-λ6- sulfanone IV-339;

6-Bromo-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-350;

6-Bromo-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-351;

3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 357;

3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 358;

3-(4-(3-(1H-Pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-360;

3-(4-(3-(1H-Pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-361;

3-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-362;

3-(4-(3-(1H-Imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-363;

6-Bromo-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-364;

6-Bromo-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-365;

3-(2-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (fully syn-diastereoisomer) IV-369;

3-(2-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (fully syn-diastereoisomer) IV-370;

6-Bromo-3-(4-(3-(2-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-374;

6-Bromo-3-(4-(3-(2-methyl-1H-imidazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-375;

3-(4-(3-(1H-Imidazol-4-yl)-2,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-376;

3-(4-(3-(1H-Imidazol-4-yl)-2,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-bromimidazo[1,2-a]pyrazine IV-377;

((5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl )imino)dimethyl-λ6-sulfanone IV-399;

((5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl )imino)dimethyl-λ6-sulfanone IV-400;

6-Bromo-3-(2-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyrazine IV- 403;

6-Bromo-3-(2-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyrazine IV- 404;

2-(1H-Imidazol-4-yl)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 405;

2-(1H-Imidazol-4-yl)-6-methyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 406;

6-Chloro-3-(2-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyrazine IV- 407;

6-Chloro-3-(2-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-4-yl)imidazo[1,2-a]pyrazine IV- 408;

6-Bromo-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-413;

6-Bromo-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-414;

3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 419;

3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 420;

3,6-Dimethyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-450;

3,6-Dimethyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-451;

3-(4-(3-Methyl-5-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyrazine IV-458;

3-(4-(3-Methyl-5-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyrazine IV-459;

3-(4-(3-Methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 460;

3-(4-(3-Methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 461;

6-(Difluoromethyl)-3-(4-(3-methyl-5-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-462;

6-(Difluoromethyl)-3-(4-(3-methyl-5-(5-methyl-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-463;

3-(4-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)-5-methylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine IV-465;

3-(4-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)-5-methylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine IV-467;

6-(Difluoromethyl)-3-(4-(3-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 468;

6-(Difluoromethyl)-3-(4-(3-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV- 469;

3-(4-(3-(5-Methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 470;

3-(4-(3-(5-Methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 471;

3-(4-(3-Methyl-5-(5-(trifluoromethyl)-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-474;

3-(4-(3-Methyl-5-(5-(trifluoromethyl)-1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-475;

3-(4-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-476;

3-(4-(3-(3,5-Dimethyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-477;

3-(4-(3-(3-Fluoro-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 491;

3-(4-(3-(3-Fluoro-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 492;

2-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-498;

2-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-499;

2,5-Dimethyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-500;

2,5-Dimethyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-carboxamide IV-501;

3-(4-(3-(1H-Imidazol-5-yl)-2,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV -538;

3-(4-(3-(1H-Pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine I -540;

3-(4-(3-(1H-Pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-541;

3-(4-(3-(Tetrahydrofuran-3-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-543;

3-(4-(3-(Tetrahydrofuran-3-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-544;

3-(4-(3-(1H-Pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-545;

3-(4-(3-(1H-Pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-546;

3-(4-(3-(1H-Imidazol-5-yl)-2,5-dimethylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV -549;

3-(4-(3-(3-Fluoro-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 562;

3-(4-(3-(3-Fluoro-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV- 563;

4-(4-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)morpholine IV-569;

3-(4-(3-(1H-1,2,3-Triazol-1-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-600;

2-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-carboxamide IV-614;

2-Methyl-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-carboxamide IV-615;

3-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-ol IV- 621;

3-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-ol IV- 622;

3-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-ol IV- 623;

3-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-4-ol IV- 624;

6-(Trifluoromethyl)-3-(4-(3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-628;

6-(Trifluoromethyl)-3-(4-(3-(3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-629;

(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl) dimethylphosphine oxide IV-632;

(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl) dimethylphosphine oxide IV-633;

2-(1H-Imidazol-4-yl)-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-638;

2-(1H-Imidazol-4-yl)-3,6-dimethyl-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV-639;

3-(6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrazin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-649;

3-(6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrazin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-650;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-6-methylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine IV-669;

3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-6-methylpyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine IV-670;

3-(4-(2,5-Dimethyl-3-(2-(trifluoromethyl)-1H-imidazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyrazine IV-673;

3-(4-(2,5-Dimethyl-3-(2-(trifluoromethyl)-1H-imidazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyrazine IV-674;

2-(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3- yl)propan-2-ol IV-682;

2-(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3- yl)propan-2-ol IV-683;

2-(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3- yl)propan-2-ol IV-684;

2-(5-(1H-Pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3- yl)propan-2-ol IV-685;

Example 76: 3-(4-(2,7-Diazaspiro[3.5]nonan-7-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine, IV-692

Step 1: tert-Butyl 7-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2- carboxylate

[001478] 3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (125 mg, 0.41 mmol) was dissolved in DMF (3 ml) and t-butyl was added -2,7-diazaspiro[3.5]nonane-2-carboxylate (190 mg, 0.84 mmol) and DIPEA (450 μl, 2.58 mmol). The reaction mixture was heated at 80°C for 1 hour, then the reaction mixture was cooled, water was added and the reaction mixture was stirred for 15 minutes. The resulting precipitate was filtered and tert-butyl 7-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan- 2-carboxylate (181 mg, 89%) as a pale yellow solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.70 (d, J=0.8 Hz , 1H), 8.38 (d, J=6.3 Hz, 1H), 6.90 (d, J=6.4 Hz, 1H), 3.65 (br s, 8H), 1.78 ( t, J=5.6 Hz, 4H), 1.40 (s, 9H); ES+ [M+H]= 490.0.

Step 2: 3-(4-(2,7-Diazaspiro[3.5]nonan-7-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

[001479] tert-Butyl 7-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2- carboxylate (181 mg, 0.37 mmol) was dissolved in DCM (5 ml) and TFA (1 ml, 13.0 mmol) was added. The reaction mixture was stirred at ambient temperature overnight. The mixture was passed through an SCX-2 cartridge, washed with methanol and then the product was eluted with 2 M methanol ammonia and after drying, 3-(4-(2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-2-yl)- 6-(trifluoromethyl)imidazo[1,2-a]pyrazine (143 mg, 99%); 1H NMR (500 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.37 (d, J=6.4 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 3.31(br s, 4H) 3.68 (d, J=18.7 Hz, 4H), 1.80 ( t, J=5.7 Hz, 4H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) -65.84 (d, J=7.1 Hz); ES+ [M+H]= 390.1.

[001480] The following compounds were prepared using a methodology similar to that described in Example 76:

1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)azepan-4-amine IV-118;

4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1-methyl-1,4,9-triazaspiro[5.5]undecane IV-123 ;

(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)(piperazin-1-yl)methanone IV-139;

2-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane IV-140;

(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methanamine IV-143;

2-Amino-N-(3-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)acetamide IV-167;

3-(6-(4-Methylpiperazin-1-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-212;

6-Chloro-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-213;

6-Chloro-3-(4-(3-methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-214;

3-Methyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)morpholine IV- 218;

3-(4-(3-Aminopiperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-256;

3-(4-(3-(Azetidin-3-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-696;

Example 77: 3-(4-(7-(Methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine , IV-698

Step 1: tert-Butyl-2-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7 -carboxylate

[001481] DIPEA (450 μl, 2.58 mmol) was added to a solution of 3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (125 mg, 0.417 mmol) and tert-butyl-2,7-diazaspiro[3.5]nonane-7-carboxylate (hydrochloride) (160 mg, 0.609 mmol) in DMF (3 ml). The reaction mixture was heated at 80°C for 1 hour, then cooled, water was added and the resulting precipitate was filtered and dried to obtain tert-butyl-2-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin- 3-yl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (187 mg, 91%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.36 (d, J=1.2 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.64 (s , 1H), 8.36 (d, J=6.0 Hz, 1H), 6.41 (d, J=6.0 Hz, 1H), 3.91 (s, 2H), 3.34 (s , 2H), 1.76 (t, J=5.5 Hz, 4H), 1.42 (s, 9H), 1.41-1.37 (m, 2H), 1.26 (q, J= 7.2 Hz, 2H); ES+ [M+H] = 490.1.

Step 2: 3-(4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

[001482] To a solution of tert-butyl-2-[2-[6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]-2,7-diazaspiro[3.5]nonane -7-carboxylate (187 mg, 0.38 mmol) in DCM (5 ml) was added TFA (1 ml, 13.0 mmol). The mixture was stirred at ambient temperature overnight, then passed through an SCX-2 cartridge, and the product was eluted with 2 M methanolic ammonia. The ammonia wash solutions were concentrated in vacuo to give 3-(4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine ( 73.4 mg, 47%); ES+ [M+H] = 390.0

Step 3: 3-(4-(7-(Methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

[001483] 3-[4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (20 mg, 0.048 mmol ) and DIPEA (26 µl, 0.15 mmol) were mixed in DCM (1 ml) and methanesulfonyl chloride (4 µl, 0.052 mmol) was added. The reaction mixture was stirred at ambient temperature overnight, then the reaction was stopped with saturated aqueous NaHCO ₃ solution, diluted with DCM and the layers were separated. The aqueous layer was extracted with DCM (×3) and the combined organics were passed through a phase separation cartridge and concentrated in vacuo. Purification by column chromatography (silica, eluting with 0-15% MeOH in DCM gradient) gave 3-(4-(7-(methylsulfonyl)-2,7-diazaspiro[3.5]nonan-2-yl )pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (12.4 mg, 54%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.35 (dt, J=1.5, 0.8 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8 .64 (s, 1H), 8.38 (d, J=5.9 Hz, 1H), 6.41 (d, J=6.0 Hz, 1H), 3.93 (s, 4H), 3 .15 (s, 4H), 2.89 (s, 3H), 1.92 (t, J=5.5 Hz, 4H); ES+ [M+H]= 468.0.

[001484] The following compounds were prepared using a methodology similar to that described in Example 77:

(S)-N-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)-N-methylmethanesulfonamide IV- 125;

6-(Difluoromethyl)-3-(4-(8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV -126;

N-(1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl)methanesulfonamide IV-127;

6-(Difluoromethyl)-3-(4-(1-(methylsulfonyl)octahydro-6H-pyrrolo[2,3-c]pyridin-6-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-144.

Example 78: N-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)azepan-4-yl)methanesulfonamide, IV-124

[001485] 1-[2-[6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]azepan-4-amine trifluoroacetate (20 mg, 0.0312 mmol) was dissolved in DCM (1 ml). DIPEA (20.3 mg, 27 µl, 0.16 mmol) was added, then methanesulfonyl chloride (5 µl, 0.0628 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 2 hours, then the solvents were removed and the residue was immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give N-(1-(2 -(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)azepan-4-yl)methanesulfonamide (4.4 mg, 32%); ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.94 (d, J=7.5 Hz, 1H), 9.37-9.32 (m, 1H), 8.81 (s, 1H) , 8.30 (d, J=7.4 Hz, 1H), 7.07-6.96 (m, 2H), 4.16 (s, 1H), 3.97 (s, 1H), 3, 84 (s, 2H), 3.63 (s, 1H), 2.98 (s, 3H), 2.68 (s, 1H), 2.40 (s, 1H), 2.18 (s, 1H ), 2.07 (s, 2H), 2.04 (s, 1H), 1.86-1.75 (m, 1H); ES+ [M+H]= 438.6.

[001486] The following compounds were prepared using a methodology similar to that described in Example 78:

2-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-8-(methylsulfonyl)-2,8-diazaspiro[4.5]decane IV-145 ;

6-(Difluoromethyl)-3-(4-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-151 ;

N-((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)methanesulfonamide IV-152;

N-(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)-2-(methylsulfonamido)acetamide IV-173.

Example 79: 1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxamide, IV-107

[001487] Solution of methyl 1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxylate (42 mg, 0 .10 mmol) and ammonium hydroxide (610 mg, 678 µl, 5.22 mmol) in NMP (0.2 ml) were stirred in a sealed tube at 100°C for 3 days. The mixture was filtered, diluted with DMSO and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give 1-(2-(6-(difluoromethyl)imidazo[1,2 -a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxamide (0.6 mg, 1%); ES+ [M+H]= 388.3.

Example 80: 3-(4-(3-((Methylsulfinyl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine and 3-(4- (3-((methylsulfonyl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine, IV-603 and IV-604

[001488] 3-(4-(3-((Methylthio)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (40 mg, 0. 10 mmol) was dissolved in DCM (3 ml) and the solution was cooled to 0°C. m-CPBA (28 mg, 0.11 mmol) was added in portions over 5 min and the reaction was quenched with sodium thiosulfate (2 mL) immediately after addition was complete. After stirring for 5 minutes, the mixture was diluted with DCM (20 ml), the layers were separated and the aqueous layer was extracted with DCM (2×20 ml). The combined organics were filtered through a hydrophobic frit and concentrated in vacuo. Purification by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide eluent) gave: 3-(4-(3-((methylsulfinyl)methyl)pyrrolidin-1-yl)pyrimidin-2- yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (24 mg, 58%) as a white solid; ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.40 (s, 1H), 9.10 (dd, J=1.4, 0.8 Hz, 1H), 8.56 (d, J= 1.7 Hz, 1H), 8.19 (d, J=6.2 Hz, 1H), 6.38 (dd, J=6.2, 4.5 Hz, 1H), 3.98 (d, J=91.0 Hz, 1H), 3.71 (s, 1H), 3.45 (s, 2H), 2.95 (d, J=6.4 Hz, 2H), 2.82 (s, 1H), 2.63 (s, 3H), 2.35 (s, 1H), 1.92 (s, 1H); ES+ [M+H]= 411.0; and 3-(4-(3-((methylsulfonyl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (4 mg, 9%) in as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.36 (d, J=30.4 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.66 (d , J=12.8 Hz, 1H), 8.36 (d, J=6.0 Hz, 1H), 6.50 (d, J=7.9 Hz, 1H), 3.96 (d, J =82.8 Hz, 1H), 3.79-3.60 (m, 1H), 3.57 (s, 1H), 3.51-3.36 (m, 2H), 3.32-3, 24 (m, 1H), 3.06 (s, 3H), 2.87 (s, 1H), 2.33 (s, 1H), 1.92 (d, J=12.3 Hz, 1H); ES+ [M+H]= 427.1.

Example 81: Imino(methyl)((1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-λ6 -sulfanone, IV-607

[001489] 3-(4-(3-((Methylsulfinyl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (16 mg, 0.039 mmol ), ammonium carbamate (13 mg, 0.17 mmol) and (diacetoxyiodo)benzene (38 mg, 0.12 mmol) were dissolved in methanol (400 μL) and DCM (100 μL). The reaction mixture was stirred at ambient temperature in an open flask for 1 hour. The crude mixture was purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give imino(methyl)((1 -(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)-λ6-sulfanone (9 mg, 52%) in as a white solid; ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.47 (s, 1H), 9.20 (d, J=1.3 Hz, 1H), 8.68-8.63 (m, 1H) , 8.29 (d, J=6.1 Hz, 1H), 6.50-6.44 (m, 1H), 4.88-4.79 (m, 1H), 4.10 (d, J =111.6 Hz, 1H), 3.88 (s, 1H), 3.70 (s, 1H), 3.65 (s, 1H), 3.54 (s, 2H), 3.14 (s , 3H), 3.02 (s, 1H), 2.48 (s, 1H), 2.04 (dd, J=17.6, 9.7 Hz, 1H); ES+ [M+H]= 426.1.

Example 82: ((1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)( imino)(methyl)-λ6-sulfanone, IV-366, IV-367 and IV-368

[001490] 6-(Difluoromethyl)-3-(4-(2,5-dimethyl-3-((methylsulfinyl)methyl)piperidin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine (130 mg, 0.30 mmol), ammonium carbamate (94 mg, 1.20 mmol) and (diacetoxyiodo)benzene (293 mg, 0.91 mmol) were dissolved in MeOH (600 μl). The reaction mixture was stirred at ambient temperature in an open flask for 1 hour. The crude mixture was diluted with DMSO and purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent). Additional purification with SFC gave:

((1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)( methyl)-λ6-sulfanone IV-366 (7.5 mg, 5%); ES+ [M+H]= 450.1.

[((1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino) (methyl)-λ6-sulfanone IV-367 (8.5 mg, 6%); ES+ [M+H]= 450.1.

((1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-2,5-dimethylpiperidin-3-yl)methyl)(imino)( methyl)-λ6-sulfanone IV-368 (11.9 mg, 8%); ES+ [M+H]= 450.1.

Example 83: (3-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)benzyl)(imino)(methyl)-λ6-sulfanone, IV- 79

[001491] (Diacetoxyiodo)benzene (51.4 mg, 0.16 mmol) was added to a solution of 6-(difluoromethyl)-3-(4-(3-((methylsulfinyl)methyl)phenyl)pyrimidin-2-yl)imidazo [1,2-a]pyrazine (41 mg, 0.11 mmol), MgO (17.2 mg, 0.43 mmol), diacetoxyrhodium (1.2 mg, 0.005 mmol) in DCM (3 ml). 2,2,2-Trifluoroacetamide (24.1 mg, 0.21 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. After additional addition of MgO (17.2 mg, 0.43 mmol), diacetoxyrhodium (1.2 mg, 0.005 mmol), (diacetoxyiodo)benzene (51.4 mg, 0.16 mmol) and 2,2,2-trifluoroacetamide (24.1 mg, 0.21 mmol), the reaction mixture was kept at ambient temperature for an additional 18 h, then filtered and concentrated in vacuo. The mixture was purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) and the trifluoroacetamide protecting group was removed by soaking in a basic solvent to give (3-(2-(6-(difluoromethyl) imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)benzyl)(imino)(methyl)-λ6-sulfanone (0.6 mg, 1%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.15 (d, J=1.5 Hz, 1H), 9.41 (d, J=1.3 Hz, 1H), 9.14 (d , J=5.3 Hz, 1H), 8.90 (s, 1H), 8.86 (t, J=1.8 Hz, 1H), 8.61 (dt, J=7.9, 1, 4 Hz, 1H), 8.22-8.15 (m, 2H), 7.88 (t, J=7.8 Hz, 1H), 7.29 (t, J=54.2 Hz, 1H) , 6.32 (s, 2H), 3.22 (d, J=1.1 Hz, 3H); ES+ [M+H]= 401.3.

Example 84: 1-(4-(2-(6-(3-(Hydroxymethyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethane- 1-on, IV-308

[001492] 1-(4-(2-(6-Bromimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one (15 mg, 0 .04 mmol), tetrakis(triphenylphosphine) palladium(0) (2.2 mg, 0.002 mmol), aqueous solution of Na ₂ CO ₃ (28 μl 2 M, 0.06 mmol) and [3-(hydroxymethyl)phenyl]boronic acid (6.8 mg, 0.04 mmol) was combined in NMP (1 ml) and heated at 140°C for 2 h in a microwave oven. The mixture was diluted with DMSO (2 ml) and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give 1-(4-(2-(6-(1- methyl-1H-imidazol-5-yl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one as an almost white solid (4, 7 mg, 29%); ¹ H NMR (400 MHz, methanol-d ₄ ) δ 10.15 (d, J=1.4 Hz, 1H), 9.16 (d, J=1.4 Hz, 1H), 8.54 (s , 1H), 8.34 (d, J=6.2 Hz, 1H), 7.97 (s, 1H), 7.89 (dt, J=7.7, 1.5 Hz, 1H), 7 .50 (t, J=7.6 Hz, 1H), 7.43 (dt, J=7.7, 1.4 Hz, 1H), 6.63 (d, J=6.3 Hz, 1H) , 3.91 (t, J=5.2 Hz, 2H), 3.83-3.71 (m, 7H), 3.33 (p, J=1.6 Hz, 2H), 2.20 ( s, 3H); ES+ [M+H]= 430.0

[001493] The following intermediates were prepared using a methodology similar to that described in Example 84:

3-(4-(Methylthio)pyrimidin-2-yl)-6-(pyridin-4-yl)imidazo[1,2-a]pyrazine;

3-(4-(Methylthio)pyrimidin-2-yl)-6-(1H-pyrazol-3-yl)imidazo[1,2-a]pyrazine;

tert-Butyl-4-(3-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)benzoyl)piperazine-1-carboxylate;

tert-butyl-4-(6-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyridin-2-yl)piperazin-1-carboxylate.

The following compounds were prepared using a methodology similar to that described in Example 84:

1-(4-(2-(6-Vinylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-37;

N-(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)benzyl)methanesulfonamide IV-146;

N-(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)methanesulfonamide IV-147;

((3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)sulfonyl)methanamine IV-148;

6-(Difluoromethyl)-3-(4-(3-((4-methylpiperazin-1-yl)methyl)phenyl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-166;

1-(4-(2-(6-(Pyridin-3-yl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV -289;

1-(4-(2-(6-Phenylimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-297;

N-(4-(3-(4-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-yl)phenyl)acetamide IV-298;

1-(4-(2-(6-(3-Ethoxyphenyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-299 ;

1-(4-(2-(6-(3-Methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl) ethan-1-one IV-300;

2-(3-(4-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-yl)benzonitrile IV-301;

1-(4-(2-(6-(4-(Hydroxymethyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-302;

4-(3-(4-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazin-6-yl)benzamide IV-303;

1-(4-(2-(6-(1,3-Dimethyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1- yl)ethan-1-one IV-307;

1-(4-(2-(6-(3-Hydroxyphenyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-one IV-309 ;

2-(4-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol IV- 431;

3-(4-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV -448;

3-(4-(1-(Tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine IV-449.

Example 85: (3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)(piperazin-1-yl)methanone, IV-150

[001494] tert-Butyl-4-(3-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)benzoyl)piperazine-1-carboxylate (20 mg, 0.037 mmol) was dissolved in DCM (1 ml) and TFA (0.1 ml) was added. After stirring at ambient temperature for 3 hours, the reaction mixture was concentrated in vacuo to give (3-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl )(piperazin-1-yl)methanone trifluoroacetate (2.2 mg, 11%); ES+ [M+H]= 436.3.

[001495] The following compound was prepared using a methodology similar to that described in Example 85:

6-(Difluoromethyl)-3-(4-(6-(piperazin-1-yl)pyridin-2-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-149.

Example 86: Cis-6-Bromo-3-(4-(4-ethyl-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1, 2-a]pyrazine, IV-390

[001496] 6-Bromo-3-(4-(2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1. 2-a]pyrazine (20 mg, 0.045 mmol), acetaldehyde (20 µl, 0.36 mmol) and AcOH (5 µl, 0.09 mmol) in THF (0.5 ml). The reaction mixture was stirred at ambient temperature for 10 minutes, then Na(OAc) ₃ BH (238 mg, 1.12 mmol) was added. After 1 h, the reaction mixture was filtered, diluted with DMSO and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give 6-bromo-3-[4-[4 -ethyl-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]imidazo[1,2-a]pyrazine (7.9 mg, 37%); ES+ [M+H]= 470.3.

[001497] The following compounds were prepared using a methodology similar to that described in Example 86:

Cis-6-Bromo-3-(4-(4-ethyl-3-methyl-2-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-391;

Cis-6-Bromo-3-(4-(2,4-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-392;

Cis-6-Bromo-3-(4-(3,4-dimethyl-2-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-393.

[001498] The following compounds were prepared using a methodology similar to that described in Example 86 and were further purified using chiral SFC:

Cis-6-Bromo-3-(4-(4-ethyl-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-401;

Cis-6-Bromo-3-(4-(4-ethyl-2-methyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)imidazo[1,2-a ]pyrazine IV-402;

Example 87: 3-(6-(1H-Indol-6-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine, IV-1

[001499] 3-(6-Chloropyridin-2-yl)imidazo[1,2-a]pyrazine (35 mg, 0.152 mmol), 1H-indol-4-ylboronic acid (29.3 mg, 0.18 mmol) , tetrakis(triphenylphosphine)palladium(0) (8.8 mg, 0.008 mmol), 2 M aqueous Na ₂ CO ₃ (228 μl, 0.46 mmol) and dioxane (1 ml) were mixed and heated for 16 h at 90°C. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried (MgSO ₄ ) and concentrated in vacuo. Purification by reverse phase chromatography (C18; MeCN/water/0.05% TFA as eluent) gave 3-(6-(1H-indol-6-yl)pyridin-2-yl)imidazo[1,2- a]pyrazine as a pale yellow solid (11 mg, 22%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.40 (s, 1H), 9.92 (dd, J=4.7, 1.4 Hz, 1H), 9.23 (d, J= 1.4 Hz, 1H), 8.74 (s, 1H), 8.21-7.96 (m, 3H), 7.86 (d, J=6.7 Hz, 1H), 7.66- 7.54 (m, 2H), 7.51 (t, J=2.7 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 6.87 (s, 1H).

[001500] The following intermediate was prepared using a methodology similar to that described in Example 87:

6-(Difluoromethyl)-3-(4-(3-(methylsulfinyl)phenyl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine.

[001501] The following compounds were prepared using a methodology similar to that described in Example 87:

6-(Difluoromethyl)-3-(4-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-153;

6-(Difluoromethyl)-3-(4-(1-ethyl-1H-pyrazol-4-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-154;

2-(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)acetamide IV-155;

1-(4-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-3,6-dihydropyridin-1(2H)-yl)ethane- 1-on IV-156;

2-(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)acetonitrile IV-157;

6-(Difluoromethyl)-3-(4-(1-methyl-1H-indol-5-yl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine IV-158;

(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)methanamine IV-159;

N-(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)benzyl)methanesulfonamide IV-160;

3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenol IV-161;

(3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)methanol IV-162;

3-(4-(Cyclopent-1-en-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-163;

(5-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)thiophen-2-yl)methanol IV-175;

3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-4-fluorobenzamide IV-176;

3-(6-(1H-Indol-4-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carboxamide IV-225;

3-(6-(1H-Indol-4-yl)pyridin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-233;

3-(6-(1H-Indol-4-yl)pyridin-2-yl)imidazo[1,2-a]pyrazine-6-carbonitrile IV-234.

Example 88: (3-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)(imino)(methyl)-λ6-sulfanone, IV- 79

Step 1: 6-(Difluoromethyl)-3-(4-(3-(methylsulfinyl)phenyl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine

[001502] Mixture of 3-(4-chloropyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine (30 mg, 0.107 mmol), (3-methylsulfinylphenyl)boronic acid (19.6 mg , 0.11 mmol), 2 M NaHCO ₃ (266 μl, 0.53 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.3 mg, 0.011 mmol) in dioxane (3 ml) were heated at 60°C in for 3 hours, then concentrated in vacuo. The residue was partitioned between DCM and water and the organic extract was dried (MgSO ₄ ) and concentrated in vacuo to give 6-(difluoromethyl)-3-(4-(3-(methylsulfinyl)phenyl)pyrimidin-2-yl)imidazo[1. 2-a]pyrazine, which was used without further purification.

Step 2: (3-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl)(imino)(methyl)-λ6-sulfanone

[001503] To a mixture of 6-(difluoromethyl)-3-(4-(3-(methylsulfinyl)phenyl)pyrimidin-2-yl)imidazo[1,2-a]pyrazine (41 mg, 0.11 mmol), oxide magnesium (17.2 mg, 0.43 mmol), diacetoxyrhodium (1.2 mg, 0.0053 mmol) in DCM (3 ml) was added (diacetoxyiodo)benzene (51.4 mg, 0.16 mmol) and 2, 2,2-trifluoroacetamide (24.1 mg, 0.21 mmol). The mixture was stirred for 16 hours, then additional magnesium oxide (17.2 mg, 0.43 mmol), diacetoxyrhodium (1.2 mg, 0.0053 mmol), (diacetoxyiodo)benzene (51.4 mg, 0.16) was added mmol), 2,2,2-trifluoroacetamide (24.1 mg, 0.21 mmol). The reaction mixture was stirred for another 24 hours, then filtered and concentrated in vacuo. The residue was immediately purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent). The fractions were kept in alkaline media, which led to the removal of the protecting trifluoroacetamide group, and received (3-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)phenyl) (imino)(methyl)-λ6-sulfanone (0.6 mg, 1.1% in two steps); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.15 (d, J=1.5 Hz, 1H), 9.41 (d, J=1.3 Hz, 1H), 9.14 (d , J=5.3 Hz, 1H), 8.90 (s, 1H), 8.86 (t, J=1.8 Hz, 1H), 8.61 (dt, J=7.9, 1, 4 Hz, 1H), 8.22-8.15 (m, 2H), 7.88 (t, J=7.8 Hz, 1H), 7.29 (t, J=54.2 Hz, 1H) , 6.32 (s, 2H), 3.22 (d, J=1.1 Hz, 3H); ES+ [M+H]= 401.3.

Example 89: 3-(4-(3-((1H-Pyrazol-4-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine , IV-635

Step 1: 3-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl)propanal

[001504] 3-[1-[2-[6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]pyrrolidin-3-yl]propan-1-ol (552 mg, 1.41 mmol) was suspended in DCM (50 ml) and the mixture was cooled to 0°C. Dess-Martin periodinane (660 mg, 1.56 mmol) was added and the reaction mixture was allowed to warm to ambient temperature overnight. The reaction was stopped by adding a 1:1 mixture of saturated aqueous NaHCO ₃ and saturated aqueous Na ₂ S ₂ O ₃ (total 100 ml) and stirred vigorously for 10 minutes. The layers were separated and the aqueous phase was extracted with DCM. The combined organics were washed with brine, dried ( _Na2SO4 ), filtered and concentrated _in vacuo to give 3-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidine -4-yl)pyrrolidin-3-yl) (517 mg, 91%) as an off-white solid; ES+ [M+H]= 391.0.

Step 2: 3-(4-(3-((1H-Pyrazol-4-yl)methyl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

[001505] 3-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)pyrrolidin-3-yl) (517 mg, 1.29 mmol) was suspended in DMF (10 ml) and heated at 40°C. DMF-DMA (400 μl, 3.01 mmol) was added and the resulting brown solution was stirred overnight at 80°C, then cooled to ambient temperature and concentrated in vacuo. The residue was suspended in EtOH (10 ml) and hydrazine hydrate (130 μl, 2.65 mmol) was added and the mixture was heated at 45°C. After 3 h, the reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was taken up in DMSO and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give 3-(4-(3-((1H-pyrazol-4-yl)methyl )pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine, (17.4 mg, 3%) as a pale yellow solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.58 (s, 1H), 10.38 (d, J=13.3 Hz, 1H), 9.36 (d, J=1.3 Hz , 1H), 8.66 (s, 1H), 8.32 (d, J=5.6 Hz, 1H), 7.58 (br s, 1H), 7.40 (br s, 1H), 6 .50 (d, J=6.0 Hz, 1H), 3.92-3.81 (m, 1H), 3.67-3.50 (m, 2H), 3.49-3.34 (m , 1H), 2.63-2.55 (m, 3H), 2.15 (br s, 1H), 1.82-1.70 (m, 1H). ES+ [M+H]= 415.0.

Example 90: 2-((6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-2-(6-(trifluoromethyl)imidazo[1,2-a] pyrazin-3-yl)pyrimidin-4-yl)oxy)ethan-1-ol, IV-640

[001506] Mixture of 3-[4-chloro-6-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo [1,2-a]pyrazine (40 mg, 0.084 mmol), ethylene glycol (15 μl, 0.27 mmol) and sodium tert-butoxide (30 mg, 0.31 mmol) in DME (2 ml) were stirred at 80° C for 18 hours. The reaction mixture was immediately purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give 2-((6-(2,5-dimethyl-3- (1H-pyrazol-4-yl)piperazin-1-yl)-2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)oxy)ethane-1- ol (2 mg, 4%); ES+ [M+H]= 502.4.

Example 91: 3-(4-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-6-methoxypyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1 ,2-a]pyrazine, IV-593

[001507] Mixture of 3-[4-chloro-6-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo [1,2-a]pyrazine (20 mg, 0.042 mmol) and NaOMe (15 mg, 0.28 mmol) in methanol (500 μl) were stirred at 100 °C for 18 h. The reaction mixture was allowed to cool to ambient temperature and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give 3-[4-[2,5-dimethyl-3-(1H-pyrazol-4-yl )piperazin-1-yl]-6-methoxypyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (3 mg, 15%); ¹ H NMR (500 MHz, methanol- _d4 ) δ 10.30 (s, 1H), 9.20 (s, 1H), 8.67 (s, 1H), 7.74 (s, 2H), 6 .08 (s, 1H), 5.00-4.80 (masked, 2H), 4.39 (m, 1H), 4.06 (s, 3H), 3.15 (m, 1H), 2, 90 (m, 1H), 1.35 (d, 3H), 1.14 (d, 3H); ES+ [M+H]= 474.3.

Example 92: ((6-(2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)-2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin- 3-yl)pyrimidin-4-yl)imino)dimethyl-λ6-sulfanone, IV-648

[001508] 3-[4-Chloro-6-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[ 1,2-a]pyrazine (50 mg, 0.10 mmol), iminodimethyl-λ6-sulfanone (10 mg, 0.10 mmol), Xantphos (6 mg, 0.010 mmol) and cesium carbonate (40 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 ml) and tris(benzylideneacetone)dipalladium(0) (5 mg, 0.0055 mmol) was added. The reaction mixture was degassed and stirred at reflux for 18 hours, then concentrated in vacuo. Purification by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide eluent) gave ((6-(2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1 -yl)-2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)imino)dimethyl-λ6-sulfanone (10 mg, 17%); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.68 (s, 1H), 10.32 (m, 1H), 9.34 (m, 1H), 8.66 (m, 1H), 7 .70-7.48 (m, 2H), 5.97 (m, 1H), 5.01-4.71 (m, 1H), 4.05 (m, 2H), 3.45 (m, 6H ), 2.85 (m, 1H), 2.50 (masked, 2H), 1.16 (m, 3H), 0.91 (m, 3H); ES+ [M+H]= 535.3.

Example 93: 2-(3,6-Dimethyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidine -4-yl)piperazin-1-yl)ethan-1-ol, IV-636

[001509] Mixture of 3-[4-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine (10 mg, 0.023 mmol), 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde (8 µl, 0.042 mmol) and AcOH (2 µl, 0.04 mmol) in THF (1 ml) were stirred at ambient temperature for 10 min, then Na(OAc) ₃ BH (140 mg, 0.66 mmol) was added. After 1 hour, sodium borohydride (50 mg, 1.32 mmol) was added and the reaction mixture was heated at 45°C for 3 hours. The reaction was stopped by adding 1 M hydrochloric acid (800 μl, 0.80 mmol), filtered and immediately purified reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give 2-(3,6-dimethyl-2-(1H-pyrazol-4-yl)-4-(2- (6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperazin-1-yl)ethan-1-ol (5.2 mg, 28%); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.24 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.69 (s, 1H), 8.45 (d, J=6.3 Hz, 1H), 7.86 (s, 2H), 7.41 (s, 2H), 6.89 (d, J=6.2 Hz, 1H), 5.01 (s, 2H), 3.87-3.63 (m, 2H), 3.53-3.34 (m, 4H), 3.20-3.05 (m, 1H), 1.61 (d , J=6.3 Hz, 3H), 1.47 (d, J=7.0 Hz, 3H); ES+ [M+H]= 488.4.

Example 94: 3-(4-(3,4-Dimethyl-5-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine, IV-195

[001510] 3-[4-[3-Methyl-5-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2-a] solution ]pyrazine (9.6 mg, 0.017 mmol), formaldehyde (2.8 mg, 2.6 μl, 0.035 mmol) and AcOH (1.0 mg, 1 μl, 0.017 mmol) in THF (376 μl) were stirred at environment for 10 min, then Na(OAc) ₃ BH (7.3 mg, 0.035 mmol) was added. The reaction mixture was stirred at ambient temperature for 10 min, then additional Na(OAc) ₃ BH (7.3 mg, 0.035 mmol) was added, then two additional portions of Na(OAc) ₃ BH (7.3 mg, 0.035 mmol) were added mmol) at intervals of 10 minutes. The reaction mixture was filtered, diluted with DMSO and purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give 3-(4-(3,4-dimethyl-5-(1H -pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (7.5 mg, 68%); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.34-10.23 (m, 1H), 9.21 (dd, J=1.3, 0.7 Hz, 1H), 8.71 ( s, 1H), 8.51 (d, J=6.3 Hz, 1H), 7.92 (s, 2H), 6.96 (d, J=6.3 Hz, 1H), 4.88 ( s, 2H), 4.62-4.44 (m, 1H), 3.71 (t, J=13.1 Hz, 1H), 3.62-3.47 (m, 1H), 3.36 -3.32 (m, 1H), 2.80 (s, 3H), 1.60 (d, J=6.4 Hz, 3H); ES+ [M+H]= 444.3.

[001511] The following compound was prepared using a methodology similar to that described in Example 94:

3-(4-(4-Ethyl-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine IV-292.

[001512] The following compounds were prepared using a methodology similar to that described in Example 94 and were further purified using chiral SFC:

3-(4-(4-Ethyl-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine (fully syn-diastereoisomer) IV-295;

3-(4-(4-Ethyl-2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine (fully syn-diastereoisomer) IV-296;

Example 95: 3-(4-(3-(5-Chloro-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a] pyrazine, IV-601

Step 1: N, N-Dimethyl-4-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)- 1H-pyrazole-1-sulfonamide

[001513] 3-(4-(3-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2] was added to the oven-dried flask -a]pyrazine (76 mg, 0.18 mmol) and THF (1 ml) and the solution was stirred under nitrogen at -5°C. Sodium hydride (8.8 mg 60% w/w, 0.22 mmol) was added and the reaction mixture was stirred for 30 min at 0°C, then N,N-dimethylsulfamoyl chloride (25 µl, 0.23 mmol). The reaction mixture was stirred at 0°C for 30 min, then the reaction was stopped with isopropanol and saturated aqueous NaHCO ₃ solution. The mixture was extracted with DCM and the organic layer was passed through a phase separation cartridge and concentrated in vacuo. The residue was purified by column chromatography (silica, eluting with 0-15% DCM/MeOH gradient) to give N,N-dimethyl-4-(1-(2-(6-(trifluoromethyl)imidazo[1 ,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-pyrazol-1-sulfonamide (19.9 mg, 10%); ES+ [M+H]= 522.1.

Step 2: 5-Chloro-N,N-dimethyl-4-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3 -yl)-1H-pyrazole-1-sulfonamide

[001514] N, N-Dimethyl-4-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)- 1H-pyrazole-1-sulfonamide (19.9 mg, 0.018 mmol) was dissolved in THF (1 ml) and cooled to -78°C. LiHMDS (26 μl of 1 M, 0.026 mmol) was added and the reaction mixture was stirred at -78°C for 30 min, then a solution of hexachloroethane (8 mg, 0.034 mmol) in THF (1 ml) was added. After 1 hour, the reaction mixture was warmed to ambient temperature and stirred overnight, then the reaction was quenched with saturated aqueous NH ₄ Cl and diluted with EtOAc. The layers were separated, the aqueous layer was extracted with EtOAc (×3) and the combined organic layers were passed through a phase separation cartridge and concentrated in vacuo. The residue was purified by column (silica, eluting with 0-100% EtOAc/petroleum ether) to give 5-chloro-N,N-dimethyl-4-(1-(2-(6-(trifluoromethyl)imidazo[1 ,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-pyrazol-1-sulfonamide (4 mg, 36%); ES+ [M+H]= 556.3.

Step 3: 3-(4-(3-(5-Chloro-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a] pyrazine

[001515] TFA (0.1 mL, 1.30 mmol) was added to a solution of 5-chloro-N,N-dimethyl-4-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a] pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1H-pyrazol-1-sulfonamide (4 mg, 0.006 mmol) in DCM (2 ml). The reaction mixture was stirred at ambient temperature for 30 min, then concentrated in vacuo, diluted with DMSO and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give 3 -(4-(3-(5-chloro-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (1, 2 mg, 34%); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.35-10.31 (m, 1H), 9.18 (dd, J=1.4, 0.7 Hz, 1H), 8.64 ( s, 1H), 8.33 (d, J=6.4 Hz, 1H), 7.66-7.61 (m, 1H), 6.77 (d, J=6.4 Hz, 1H), 4.62 (s, 2H), 3.26-3.09 (m, 2H), 2.81 (tt, J=11.0, 3.8 Hz, 1H), 2.18-2.11 ( m, 1H), 1.97-1.66 (m, 3H), 1.28 (s, 1H); ES+ [M+H]= 449.0.

Example 96: 3-(4-(3-(5-Chloro-1H-pyrazol-4-yl)-5-methylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine, IV-651 and IV-652

Step 1: 2-Methyl-6-(1H-pyrazol-4-yl)pyrazine

[001516] 2-Chloro-6-methylpyrazine (2.06 g, 16.02 mmol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrazole-1-carboxylate (5.18 g, 17.6 mmol), Pd(dppf)Cl ₂ DCM (654 mg, 0.80 mmol) and aqueous Na ₂ CO ₃ (20 ml 2 M , 40.1 mmol) in 1,4-dioxane (80 ml) was heated at 90°C for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with brine, dried (MgSO ₄ ) and concentrated in vacuum. Purification by column chromatography (silica, eluting with 0-100% EtOAc/petroleum ether) gave 2-methyl-6-(1H-pyrazol-4-yl)pyrazine as a white solid (1.97 g, 77%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.19 (s, 1H), 8.79 (s, 1H), 8.41 (s, 1H), 8.29 (s, 1H), 8 .25-7.98 (m, 1H), 2.49 (s, 3H).

Step 2: tert-Butyl 4-(6-methylpyrazin-2-yl)-1H-pyrazole-1-carboxylate

[001517] Et ₃ N (1.37 g, 1.89 ml, 13.5 mmol), Boc ₂ O (3.22 g, 14.8 mmol) and DMAP (150 mg, 1.23 mmol) were added to a solution of 2-methyl-6-(1H-pyrazol-4-yl)pyrazine (1.97 g, 12.3 mmol) in THF (60 ml). The reaction mixture was stirred at ambient temperature for 3 hours, then diluted with EtOAc and washed with 1 M HCl. The organics were dried (MgSO ₄ ) and concentrated in vacuo and the residue was purified by column chromatography (silica, eluting with 0-100% EtOAc/petroleum ether) to give tert-butyl-4-(6-methylpyrazine-2 -yl)-1H-pyrazole-1-carboxylate as a white solid (2.84 g, 89%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 8.93 (d, J=0.7 Hz, 1H), 8.43 (s, 1H), 8.40 (d, J=0.7 Hz, 1H), 2.53 (s, 3H), 1.62 (s, 9H).

Step 3: tert-Butyl 5-chloro-4-(6-methylpyrazin-2-yl)-1H-pyrazole-1-carboxylate

[001518] LiHMDS (1.56 mL of 1 M, 1.56 mmol) was added dropwise to a solution of 4-(6-methylpyrazin-2-yl)-1H-pyrazol-1-carboxylate (270 mg, 1.04 mmol) in THF (5.1 ml) was stirred at -78°C. After 30 minutes, 1,1,1,2,2,2-hexachloroethane (491 mg, 2.07 mmol) in THF (2.5 ml) was added and the reaction mixture was stirred at -78°C for 1 hour and then at ambient temperature for 1 hour. The reaction was stopped with saturated aqueous NH ₄ Cl, extracted with EtOAc, dried (MgSO ₄ ), filtered and concentrated in vacuo. Purification by column chromatography (silica, eluting with 0-100% EtOAc/petroleum ether) gave tert-butyl 5-chloro-4-(6-methylpyrazin-2-yl)-1H-pyrazol-1-carboxylate as a white solid (223 mg, 73%); ¹ H NMR (500 MHz, chloroform-d) δ 8.98 (s, 1H), 8.62 (s, 1H), 8.40 (s, 1H), 2.60 (s, 3H), 1, 68 (s, 9H).

Step 4: tert-Butyl 5-chloro-4-(6-methylpiperazin-2-yl)-1H-pyrazole-1-carboxylate

[001519] tert-Butyl-5-chloro-4-(6-methylpyrazin-2-yl)-1H-pyrazol-1-carboxylate (220 mg, 0.75 mmol), zinc dibromide (67.3 mg, 16, 0 µl, 0.30 mmol) and PtO ₂ (34.4 mg, 0.15 mmol) were suspended in methanol (15 ml) and HCl (1.24 ml 3 M, 3.73 mmol) was added. The mixture was degassed and stirred with H ₂ supplied from a cylinder. After 2 hours, the reaction mixture was filtered through Celite and concentrated to give tert-butyl-5-chloro-4-(6-methylpiperazin-2-yl)-1H-pyrazol-1-carboxylate as the hydrochloride and as one diastereoisomer (250 mg , 100%); ES+ [M+H]= 301.2.

Step 5: 3-(4-(3-(5-Chloro-1H-pyrazol-4-yl)-5-methylpiperazin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine

And

[001520] 3-(4-Chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (100 mg, 0.33 mmol), tert-butyl-5-chloro-4-( 6-Methylpiperazin-2-yl)-1H-pyrazol-1-carboxylate (hydrochloride) (169 mg, 0.50 mmol) and DIPEA (300 µl, 1.72 mmol) were combined in DMF (1.7 ml) and heated at 80°C. After 2 h, 2 M aqueous KOH (850 μL, 1.70 mmol) was added and heating continued for 1 h. The reaction mixture was filtered and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as an eluent). Additional purification using chiral SFC gave:

IV-651: 3-[4-[3-(5-Chloro-1H-pyrazol-4-yl)-5-methylpiperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1, 2-a]pyrazine (4.0 mg, 18%) as trifluoroacetate; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H), 10.19 (s, 1H), 9.68-9.43 (m, 1H), 9.38 (s, 1H), 9.18-8.94 (m, 1H), 8.80 (s, 1H), 8.54 (d, J=6.2 Hz, 1H), 8.12 (s, 1H), 7.08 (d, J=6.3 Hz, 1H), 5.21-4.51 (m, 2H), 4.50-4.36 (m, 1H), 3.75-3.63 ( m, 2H), 3.20-3.06 (m, 1H), 1.36 (d, J=6.4 Hz, 3H); ES+ [M+H]= 464.2.

And

IV-652: 3-[4-[3-(5-Chloro-1H-pyrazol-4-yl)-5-methylpiperazin-1-yl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1, 2-a]pyrazine (3.9 mg, 17%); ES+ [M+H]= 464.2.

Example 97: N-(((3S,5S)-1-(6-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)-4,4-difluoro -5-methylpiperidin-3-yl)methyl)methanesulfonamide, IV-275

[001521] 3-(6-Chloropyridin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine (23.0 mg, 0.08 mmol), N-(((3S,5S) -4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide (10.0 mg, 0.04 mmol) and sodium tert-butoxide (8.0 mg, 0.08 mmol) were suspended in dioxane (400 µl) and purged with nitrogen for several minutes. (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) chloride (2.5 mg, 0.004 mmol) was added and the mixture was heated at 125°C for 70 min in a microwave oven and then 160°C for 3 days in a heating block. The mixture was then filtered, diluted with DMSO and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give N-(((3S,5S)-1-(6- (6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyridin-2-yl)-4,4-difluoro-5-methylpiperidin-3-yl)methyl)methanesulfonamide (0.8 mg, 4%); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.06 (s, 1H), 9.12 (d, J=1.3 Hz, 1H), 8.43 (s, 1H), 7.74 (dd, J=8.6, 7.5 Hz, 1H), 7.38-7.34 (m, 1H), 7.10-6.83 (m, 2H), 4.64-4.50 (m, 2H), 3.56 (dd, J=13.7, 3.9 Hz, 1H), 3.14 (dd, J=13.7, 9.3 Hz, 1H), 3.03- 2.97 (m, 1H), 2.96 (s, 3H), 2.94-2.86 (m, 1H), 2.38-2.07 (m, 2H), 1.13 (d, J=6.7 Hz, 3H).

Example 98: 2-(1-(2-(6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1,3,4- thiadiazole, IV-671

[001522] A solution of 2-bromo-5-(3-pyridyl)-1,3,4-thiadiazole (100 mg, 0.41 mmol) in EtOH (10 mL) and TFA (200 μL, 2.60 mmol) was passed through through an H-cube (cartridge with 5% palladium on carbon, 100°C, 100 atm. H ₂ , 0.5 ml/min) and the mixture was recirculated for 2 hours. The residue was redissolved in NMP (1 ml) and DIPEA was added (100 µl, 0.57 mmol) and 3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (10 mg, 0.033 mmol). The mixture was stirred at 80°C for 2 hours, then filtered, diluted in acetonitrile/water (3:1) and purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) and obtained 2-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)-1,3,4-thiadiazole (0.7 mg, 0.4%); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.33 (s, 1H), 9.40 (s, 1H), 9.20 (d, J=1.4 Hz, 1H), 8.67 (s, 1H), 8.37 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 4.74 (s, 1H), 4.33 (s, 1H), 3.72 (dd, J=13.3, 9.5 Hz, 1H), 3.61 (dd, J=8.9, 5.1 Hz, 1H), 3.52- 3.42 (m, 1H), 2.38 (dd, J=13.1, 4.4 Hz, 1H), 2.16-2.05 (m, 1H), 1.98 (dt, J= 8.6, 4.4 Hz, 1H), 1.89-1.75 (m, 1H); ES+ [M+H]= 433.1.

Example 99: 3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a] pyrazine, IV-688 and IV-689

Step 1: tert-Butyl-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate

[001523] A solution of tert-butyl-2-methyl-3-oxopyrrolidine-1-carboxylate (580 mg, 2.91 mmol) in THF (3 ml) was cooled to -78°C and [bis(trimethylsilyl)amino] was added dropwise ]lithium (3.78 ml 1 M, 3.78 mmol). After 30 min at this temperature, a solution of N-(5-chloro-2-pyridyl)-1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide (1.49 g, 3.78 mmol) in THF (3 ml) was added ). The mixture was stirred at -78°C for 1 hour, then the reaction was stopped by adding 2 M aqueous Na ₂ CO ₃ solution (2 ml) and kept at 4°C overnight. The mixture was partitioned between EtOAc and saturated NaHCO ₃ solution, the layers were separated and the organic layer was dried (MgSO ₄ ) and concentrated in vacuo to give tert-butyl-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2.5 -dihydro-1H-pyrrole-1-carboxylate as an amber oil, which was used without further purification.

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

[001524] tert-Butyl-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (964 mg, 2.91 mmol), 2 M aqueous solution Na ₂ CO ₃ (3.20 ml, 6.40 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (1.07 g, 3.64 mmol) were combined in dioxane (15 ml) and the mixture was degassed. Tetrakis(triphenylphosphine)palladium(0) (336 mg, 0.291 mmol) was added and the mixture was heated at 80°C under nitrogen. After 1.5 h, 2 M aqueous LiOH (2.91 mL, 5.82 mmol) was added and the temperature was raised to 100°C. After 1.5 hours, the reaction mixture was cooled and diluted with saturated aqueous NaHCO ₃ and ethyl acetate. The layers were separated and the organic layer was dried (MgSO ₄ ) and concentrated in vacuo. Purification by column chromatography (silica, eluting with 0-70% ethyl acetate/petroleum ether) gave tert-butyl-2-methyl-3-(1H-pyrazol-4-yl)-2,5-dihydro-1H -pyrrole-1-carboxylate (498 mg, 69% in two stages); ES+ [M+H]= 250.2.

Step 3: 4-(2-Methylpyrrolidin-3-yl)-1H-pyrazole

[001525] To a solution of tert-butyl-2-methyl-3-(1H-pyrazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (250 mg, 1.003 mmol) in DCM (3 ml ) TFA (1 ml, 13.0 mmol) was added. The reaction mixture was stirred at ambient temperature for 40 minutes, then concentrated in vacuo. Palladium on carbon (106.7 mg 10% w/w, 0.100 mmol) and methanol were added to the residue and the mixture was shaken in a Parr hydrogenator at ⁶⁰ psi hydrogen pressure at ambient temperature for 2 h. Filtration through celite gave 4-(2-methylpyrrolidin-3-yl)-1H-pyrazole, which was used in the next step without further purification.

Step 4: 3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a] pyrazine

[001526] A solution of 4-(2-methylpyrrolidin-3-yl)-1H-pyrazole (53.8 mg, 0.20 mmol), DIPEA (88 μl, 0.51 mmol) and 3-(4-chloropyrimidine-2 -yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (50.7 mg, 0.17 mmol) in NMP (1 ml) was heated at 90°C for 3 h in a sealed tube. The reaction mixture was cooled to ambient temperature, diluted with DMSO and purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide eluent) to give:

IV-688: 3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyrazine (19 mg, 26%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.71 (s, 1H), 10.34 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8 .35 (d, J=6.4 Hz, 1H), 7.68 (s, 1H), 7.46 (s, 1H), 6.67-6.42 (m, 1H), 4.44 ( d, J=205.3 Hz, 1H), 3.78 (d, J=89.4 Hz, 1H), 3.59-3.39 (m, 1H), 2.36 (d, J=47 .5 Hz, 2H), 1.26 (d, J=11.7 Hz, 1H), 1.03-0.84 (m, 3H); ES+ [M+H]= 415.3.

And

IV-689: 3-(4-(2-Methyl-3-(1H-pyrazol-4-yl)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a ]pyrazine (4 mg, 6%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 10.34 (s, 1H), 9.35 (d, J=1.4 Hz, 1H), 8.67 (s, 1H), 8.35 (d, J=6.0 Hz, 1H), 7.49 (d, J=95.5 Hz, 2H), 6.53 (s, 1H), 4.22 (d, 1H) 3.59 (s, 2H), 2.16-1.92 (m, 1H), 1.34 (d, J=95.4 Hz, 5H); ES+ [M+H]= 415.3.

Example 100: 1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxamide, IV-107

Step 1: Methyl 1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxylate

[001527] 3-(4-chloropyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine (30 mg, 0.1044 mmol), 1-piperazin-1-ylethanone was placed in a round bottom flask (20.2 mg, 0.104 mmol) and DIPEA (54.5 µl, 0.3132 mmol) in NMP (0.2 ml). The vessel was sealed and then stirred at 80°C for 20 minutes. The reaction mixture was cooled to ambient temperature and the mixture was filtered through a Whatman 0.45 μm syringe filter and diluted with DMSO. The solution was purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent). The product fractions were then combined and lyophilized to yield methyl 1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxylate

Step 2: 1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxamide

[001528] Methyl 1-[2-[6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]-5-methylpiperidin-3-carboxylate was placed in a microwave-safe vessel (42 mg, 0.1044 mmol) in NMP (0.2 ml) and NH ₄ OH (approximately 610 mg, 677.6 μl, 5.220 mmol). The vessel was sealed and then heated at 100°C for 3 days. The reaction mixture was cooled to ambient temperature and then filtered and diluted with DMSO. The resulting solution was purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent). The product fractions were combined and lyophilized to give 1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-carboxamide (0.6 mg, 0.88%) as a 2:1 mixture of diastereoisomers; MS m/z: 388.3 (M+H) ⁺ .

Example 101: 3-(4-((8aS)-4-(1H-pyrazol-4-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2-yl)-6- (trifluoromethyl)imidazo[1,2-a]pyrazine, IV-679

Step 1: 1-(1-Benzyl-1H-pyrazol-4-yl)-2-bromoethan-1-one

[001529] Bromine (390 μL, 7.570 mmol) was added dropwise to an ice-cold solution of 1-(1-benzylpyrazol-4-yl)ethanone (1.5 g, 7.491 mmol) in chloroform (20 mL) under N ₂ atmosphere. After 5 minutes, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 20 hours. Then additional bromine (0.2 ml, 0.39 mmol) was added and the reaction mixture was stirred at ambient temperature for an additional 24 hours. Reaction stopped by adding 30 ml of saturated NaHCO ₃ solution. The organic layer was further washed with saturated aqueous NaHCO ₃ solution, brine, dried over MgSO ₄ and concentrated under reduced pressure. The crude material was purified by column chromatography (silica, 0-100% EtOAc/hexanes) to give 1-(1-benzylpyrazol-4-yl)-2-bromoethanone (1.34 g, 61%) as a yellow oil; MS m/z 281.1 (M+H) ⁺ .

Step 2: tert-Butyl-(S)-2-(((2-(1-benzyl-1H-pyrazol-4-yl)-2-oxoethyl)((benzyloxy)carbonyl)amino)methyl)pyrrolidin-1- carboxylate

[001530] 1-(1-Benzylpyrazol-4-yl)-2-bromoethanone (280 mg, 0.95 mmol) was dissolved in DCM (10 ml), then tert-butyl-(2S)-2-(aminomethyl) was added pyrrolidine-1-carboxylate (200 mg, 1.00 mmol) and triethylamine (150 μl, 1.08 mmol). The resulting solution was stirred at ambient temperature for 1 hour. CBz-Cl (130 µl, 0.91 mmol) and Et ₃ N (400 µl, 2.87 mmol) were added and the resulting mixture was stirred for 90 minutes and then concentrated in vacuum. The crude mixture was purified by column chromatography (silica, 0-100% EtOAc/petroleum ether in DCM). The product fractions were combined and concentrated under reduced pressure to give tert-butyl (2S)-2-[[benzyloxycarbonyl-[2-(1-benzylpyrazol-4-yl)-2-oxoethyl]amino]methyl]pyrrolidine-1-carboxylate (240 mg, 47%); MS m/z 533.2 (M+H) ⁺ .

Step 3: Benzyl-(S)-4-(1-benzyl-1H-pyrazol-4-yl)-6,7,8,8a-tetrahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

[001531] tert-Butyl-(2S)-2-[[benzyloxycarbonyl-[2-(1-benzylpyrazol-4-yl)-2-oxoethyl]amino]methyl]pyrrolidine-1-carboxylate (240 mg, 0.45 mmol) was dissolved in DCM (3 ml) and then cooled to 0°C. TFA (2 ml) was then added slowly and the reaction mixture was warmed to ambient temperature. After 3 h, the reaction mixture was concentrated under reduced pressure with DCM to co-evaporate residual TFA (×5). The crude orange residue was dissolved in DCE (5 ml) and then acetic acid (20 µl, 0.35 mmol) was added, followed by Na(OAc) ₃ BH (300 mg, 1.42 mmol). The resulting mixture was stirred at ambient temperature for 30 minutes. The reaction was then quenched with saturated aqueous NaHCO ₃ solution, then separated and extracted with DCM (2×40 ml). The combined organic extracts were washed with brine (20 ml), passed through a hydrophobic frit and concentrated to give benzyl-(8aS)-4-(1-benzylpyrazol-4-yl)-6,7,8,8a-tetrahydro-1H-pyrrolo[ 1,2-a]pyrazine-2-carboxylate (150 mg, 80%) as a colorless resinous substance; MS m/z 415.3 (M+H) ⁺ .

Step 4: 3-(4-((8aS)-4-(1H-pyrazol-4-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2-yl)-6- (trifluoromethyl)imidazo[1,2-a]pyrazine

[001532] Benzyl-(8aS)-4-(1-benzylpyrazol-4-yl)-6,7,8,8a-tetrahydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylate (40 mg, 0.097 mmol), Pd at C, wet Degussa (15 mg 10% w/w, 0.014 mmol) and concentrated HCl (40 µl 12 M, 0.480 mmol) were transferred to methanol (2 ml) and stirred at ambient temperature in for 22 hours and with the supply of H ₂ from a cylinder for 24 hours. The catalyst was filtered through celite and the filtrate was partially concentrated to obtain crude (8aS)-4-(1H-pyrazol-4-yl)-1,2,3,4, 6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine. Crude (8a,S)-4-(1H-pyrazol-4-yl)-1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine was dissolved in NMP (1 ml ) and added DIPEA (100 μl, 0.5741 mmol) and 3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (30 mg, 0.1001 mmol) and stirred at 90°C for 3 hours. The substance was purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give: 3-(4-((8aS)-4- (1H-pyrazol-4-yl)hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (trifluoroacetate) (2.4 mg, 4%); MS m/z 456.3 (M+H) ⁺ .

Example 102: 3-(4-(3-((1H-Pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine , IV-695

Step 1: tert-Butyl 3-((1-benzyl-1H-pyrazol-4-yl)oxy)pyrrolidine-1-carboxylate

[001533] Tert-butyl-3-bromopyrrolidine-1-carboxylate (480 mg, 1.92 mmol), 1-benzylpyrazol-4-ol (330 mg, 1.89 mmol) and K ₂ CO ₃ ( 850 mg, 6.15 mmol) in DMF (3 ml) and the reaction mixture was stirred at 110°C for 4 hours. The crude mixture was immediately purified by column chromatography (silica, eluting with 0-100% EtOAc/petroleum ether) to obtain tert-butyl 3-((1-benzyl-1H-pyrazol-4-yl)oxy)pyrrolidine-1-carboxylate (260 mg, 40%) as a pale brown solid; ES+ [M+H]= 344.3.

Step 2: 4-(Pyrrolidin-3-yloxy)-1H-pyrazole

[001534] tert-Butyl-3-((1-benzyl-1H-pyrazol-4-yl)oxy)pyrrolidine-1-carboxylate (68 mg, 0.20 mmol), palladium on carbon (10% w/w .wet, Degussa, 35 mg, 0.033 mmol) and concentrated HCl (100 µl 12 M, 1.20 mmol) were dissolved in methanol (2 ml) and the mixture was stirred at ambient temperature with a hydrogen supply from a cylinder for 22 hours. the mixture was filtered through celite and concentrated in vacuo. The residue was dissolved in DCM (2 ml) and TFA (1.5 ml, 19.5 mmol) was added. After stirring for 4 hours at ambient temperature, the reaction mixture was concentrated in vacuo to give 4-(pyrrolidin-3-yloxy)-1H-pyrazole, which was immediately used in the next step.

Step 3: 3-(4-(3-((1H-Pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine

[001535] Crude 4-(pyrrolidin-3-yloxy)-1H-pyrazole was dissolved in DMSO (1 ml) and DIPEA (200 μl, 1.15 mmol) and 3-(4-chloropyrimidin-2-yl)-6 was added -(trifluoromethyl)imidazo[1,2-a]pyrazine (30.0 mg, 0.099 mmol). The reaction mixture was stirred at 90°C for 3 hours. The mixture was purified by reverse phase chromatography (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give 3-(4-(3-((1H -pyrazol-4-yl)oxy)pyrrolidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (23.5 mg, 57% in 3 steps); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.44 (d, J=5.2 Hz, 1H), 9.18 (s, 1H), 8.64 (d, J=3.8 Hz , 1H), 8.34-8.21 (m, 1H), 7.40 (s, 2H), 6.50 (s, 1H), 4.93 (s, 1H), 4.56 (s, 1H), 3.91 (d, J=9.2 Hz, 1H), 3.77-3.58 (m, 1H), 2.43 (s, 1H), 2.32 (d, J=16 ,0 Hz, 1H), 1.30 (d, J=6.7 Hz, 1H); ES+ [M+H]= 417.3.

Example 103: 6-(Difluoromethyl)-3-[4-[(3S)-3-(sulfamoylamino)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyrazine, IV-179

Step 1: (S)-1-(2-(6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-amine

[001536] 3-(4-Chloropyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine (30 mg, 0.11 mmol), tert-butyl-N-[(3S)- 3-piperidyl]carbamate (42.66 mg, 0.21 mmol) and DIPEA (68.82 mg, 92.75 μL, 0.53 mmol) were dissolved in NMP and heated at 120 °C in a microwave oven for 30 min. . TFA (0.2 ml) was added and the resulting mixture was stirred at ambient temperature for 1 hour and then the mixture was heated in a microwave oven for 30 minutes at 100°C. The reaction mixture was then diluted with DMSO (2 ml) and purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent). The remaining oily solid was then immediately reacted (20.0 mg, 34%); MS m/z 446.1 (M+H) ⁺ .

Step 2: 6-(Difluoromethyl)-3-[4-[(3S)-3-(sulfamoylamino)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyrazine

[001537] (3S)-1-[2-[6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]piperidin-3-amine (10 mg, 0.029 mmol) and sulfamide (27.83 mg, 17.27 μl, 0.290 mmol) were combined in dioxane (1 ml) and heated at 100°C for 1 h in a sealed tube. The reaction mixture was cooled to ambient temperature, DMSO (1 ml) was added and the mixture was immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give 6-(difluoromethyl)-3- [4-[(3S)-3-(sulfamoylamino)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyrazine (3.6 mg, 23%); ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.96 (d, J=1.4 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H), 8.71 (s , 1H), 8.29 (d, J=7.0 Hz, 1H), 6.97-6.87 (m, 2H), 4.45 (s, 1H), 4.18 (s, 1H) , 3.63 (d, J=19.7 Hz, 1H), 3.61-3.52 (m, 3H), 2.18 (s, 1H), 1.77 (s, 2H); MS m/z 425.1 (M+H) ⁺ .

The following compound was prepared using a methodology similar to that described in Example 103:

6-(Difluoromethyl)-3-[4-[(3R)-3-(sulfamoylamino)-1-piperidyl]pyrimidin-2-yl]imidazo[1,2-a]pyrazine IV-181.

Example 104: (3S)-N-(Diaminohydroxyoxo-λ6-sulfanyl)-1-[2-[6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]piperidin- 3-amine, IV-180

[001538] (3S)-1-[2-[6-(Difluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]piperidin-3-amine (10 mg, 0.029 mmol) and sulfonamide (27.83 mg, 17.27 μl, 0.290 mmol) were combined in dioxane (1 ml) and heated at 100°C for 16 h in a sealed tube. The mixture was diluted with DMSO (1 ml) and immediately purified by reverse phase chromatography (C18; MeCN/water - 0.05% TFA as eluent) to give (3S)-N-(diaminohydroxyoxo-λ6-sulfanyl)- 1-[2-[6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]piperidin-3-amine (10.4 mg, 53%) as TFA salt ; ¹ H NMR (400 MHz, methanol-d ₄ ) δ 9.82 (s, 1H), 9.33 (dd, J=1.6, 0.8 Hz, 1H), 8.78 (d, J= 0.9 Hz, 1H), 8.32 (dd, J=7.4, 0.9 Hz, 1H), 7.12-7.00 (m, 2H), 4.85 (s, 1H), 4.41 (s, 1H), 4.02 (td, J=9.9, 4.8 Hz, 1H), 3.55-3.39 (m, 2H), 2.23-2.13 ( m, 1H), 2.07 (dq, J=11.8, 4.1, 3.6 Hz, 1H), 1.95-1.76 (m, 2H); MS m/z 442.2 (M+H) ⁺ .

[001539] The following compound was prepared using a methodology similar to that described in Example 104:

(R)-3-(4-(3-((Diamino-(hydroxy)sulfinyl)amino)piperidin-1-yl)pyrimidin-2-yl)-6-(difluoromethyl)imidazo[1,2-a]pyrazine IV-178.

Example 105: 3-(4-(3-(4H-1,2,4-Triazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine and N-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)formamide, IV-752 and IV-332

Step 1: 3-(4H-1,2,4-Triazol-4-yl)piperidine

[001540] To a solution of 1-benzylpiperidin-3-amine (dihydrochloride) (101 mg, 0.384 mmol), N-formamidoformamide (112 mg, 1.272 mmol), Et ₃ N (550 μl, 3.946 mmol) in pyridine (5 ml) TMSCl (750 μl, 5.909 mmol) was added and the mixture was heated at 100°C for 16 hours. The reaction mixture was cooled to ambient temperature and partitioned between DCM and saturated aqueous NaHCO ₃ solution. The organic layers were separated, dried over MgSO ₄ and concentrated in vacuo. The substance was dissolved in methanol (10 ml), Pd(OH) ₂ (53.88 mg, 0.384 mmol) was added and the mixture was stirred for 16 hours under H ₂ atmosphere. The catalyst was filtered off and the filtrate concentrated in vacuo to give 3-(4H-1,2,4-triazol-4-yl)piperidine, which was used in the next step without further purification, assuming quantitative yield.

Step 2: 3-(4-(3-(4H-1,2,4-Triazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2- a]pyrazine and N-(1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)formamide

And

[001541] Mixture of 3-(1,2,4-triazol-4-yl)piperidine (60 mg, 0.394 mmol), 3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine (62.1 mg, 0.197 mmol) and DIPEA (152.8 mg, 205.9 μl, 1.182 mmol) in NMP (3 ml) were heated at 75°C for 16 h. The crude mixture was immediately purified with using reverse phase preparative HPLC [Waters Sunfire C18, 10 µM, 100 Å column, 10% - 95% B gradient (solvent A: 0.05% TFA in water; solvent B: CH ₃ CN) over 16 min at 25 ml/min]. The product fractions were combined and lyophilized to give:

N-[1-[2-[6-(Trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl]pyrimidin-4-yl]-3-piperidyl]formamide (trifluoroacetate) (4.03 mg, 1 %); ^1H NMR (500 MHz, DMSO- _d6 ) δ 10.19 (s, 1H), 9.42-9.30 (m, 1H), 8.71 (s, 1H), 8.39 (d, J=6.3 Hz, 1H), 8.26-8.18 (m, 1H), 8.00 (dd, J=1.7, 0.9 Hz, 1H), 6.85 (d, J =6.4 Hz, 1H), 4.09 (d, J=83.8 Hz, 2H), 3.92-3.77 (m, 1H), 3.5 1 (dt, J=20.2 , 7.0 Hz, 1H), 3.42-3.31 (m, 1H), 2.00-1.74 (m, 2H), 1.61 (tt, J=12.0, 9.4 Hz, 2H); MS m/z 392.2 (M+H) ⁺ .

And

3-[4-[3-(1,2,4-Triazol-4-yl)-1-piperidyl]pyrimidin-2-yl]-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (trifluoroacetate ( 0.5)), (4.75 mg, 1.3%); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.21 (d, J=1.5 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 9.15-9 .01 (m, 2H), 8.79 (s, 1H), 8.46 (d, J=6.3 Hz, 1H), 7.00 (d, J=6.3 Hz, 1H), 4 .67 (d, J=23.8 Hz, 1H), 4.58-4.46 (m, 1H), 4.41 (d, J=40.7 Hz, 1H), 3.62 (dd, J=13.1, 9.8 Hz, 1H), 3.24 (ddd, J=13.9, 11.3, 3.1 Hz, 1H), 2.28 (dq, J=12.9, 4.2 Hz, 1H), 2.23-2.08 (m, 1H), 1.99-1.86 (m, 1H), 1.67 (dtt, J=13.5, 11.3, 4.0 Hz, 1H); MS m/z 416.2 (M+H) ⁺ .

Example 106: 3-(4-(3-(Piperidin-3-yl)-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine, IV -634

[001542] 3-(1H-Pyrazol-3-yl)piperidine (50 mg, 0.33 mmol) was dissolved in dioxane (2.6 ml) and water (0.6 2.1 mm x 50 mm, 1.7 µl), then sodium carbonate (52.5 mg, 0.50 mmol) was added, then tert-butoxycarbonyl-tert-butyl carbonate (144.3 mg, 0.66 mmol). The suspension was stirred at ambient temperature for 2 hours. The reaction was quenched with K ₂ CO ₃ (2 M, 0.5 ml), then extracted with DCM (2 x 2 ml). The organic layer was then filtered through a hydrophobic frit and concentrated in vacuo. The crude oil was dissolved in DMF and cooled to 0°C, then NaH (15.8 mg, 0.40 mmol) was added. The suspension was stirred for 15 min, then 3-(4-chloropyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (69.4 mg, 0.23 mmol) was added and the resulting mixture was heated at 80°C for 45 minutes and then at 100°C for another 5 hours. The reaction mixture was purified using (C18; MeCN/water - 0.1% ammonium hydroxide as eluent). The purified substance was dissolved in HCl in MeOH (110 µl, 0.33 mmol, 3 M solution) and the resulting mixture was stirred at ambient temperature for 3 hours and then additional HCl in MeOH (110 µl, 0.33 mmol, 3 M) was added solution) and the resulting mixture was stirred at ambient temperature for 24 hours. The resulting suspension was diluted with DCM and purified with (C18; MeCN/water - 0.1% ammonium hydroxide as eluent) to give 3-(4-( 3-(piperidin-3-yl)-1H-pyrazol-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine (18 mg, 12%); ¹ H NMR (500 MHz, methanol-d ₄ ) δ 10.31 (dd, J=1.5, 0.8 Hz, 1H), 9.30-9.21 (m, 1H), 8.97 ( d, J=5.6 Hz, 1H), 8.87 (s, 1H), 8.77 (d, J=2.8 Hz, 1H), 7.87 (d, J=5.6 Hz, 1H), 6.67 (d, J=2.8 Hz, 1H), 3.72-3.61 (m, 1H), 3.47-3.33 (m, 2H), 3.33-3 .21 (m, 1H), 3.11 (ddd, J=12.8, 11.0, 3.6 Hz, 1H), 2.33-2.24 (m, 1H), 2.10-1 .99 (m, 1H), 2.00-1.84 (m, 2H); MS m/z 415.1 (M+H) ⁺ .

Table 7: Analysis data for compounds of formula IV

[001543] The purity and retention time of the compounds of the present invention were determined using HPLC.

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, pH9). Study duration 5 min

IV-No. LCMS_Plus LCMS_RT NMR IV-1 312.1 0.76 1H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 9.92 (dd, J=4.7, 1.4 Hz, 1H), 9.23 (d, J=1.4 Hz , 1H), 8.74 (s, 1H), 8.21-7.96 (m, 3H), 7.86 (d, J=6.7 Hz, 1H), 7.66-7.54 ( m, 2H), 7.51 (t, J=2.7 Hz, 1H), 7.30 (t, J=7.7 Hz, 1H), 6.87 (s, 1H). IV-2 323.2 1.83 1H NMR (500 MHz, DMSO) δ 9.54 (dd, J=4.5, 1.6 Hz, 1H), 9.17 (t, J=1.9 Hz, 1H), 8.49 (s , 1H), 8.08 (d, J=4.5 Hz, 1H), 7.72 (dd, J=8.6, 7.4 Hz, 1H), 7.37 (d, J=7, 4 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 3.72-3.62 (m, 6H), 3.62-3.54 (m, 2H), 2, 09 (d, J=2.8 Hz, 3H). IV-3 417.1 2.23 IV-4 389.2 2.09 1H NMR (500 MHz, methanol-d4) δ 9.49-9.41 (m, 1H), 9.12 (d, J=1.4 Hz, 1H), 8.65 (s, 1H), 8 .32 (d, J=7.2 Hz, 1H), 7.78 (s, 2H), 7.04 (d, J=7.2 Hz, 1H), 4.79 (dd, J=10, 8, 2.5 Hz, 1H), 4.25-4.18 (m, 1H), 3.89 (td, J=11.8, 2.8 Hz, 1H), 3.61-3.47 (m, 2H), 2.03 (s, 2H), 1.30 (s, 2H). IV-5 472.1 2.65 1H NMR (500 MHz, DMSO-d6) δ 9.85 (d, J=1.4 Hz, 1H), 9.15 (d, J=1.4 Hz, 1H), 8.72 (s, 1H ), 8.48 (d, J=6.3 Hz, 1H), 7.46-7.30 (m, 1H), 6.95 (d, J=6.3 Hz, 1H), 5.23 -4.33 (m, 2H), 3.52-3.41 (m, 1H), 3.06-2.99 (m, 1H), 2.98 (s, 3H), 2.94-2 .82 (m, 2H), 2.20 (d, J=27.3 Hz, 2H), 1.08 (d, J=6.7 Hz, 3H). IV-6 383.1 2.05 1H NMR (500 MHz, DMSO-d6) δ 9.80 (d, J=1.5 Hz, 1H), 9.14 (d, J=1.3 Hz, 1H), 8.67 (s, 1H ), 8.44 (d, J=6.3 Hz, 1H), 7.72 (s, 2H), 6.95 (d, J=6.4 Hz, 1H), 4.61 (dd, J =10.4, 2.7 Hz, 1H), 4.57-4.20 (m, 2H), 4.06 (ddd, J=11.6, 3.6, 1.7 Hz, 1H), 3.72 (td, J=11.6, 2.8 Hz, 1H), 3.28-3.14 (m, 2H). IV-7 417.1 2.23 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 10.23 (s, 1H), 9.36 (d, J=1.4 Hz, 1H), 8.75 (s , 1H), 8.45 (d, J=6.3 Hz, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 6.96 (d, J=6.4 Hz , 1H), 4.60 (dd, J=10.5, 2.7 Hz, 1H), 4.47 (s, 2H), 4.09-4.01 (m, 1H), 3.72 ( td, J=11.6, 2.8 Hz, 1H), 3.27-3.15 (m, 2H). IV-8 417.1 2.23 1H NMR (500 MHz, DMSO-d6) δ 12.83 (s, 1H), 10.23 (s, 1H), 9.36 (d, J=1.4 Hz, 1H), 8.75 (s , 1H), 8.45 (d, J=6.3 Hz, 1H), 7.82 (s, 1H), 7.58 (s, 1H), 6.96 (d, J=6.4 Hz , 1H), 4.60 (dd, J=10.5, 2.7 Hz, 1H), 4.47 (s, 2H), 4.09-4.01 (m, 1H), 3.72 ( td, J=11.6, 2.8 Hz, 1H), 3.27-3.15 (m, 2H). IV-9 397.2 2.24 1H NMR (500 MHz, methanol-d4) δ 9.95 (d, J=1.3 Hz, 1H), 8.98 (d, J=1.3 Hz, 1H), 8.62 (s, 1H ), 8.38 (d, J=6.3 Hz, 1H), 7.66 (s, 2H), 6.79 (d, J=6.4 Hz, 1H), 4.90 (d, J =3.0 Hz, 1H), 4.56 (s, 2H), 4.22 (dd, J=11.5, 4.2 Hz, 1H), 3.87 (td, J=11.8, 3.1 Hz, 1H), 3.49-3.36 (m, 1H), 1.14 (d, J=6.8 Hz, 3H). IV-10 431.2 2.39 IV-11 431.2 2.4 1H NMR (500 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.24 (dd, J=1.5, 0.8 Hz, 1H), 9.36 (dd, J=1, 5, 0.6 Hz, 1H), 8.76 (s, 1H), 8.42 (d, J=6.3 Hz, 1H), 7.57 (s, 2H), 6.94 (s, 1H), 5.08 (t, J=4.1 Hz, 1H), 3.93 (s, 1H), 3.77 (s, 1H), 3.25 (d, J=7.9 Hz, 1H), 1.20 (d, J=6.3 Hz, 3H), 2H is not observed. IV-12 431.2 2.42 1H NMR (500 MHz, DMSO-d6) δ 12.81 (s, 1H), 10.23 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.75 (s , 1H), 8.43 (d, J=6.3 Hz, 1H), 7.69 (s, 2H), 6.97 (d, J=6.3 Hz, 1H), 4.62 (dd , J=10.8, 2.6 Hz, 1H), 3.85-3.73 (m, 1H), 3.07 (t, J=12.0 Hz, 1H), 2.78 (t, J=11.9 Hz, 1H), 1.25 (d, J=6.2 Hz, 3H), 2H not observed. IV-13 430.9 2.4 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.22 (s, 1H), 9.43-9.25 (m, 1H), 8.74 (s, 1H) , 8.43 (d, J=6.2 Hz, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 6.96 (d, J=6.3 Hz, 1H) , 4.62 (dd, J=11.0, 2.7 Hz, 1H), 4.46 (s, 2H), 3.79 (ddd, J=10.8, 6.2, 2.7 Hz , 1H), 3.07 (dd, J=13.1, 11.0 Hz, 1H), 2.85-2.69 (m, 1H), 1.25 (d, J=6.2 Hz, 3H). IV-14 431.1 2.41 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 10.22 (s, 1H), 9.43-9.25 (m, 1H), 8.74 (s, 1H) , 8.43 (d, J=6.2 Hz, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 6.96 (d, J=6.3 Hz, 1H) , 4.62 (dd, J=11.0, 2.7 Hz, 1H), 4.46 (s, 2H), 3.79 (ddd, J=10.8, 6.2, 2.7 Hz , 1H), 3.07 (dd, J=13.1, 11.0 Hz, 1H), 2.85-2.69 (m, 1H), 1.25 (d, J=6.2 Hz, 3H). IV-15 431.3 2.37 IV-16 431.1 2.37 IV-17 506.1 2.85 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.79 (s, 1H), 8.50 (d , J=6.3 Hz, 1H), 7.37 (s, 1H), 7.00-6.91 (m, 1H), 5.13-4.34 (m, 2H), 3.46 ( ddd, J=13.5, 6.3, 3.4 Hz, 1H), 3.05-2.95 (m, 4H), 2.93-2.80 (m, 2H), 2.29- 2.11 (m, 2H), 1.06 (d, J=6.7 Hz, 3H). IV-18 374.2 1.92 1H NMR (500 MHz, DMSO-d6) δ 10.29 (d, J=1.4 Hz, 1H), 9.31 (d, J=1.4 Hz, 1H), 8.75 (s, 1H ), 8.44 (d, J=6.3 Hz, 1H), 7.70 (s, 2H), 6.96 (d, J=6.3 Hz, 1H), 4.59 (dd, J =10.4, 2.7 Hz, 1H), 4.05 (ddd, J=11.7, 3.6, 1.7 Hz, 1H), 3.70 (td, J=11.6, 2 ,8 Hz, 1H), 3.26-3.11 (m, 2H), 3H is not observed. IV-19 429.1 2.08 1H NMR (500 MHz, DMSO-d6) δ 9.90 (d, J=1.4 Hz, 1H), 9.10 (d, J=1.3 Hz, 1H), 8.64 (s, 1H ), 8.43 (d, J=6.3 Hz, 1H), 7.71 (s, 2H), 6.93 (d, J=6.4 Hz, 1H), 4.59 (dd, J =10.5, 2.7 Hz, 1H), 4.05 (ddd, J=11.7, 3.6, 1.7 Hz, 1H), 3.75-3.67 (m, 1H), 3.19 (td, J=13.5, 9.9 Hz, 2H), 3H is not observed. IV-20 363.2 1.86 1H NMR (500 MHz, DMSO-d6) δ 9.49 (s, 1H), 9.15 (d, J=1.4 Hz, 1H), 8.58 (s, 1H), 8.41 (d , J=6.3 Hz, 1H), 7.71 (s, 2H), 6.93 (d, J=6.4 Hz, 1H), 4.61 (dd, J=10.6, 2, 7 Hz, 1H), 4.10-4.00 (m, 1H), 3.73 (dd, J=11.6, 2.8 Hz, 1H), 3.21 (dd, J=13.3 , 10.4 Hz, 2H), 2.48 (s, 3H), 3H not observed. IV-21 488.1 2.57 1H NMR (500 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.33 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.49 (d , J=6.3 Hz, 1H), 7.38 (s, 1H), 7.23 (t, J=54.6 Hz, 1H), 6.95 (d, J=8.1 Hz, 1H ), 3.48-3.45 (m, 1H), 3.03-2.98 (m, 4H), 2.90-2.85 (m, 2H), 2.21 (br d, J= 28.0 Hz, 2H), 1.07 (d, J=6.7 Hz, 3H). One×CH2 is not observed. IV-22 374.1 1.94 1H NMR (500 MHz, DMSO-d6) δ 10.06 (d, J=1.5 Hz, 1H), 9.32 (d, J=1.3 Hz, 1H), 8.68 (s, 1H ), 8.43 (d, J=6.3 Hz, 1H), 7.24 (t, J=54.5 Hz, 1H), 6.87 (d, J=6.3 Hz, 1H), 3.80 (br d, J=30.3 Hz, 4H), 3.63-3.61 (m, 4H), 2.08 (s, 3H). IV-23 440.1 2.01 1H NMR (500 MHz, DMSO-d6) δ 10.06 (d, J=1.1 Hz, 1H), 9.32 (d, J=1.3 Hz, 1H), 8.71 (s, 1H ), 8.45 (d, J=6.3 Hz, 1H), 7.37-7.03 (m, 2H), 6.85 (d, J=6.3 Hz, 1H), 4.04 -4.01 (m, 1H), 3.63-3.56 (m, 3H), 3.21-3.11 (m, 4H), 2.96 (s, 3H), 2.89-2 .84 (m, 1H). IV-24 392.2 2.22 1H NMR (500 MHz, methanol-d4) δ 10.35 (dd, J=1.5, 0.8 Hz, 1H), 9.23 (dd, J=1.3, 0.7 Hz, 1H) , 8.68 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 7.29 (d, J=5.2 Hz, 1H), 4.05-3.98 ( m, 2H), 3.98-3.91 (m, 2H), 3.80-3.74 (m, 2H), 3.74-3.69 (m, 2H), 2.19 (s, 3H). IV-25 354.2 1.9 1H NMR (500 MHz, methanol-d4) δ 9.39 (d, J=1.4 Hz, 1H), 8.90 (d, J=1.4 Hz, 1H), 8.55 (s, 1H ), 8.42 (d, J=5.3 Hz, 1H), 7.23 (d, J=5.3 Hz, 1H), 4.05 (s, 3H), 4.04-3.98 (m, 2H), 3.98-3.91 (m, 2H), 3.75 (ddd, J=13.2, 6.6, 4.3 Hz, 4H), 2.19 (s, 3H ). IV-26 354.2 1.61 1H NMR (500 MHz, DMSO-d6) δ 9.82 (q, J=1.4 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.73 (s, 1H ), 8.49 (d, J=5.2 Hz, 1H), 7.34 (d, J=5.2 Hz, 1H), 4.74 (d, J=1.4 Hz, 2H), 3.93-3.90 (m, 2H), 3.86-3.84 (m, 2H), 3.63-3.59 (m, 4H), 2.08 (s, 3H). IV-27 454.1 2.2 1H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.12 (s, 1H), 8.58 (s, 1H), 8.34 (d, J=6.2 Hz , 1H), 7.22 (t, J=6.3 Hz, 1H), 6.50 (s, 1H), 3.91-3.66 (m, 4H), 3.24 (s, 1H) , 3.08-3.05 (m, 2H), 2.94 (s, 3H), 2.16 (s, 1H), 1.85 (s, 1H). IV-28 399 1.94 1H NMR (500 MHz, DMSO-d6) δ 10.04 (q, J=1.3 Hz, 1H), 9.31 (d, J=1.4 Hz, 1H), 8.70 (s, 1H ), 8.44 (d, J=6.3 Hz, 1H), 7.70 (s, 2H), 7.19 (t, J=54.6 Hz, 1H), 6.95 (d, J =6.3 Hz, 1H), 4.60 (dd, J=10.4, 2.7 Hz, 2H), 4.07-4.04 (m, 1H), 3.72 (td, J= 11.6, 2.8 Hz, 1H), 3.25-3.17 (m, 3H). IV-29 438.1 2.25 1H NMR (500 MHz, DMSO-d6) δ 10.08-10.07 (m, 1H), 9.31 (d, J=1.4 Hz, 1H), 8.67 (s, 1H), 8 .38 (d, J=6.3 Hz, 1H), 7.22 (t, J=54.5 Hz, 1H), 7.15 (t, J=6.0 Hz, 1H), 6.83 (d, J=6.4 Hz, 1H), 4.36 (br s, 2H), 3.12 (ddd, J=13.8, 11.3, 3.1 Hz, 1H), 2.97 -2.86 (m, 3H), 2.92 (s, 3H), 1.90-1.85 (m, 1H), 1.80-1.77 (m, 1H), 1.73-1 .70 (m, 1H), 1.53-1.45 (m, 1H), 1.38-1.30 (m, 1H). IV-30 368.2 1.23 1H NMR (500 MHz, methanol-d4) δ 10.77 (d, J=1.4 Hz, 1H), 9.17 (d, J=1.3 Hz, 1H), 8.68 (s, 1H ), 8.48 (d, J=5.2 Hz, 1H), 7.29 (d, J=5.2 Hz, 1H), 4.02 (ddd, J=26.6, 6.5, 4.0 Hz, 4H), 3.75 (dt, J=21.9, 5.3 Hz, 4H), 2.20 (s, 3H). IV-31 349.3 1.88 1H NMR (500 MHz, methanol-d4) δ 10.25 (d, J=1.4 Hz, 1H), 9.19 (d, J=1.4 Hz, 1H), 8.68 (s, 1H ), 8.50 (d, J=5.2 Hz, 1H), 7.28 (d, J=5.2 Hz, 1H), 4.08-3.99 (m, 2H), 3.99 -3.92 (m, 2H), 3.82-3.71 (m, 4H), 2.20 (s, 3H). IV-32 404.2 2.05 1H NMR (500 MHz, methanol-d4) δ 10.00 (d, J=1.3 Hz, 1H), 9.00 (d, J=1.3 Hz, 1H), 8.60 (s, 1H ), 8.46 (d, J=5.2 Hz, 1H), 7.26 (d, J=5.3 Hz, 1H), 4.05-3.97 (m, 2H), 3.97 -3.90 (m, 2H), 3.82-3.69 (m, 4H), 2.20 (s, 3H). IV-33 364.1 2.04 1H NMR (500 MHz, methanol-d4) δ 9.57 (d, J=1.5 Hz, 1H), 9.08 (d, J=1.4 Hz, 1H), 8.59 (s, 1H ), 8.34 (d, J=6.8 Hz, 1H), 6.89 (d, J=6.9 Hz, 1H), 4.06-3.98 (m, 2H), 3.98 -3.91 (m, 2H), 3.86-3.76 (m, 4H), 2.26-2.21 (m, 1H), 2.20 (s, 3H), 1.12-1 .01 (m, 4H). IV-34 440.3 2.26 1H NMR (500 MHz, DMSO-d6) δ 10.25 (d, J=3.9 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.73 (d, J =8.5 Hz, 1H), 8.43 (dd, J=6.3, 1.5 Hz, 1H), 6.84 (d, J=6.3 Hz, 1H), 4.74-3 .03 (m, 10H), 2.43-2.29 (m, 1H), 2.07 (s, 2H), 2.05-1.95 (m, 1H), 1.82-1.74 (m, 1H), 1.66-1.50 (m, 2H). IV-35 358.3 2.03 1H NMR (500 MHz, DMSO-d6) δ 9.83 (d, J=1.3 Hz, 1H), 9.13 (d, J=1.3 Hz, 1H), 8.65 (s, 1H ), 8.42 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.3 Hz, 1H), 3.88-3.78 (m, 2H), 3.78 -3.69 (m, 2H), 3.65-3.55 (m, 4H), 2.07 (s, 3H). IV-36 367.3 1.6 1H NMR (500 MHz, DMSO-d6) δ 10.40 (d, J=1.4 Hz, 1H), 9.27 (s, 1H), 9.21 (d, J=1.4 Hz, 1H ), 8.66 (s, 1H), 8.44 (d, J=6.2 Hz, 1H), 8.19 (d, J=16.6 Hz, 1H), 7.81 (s, 1H ), 6.86 (d, J=6.3 Hz, 1H), 3.89-3.80 (m, 2H), 3.80-3.72 (m, 2H), 3.64-3, 58 (m, 4H), 2.08 (s, 3H). IV-37 350.3 2.03 1H NMR (500 MHz, DMSO-d6) δ 9.63 (d, J=1.4 Hz, 1H), 9.21 (d, J=1.3 Hz, 1H), 8.55 (s, 1H ), 8.40 (d, J=6.3 Hz, 1H), 6.95 (dd, J=17.0, 10.6 Hz, 1H), 6.84 (d, J=6.4 Hz , 1H), 6.29 (dd, J=17.0, 1.9 Hz, 1H), 5.49 (dd, J=10.6, 1.9 Hz, 1H), 3.87-3, 79 (m, 2H), 3.79-3.70 (m, 2H), 3.65-3.60 (m, 4H), 2.08 (s, 3H). IV-38 392.4 1.46 IV-39 349.3 1.68 1H NMR (500 MHz, methanol-d4) δ 9.67 (dd, J=4.7, 1.5 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H), 8.68 (s, 1H), 8.36 (d, J=6.9 Hz, 1H), 8.20 (d, J=4.7 Hz, 1H), 7.78 (s, 2H), 6.98 (d, J=6.9 Hz, 1H), 4.77 (dd, J=10.4, 2.8 Hz, 1H), 4.67-4.46 (m, 2H), 4.24- 4.17 (m, 1H), 3.88 (td, J=11.7, 2.8 Hz, 1H), 3.51-3.38 (m, 2H). IV-40 417.3 2.19 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.37 (d, J=1.4 Hz, 1H), 8.90 (s, 1H), 8.56 (d , J=5.2 Hz, 1H), 7.66 (s, 2H), 7.42 (d, J=5.2 Hz, 1H), 4.63-4.54 (m, 2H), 4 .52-4.42 (m, 1H), 4.05 (ddd, J=11.6, 3.5, 1.6 Hz, 1H), 3.76-3.67 (m, 1H), 3 .26-3.17 (m, 1H), 2H not observed. IV-41 403.15 1.96 IV-42 374.15 1.86 IV-43 452.05 2.38 IV-44 387.95 1.95 IV-45 402 2.12 IV-46 488.01 2.61 1H NMR (400 MHz, chloroform-d) δ 10.07 (s, 1H), 9.37-9.31 (m, 1H), 8.53-8.43 (m, 2H), 7.07 ( d, J=5.5 Hz, 1H), 6.93 (s, 1H), 5.02 (d, J=13.8 Hz, 1H), 4.78 (d, J=14.1 Hz, 2H), 3.48 (ddd, J=112.4, 13.9, 6.1 Hz, 2H), 3.08 (t, J=12.9 Hz, 1H), 3.00 (s, 3H ), 3.00-2.90 (m, 1H), 2.42-2.02 (m, 2H), 1.17 (d, J=6.8 Hz, 3H). IV-47 404.3 1.83 1H NMR (500 MHz, DMSO-d6) δ 9.56-9.48 (m, 1H), 9.14 (d, J=1.4 Hz, 1H), 8.57 (s, 1H), 8 .41 (d, J=6.3 Hz, 1H), 7.23 (t, J=6.2 Hz, 1H), 6.81 (d, J=6.4 Hz, 1H), 4.50 (s, 1H), 4.26 (s, 1H), 4.07-3.97 (m, 1H), 3.65-3.54 (m, 2H), 3.22-3.09 (m , 3H), 2.95 (s, 3H), 2.87 (dd, J=13.2, 10.5 Hz, 1H), 2.55 (d, J=0.9 Hz, 3H). IV-48 376.2 1.79 1H NMR (500 MHz, DMSO-d6) δ 10.03 (d, J=1.5 Hz, 1H), 9.32 (d, J=1.3 Hz, 1H), 8.63 (s, 1H ), 8.43 (d, J=6.2 Hz, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.24 (t, J=54.2 Hz, 1H ), 6.88 (d, J=6.3 Hz, 1H), 4.48 (s, 1H), 4.20 (s, 1H), 4.10-3.98 (m, 2H), 3 .69 (td, J=11.2, 2.9 Hz, 1H), 3.34-3.17 (m, 2H). IV-49 360.2 1.72 1H NMR (500 MHz, DMSO-d6) δ 10.00 (d, J=1.5 Hz, 1H), 9.31 (d, J=1.3 Hz, 1H), 8.68 (s, 1H ), 8.41 (d, J=6.3 Hz, 1H), 7.69 (t, J=5.5 Hz, 1H), 7.23 (t, J=54.6 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 3.92 (d, J=15.5 Hz, 4H), 3.33-3.27 (m, 2H), 2.66-2 .57 (m, 2H). IV-50 374.3 1.88 1H NMR (500 MHz, DMSO-d6) δ 10.00 (d, J=1.6 Hz, 1H), 9.32 (d, J=1.3 Hz, 1H), 8.66 (s, 1H ), 8.37 (d, J=6.4 Hz, 1H), 7.40 (s, 1H), 7.21 (t, J=54.5 Hz, 1H), 6.98-6.93 (m, 1H), 6.91 (d, J=6.5 Hz, 1H), 4.69-4.11 (m, 2H), 3.22 (dd, J=13.4, 10.6 Hz, 1H), 3.13 (ddd, J=13.9, 11.7, 2.9 Hz, 1H), 2.43-2.32 (m, 1H), 2.00-1.90 ( m, 1H), 1.86-1.66 (m, 2H), 1.56-1.41 (m, 1H). IV-51 399.3 1.58 1H NMR (500 MHz, DMSO-d6) δ 10.02 (t, J=1.5 Hz, 1H), 9.31 (d, J=1.4 Hz, 1H), 8.70 (s, 1H ), 8.40 (d, J=6.3 Hz, 1H), 7.20 (t, J=54.5 Hz, 1H), 6.93 (d, J=6.4 Hz, 1H), 4.71 (s, 1H), 4.34 (s, 1H), 3.38-3.21 (m, 3H), 2.28-2.16 (m, 1H), 2.03-1, 82 (m, 2H), 1.75-1.59 (m, 1H). IV-52 408.3 2.51 1H NMR (500 MHz, methanol-d4) δ 9.88 (s, 1H), 9.23-9.17 (m, 1H), 8.94 (dd, J=2.1, 0.9 Hz, 1H), 8.83 (ddd, J=5.6, 1.4, 0.7 Hz, 1H), 8.69 (t, J=1.8 Hz, 1H), 8.67 (s, 1H ), 8.32 (d, J=6.8 Hz, 1H), 8.09 (ddd, J=8.2, 5.7, 0.7 Hz, 1H), 6.97 (d, J= 6.9 Hz, 1H), 6.80 (t, J=55.1 Hz, 1H), 4.87-4.74 (m, 1H), 4.72-4.44 (m, 1H), 3.47 (dd, J=13.1, 11.5 Hz, 1H), 3.39-3.34 (m, 1H), 3.25 (ddd, J=11.5, 7.7, 3 .9 Hz, 1H), 2.31-2.18 (m, 1H), 2.15-2.00 (m, 2H), 1.95-1.77 (m, 1H). IV-53 397.3 2.12 1H NMR (500 MHz, methanol-d4) δ 9.98 (d, J=1.6 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.90 (d, J =1.4 Hz, 1H), 8.64 (s, 1H), 8.32 (d, J=6.6 Hz, 1H), 7.49 (t, J=1.0 Hz, 1H), 7.02-6.78 (m, 2H), 4.56-4.32 (m, 1H), 3.41 (dd, J=13.2, 10.7 Hz, 1H), 3.21- 3.10 (m, 1H), 2.33-2.22 (m, 1H), 2.05-1.86 (m, 2H), 1.86-1.70 (m, 1H). IV-54 388.3 1.99 1H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.32 (d, J=1.4 Hz, 1H), 8.67 (s, 1H), 8.43-8 .33 (m, 1H), 7.45 (s, 1H), 7.22 (t, J=54.5 Hz, 1H), 7.04 (s, 1H), 6.88 (d, J= 6.5 Hz, 1H), 3.13-2.89 (m, 1H), 1.94-1.76 (m, 2H), 1.76-1.61 (m, 1H), 1.56 -1.35 (m, 1H), 1.12 (d, J=6.8 Hz, 3H). IV-55 373.3 2.09 1H NMR (500 MHz, DMSO-d6) δ 10.02 (d, J=1.3 Hz, 1H), 9.25 (d, J=1.3 Hz, 1H), 8.61 (s, 1H ), 7.70 (dd, J=8.6, 7.5 Hz, 1H), 7.40-7.29 (m, 2H), 7.14 (t, J=54.5 Hz, 1H) , 6.98-6.86 (m, 2H), 4.35-4.24 (m, 2H), 3.09 (dd, J=13.1, 10.9 Hz, 1H), 2.98 (td, 1H), 2.43-2.34 (m, 1H), 1.99-1.91 (m, 1H), 1.81-1.63 (m, 2H), 1.60-1 .48 (m, 1H). IV-56 410.1 1.96 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.31 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.42 (d , J=6.2 Hz, 1H), 7.21 (t, J=54.2 Hz, 1H), 7.04 (s, 2H), 6.87 (d, J=6.3 Hz, 1H ), 4.33 (s, 1H), 3.18-2.98 (m, 3H), 2.28-2.17 (m, 1H), 1.95-1.85 (m, 1H), 1.85-1.72 (m, 1H), 1.63-1.43 (m, 1H). IV-57 388.2 2.08 1H NMR (500 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.32 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.33 (d , J=6.5 Hz, 1H), 7.27 (s, 1H), 7.15 (t, J=54.5 Hz, 1H), 6.95 (s, 1H), 6.91 (d , J=6.4 Hz, 1H), 4.30 (s, 1H), 3.96 (s, 1H), 2.18-2.09 (m, 1H), 1.74-1.65 ( m, 1H), 1.65-1.47 (m, 2H), 1.13 (s, 4H). IV-58 397.1 2.32 1H NMR (500 MHz, DMSO-d6) δ 10.00 (d, J=1.7 Hz, 1H), 9.32 (d, J=1.3 Hz, 1H), 8.66 (s, 1H ), 8.37 (d, J=6.4 Hz, 1H), 7.60 (s, 2H), 7.15 (t, J=54.6 Hz, 1H), 6.96 (d, J =6.5 Hz, 1H), 3.22-3.08 (m, 2H), 2.82-2.69 (m, 1H), 2.15-2.02 (m, 1H), 1, 89-1.78 (m, 1H), 1.71 (qd, J=11.8, 3.2 Hz, 1H), 1.66-1.52 (m, 1H). IV-59 415.1 2.59 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.71 (s, 1H), 8.38 (d , J=6.4 Hz, 1H), 7.59 (s, 2H), 6.96 (d, J=6.5 Hz, 1H), 3.20-3.08 (m, 2H), 2 .80-2.70 (m, 1H), 2.13-2.04 (m, 1H), 1.83 (dt, J=13.2, 3.5 Hz, 1H), 1.71 (qd , J=11.9, 3.5 Hz, 1H), 1.66-1.52 (m, 1H). IV-60 392.1 2.14 1H NMR (500 MHz, DMSO-d6) δ 10.27-10.20 (m, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8 .37 (d, J=6.3 Hz, 1H), 7.39 (s, 1H), 6.95-6.86 (m, 2H), 4.41 (s, 1H), 3.17 ( dd, J=13.3, 10.8 Hz, 1H), 3.08 (td, J=13.0, 12.5, 2.8 Hz, 1H), 2.41-2.30 (m, 1H), 1.99-1.88 (m, 1H), 1.84-1.66 (m, 2H), 1.57-1.39 (m, 1H). IV-61 454.3 2.13 1H NMR (500 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.32 (d, J=1.4 Hz, 1H), 8.70 (s, 1H), 8.44 (d , J=6.3 Hz, 1H), 7.28 (d, J=54.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 6.86 (d, J =6.4 Hz, 1H), 4.12-4.00 (m, 1H), 3.61-3.51 (m, 1H), 3.46-3.40 (m, 1H), 3, 11 (d, J=13.1 Hz, 1H), 3.02-2.98 (m, 1H), 2.97 (s, 3H), 1.23 (d, J=6.8 Hz, 3H ). 2 C-H missing IV-62 454.3 2.15 1H NMR (500 MHz, DMSO-d6) δ 10.05 (d, J=1.7 Hz, 1H), 9.32 (d, J=1.3 Hz, 1H), 8.66 (s, 1H ), 8.45 (d, J=6.3 Hz, 1H), 7.29 (d, J=47.9 Hz, 1H), 7.23 (d, J=1.9 Hz, 1H), 6.84 (d, J=6.3 Hz, 1H), 4.78-4.18 (m, 2H), 4.09-4.02 (m, 1H), 3.58 (td, J= 11.7, 2.8 Hz, 1H), 3.47 (dp, J=9.0, 6.6 Hz, 1H), 3.34 (ddd, J=10.6, 6.5, 2, 5 Hz, 1H), 3.18-3.07 (m, 1H), 3.00 (s, 3H), 2.89 (t, J=12.1 Hz, 1H), 1.23 (d, J=6.7 Hz, 3H). IV-63 360.1 1.7 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.34 (d, J=1.3 Hz, 1H), 8.67 (s, 1H), 8.35 (d , J=6.3 Hz, 1H), 7.58 (s, 1H), 7.30 (d, J=55.0 Hz, 1H), 7.07 (s, 1H), 6.57 (s , 1H), 4.00-3.46 (m, 2H), 2.36-2.13 (m, 2H), 1.31-1.21 (m, 3H). IV-64 383.2 2.17 IV-65 397 2.3 IV-66 424.15 2.04 IV-67 383.1 1.95 IV-68 393.85 2.33 IV-69 385.8 1.9 IV-70 410.05 1.93 IV-71 410.1 1.97 IV-72 333.14 1.84 1H NMR (400 MHz, DMSO-d6) δ 10.08 (d, J=4.3 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.69 (s, 1H ), 8.35 (s, 1H), 7.25 (s, 1H), 6.59 (s, 1H), 4.49 (s, 1H), 3.93-3.67 (m, 2H) , 3.58 (s, 2H), 3.38 (d, J=11.4 Hz, 1H), 2.17-2.06 (m, 1H), 2.02 (s, 1H). IV-73 373.2 2.23 IV-74 439.3 2.1 1H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.33 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8.38 (d , J=6.4 Hz, 1H), 7.22 (t, J=54.6 Hz, 1H), 6.88 (d, J=6.5 Hz, 1H), 6.80-6.41 (m, 3H), 3.18 (ddd, J=13.8, 11.2, 3.1 Hz, 1H), 2.93 (dd, J=13.3, 10.1 Hz, 1H), 2.88 (d, J=6.9 Hz, 2H), 1.87 (dt, J=12.9, 4.0 Hz, 1H), 1.78 (th, J=10.4, 3, 5 Hz, 2H), 1.57-1.43 (m, 1H), 1.43-1.29 (m, 1H). 2C-H missing IV-75 357.05 3.04 IV-76 394.05 2.34 IV-77 394 2.49 IV-78 388.3 2.09 1H NMR (500 MHz, DMSO-d6) δ 10.07 (d, J=1.4 Hz, 1H), 9.31 (d, J=1.3 Hz, 1H), 8.68 (s, 1H ), 8.43 (d, J=6.3 Hz, 1H), 6.87 (d, J=6.4 Hz, 1H), 3.80 (d, J=31.0 Hz, 4H), 3.66-3.60 (m, 4H), 2.11 (t, J=19.1 Hz, 2H), 2.08 (s, 3H). IV-79 401.3 1.98 1H NMR (500 MHz, DMSO-d6) δ 10.15 (q, J=1.5 Hz, 1H), 9.41 (d, J=1.4 Hz, 1H), 9.14 (d, J =5.3 Hz, 1H), 8.90 (s, 1H), 8.86 (t, J=1.8 Hz, 1H), 8.61 (dt, J=7.9, 1.4 Hz , 1H), 8.24-8.04 (m, 2H), 7.88 (t, J=7.8 Hz, 1H), 7.29 (t, J=54.2 Hz, 1H), 6 .32 (s, 2H), 3.22 (d, J=1.2 Hz, 3H). IV-80 365.05 1.62 IV-81 347.04 2.28 IV-82 370.15 2.43 IV-83 386.25 1.63 IV-84 381.1 1.85 IV-85 345.19 2.92 IV-86 401.3 1.8 1H NMR (500 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.33 (d, J=1.3 Hz, 1H), 8.64 (s, 1H), 8.45 (d , J=6.2 Hz, 1H), 8.23 (s, 1H), 7.26 (t, J=54.0 Hz, 1H), 6.92 (d, J=6.3 Hz, 1H ), 4.59-4.30 (m, 1H), 3.49-3.13 (m, 8H), 2.96-2.62 (m, 2H). IV-87 415.95 1.97 IV-88 375.05 2.3 IV-89 389 1.73 IV-90 375.05 2.18 IV-91 359.1 2.25 IV-92 441.05 2.11 IV-93 427 2.04 IV-94 440.3 1.96 IV-95 454.1 2.05 IV-96 409.3 2.4 1H NMR (500 MHz, methanol-d4) δ 10.14 (s, 1H), 9.21 (d, J=1.3 Hz, 1H), 8.67 (s, 1H), 8.35 (d , J=6.6 Hz, 1H), 7.68 (s, 1H), 7.00 (t, J=55.1 Hz, 1H), 6.91 (d, J=6.6 Hz, 1H ), 6.08 (p, J=2.4 Hz, 1H), 4.50 (s, 2H), 4.04 (s, 2H), 2.59-2.46 (m, 2H), 2 .39 (s, 3H). IV-97 411.4 2.4 1H NMR (500 MHz, methanol-d4) δ 9.92-9.85 (m, 1H), 9.29-9.25 (m, 1H), 8.71 (s, 1H), 8.28 ( d, J=7.2 Hz, 1H), 7.76 (s, 1H), 7.01 (d, J=7.2 Hz, 1H), 6.87 (t, J=55.2 Hz, 1H), 4.79-4.37 (m, 2H), 3.43-3.33 (m, 2H), 2.91 (tt, J=11.3, 3.9 Hz, 1H), 2 .32 (s, 3H), 2.19-2.10 (m, 1H), 2.10-1.98 (m, 1H), 1.98-1.69 (m, 2H). IV-98 386.1 1.91 IV-99 400.15 2.04 IV-100 388.1 1.91 IV-101 424.85 1.92 IV-102 401.05 2.61 1H NMR (400 MHz, DMSO-d6) δ 10.04 (d, J=6.9 Hz, 1H), 9.34 (d, J=1.3 Hz, 1H), 8.69 (d, J =6.2 Hz, 1H), 8.32 (d, J=6.4 Hz, 1H), 7.22 (td, J=54.3, 4.6 Hz, 1H), 6.57 (dd , J=18.4, 6.5 Hz, 1H), 4.04-3.84 (m, 3H), 3.74-3.53 (m, 1H), 3.38-3.01 (m , 3H), 2.22-2.06 (m, 3H), 1.75-1.63 (m, 3H), 1.53 (d, J=11.0 Hz, 1H), 1.30 ( qd, J=12.2, 11.8, 5.1 Hz, 2H). IV-103 330.92 2.74 1H NMR (400 MHz, DMSO-d6) δ 9.98 (d, J=1.4 Hz, 1H), 9.34 (d, J=1.3 Hz, 1H), 8.67 (s, 1H ), 8.36 (d, J=6.5 Hz, 1H), 7.30 (d, J=54.6 Hz, 1H), 6.89 (d, J=6.6 Hz, 1H), 3.79 (d, J=6.4 Hz, 4H), 1.71 (q, J=6.2, 5.4 Hz, 2H), 1.68-1.57 (m, 4H). IV-104 333.04 2.11 IV-105 344.99 2.88 1H NMR (400 MHz, DMSO-d6) δ 10.00 (d, J=1.4 Hz, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.69 (s, 1H ), 8.34 (d, J=6.5 Hz, 1H), 7.23 (t, J=54.7 Hz, 1H), 6.77 (d, J=6.6 Hz, 1H), 3.93 (s, 2H), 3.65 (s, 2H), 1.82 (d, J=21.9 Hz, 4H), 1.54 (p, J=2.6 Hz, 4H). IV-106 388.3 2.02 1H NMR (500 MHz, DMSO-d6) δ 10.03 (q, J=1.3 Hz, 1H), 9.30 (d, J=1.3 Hz, 1H), 8.62 (s, 1H ), 8.36 (d, J=6.3 Hz, 1H), 7.45 (d, J=3.2 Hz, 1H), 7.20 (t, J=54.5 Hz, 1H), 7.02-6.93 (m, 1H), 6.85 (d, J=6.4 Hz, 1H), 3.14-2.99 (m, 1H), 2.41-2.26 ( m, 1H), 1.89-1.74 (m, 2H), 1.74-1.67 (m, 2H), 1.22 (d, J=6.8 Hz, 3H), 2H not observed . IV-107 388.3 2.07 IV-108 388.3 2.04 1H NMR (500 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.29 (s, 1H), 8.60 (s, 1H), 8.31 (d, J=6.3 Hz , 1H), 7.30 (s, 1H), 7.14 (t, J=54.4 Hz, 1H), 6.89-6.83 (m, 1H), 6.80 (d, J= 6.3 Hz, 1H), 3.87 (s, 2H), 3.78-3.66 (m, 1H), 3.66-3.53 (m, 1H), 2.30-2.15 (m, 1H), 1.84-1.70 (m, 1H), 1.70-1.58 (m, 1H), 1.01 (d, J=7.0 Hz, 3H), 1H not observed. IV-109 388.3 2.01 1H NMR (500 MHz, methanol-d4) δ 9.92 (s, 1H), 9.31-9.24 (m, 1H), 8.73 (s, 1H), 8.30 (d, J= 7.1 Hz, 1H), 7.15-6.85 (m, 2H), 2.79-2.67 (m, 1H), 2.14-2.05 (m, 1H), 2.05 -1.97 (m, 1H), 1.92-1.83 (m, 1H), 1.73-1.59 (m, 1H), 1.36 (d, J=6.9 Hz, 3H ), 3H is not observed. IV-110 389.3 1.57 IV-111 359.05 2.05 IV-112 411.15 2.46 IV-113 427.35 1.63 IV-114 424.15 2.07 IV-115 379.15 2.96 IV-116 387.1 2.22 IV-117 390 1.69 IV-118 359.85 1.88 IV-119 361.05 2.52 IV-120 347.09 2.02 IV-121 361.1 2.16 IV-122 359.45 3.08 IV-123 415.1 1.94 1H NMR (400 MHz, methanol-d4) δ 10.18 (d, J=1.6 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.65 (s, 1H ), 8.53-8.44 (m, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.14-6.54 (m, 2H), 4.38 (s, 1H), 4.08 (d, J=6.7 Hz, 2H), 3.47 (d, J=5.1 Hz, 3H), 3.37 (d, J=2.8 Hz, 1H) , 3.33 (p, J=1.6 Hz, 2H), 2.93 (d, J=1.5 Hz, 2H), 2.43 (td, J=13.6, 4.9 Hz, 2H), 2.17 (d, J=14.0 Hz, 2H), 1.25 (s, 2H). IV-124 438.56 2.12 1H NMR (400 MHz, methanol-d4) δ 10.18 (d, J=1.6 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.65 (s, 1H ), 8.53-8.44 (m, 1H), 7.45 (d, J=1.5 Hz, 1H), 7.14-6.54 (m, 2H), 4.38 (s, 1H), 4.08 (d, J=6.7 Hz, 2H), 3.47 (d, J=5.1 Hz, 3H), 3.37 (d, J=2.8 Hz, 1H) , 3.33 (p, J=1.6 Hz, 2H), 2.93 (d, J=1.5 Hz, 2H), 2.43 (td, J=13.6, 4.9 Hz, 2H), 2.17 (d, J=14.0 Hz, 2H), 1.25 (s, 2H). IV-125 424.41 2.16 1H NMR (400 MHz, methanol-d4) δ 10.20 (s, 1H), 9.25 (s, 1H), 8.74 (s, 1H), 8.29 (d, J=6.6 Hz , 1H), 6.96 (t, J=55.0 Hz, 1H), 6.61 (d, J=6.7 Hz, 1H), 4.16 (s, 1H), 3.83 (s , 2H), 3.58 (d, J=61.8 Hz, 1H), 2.97 (d, J=15.0 Hz, 6H), 2.67 (s, 1H), 2.41 (s , 2H). IV-126 436.3 2.25 1H NMR (400 MHz, methanol-d4) δ 10.12 (s, 1H), 9.21 (s, 1H), 8.67 (s, 1H), 8.38 (d, J=6.4 Hz , 1H), 6.95 (t, J=55.1 Hz, 1H), 6.74 (d, J=6.5 Hz, 1H), 4.47 (s, 2H), 3.46-3 .37 (m, 2H), 3.08 (s, 3H), 2.13 (d, J=9.5 Hz, 2H), 2.04 (s, 2H), 1.87 (t, J= 7.1 Hz, 2H). IV-127 438.3 2.2 1H NMR (400 MHz, methanol-d4) δ 9.84 (s, 1H), 8.96 (d, J=0.9 Hz, 1H), 8.44 (s, 1H), 8.08 (d , J=6.5 Hz, 1H), 6.72 (t, J=54.9 Hz, 1H), 6.48 (d, J=6.6 Hz, 1H), 3.38-3.21 (m, 1H), 2.92 (t, J=12.9 Hz, 1H), 2.76 (s, 3H), 2.43 (s, 3H), 1.78-1.44 (m, 4H), 1.12 (d, J=6.9 Hz, 3H). IV-128 390.3 1.72 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.32 (d, J=1.1 Hz, 1H), 8.66 (s, 1H), 8.40 (d , J=6.2 Hz, 1H), 7.48 (s, 1H), 7.22 (t, J=54.5 Hz, 1H), 7.05 (s, 1H), 6.89 (s , 1H), 4.45 (s, 1H), 4.10-3.51 (m, 6H), 2.95 (s, 2H). IV-129 344.87 2.96 1H NMR (400 MHz, DMSO-d6) δ 9.75 (d, J=1.4 Hz, 1H), 9.09 (d, J=1.3 Hz, 1H), 8.43 (s, 1H ), 8.11 (d, J=6.5 Hz, 1H), 6.99 (t, J=54.7 Hz, 1H), 6.66 (d, J=6.6 Hz, 1H), 2.84 (ddd, J=13.3, 11.7, 2.9 Hz, 1H), 2.54 (dd, J=13.1, 10.6 Hz, 1H), 1.70-1, 31 (m, 2H), 1.32-0.93 (m, 2H), 0.73 (d, J=6.6 Hz, 3H). The peak of the water obscures some signals. IV-130 370.88 3.17 1H NMR (400 MHz, DMSO-d6) δ 10.01 (d, J=1.6 Hz, 1H), 9.33 (d, J=1.4 Hz, 1H), 8.67 (s, 1H ), 8.36 (d, J=6.4 Hz, 1H), 7.23 (t, J=54.7 Hz, 1H), 6.90-6.80 (m, 1H), 2.99 (td, J=12.8, 3.0 Hz, 1H), 2.06 (dq, J=11.7, 5.8 Hz, 1H), 1.99-1.58 (m, 8H), 1.57-1.27 (m, 3H). The peak of the water obscures some signals. IV-131 359.43 3.04 IV-132 472.38 3.07 IV-133 486.23 3.13 IV-134 359.58 3.1 IV-135 343.27 2.83 1H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.08 (s, 1H), 8.41 (s, 1H), 8.18 (d, J=6.3 Hz , 1H), 6.98 (t, J=54.6 Hz, 1H), 6.62 (d, J=6.4 Hz, 1H), 2.58 (t, J=7.5 Hz, 1H ), 1.76 (tt, J=11.9, 5.7 Hz, 1H), 1.61-1.43 (m, 3H), 1.29-1.08 (m, 3H), 0, 80 (dt, J=10.5, 5.8 Hz, 1H), 0.07 (d, J=4.2 Hz, 1H). IV-136 361.43 2.26 IV-137 345.12 2.95 IV-138 361.3 2.16 IV-139 443.1 0.64 IV-140 386.1 0.69 IV-141 422 1.99 1H NMR (500 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.30 (s, 1H), 8.62 (s, 1H), 8.35 (d, J=6.3 Hz , 1H), 7.22 (t, J=54.5 Hz, 1H), 6.78 (d, J=6.2 Hz, 1H), 4.25 (br s, 1H), 3.29- 3.24 (m, 2H), 3.18-3.07 (m, 1H), 3.05 (s, 3H), 3.02 (s, 3H), 2.95-2.85 (m, 1H), 1.95-1.84 (m, 1H), 1.83-1.69 (m, 1H), 1.57-1.44 (m, 2H). IV-142 361.15 2.15 IV-143 357.45 2.06 1H NMR (400 MHz, methanol-d4) δ 9.93 (s, 1H), 9.33-9.28 (m, 1H), 8.77 (d, J=0.8 Hz, 1H), 8 .33 (dd, J=7.2, 0.8 Hz, 1H), 7.08-7.01 (m, 2H), 4.62 (s, 2H), 3.33 (pd, J=1 ,7, 0.7 Hz, 4H), 3.19 (dd, J=13.3, 10.7 Hz, 1H), 3.13-2.90 (m, 2H), 2.16-1, 99 (m, 2H), 1.81-1.67 (m, 1H), 1.64-1.50 (m, 1H). IV-144 450.1 2.29 1H NMR (400 MHz, methanol-d4) δ 9.86 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.80 (s, 1H), 8.29 (d , J=7.5 Hz, 1H), 7.26-6.89 (m, 2H), 3.99 (dt, J=7.5, 4.9 Hz, 1H), 3.81-3, 61 (m, 1H), 3.50 (s, 1H), 2.83-2.69 (m, 1H), 2.68 (s, 3H), 2.24-2.07 (m, 1H) , 1.69-1.13 (m, 7H). IV-145 464.15 2.38 1H NMR (400 MHz, methanol-d4) δ 10.14 (s, 1H), 9.36 (s, 1H), 8.84 (d, J=4.6 Hz, 1H), 8.28 (d , J=7.4 Hz, 1H), 7.20-7.03 (m, 1H), 6.94-6.80 (m, 1H), 4.12 (t, J=7.3 Hz, 1H), 3.94 (s, 1H), 3.87 (t, J=7.3 Hz, 1H), 3.68 (s, 1H), 3.52 (dt, J=10.5, 5 ,3 Hz, 1H), 3.18 (td, J=14.1, 12.4, 6.9 Hz, 1H), 2.90 (d, J=4.9 Hz, 3H), 2.68 (s, 1H), 1.91-1.83 (m, 4H), 1.68-1.51 (m, 1H), 1.43-1.30 (m, 2H). IV-146 431.1 2.34 1H NMR (400 MHz, DMSO-d6) δ 10.16 (q, J=1.3 Hz, 1H), 9.39 (d, J=1.3 Hz, 1H), 9.07 (d, J =5.3 Hz, 1H), 8.89 (s, 1H), 8.36 (d, J=2.0 Hz, 1H), 8.29-8.21 (m, 1H), 8.04 (d, J=5.4 Hz, 1H), 7.71 (q, J=6.4 Hz, 1H), 7.67-7.53 (m, 2H), 7.28 (t, J= 54.5 Hz, 1H), 4.34 (d, J=6.2 Hz, 2H), 2.93 (s, 3H). IV-147 416.7 2.25 1H NMR (400 MHz, DMSO-d6) δ 10.09 (d, J=1.4 Hz, 1H), 10.02 (s, 1H), 9.39 (d, J=1.3 Hz, 1H ), 9.07 (d, J=5.4 Hz, 1H), 8.83 (s, 1H), 8.23 (s, 1H), 8.08-7.95 (m, 2H), 7 .60 (t, J=7.9 Hz, 1H), 7.51-7.38 (m, 1H), 7.20 (d, J=54.2 Hz, 1H), 3.10 (s, 3H). IV-148 417 2.37 1H NMR (400 MHz, DMSO-d6) δ 10.12 (q, J=1.4 Hz, 1H), 9.40 (d, J=1.3 Hz, 1H), 9.14 (d, J =5.4 Hz, 1H), 8.90 (s, 1H), 8.72 (t, J=1.8 Hz, 1H), 8.60 (dt, J=7.8, 1.4 Hz , 1H), 8.14 (d, J=5.4 Hz, 1H), 8.03 (dt, J=7.9, 1.3 Hz, 1H), 7.88 (t, J=7, 8 Hz, 1H), 7.68 (q, J=5.0 Hz, 1H), 7.26 (t, J=54.3 Hz, 1H). Some peaks are masked by solvent peaks IV-149 409.2 2.49 IV-150 436.25 1.99 IV-151 487.26 2.68 IV-152 438.4 2.23 1H NMR (400 MHz, methanol-d4) δ 9.86 (s, 1H), 9.34 (d, J=1.3 Hz, 1H), 8.77 (s, 1H), 8.26 (d , J=7.5 Hz, 1H), 7.12-7.03 (m, 2H), 3.68-3.58 (m, 2H), 3.11 (d, J=7.0 Hz, 2H), 2.93 (s, 3H), 2.68 (s, 2H), 2.12-1.96 (m, 3H), 1.65-1.53 (m, 2H), 1.40 (dd, J=6.7, 3.8 Hz, 1H). IV-153 384 2.17 IV-154 342.19 2.27 1H NMR (400 MHz, DMSO-d6) δ 10.13 (q, J=1.4 Hz, 1H), 9.36 (dd, J=4.8, 1.3 Hz, 1H), 8.91 -8.78 (m, 2H), 8.69 (d, J=5.3 Hz, 1H), 8.32 (s, 1H), 7.72-7.64 (m, 1H), 7, 30 (t, J=54.4 Hz, 1H), 4.26 (q, J=7.3 Hz, 2H), 1.48 (t, J=7.3 Hz, 3H). IV-155 381 2.06 IV-156 371.1 2.06 IV-157 363 2.56 1H NMR (400 MHz, DMSO-d6) δ 10.14 (q, J=1.4 Hz, 1H), 9.39 (d, J=1.3 Hz, 1H), 9.08 (d, J =5.3 Hz, 1H), 8.89 (s, 1H), 8.38 (s, 1H), 8.30 (dt, J=7.4, 1.8 Hz, 1H), 8.06 (d, J=5.4 Hz, 1H), 7.71-7.60 (m, 2H), 7.29 (t, J=54.4 Hz, 1H), 4.21 (s, 2H) . IV-158 377 2.96 IV-159 353 2.6 IV-160 430.75 2.3 IV-161 340.04 2.35 IV-162 354.05 2.25 1H NMR (400 MHz, DMSO-d6) δ 10.18-10.05 (m, 1H), 9.35 (d, J=1.3 Hz, 1H), 9.10-8.98 (m, 1H), 8.82 (s, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.23-8.06 (m, 1H), 8.00 (d, J=5 ,4 Hz, 1H), 7.63-7.52 (m, 2H), 7.26 (t, J=54.5 Hz, 1H), 5.32 (s, 1H), 4.66 (s , 2H). IV-163 313.84 2.88 IV-164 424.1 2.15 IV-165 409.05 2.06 IV-166 436.15 2.53 IV-167 396 2.12 IV-168 438.05 2.3 1H NMR (400 MHz, methanol-d4) δ 9.80 (d, J=1.8 Hz, 1H), 9.31 (d, J=1.4 Hz, 1H), 8.76 (d, J =1.2 Hz, 1H), 8.29 (dd, J=7.4, 1.2 Hz, 1H), 7.29-6.75 (m, 2H), 3.96-3.83 ( m, 1H), 3.53-3.40 (m, 1H), 3.36-3.19 (m, 3H), 2.96 (dd, J=11.5, 1.3 Hz, 6H) , 2.08 (dq, J=8.1, 4.6 Hz, 3H), 1.82 (dp, J=18.9, 6.3, 5.0 Hz, 1H). IV-169 424.55 2.09 1H NMR (400 MHz, methanol-d4) δ 9.82 (s, 1H), 9.34 (d, J=1.4 Hz, 1H), 8.78 (d, J=6.8 Hz, 1H ), 8.29 (dd, J=7.3, 1.5 Hz, 1H), 7.13-7.04 (m, 2H), 4.13 (s, 1H), 3.82 (dd, J=13.3, 7.6 Hz, 1H), 3.65 (dq, J=8.0, 3.9 Hz, 1H), 3.00 (s, 3H), 2.18 (d, J =10.0 Hz, 2H), 2.04 (ddd, J=12.6, 7.7, 4.2 Hz, 2H), 1.91-1.78 (m, 3H). IV-170 438.05 2.39 IV-171 478.16 2.7 IV-172 480.11 2.34 IV-173 474 2.19 IV-174 414.3 2.65 1H NMR (500 MHz, DMSO-d6) δ 10.01 (d, J=1.8 Hz, 1H), 9.31 (d, J=1.4 Hz, 1H), 9.09 (d, J =1.9 Hz, 1H), 8.64 (s, 1H), 8.37 (d, J=6.4 Hz, 1H), 7.52 (d, J=1.9 Hz, 1H), 7.17 (t, J=54.5 Hz, 1H), 6.92 (d, J=6.4 Hz, 1H), 3.30 (t, J=12.3 Hz, 1H), 3, 20 (td, J=12.6, 11.7, 2.8 Hz, 1H), 3.12-3.01 (m, 1H), 2.24-2.10 (m, 1H), 1, 98-1.79 (m, 2H), 1.65 (d, J=12.2 Hz, 1H), 2H not observed. IV-175 359.8 2.16 IV-176 385.1 2.16 IV-177 410 1.97 IV-178 442.1 2.52 1H NMR (400 MHz, methanol-d4) δ 9.98 (s, 1H), 9.56-9.02 (m, 1H), 8.73 (s, 1H), 8.30 (d, J= 6.8 Hz, 1H), 7.56 (s, 1H), 7.14-6.59 (m, 2H), 3.96 (tt, J=9.8, 4.2 Hz, 1H), 3.43-3.13 (m, 7H), 2.26-1.66 (m, 5H). 1 exchanging proton is not observed. IV-179 425.1 1.97 1H NMR (400 MHz, methanol-d4) δ 10.08-9.84 (m, 1H), 9.35-9.20 (m, 1H), 8.71 (s, 1H), 8.29 ( d, J=6.9 Hz, 1H), 7.22-6.84 (m, 2H), 4.45 (s, 1H), 4.18 (s, 1H), 3.73-3.46 (m, 3H), 2.18 (d, J=4.9 Hz, 1H), 2.00 (td, J=8.3, 6.7, 4.8 Hz, 1H), 1.77 ( ddt, J=8.8, 5.7, 3.5 Hz, 2H). no exchanging protons are observed IV-180 442.2 2.48 1H NMR (400 MHz, methanol-d4) δ 9.98 (s, 1H), 9.56-9.02 (m, 1H), 8.73 (s, 1H), 8.30 (d, J= 6.8 Hz, 1H), 7.56 (s, 1H), 7.14-6.59 (m, 2H), 3.96 (tt, J=9.8, 4.2 Hz, 1H), 3.43-3.13 (m, 7H), 2.26-1.66 (m, 5H). 1 exchanging proton is not observed. IV-181 424.7 1.96 1H NMR (400 MHz, methanol-d4) δ 9.82 (s, 1H), 9.36-9.30 (m, 1H), 8.78 (d, J=0.8 Hz, 1H), 8 .32 (dd, J=7.4, 0.8 Hz, 1H), 7.19-6.88 (m, 2H), 4.80 (s, 1H), 4.41 (s, 1H), 4.02 (dq, J=9.6, 4.8, 4.1 Hz, 1H), 3.47 (ddd, J=19.8, 13.4, 10.5 Hz, 2H), 2, 17 (dd, J=10.3, 5.8 Hz, 1H), 2.12-2.02 (m, 1H), 1.93-1.77 (m, 2H). No exchanged protons are observed. IV-182 367.1 1.67 1H NMR (400 MHz, methanol-d4) δ 10.60 (s, 1H), 9.12 (s, 1H), 8.50 (s, 1H), 8.44 (dd, J=5.3, 0.6 Hz, 1H), 7.53 (d, J=0.6 Hz, 2H), 7.13 (d, J=5.2 Hz, 1H), 4.05 (dd, J=6, 5, 4.2 Hz, 2H), 4.01-3.93 (m, 2H), 3.76 (ddd, J=11.1, 6.7, 4.2 Hz, 4H), 2.20 (s, 3H). IV-183 367.05 1.56 1H NMR (400 MHz, methanol-d4) δ 10.51 (d, J=1.4 Hz, 1H), 9.15 (d, J=1.4 Hz, 1H), 8.69-8.49 (m, 2H), 8.27 (d, J=7.1 Hz, 2H), 6.74 (d, J=74.5 Hz, 1H), 3.90-3.73 (m, 9H) , 2.24-2.11 (m, 2H). IV-184 366.15 1.83 1H NMR (400 MHz, methanol-d4) δ 10.51 (d, J=1.4 Hz, 1H), 9.15 (d, J=1.4 Hz, 1H), 8.69-8.49 (m, 2H), 8.27 (d, J=7.1 Hz, 2H), 6.74 (d, J=74.5 Hz, 1H), 3.90-3.73 (m, 9H) , 2.24-2.11 (m, 2H). IV-185 417.1 2.21 IV-186 417 2.21 IV-187 337.94 2.35 1H NMR (400 MHz, DMSO-d6) δ 10.37 (d, J=1.4 Hz, 1H), 9.23 (d, J=1.4 Hz, 1H), 8.65 (s, 1H ), 8.36 (d, J=6.4 Hz, 1H), 8.19 (s, 1H), 7.83 (s, 1H), 6.88 (d, J=6.5 Hz, 1H ), 3.07 (t, J=12.1 Hz, 1H), 2.82-2.68 (m, 1H), 1.85-1.74 (m, 2H), 1.66 (s, 1H), 1.51 (d, J=12.4 Hz, 1H), 1.27 (d, J=12.3 Hz, 1H), 1.16 (s, 1H), 1.01 (d, J=6.6 Hz, 3H). 1 proton peak is masked by solvent peaks IV-188 381.1 1.86 1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 9.23 (s, 1H), 8.77 (s, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 7.30 (s, 1H), 3.90 (dt, J=29.0, 5.2 Hz, 4H), 3.61 (q, J=6.0 Hz, 4H) , 2.39 (s, 3H), 2.09 (s, 3H). IV-189 430.3 2.19 1H NMR (500 MHz, methanol-d4) δ 10.30 (dd, J=1.5, 0.7 Hz, 1H), 9.24-9.18 (m, 1H), 8.72 (s, 1H), 8.51 (d, J=6.3 Hz, 1H), 7.92 (s, 2H), 6.98 (d, J=6.3 Hz, 1H), 5.04-4, 85 (m, 2H), 4.64 (dd, J=11.9, 3.5 Hz, 1H), 3.63 (ddd, J=11.6, 6.6, 3.6 Hz, 1H) , 3.55 (dd, J=14.4, 11.9 Hz, 1H), 3.15 (dd, J=14.5, 11.5 Hz, 1H), 1.50 (d, J=6 ,6 Hz, 3H). IV-190 381.24 1.58 1H NMR (400 MHz, methanol-d4) δ 10.51-10.42 (m, 1H), 9.21 (dd, J=5.3, 1.4 Hz, 1H), 8.71 (d, J=1.5 Hz, 1H), 8.32 (dd, J=11.9, 6.8 Hz, 1H), 6.89 (d, J=7.1 Hz, 1H), 4.25 ( s, 2H), 3.94 (s, 5H), 3.65 (dt, J=22.5, 6.0 Hz, 2H), 2.21 (s, 1H), 2.10 (d, J =7.3 Hz, 3H), 1.39 (dd, J=6.7, 3.3 Hz, 1H). one proton peak is masked by solvent peaks IV-191 388.3 2.05 IV-192 397.2 2.19 IV-193 397.3 2.24 IV-194 388.3 2.1 IV-195 444.3 2.35 1H NMR (500 MHz, methanol-d4) δ 10.34-10.23 (m, 1H), 9.21 (dd, J=1.3, 0.7 Hz, 1H), 8.71 (s, 1H), 8.51 (d, J=6.3 Hz, 1H), 7.92 (s, 2H), 6.96 (d, J=6.3 Hz, 1H), 4.88 (s, 2H), 4.62-4.44 (m, 1H), 3.71 (t, J=13.1 Hz, 1H), 3.62-3.47 (m, 1H), 3.36-3 .32 (m, 1H), 2.80 (s, 3H), 1.60 (d, J=6.4 Hz, 3H). IV-196 381.09 1.72 1H NMR (400 MHz, methanol-d4) δ 10.45 (d, J=1.3 Hz, 1H), 8.93 (d, J=1.4 Hz, 1H), 8.46 (s, 1H ), 7.61 (d, J=0.6 Hz, 2H), 6.44 (s, 1H), 3.78 (t, J=5.2 Hz, 2H), 3.60 (dt, J =10.8, 4.0 Hz, 6H), 2.31 (s, 3H), 2.02 (s, 3H). IV-197 373.05 2.1 1H NMR (400 MHz, methanol-d4) δ 10.21 (d, J=1.8 Hz, 1H), 9.19-9.13 (m, 1H), 8.49 (s, 1H), 7 .75 (dd, J=8.6, 7.5 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.14-6.82 (m, 2H), 3, 84-3.68 (m, 8H), 2.20 (s, 3H). IV-198 347.54 1.99 1H NMR (400 MHz, methanol-d4) δ 10.32 (d, J=1.4 Hz, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.53 (s, 1H ), 7.80 (dd, J=8.6, 7.5 Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 6.98 (d, J=8.6 Hz , 1H), 3.97-3.68 (m, 8H), 2.24 (s, 3H). IV-199 431.1429 2.41 IV-200 431.1 2.39 IV-201 431 2.39 IV-202 431.1 2.41 IV-203 390.3 1.81 IV-204 322.79 2.42 1H NMR (400 MHz, methanol-d4) δ 10.65 (s, 1H), 9.10 (s, 1H), 8.45 (s, 1H), 7.80-7.55 (m, 1H) , 7.28 (d, J=7.4 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 3.74 (s, 5H), 3.60-3.37 ( m, 1H), 3.24-3.01 (m, 4H), 2.27-1.95 (m, 2H). IV-205 337.09 2.67 1H NMR (400 MHz, DMSO-d6) δ 10.44 (d, J=1.4 Hz, 1H), 9.16 (d, J=1.3 Hz, 1H), 8.60 (s, 1H ), 8.12 (s, 1H), 7.76 (s, 1H), 7.67 (dd, J=8.6, 7.5 Hz, 1H), 7.34 (d, J=7, 4 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 4.42-4.21 (m, 2H), 2.92 (td, J=12.4, 2.8 Hz, 1H), 2.71-2.57 (m, 1H), 1.91-1.46 (m, 4H), 1.32-1.10 (m, 1H), 1.01 (d, J=6.5 Hz, 3H). IV-206 396.3 2.01 1H NMR (500 MHz, methanol-d4) δ 9.92 (d, J=1.4 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H), 8.64 (s, 1H ), 8.50 (d, J=6.2 Hz, 1H), 7.93 (s, 2H), 6.95 (d, J=6.3 Hz, 1H), 5.08-4.95 (m, 1H), 4.93-4.86 (m, 1H), 4.64 (dd, J=11.9, 3.5 Hz, 1H), 3.70-3.58 (m, 1H ), 3.54 (dd, J=14.4, 11.9 Hz, 1H), 3.34-3.32 (m, 1H), 3.21-3.04 (m, 1H), 1, 50 (d, J=6.6 Hz, 3H). IV-207 430.4 2.13 IV-208 430.3 2.19 IV-209 389.05 2.4 1H NMR (400 MHz, chloroform-d) δ 10.59 (d, J=1.4 Hz, 1H), 9.29 (d, J=1.4 Hz, 1H), 8.57 (dd, J =2.5, 0.7 Hz, 1H), 8.37 (s, 1H), 7.79-7.66 (m, 2H), 7.21 (d, J=7.5 Hz, 1H) , 6.74 (d, J=8.6 Hz, 1H), 6.56 (dd, J=2.6, 1.7 Hz, 1H), 4.36 (s, 7H), 3.91 ( dt, J=7.2, 2.5 Hz, 4H), 3.77 (ddd, J=11.0, 6.7, 4.0 Hz, 4H), 2.27 (s, 3H). IV-210 392.1 1.58 1H NMR (400 MHz, chloroform-d) δ 10.46 (d, J=1.4 Hz, 1H), 9.11 (d, J=1.4 Hz, 1H), 8.18 (s, 1H ), 7.86 (d, J=4.5 Hz, 1H), 7.50 (dd, J=8.6, 7.5 Hz, 1H), 7.25 (s, 1H), 7.02 (d, J=7.5 Hz, 1H), 6.55 (d, J=8.6 Hz, 1H), 4.59 (dt, J=13.3, 3.0 Hz, 1H), 4 ,46-4.38 (m, 1H), 3.87 (d, J=12.7 Hz, 1H), 3.48 (d, J=11.1 Hz, 1H), 3.02-2, 78 (m, 2H), 2.71 (dd, J=13.0, 10.9 Hz, 1H), 2.45 (d, J=17.8 Hz, 1H), 2.31 (ddd, J =17.5, 10.9, 5.8 Hz, 1H), 2.07-1.98 (m, 1H), 1.76 (dd, J=12.3, 3.1 Hz, 1H), 1.68-1.54 (m, 1H), 1.55-1.42 (m, 1H). IV-211 416.3 2.08 1H NMR (500 MHz, methanol-d4) δ 10.32 (s, 1H), 9.26-9.13 (m, 1H), 8.68 (s, 1H), 8.44 (d, J= 6.3 Hz, 1H), 7.80 (s, 2H), 6.88 (d, J=6.3 Hz, 1H), 4.71 (s, 1H), 4.55 (s, 2H) , 4.28 (d, J=10.4 Hz, 1H), 3.51-3.34 (m, 2H), 3.25-3.12 (m, 1H). IV-212 339.34 1.96 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 10.14-9.91 (m, 1H), 9.21 (s, 1H), 8.68 (s, 1H) , 8.19 (s, 1H), 7.88-7.73 (m, 2H), 7.51 (d, J=7.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 4.53 (d, J=14.3 Hz, 2H), 3.59 (d, J=12.0 Hz, 2H), 3.37 (t, J=13.1 Hz, 2H), 3.19 (dt, J=26.6, 13.0 Hz, 3H), 2.95-2.83 (m, 3H). no exchanging protons are observed IV-213 396.3 2.1 1H NMR (500 MHz, methanol-d4) δ 9.92 (d, J=1.4 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H), 8.64 (s, 1H ), 8.50 (d, J=6.2 Hz, 1H), 7.93 (s, 2H), 6.95 (d, J=6.3 Hz, 1H), 5.08-4.95 (m, 1H), 4.93-4.86 (m, 1H), 4.64 (dd, J=11.9, 3.5 Hz, 1H), 3.70-3.58 (m, 1H ), 3.54 (dd, J=14.4, 11.9 Hz, 1H), 3.34-3.32 (m, 1H), 3.21-3.04 (m, 1H), 1, 50 (d, J=6.6 Hz, 3H). IV-214 396.3 2.09 1H NMR (500 MHz, methanol-d4) δ 9.92 (d, J=1.4 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H), 8.64 (s, 1H ), 8.50 (d, J=6.2 Hz, 1H), 7.93 (s, 2H), 6.95 (d, J=6.3 Hz, 1H), 5.08-4.95 (m, 1H), 4.93-4.86 (m, 1H), 4.64 (dd, J=11.9, 3.5 Hz, 1H), 3.70-3.58 (m, 1H ), 3.54 (dd, J=14.4, 11.9 Hz, 1H), 3.34-3.32 (m, 1H), 3.21-3.04 (m, 1H), 1, 50 (d, J=6.6 Hz, 3H). IV-215 431.3 2.45 1H NMR (500 MHz, methanol-d4) δ 10.19 (s, 1H), 9.25 (d, J=1.3 Hz, 1H), 8.71 (s, 1H), 8.37 (d , J=6.6 Hz, 1H), 7.65 (s, 2H), 6.91 (d, J=6.7 Hz, 1H), 4.90 (d, J=3.0 Hz, 1H ), 4.27-4.18 (m, 1H), 3.88 (td, J=12.0, 3.2 Hz, 1H), 3.61-3.46 (m, 1H), 1, 18 (d, J=6.8 Hz, 3H). IV-216 397.2 2.29 1H NMR (500 MHz, methanol-d4) δ 9.88 (d, J=1.3 Hz, 1H), 8.95 (d, J=1.3 Hz, 1H), 8.56 (s, 1H ), 8.34 (d, J=6.3 Hz, 1H), 7.75 (s, 2H), 6.78 (d, J=6.3 Hz, 1H), 4.73 (dd, J =10.9, 2.7 Hz, 1H), 4.66-4.48 (m, 1H), 4.48-4.31 (m, 1H), 3.88 (ddd, J=10.8 , 6.3, 2.7 Hz, 1H), 3.10 (dd, J=13.1, 11.0 Hz, 1H), 2.85 (dd, J=13.1, 10.7 Hz, 1H), 1.35 (d, J=6.2 Hz, 3H). IV-217 397.2 2.29 1H NMR (500 MHz, methanol-d4) δ 9.88 (d, J=1.3 Hz, 1H), 8.95 (d, J=1.3 Hz, 1H), 8.56 (s, 1H ), 8.34 (d, J=6.3 Hz, 1H), 7.75 (s, 2H), 6.78 (d, J=6.3 Hz, 1H), 4.73 (dd, J =10.9, 2.7 Hz, 1H), 4.66-4.48 (m, 1H), 4.48-4.31 (m, 1H), 3.88 (ddd, J=10.8 , 6.3, 2.7 Hz, 1H), 3.10 (dd, J=13.1, 11.0 Hz, 1H), 2.85 (dd, J=13.1, 10.7 Hz, 1H), 1.35 (d, J=6.2 Hz, 3H). IV-218 431.3 2.47 IV-219 339.19 1.9 1H NMR (400 MHz, methanol-d4) δ 10.64 (s, 1H), 9.11 (s, 1H), 8.45 (d, J=26.0 Hz, 1H), 7.68 (dd , J=8.6, 7.4 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.45 -3.78 (m, 2H), 3.72-3.42 (m, 1H), 2.43-1.82 (m, 3H), 1.63 (d, J=9.6 Hz, 1H ). 3 proton peaks masked by solvent peaks IV-220 352.89 2.13 1H NMR (400 MHz, DMSO-d6) δ 10.44 (d, J=1.4 Hz, 1H), 9.16 (s, 1H), 8.61 (s, 1H), 8.11 (s , 1H), 7.78-7.61 (m, 2H), 7.38 (d, J=7.4 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4 .62-4.04 (m, 2H), 3.42 (dd, J=15.3, 6.2 Hz, 1H), 3.15-2.91 (m, 2H), 2.09 (dd , J=9.7, 4.5 Hz, 1H), 1.97-1.71 (m, 3H), 1.65-1.50 (m, 1H), 1.42 (dd, J=11 ,9, 3.4 Hz, 1H). 1 exchanging proton not observed IV-221 353.45 2.06 1H NMR (400 MHz, DMSO-d6) δ 10.47 (dd, J=3.0, 1.4 Hz, 1H), 9.16 (s, 1H), 8.61 (s, 1H), 8 .12 (s, 1H), 7.83-7.56 (m, 2H), 7.35 (dd, J=11.1, 7.4 Hz, 1H), 7.00-6.75 (m , 1H), 4.43 (s, 1H), 4.33 (d, J=6.6 Hz, 1H), 3.30 (d, J=6.2 Hz, 1H), 2.99 (dtd , J=18.3, 12.8, 2.7 Hz, 2H), 2.21-2.01 (m, 1H), 1.91-1.60 (m, 2H), 1.49-1 .10 (m, 3H). 1 proton peak is not observed - masked by the solvent peak IV-222 444.4 2.41 1H NMR (500 MHz, methanol-d4) δ 10.20 (d, J=44.8 Hz, 1H), 9.15 (d, J=1.4 Hz, 1H), 8.59 (s, 1H ), 8.28 (d, J=6.3 Hz, 1H), 7.69 (s, 2H), 6.75 (d, J=6.4 Hz, 1H), 5.15-4.53 (m, 1H), 4.25 (d, J=3.6 Hz, 1H), 3.93-3.71 (m, 1H), 3.09-2.97 (m, 1H), 2, 97-2.71 (m, 1H), 1.30 (d, J=6.3 Hz, 3H), 1.11 (d, J=6.7 Hz, 3H). IV-223 444.4 2.41 1H NMR (500 MHz, methanol-d4) δ 10.35-9.99 (m, 1H), 9.18-9.13 (m, 1H), 8.59 (s, 1H), 8.28 ( d, J=6.3 Hz, 1H), 7.69 (s, 2H), 6.76 (d, J=6.4 Hz, 1H), 5.17-4.97 (m, 1H), 4.76-4.59 (m, 1H), 4.25 (d, J=3.6 Hz, 2H), 3.92-3.74 (m, 1H), 3.08-2.97 ( m, 1H), 2.97-2.70 (m, 1H), 1.30 (d, J=6.2 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H). IV-224 444.3 2.38 1H NMR (500 MHz, methanol-d4) δ 10.35-9.99 (m, 1H), 9.18-9.13 (m, 1H), 8.59 (s, 1H), 8.28 ( d, J=6.3 Hz, 1H), 7.69 (s, 2H), 6.76 (d, J=6.4 Hz, 1H), 5.17-4.97 (m, 1H), 4.76-4.59 (m, 1H), 4.25 (d, J=3.6 Hz, 2H), 3.92-3.74 (m, 1H), 3.08-2.97 ( m, 1H), 2.97-2.70 (m, 1H), 1.30 (d, J=6.2 Hz, 3H), 1.11 (d, J=6.6 Hz, 3H). IV-225 354.7 2.3 1H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1H), 10.61 (d, J=1.4 Hz, 1H), 9.23 (d, J=1.4 Hz, 1H ), 8.79 (s, 1H), 8.17-8.06 (m, 3H), 7.95 (dd, J=6.8, 1.9 Hz, 1H), 7.78 (dd, J=7.4, 1.0 Hz, 1H), 7.73-7.67 (m, 1H), 7.57 (dt, J=8.1, 1.0 Hz, 1H), 7.48 (t, J=2.8 Hz, 1H), 7.34-7.25 (m, 1H), 6.86 (ddd, J=3.2, 2.0, 1.0 Hz, 1H). IV-226 381.15 2.28 1H NMR (400 MHz, DMSO-d6) δ 10.49 (d, J=1.4 Hz, 1H), 9.16 (d, J=1.3 Hz, 1H), 8.59 (s, 1H ), 8.11 (d, J=2.4 Hz, 1H), 7.76-7.63 (m, 2H), 7.34 (d, J=7.4 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 4.49 (d, J=12.8 Hz, 2H), 4.13 (s, 1H), 2.87 (td, J=12.8, 2.5 Hz, 2H), 1.91-1.82 (m, 2H), 1.50 (tt, J=12.1, 3.2 Hz, 1H), 1.39-1.23 (m , 2H), 1.07 (s, 6H). IV-227 379 1.84 IV-228 392.1 2.02 1H NMR (400 MHz, methanol-d4) δ 10.57-10.51 (m, 1H), 9.05 (t, J=1.0 Hz, 1H), 8.32 (s, 1H), 7 .74-7.60 (m, 2H), 7.27 (d, J=7.4 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 4.71 (t, J=3.0 Hz, 1H), 4.68 (d, J=2.9 Hz, 1H), 4.63-4.53 (m, 1H), 4.28-4.18 (m, 1H ), 3.68 (dq, J=11.3, 4.1, 3.6 Hz, 1H), 3.17-3.05 (m, 1H), 3.04-2.84 (m, 2H ), 2.49-2.36 (m, 2H), 2.26 (dt, J=13.2, 4.7 Hz, 1H), 1.95 (dt, J=8.3, 4.0 Hz, 1H), 1.80 (dd, J=10.2, 4.9 Hz, 1H), 1.79-1.64 (m, 1H). IV-229 396 1.95 1H NMR (500 MHz, methanol-d4) δ 9.89 (d, J=1.4 Hz, 1H), 8.96 (d, J=1.3 Hz, 1H), 8.57 (s, 1H ), 8.33 (d, J=6.3 Hz, 1H), 7.69 (s, 2H), 6.75 (d, J=6.4 Hz, 1H), 4.21 (d, J =3.8 Hz, 1H), 3.29-3.22 (m, 1H), 3.06-2.94 (m, 1H), 1.13 (d, J=6.8 Hz, 3H) , 3H is not observed. IV-230 396 1.95 IV-231 416 2.03 1H NMR (500 MHz, methanol-d4) δ 10.31 (s, 1H), 9.19 (dd, J=1.3, 0.6 Hz, 1H), 8.64 (s, 1H), 8 .36 (d, J=6.3 Hz, 1H), 7.72 (s, 2H), 6.80 (d, J=6.4 Hz, 1H), 4.66-4.31 (m, 2H), 3.95 (dd, J=10.6, 3.3 Hz, 1H), 3.27-3.13 (m, 3H), 3.03-2.93 (m, 1H). IV-232 416 2.03 1H NMR (500 MHz, methanol-d4) δ 10.31 (s, 1H), 9.19 (dd, J=1.3, 0.6 Hz, 1H), 8.64 (s, 1H), 8 .36 (d, J=6.3 Hz, 1H), 7.72 (s, 2H), 6.80 (d, J=6.4 Hz, 1H), 4.66-4.31 (m, 2H), 3.95 (dd, J=10.6, 3.3 Hz, 1H), 3.27-3.13 (m, 3H), 3.03-2.93 (m, 1H). IV-233 362.1 2.72 1H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 1H), 10.41 (d, J=1.5 Hz, 1H), 9.35 (s, 1H), 8.88 (s , 1H), 8.24-8.10 (m, 2H), 7.95 (dd, J=7.7, 1.0 Hz, 1H), 7.70-7.49 (m, 4H), 7.40-7.28 (m, 1H), 6.97-6.89 (m, 1H). IV-234 337.09 2.65 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 10.62 (d, J=1.4 Hz, 1H), 9.32 (d, J=1.4 Hz, 1H ), 8.93 (s, 1H), 8.21 (dd, J=7.8, 1.0 Hz, 1H), 8.13 (t, J=7.9 Hz, 1H), 7.92 (dd, J=7.8, 0.9 Hz, 1H), 7.66-7.45 (m, 3H), 7.30 (dd, J=8.1, 7.4 Hz, 1H), 6.96 (ddd, J=3.1, 2.0, 0.9 Hz, 1H). IV-235 397.1 1.79 IV-236 397.3 1.81 IV-237 382 1.84 IV-238 382 1.84 IV-239 338.64 1.68 1H NMR (400 MHz, DMSO-d6) δ 10.37 (d, J=1.4 Hz, 1H), 10.00 (s, 1H), 9.24 (d, J=1.4 Hz, 1H ), 8.74 (s, 1H), 8.55 (d, J=6.2 Hz, 1H), 8.21 (s, 1H), 7.83 (d, J=2.4 Hz, 1H ), 6.97 (d, J=6.3 Hz, 1H), 4.71 (s, 2H), 3.58 (s, 2H), 3.33 (s, 6H). IV-240 325.84 1.64 1H NMR (400 MHz, chloroform/methanol-d4) δ 10.54 (s, 1H), 9.09 (s, 1H), 8.65 (s, 1H), 8.34 (d, J=6, 3 Hz, 1H), 7.44 (s, 2H), 6.59 (d, J=6.4 Hz, 1H), 4.30 (s, 11H), 3.92-3.77 (m, 10H), 3.42 (t, J=7.1 Hz, 2H), 3.33 (p, J=1.6 Hz, 4H), 3.21-3.14 (m, 2H), 2, 83 (d, J=1.1 Hz, 3H), 2.37 (t, J=8.2 Hz, 2H), 2.10-1.98 (m, 2H). IV-241 353.85 1.83 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.26 (s, 1H), 8.78-8.68 (m, 1H), 8.36 (d, J= 6.7 Hz, 1H), 7.90 (s, 1H), 6.91 (d, J=6.8 Hz, 1H), 3.81-3.54 (m, 2H), 3.34- 3.25 (m, 1H), 3.14 (qt, J=8.7, 4.4 Hz, 1H), 2.74-2.67 (m, 2H), 1.99-1.77 ( m, 3H), 1.75-1.43 (m, 4H). IV-242 353.9 1.74 1H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J=1.5 Hz, 1H), 9.04 (d, J=1.4 Hz, 1H), 8.46 (s, 1H ), 8.17 (d, J=6.5 Hz, 1H), 8.01 (s, 1H), 7.65 (s, 1H), 6.66 (d, J=6.6 Hz, 1H ), 3.28-3.15 (m, 2H), 3.03-2.63 (m, 2H), 1.71-1.39 (m, 4H), 1.38-1.01 (m , 3H). 1 proton masked by solvent peak IV-243 354 1.69 1H NMR (400 MHz, methanol-d4) δ 10.50 (d, J=1.4 Hz, 1H), 9.15-9.07 (m, 1H), 8.68 (s, 1H), 8 .27 (dd, J=17.3, 6.7 Hz, 1H), 7.40 (d, J=0.6 Hz, 3H), 6.64 (dd, J=15.8, 6.7 Hz, 1H), 4.28 (d, J=6.5 Hz, 2H), 3.33 (dtd, J=3.2, 1.6, 0.6 Hz, 5H), 3.15 (s , 1H), 2.21 (dt, J=11.6, 6.2 Hz, 1H), 2.01 (d, J=0.6 Hz, 1H), 1.51-1.34 (m, 1H). IV-244 397.2 2.24 1H NMR (500 MHz, methanol-d4) δ 9.95 (d, J=1.3 Hz, 1H), 8.98 (d, J=1.3 Hz, 1H), 8.62 (s, 1H ), 8.38 (d, J=6.3 Hz, 1H), 7.66 (s, 2H), 6.79 (d, J=6.4 Hz, 1H), 4.90 (d, J =3.0 Hz, 1H), 4.56 (s, 2H), 4.22 (dd, J=11.5, 4.2 Hz, 1H), 3.87 (td, J=11.8, 3.1 Hz, 1H), 3.49-3.36 (m, 1H), 1.14 (d, J=6.8 Hz, 3H). IV-245 397.2 2.2 1H NMR (500 MHz, methanol-d4) δ 9.94 (d, J=1.3 Hz, 1H), 8.96 (d, J=1.3 Hz, 1H), 8.61 (s, 1H ), 8.40 (d, J=6.3 Hz, 1H), 7.59 (s, 2H), 6.77 (d, J=6.3 Hz, 1H), 5.07-4.99 (m, 1H), 4.94 (d, J=1.6 Hz, 1H), 4.12-4.04 (m, 1H), 3.84-3.69 (m, 2H), 3, 55-3.45 (m, 1H), 1.52 (d, J=6.7 Hz, 3H). IV-246 410.1 2.1 1H NMR (500 MHz, methanol-d4) δ 9.81 (s, 1H), 8.93 (d, J=1.3 Hz, 1H), 8.52 (s, 1H), 8.27 (d , J=6.3 Hz, 1H), 7.72 (s, 2H), 6.73 (d, J=6.4 Hz, 1H), 5.19-4.95 (m, 1H), 4 .27 (d, J=3.7 Hz, 1H), 3.92-3.70 (m, 1H), 3.10-2.96 (m, 1H), 2.96-2.67 (m , 1H), 1.31 (d, J=6.1 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H). IV-247 410 2.1 1H NMR (500 MHz, DMSO-d6) δ 9.87-9.77 (m, 1H), 9.10-8.98 (m, 1H), 8.57 (s, 1H), 8.36 ( d, J=6.2 Hz, 1H), 7.59 (s, 2H), 6.79 (d, J=6.2 Hz, 1H), 4.79-4.58 (m, 1H), 4.34-4.16 (m, 1H), 4.13 (d, J=3.6 Hz, 1H), 2.80-2.74 (m, 2H), 1.22 (d, J= 6.2 Hz, 3H), 1.06 (d, J=6.7 Hz, 3H). IV-248 381.25 1.57 1H NMR (400 MHz, DMSO-d6) δ 9.45-9.40 (m, 1H), 8.15 (d, J=1.3 Hz, 1H), 7.67 (s, 1H), 6 .62 (d, J=0.5 Hz, 1H), 5.79 (d, J=6.9 Hz, 1H), 3.05 (td, J=10.3, 5.2 Hz, 1H) , 2.51-2.35 (m, 3H), 1.83 (t, J=0.8 Hz, 2H), 1.37 (t, J=8.1 Hz, 1H), 1.17- 0.98 (m, 3H), 0.96 (s, 3H), 0.66-0.51 (m, 2H). IV-249 380.9 1.57 1H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J=1.3 Hz, 1H), 8.43 (d, J=1.4 Hz, 1H), 7.96 (s, 1H ), 7.40 (d, J=7.4 Hz, 1H), 6.84 (s, 2H), 6.12 (d, J=7.4 Hz, 1H), 3.63 (s, 1H ), 3.07 (dd, J=9.4, 4.5 Hz, 1H), 2.88-2.53 (m, 3H), 1.32-1.23 (m, 2H), 1, 15 (s, 3H), 0.95 (t, J=9.6 Hz, 2H). 1 exchanging proton not observed IV-250 417.1 1.68 1H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J=1.3 Hz, 1H), 8.43 (d, J=1.4 Hz, 1H), 7.96 (s, 1H ), 7.40 (d, J=7.4 Hz, 1H), 6.84 (s, 2H), 6.12 (d, J=7.4 Hz, 1H), 3.63 (s, 1H ), 3.07 (dd, J=9.4, 4.5 Hz, 1H), 2.88-2.53 (m, 3H), 1.32-1.23 (m, 2H), 1, 15 (s, 3H), 0.95 (t, J=9.6 Hz, 2H). 1 exchanging proton not observed IV-251 417.05 1.76 1H NMR (400 MHz, DMSO-d6) δ 10.38 (d, J=1.4 Hz, 1H), 9.23 (d, J=1.4 Hz, 1H), 8.69 (s, 1H ), 8.45 (d, J=6.3 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H), 7.91-7.86 (m, 1H), 7.20 (q, J=4.9 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 5.00 (s, 1H), 4.36 (s, 1H), 3.32 -3.21 (m, 1H), 3.19-3.05 (m, 2H), 2.62 (d, J=4.7 Hz, 3H), 2.16 (d, J=12.8 Hz, 1H), 1.94-1.74 (m, 2H), 1.65-1.51 (m, 1H). IV-252 417.05 1.67 1H NMR (400 MHz, DMSO-d6) δ 10.40 (d, J=1.4 Hz, 1H), 9.22 (d, J=1.3 Hz, 1H), 8.65 (s, 1H ), 8.42 (d, J=6.2 Hz, 1H), 8.18 (d, J=2.3 Hz, 1H), 7.83-7.78 (m, 1H), 7.03 (q, J=4.8 Hz, 1H), 6.90 (d, J=6.3 Hz, 1H), 4.66 (s, 2H), 3.49 (tt, J=11.9, 3.8 Hz, 1H), 3.13 (td, J=13.0, 2.6 Hz, 2H), 2.63 (d, J=4.6 Hz, 3H), 2.15-2, 06 (m, 2H), 1.61 (qd, J=12.5, 4.3 Hz, 2H). IV-253 362.85 1.73 1H NMR (400 MHz, DMSO-d6) δ 10.40 (d, J=1.4 Hz, 1H), 9.22 (d, J=1.4 Hz, 1H), 8.68 (s, 1H ), 8.45 (d, J=6.2 Hz, 1H), 8.18 (s, 1H), 7.81 (s, 1H), 6.87 (d, J=6.3 Hz, 1H ), 6.38 (s, 2H), 4.24 (s, 2H), 3.90 (s, 2H), 2.41 (t, J=5.9 Hz, 1H). IV-254 349.14 1.78 1H NMR (400 MHz, DMSO-d6) δ 10.37 (d, J=1.4 Hz, 1H), 9.21 (d, J=1.4 Hz, 1H), 8.64 (s, 1H ), 8.42 (d, J=6.2 Hz, 1H), 8.20-8.15 (m, 1H), 7.81 (d, J=2.5 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 4.07 (s, 2H), 3.59 (ddd, J=13.2, 9.0, 3.3 Hz, 2H), 3.27- 3.18 (m, 1H), 2.02 (ddt, J=13.5, 6.8, 3.6 Hz, 2H), 1.81 (dtd, J=12.8, 8.8, 3 ,6 Hz, 2H). IV-255 415.3 2.48 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.40-9.34 (m, 1H), 9.25 (t, J=1.4 Hz, 1H), 8 .79 (s, 1H), 8.50-8.43 (m, 1H), 8.00 (t, J=1.8 Hz, 1H), 7.78 (t, J=1.7 Hz, 1H), 6.99 (d, J=6.4 Hz, 1H), 4.89-4.66 (m, 1H), 4.57 (ddd, J=10.5, 6.3, 4, 0 Hz, 1H), 4.48-4.21 (m, 1H), 3.62 (dd, J=13.0, 10.1 Hz, 1H), 3.21 (ddd, J=13.9 , 11.5, 3.1 Hz, 1H), 2.33-2.24 (m, 1H), 2.24-2.12 (m, 1H), 2.00-1.89 (m, 1H ), 1.74-1.61 (m, 1H). IV-256 339.14 1.61 1H NMR (400 MHz, DMSO-d6) δ 10.39 (d, J=1.4 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H), 8.72 (s, 1H ), 8.47 (d, J=6.3 Hz, 1H), 8.30 (s, 1H), 8.03 (s, 3H), 7.94 (s, 1H), 6.88 (d , J=6.3 Hz, 1H), 4.58 (s, 1H), 4.04 (s, 1H), 3.39 (dd, J=12.7, 8.9 Hz, 1H), 2 .07 (s, 1H), 1.91-1.81 (m, 1H), 1.74-1.55 (m, 2H). 1 proton peak is masked by solvent peaks IV-257 392.95 1.69 1H NMR (400 MHz, DMSO-d6) δ 10.37 (d, J=1.4 Hz, 1H), 9.25 (d, J=1.4 Hz, 1H), 8.71 (s, 1H ), 8.44 (d, J=6.4 Hz, 1H), 8.21 (d, J=2.2 Hz, 1H), 7.89 (s, 1H), 6.94 (d, J =6.5 Hz, 1H), 4.53 (dt, J=13.4, 3.0 Hz, 1H), 3.55 (dt, J=8.3, 4.4 Hz, 1H), 3 .35-3.27 (m, 1H), 3.11 (td, J=12.6, 3.4 Hz, 1H), 2.94 (dd, J=13.2, 11.0 Hz, 1H ), 2.85-2.52 (m, 1H), 2.30 (dd, J=7.7, 5.0 Hz, 2H), 2.18 (dd, J=10.1, 6.1 Hz, 1H), 1.97-1.78 (m, 2H), 1.76-1.53 (m, 2H). IV-258 349.29 1.98 IV-259 391.1 2.3 1H NMR (400 MHz, DMSO-d6) δ 10.28 (d, J=1.2 Hz, 1H), 9.32 (d, J=1.2 Hz, 1H), 8.71 (s, 1H ), 7.77 (dd, J=8.6, 7.5 Hz, 1H), 7.47 (d, J=7.4 Hz, 1H), 6.95 (d, J=8.5 Hz , 1H), 3.74-3.58 (m, 8H), 2.08 (d, J=1.1 Hz, 3H). IV-260 380 1.52 1H NMR (400 MHz, methanol-d4) δ 10.68-10.49 (m, 1H), 9.14-9.00 (m, 1H), 8.52-8.34 (m, 1H), 7.78-7.69 (m, 1H), 7.45-7.27 (m, 1H), 6.94-6.82 (m, 1H), 3.96-3.66 (m, 8H ), 3.11-2.97 (m, 3H), 2.32-2.13 (m, 3H). no exchanging proton observed IV-261 337.99 2.17 1H NMR (400 MHz, DMSO-d6) δ 10.40 (d, J=1.4 Hz, 1H), 9.21 (d, J=1.4 Hz, 1H), 8.61 (s, 1H ), 8.36 (d, J=6.3 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 6.79 (d, J=6.4 Hz, 1H), 4.86 (s, 1H), 4.39 (s, 1H), 3.05 (td, J=13.2, 3.0 Hz , 1H), 1.84-1.65 (m, 5H), 1.46 (d, J=12.8 Hz, 1H), 1.25 (d, J=6.8 Hz, 3H). IV-262 392.85 1.51 1H NMR (400 MHz, DMSO-d6) δ 10.34 (d, J=1.4 Hz, 1H), 9.22 (d, J=1.3 Hz, 1H), 8.64 (d, J =1.0 Hz, 1H), 8.41 (d, J=6.2 Hz, 1H), 8.19 (d, J=2.6 Hz, 1H), 7.84 (d, J=2 ,6 Hz, 1H), 6.90 (d, J=6.3 Hz, 1H), 3.95 (q, J=7.6 Hz, 1H), 3.60-3.35 (m, 2H ), 3.26-3.17 (m, 4H), 2.78-2.63 (m, 2H), 2.26 (dt, J=11.6, 5.9 Hz, 1H), 1, 84 (dh, J=10.1, 6.3, 4.1 Hz, 2H), 1.67 (dtt, J=14.4, 6.4, 3.6 Hz, 1H). IV-263 393.1 1.67 1H NMR (400 MHz, DMSO-d6) δ 10.38 (d, J=1.4 Hz, 1H), 9.22 (d, J=1.3 Hz, 1H), 8.68 (s, 1H ), 8.44 (d, J=6.2 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 6.91 (d, J=6.2 Hz, 1H), 4.55-4.39 (m, 3H), 4.19 (d, J=17.5 Hz, 1H), 3.69-3 .49 (m, 2H), 2.60-2.51 (m, 1H), 2.03 (d, J=12.5 Hz, 1H), 1.81 (d, J=13.0 Hz, 1H), 1.68 (d, J=13.0 Hz, 1H), 1.50 (qt, J=13.2, 3.5 Hz, 1H), 1.37-1.19 (m, 2H ). IV-264 352.09 2.39 1H NMR (400 MHz, DMSO-d6) δ 10.39 (d, J=1.4 Hz, 1H), 9.21 (d, J=1.3 Hz, 1H), 8.61 (s, 1H ), 8.34 (d, J=6.2 Hz, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.82 (d, J=2.9 Hz, 1H), 6.80 (d, J=6.4 Hz, 1H), 2.97 (dq, J=10.6, 8.0, 6.6 Hz, 1H), 1.87-1.71 (m, 2H), 1.60-1.39 (m, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.03-0.90 (m, 5H). IV-265 379.1 1.89 1H NMR (400 MHz, DMSO-d6) δ 10.39 (d, J=1.4 Hz, 1H), 9.20 (d, J=1.3 Hz, 1H), 8.63 (s, 1H ), 8.37 (d, J=6.3 Hz, 1H), 8.17 (d, J=2.6 Hz, 1H), 7.85 (d, J=2.7 Hz, 1H), 6.83 (d, J=6.3 Hz, 1H), 4.39 (s, 2H), 3.09 (td, J=12.5, 3.1 Hz, 1H), 2.82 (dq , J=13.9, 3.6, 3.1 Hz, 2H), 2.70 (dd, J=13.0, 10.7 Hz, 1H), 2.14 (td, J=11.9 , 3.2 Hz, 1H), 2.02-1.84 (m, 3H), 1.79-1.70 (m, 1H), 1.65-1.43 (m, 2H), 1, 35-1.12 (m, 2H). IV-266 382 1.74 1H NMR (400 MHz, DMSO-d6) δ 10.38 (d, J=1.4 Hz, 1H), 9.21 (d, J=1.4 Hz, 1H), 8.63 (s, 1H ), 8.40 (d, J=6.3 Hz, 1H), 8.18 (d, J=2.6 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 6.89 (d, J=6.4 Hz, 1H), 3.96 (s, 4H), 3.85 (s, 4H), 1.79-1.70 (m, 4H). IV-267 381 1.49 1H NMR (400 MHz, DMSO-d6) δ 10.53-10.45 (m, 1H), 9.20 (d, J=1.3 Hz, 1H), 8.60 (d, J=4, 0 Hz, 1H), 8.36 (d, J=5.9 Hz, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 6.52 (d, J=5, 9 Hz, 1H), 5.28-5.19 (m, 1H), 4.75 (s, 1H), 4.02 (s, 1H), 2.95 (s, 2H), 2.81 ( s, 2H), 2.25 (s, 1H), 2.15 (d, J=9.8 Hz, 3H), 2.06 (s, 2H). IV-268 379 1.45 1H NMR (400 MHz, DMSO-d6) δ 10.32 (d, J=1.4 Hz, 1H), 9.13 (d, J=1.4 Hz, 1H), 8.60 (s, 1H ), 8.36 (d, J=6.2 Hz, 1H), 8.10 (s, 1H), 7.75 (d, J=2.3 Hz, 1H), 6.73 (d, J =6.2 Hz, 1H), 3.80 (d, J=17.3 Hz, 1H), 3.66 (tt, J=10.2, 4.7 Hz, 1H), 3.49-3 .36 (m, 1H), 3.35-3.25 (m, 1H), 3.20-3.10 (m, 1H), 2.91 (t, J=11.8 Hz, 1H), 2.15 (s, 2H), 1.95-1.83 (m, 1H), 1.81-1.64 (m, 1H), 1.52 (qd, J=11.3, 7.2 Hz, 1H). IV-269 380 1.9 1H NMR (400 MHz, DMSO-d6) δ 10.40 (d, J=1.4 Hz, 1H), 9.21 (d, J=1.4 Hz, 1H), 8.62 (s, 1H ), 8.37 (d, J=6.3 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.80 (d, J=2.0 Hz, 1H), 6.86 (d, J=6.4 Hz, 1H), 4.02 (s, 2H), 3.80 (t, J=6.7 Hz, 2H), 3.60 (tt, J=8 ,8, 2.5 Hz, 2H), 1.92 (dq, J=8.1, 6.8 Hz, 2H), 1.77-1.57 (m, 6H). IV-270 352.04 1.58 1H NMR (400 MHz, DMSO-d6) δ 10.46 (d, J=1.4 Hz, 1H), 9.21 (d, J=1.4 Hz, 1H), 8.58 (s, 1H ), 8.38 (d, J=5.9 Hz, 1H), 8.20-8.14 (m, 1H), 7.79 (d, J=2.3 Hz, 1H), 6.41 (d, J=6.0 Hz, 1H), 4.17 (s, 4H), 3.88 (s, 2H), 3.78 (t, J=7.0 Hz, 2H), 2.23 (t, J=7.0 Hz, 2H). IV-271 352.09 2.38 1H NMR (400 MHz, DMSO-d6) δ 10.27 (d, J=1.4 Hz, 1H), 9.07 (d, J=1.4 Hz, 1H), 8.46 (s, 1H ), 8.19 (d, J=6.3 Hz, 1H), 8.03 (s, 1H), 7.66 (s, 1H), 6.63 (d, J=6.4 Hz, 1H ), 4.63 (s, 1H), 4.01 (d, J=13.4 Hz, 1H), 3.15 (d, J=3.6 Hz, 1H), 1.95 (s, 1H ), 1.84 (qd, J=6.9, 2.9 Hz, 2H), 1.32 (d, J=11.2 Hz, 1H), 1.12 (d, J=6.7 Hz , 4H), 0.87 (d, J=6.9 Hz, 3H). IV-272 381 1.55 1H NMR (400 MHz, DMSO-d6) δ 10.40 (d, J=1.4 Hz, 1H), 9.22 (d, J=1.4 Hz, 1H), 8.65 (s, 1H ), 8.44 (dd, J=6.3, 1.7 Hz, 1H), 8.19 (s, 1H), 7.82 (d, J=2.4 Hz, 1H), 6.83 (dd, J=6.4, 2.1 Hz, 1H), 4.75 (s, 1H), 4.28 (dd, J=31.7, 13.3 Hz, 2H), 3.84 ( dd, J=58.1, 12.1 Hz, 1H), 3.46 (d, J=68.3 Hz, 1H), 3.13-2.87 (m, 1H), 2.09 (d , J=17.0 Hz, 3H), 1.25 (d, J=6.6 Hz, 2H), 1.17 (d, J=6.6 Hz, 2H). Note: the presence of rotary isomers is obvious. IV-273 393 1.59 IV-274 393 1.59 IV-275 487.2 2.72 1H NMR (500 MHz, methanol-d4) δ 10.06 (s, 1H), 9.12 (d, J=1.3 Hz, 1H), 8.43 (s, 1H), 7.74 (dd , J=8.6, 7.5 Hz, 1H), 7.38-7.34 (m, 1H), 7.10-6.83 (m, 2H), 4.64-4.50 (m , 2H), 3.56 (dd, J=13.7, 3.9 Hz, 1H), 3.14 (dd, J=13.7, 9.3 Hz, 1H), 3.03-2, 97 (m, 1H), 2.96 (s, 3H), 2.94-2.86 (m, 1H), 2.38-2.07 (m, 2H), 1.13 (d, J= 6.7 Hz, 3H). IV-276 394 1.81 1H NMR (400 MHz, methanol-d4) δ 10.26 (d, J=1.4 Hz, 1H), 9.09 (d, J=1.4 Hz, 1H), 8.44 (s, 1H ), 7.74 (dd, J=8.6, 7.5 Hz, 1H), 7.37 (d, J=7.4 Hz, 1H), 6.89 (d, J=8.6 Hz , 1H), 3.79 (tt, J=6.3, 3.8 Hz, 6H), 3.70 (dd, J=6.6, 3.9 Hz, 2H), 3.29 (s, 3H), 3.21 (s, 3H), 2.21 (s, 3H). IV-277 393 1.75 1H NMR (400 MHz, DMSO-d6) δ 10.41 (d, J=1.4 Hz, 1H), 9.22 (d, J=1.4 Hz, 1H), 8.66 (s, 1H ), 8.45 (d, J=6.2 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.82 (d, J=2.7 Hz, 1H), 6.87 (d, J=6.3 Hz, 1H), 3.87 (s, 4H), 3.79 (s, 2H), 3.66 (s, 2H), 2.04 (tt, J =7.7, 4.9 Hz, 1H), 0.78 (tt, J=7.9, 2.9 Hz, 4H). IV-278 424.3 2.25 1H NMR (500 MHz, methanol-d4) δ 9.91 (s, 1H), 9.02 (d, J=1.4 Hz, 1H), 8.66 (s, 1H), 8.51 (d , J=6.3 Hz, 1H), 7.77 (s, 1H), 6.96 (d, J=6.5 Hz, 1H), 4.80 (d, J=4.2 Hz, 1H ), 3.70 (ddd, J=11.7, 6.6, 3.7 Hz, 1H), 3.29 (s, 1H), 2.41 (s, 3H), 1.58 (d, J=6.6 Hz, 3H), 1.38 (d, J=7.2 Hz, 3H). IV-279 456.1 2.17 1H NMR (500 MHz, methanol-d4) δ 9.87 (s, 1H), 8.96 (d, J=1.3 Hz, 1H), 8.59 (s, 1H), 8.44 (d , J=6.4 Hz, 1H), 7.90 (s, 2H), 6.94 (d, J=6.4 Hz, 1H), 4.93 (d, J=4.1 Hz, 1H ), 3.68 (dtd, J=13.1, 6.5, 3.7 Hz, 1H), 3.30-3.24 (m, 1H), 1.58 (d, J=6.5 Hz, 3H), 1.36 (d, J=7.1 Hz, 3H), 2H is not observed. IV-280 388.2 2.08 1H NMR (500 MHz, methanol-d4) δ 10.07 (s, 1H), 9.26 (s, 1H), 8.81 (s, 1H), 8.37 (d, J=6.7 Hz , 1H), 7.86 (s, 2H), 7.09 (s, 1H), 5.39-5.08 (m, 1H), 5.08-4.95 (m, 1H), 4, 28 (dd, J=11.8, 3.9 Hz, 1H), 4.12-3.87 (m, 2H), 3.75-3.56 (m, 1H), 1.23 (d, J=6.2 Hz, 3H). IV-281 388.2 2.07 IV-282 424 2.21 1H NMR (500 MHz, methanol-d4) δ 10.06-9.73 (m, 1H), 8.97 (s, 1H), 8.56 (s, 1H), 8.32 (d, J= 6.3 Hz, 1H), 7.62 (s, 1H), 6.75 (d, J=6.4 Hz, 1H), 5.34-4.98 (m, 1H), 4.63- 4.44 (m, 1H), 4.15 (d, J=3.6 Hz, 1H), 3.97-3.74 (m, 1H), 3.13-2.98 (m, 1H) , 2.98-2.68 (m, 1H), 2.33 (s, 3H), 1.30 (d, J=6.5 Hz, 3H), 1.14 (d, J=6.9 Hz, 3H). IV-283 424 2.2 1H NMR (500 MHz, methanol-d4) δ 10.06-9.73 (m, 1H), 8.97 (s, 1H), 8.56 (s, 1H), 8.32 (d, J= 6.3 Hz, 1H), 7.62 (s, 1H), 6.75 (d, J=6.4 Hz, 1H), 5.34-4.98 (m, 1H), 4.63- 4.44 (m, 1H), 4.15 (d, J=3.6 Hz, 1H), 3.97-3.74 (m, 1H), 3.13-2.98 (m, 1H) , 2.98-2.68 (m, 1H), 2.33 (s, 3H), 1.30 (d, J=6.5 Hz, 3H), 1.14 (d, J=6.9 Hz, 3H). IV-284 392.15 2.02 1H NMR (400 MHz, methanol-d4) δ 10.62 (d, J=1.4 Hz, 1H), 9.06 (d, J=1.3 Hz, 1H), 8.32 (s, 1H ), 7.69 (d, J=8.0 Hz, 1H), 7.27 (d, J=7.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 4.10-3.56 (m, 8H), 2.00 (d, J=4.5 Hz, 1H), 1.01-0.80 (m, 4H). IV-285 401.05 1.91 1H NMR (400 MHz, DMSO-d6) δ 10.38-10.29 (m, 1H), 9.37 (d, J=1.4 Hz, 1H), 8.78-8.70 (m, 2H), 8.61 (d, J=10.7 Hz, 1H), 8.45 (d, J=6.2 Hz, 1H), 8.04-7.95 (m, 2H), 6, 86 (d, J=6.3 Hz, 1H), 3.94-3.71 (m, 4H), 3.67-3.59 (m, 4H), 2.10 (s, 3H). IV-286 384 2.13 1H NMR (400 MHz, DMSO-d6) δ 9.83-9.78 (m, 1H), 9.13 (d, J=1.3 Hz, 1H), 8.67 (s, 1H), 8 .40 (d, J=6.2 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 4.50 (dt, J=13.3, 3.0 Hz, 2H) , 3.56-3.44 (m, 1H), 3.03 (td, J=13.2, 12.7, 3.4 Hz, 1H), 2.90-2.68 (m, 2H) , 2.29 (dd, J=8.0, 4.8 Hz, 2H), 2.08 (ddd, J=12.3, 6.3, 3.4 Hz, 1H), 1.89-1 .76 (m, 1H), 1.75-1.48 (m, 2H), 0.97 (s, 1H). IV-287 454.2 2.17 IV-288 456.2 2.17 1H NMR (500 MHz, DMSO-d6) δ 13.10 (s, 1H), 9.89 (s, 1H), 9.81-9.66 (m, 1H), 9.28 (s, 1H) , 9.19-9.07 (m, 1H), 8.71 (s, 1H), 8.51 (d, J=6.2 Hz, 1H), 8.14-7.60 (m, 1H ), 7.02 (d, J=6.3 Hz, 1H), 5.47-4.90 (m, 1H), 4.84-4.72 (m, 1H), 4.72-4, 12 (m, 1H), 3.59-3.47 (m, 1H), 3.15-2.95 (m, 1H), 1.46 (s, 3H), 1.28-1.19 ( m, 3H). IV-289 401.1 1.89 1H NMR (400 MHz, DMSO-d6) δ 10.26 (d, J=1.5 Hz, 1H), 9.36 (d, J=1.4 Hz, 1H), 9.21 (dd, J =2.4, 0.9 Hz, 1H), 8.68 (dd, J=4.8, 1.6 Hz, 1H), 8.62 (s, 1H), 8.48-8.35 ( m, 2H), 7.60 (ddd, J=8.0, 4.8, 0.9 Hz, 1H), 6.86 (d, J=6.3 Hz, 1H), 3.81 (d , J=21.4 Hz, 4H), 3.63 (dd, J=6.6, 3.9 Hz, 4H), 2.09 (s, 3H). IV-290 388 2.05 1H NMR (500 MHz, methanol-d4) δ 10.37 (d, J=1.4 Hz, 1H), 9.16 (d, J=1.4 Hz, 1H), 8.66 (s, 1H ), 8.40 (d, J=6.3 Hz, 1H), 7.73-7.59 (m, 2H), 6.81 (d, J=6.3 Hz, 1H), 4.90 (d, J=3.0 Hz, 1H), 4.25-4.17 (m, 1H), 3.86 (td, J=12.0, 3.2 Hz, 1H), 3.65 ( d, J=5.4 Hz, 1H), 3.59 (dd, J=11.2, 4.9 Hz, 1H), 3.51 (dd, J=11.2, 6.0 Hz, 1H ), 1.13 (d, J=6.8 Hz, 3H). IV-291 388 2.05 1H NMR (500 MHz, methanol-d4) δ 10.37 (d, J=1.4 Hz, 1H), 9.16 (d, J=1.4 Hz, 1H), 8.66 (s, 1H ), 8.40 (d, J=6.3 Hz, 1H), 7.73-7.59 (m, 2H), 6.81 (d, J=6.3 Hz, 1H), 4.90 (d, J=3.0 Hz, 1H), 4.25-4.17 (m, 1H), 3.86 (td, J=12.0, 3.2 Hz, 1H), 3.65 ( d, J=5.4 Hz, 1H), 3.59 (dd, J=11.2, 4.9 Hz, 1H), 3.51 (dd, J=11.2, 6.0 Hz, 1H ), 1.13 (d, J=6.8 Hz, 3H). IV-292 472 2.6 IV-293 384 2.16 IV-294 384 2.15 IV-295 472 2.59 IV-296 472 2.59 1H NMR (500 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.16 (s, 1H), 9.30 (s, 1H), 8.65 (s, 1H), 8.37 (d, J=6.3 Hz, 1H), 7.70-7.45 (m, 2H), 6.82 (d, J=6.3 Hz, 1H), 4.26 (vbrs, 2H) , 3.92 (d, J=3.6 Hz, 1H), 3.00-2.98 (m, 1H), 2.83 (dt, J=14.5, 7.3 Hz, 1H), 2.73 -2.66 (m, 2H), 1.24 (s, 3H), 1.23 (s, 3H), 0.74 (t, J=7.1 Hz, 3H). (NB T=350K) IV-297 399.95 2.32 1H NMR (400 MHz, methanol-d4) δ 9.97 (d, J=1.5 Hz, 1H), 9.03 (d, J=1.4 Hz, 1H), 8.39 (s, 1H ), 8.20 (d, J=6.2 Hz, 1H), 7.93-7.85 (m, 2H), 7.54-7.39 (m, 3H), 6.57 (d, J=6.2 Hz, 1H), 3.80-3.65 (m, 8H), 2.20 (s, 3H). IV-298 456.9 1.96 1H NMR (400 MHz, methanol-d4) δ 10.16 (d, J=1.5 Hz, 1H), 9.16 (d, J=1.4 Hz, 1H), 8.55 (s, 1H ), 8.38 (d, J=6.2 Hz, 1H), 7.96-7.88 (m, 2H), 7.77-7.70 (m, 2H), 6.64 (d, J=6.3 Hz, 1H), 3.92 (t, J=5.2 Hz, 2H), 3.84-3.70 (m, 7H), 2.20 (s, 3H), 2, 18 (s, 3H). IV-299 444.15 2.52 1H NMR (400 MHz, methanol-d4) δ 9.91-9.85 (m, 1H), 8.99 (d, J=1.3 Hz, 1H), 8.37 (s, 1H), 8 .18 (d, J=6.1 Hz, 1H), 7.71-7.61 (m, 1H), 7.42-7.28 (m, 3H), 6.98-6.90 (m , 1H), 6.55 (d, J=6.3 Hz, 1H), 4.10 (q, J=7.0 Hz, 2H), 3.78-3.67 (m, 8H), 2 .20 (s, 3H), 1.45 (t, J=6.9 Hz, 3H). IV-300 404.65 1.77 1H NMR (400 MHz, methanol-d4) δ 9.70 (s, 1H), 8.97 (d, J=1.4 Hz, 1H), 8.35 (s, 1H), 8.15 (d , J=6.2 Hz, 1H), 7.88 (s, 1H), 6.54 (d, J=6.3 Hz, 1H), 3.81-3.65 (m, 8H), 2 .54 (s, 3H), 2.20 (s, 3H). no exchanged proton observed IV-301 424.95 2.11 1H NMR (400 MHz, methanol-d4) δ 10.35 (d, J=1.6 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H), 8.64 (d, J =1.3 Hz, 1H), 8.38 (dd, J=6.2, 1.2 Hz, 1H), 7.96 (dd, J=16.5, 7.9 Hz, 2H), 7 .85 (t, J=7.7 Hz, 1H), 7.66 (t, J=7.7 Hz, 1H), 6.74-6.66 (m, 1H), 3.95-3, 69 (m, 8H), 2.19 (d, J=1.3 Hz, 3H). IV-302 432.85 1.91 1H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J=1.6 Hz, 1H), 9.31 (d, J=1.5 Hz, 1H), 8.59 (s, 1H ), 8.44 (d, J=6.2 Hz, 1H), 8.04-7.96 (m, 2H), 7.66-7.58 (m, 1H), 7.50 (d, J=8.1 Hz, 2H), 7.43-7.36 (m, 1H), 6.84 (d, J=6.3 Hz, 1H), 5.30 (t, J=5.7 Hz, 1H), 5.20 (t, J=5.7 Hz, 1H), 4.57 (dd, J=22.5, 5.7 Hz, 3H), 3.64 (t, J=5 ,2 Hz, 4H), 2.10 (s, 3H). IV-303 443 1.84 1H NMR (400 MHz, DMSO-d6) δ 10.23 (d, J=1.5 Hz, 1H), 9.34 (d, J=1.4 Hz, 1H), 8.60 (s, 1H ), 8.53 (t, J=1.8 Hz, 1H), 8.42 (d, J=6.2 Hz, 1H), 8.25-8.14 (m, 2H), 7.97 (dt, J=7.9, 1.3 Hz, 1H), 7.65 (t, J=7.7 Hz, 1H), 7.48 (s, 1H), 6.84 (d, J= 6.3 Hz, 1H), 3.90 (s, 2H), 3.75 (s, 2H), 3.70-3.59 (m, 4H), 2.11 (s, 3H). IV-304 443 2.88 1H NMR (500 MHz, DMSO-d6) δ 12.45 (brs, 1H), 10.22 (s, 1H), 9.31 (d, J=1.2 Hz, 1H), 8.68 (s , 1H), 8.38 (d, J=6.4 Hz, 1H), 7.53 (s, 2H), 6.91 (d, J=6.3 Hz, 1H), 4.86 (vbrs , 1H), 4.38 (vbrs, 1H), 2.75 (t, J=12.5 Hz, 1H), 1.88 (dd, J=12.7, 4.0 Hz, 1H), 1 .79 (td, J=11.2, 6.0 Hz, 1H), 1.70 (q, J=12.3 Hz, 1H), 1.09 (d, J=6.4 Hz, 3H) , 1.01 (d, J=6.8 Hz, 3H). Shot at 350K IV-305 401.3 2.03 1H NMR (500 MHz, DMSO-d6) δ 10.28 (d, J=9.4 Hz, 1H), 9.71 (s, 1H), 9.34 (d, J=1.3 Hz, 1H ), 9.03 (s, 1H), 8.81 (d, J=29.4 Hz, 1H), 8.53 (dd, J=6.3, 1.6 Hz, 1H), 7.92 -7.70 (m, 2H), 7.06 (d, J=6.3 Hz, 1H), 5.39 (s, 1H), 5.14 (s, 1H), 4.90-4, 74 (m, 1H), 4.63 (s, 1H), 4.31 (s, 1H), 3.54 (d, J=11.0 Hz, 1H), 3.07 (s, 1H), 1.44 (t, J=5.9 Hz, 3H), 1.21 (d, J=7.0 Hz, 3H). IV-306 443.1 1.83 1H NMR (500 MHz, methanol-d4) δ 9.84 (s, 1H), 9.02 (d, J=1.3 Hz, 1H), 8.64 (d, J=3.9 Hz, 1H ), 8.34 (d, J=6.7 Hz, 1H), 7.70 (s, 2H), 6.91 (d, J=6.8 Hz, 1H), 4.93 (d, J =3.0 Hz, 1H), 4.25 (dd, J=11.6, 4.0 Hz, 1H), 3.90 (td, J=12.0, 3.2 Hz, 1H), 3 .63-3.48 (m, 1H), 1.20 (d, J=6.8 Hz, 3H). IV-307 418.15 1.92 1H NMR (400 MHz, methanol-d4) δ 9.98 (d, J=1.5 Hz, 1H), 9.11 (d, J=1.5 Hz, 1H), 8.54 (s, 1H ), 8.38 (d, J=6.2 Hz, 1H), 7.95 (s, 1H), 7.66 (s, 1H), 6.66 (d, J=6.3 Hz, 1H ), 3.92 (s, 3H), 3.90 (dd, J=6.9, 3.6 Hz, 2H), 3.86-3.68 (m, 6H), 2.54 (s, 3H), 2.19 (s, 3H). IV-308 430.05 2.01 1H NMR (400 MHz, methanol-d4) δ 10.15 (d, J=1.4 Hz, 1H), 9.16 (d, J=1.4 Hz, 1H), 8.54 (s, 1H ), 8.34 (d, J=6.2 Hz, 1H), 7.97 (s, 1H), 7.89 (dt, J=7.7, 1.5 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.43 (dt, J=7.7, 1.4 Hz, 1H), 6.63 (d, J=6.3 Hz, 1H), 3 .91 (t, J=5.2 Hz, 2H), 3.83-3.71 (m, 6H), 3.33 (p, J=1.6 Hz, 2H), 2.20 (s, 3H). IV-309 416 2.03 1H NMR (400 MHz, methanol-d4) δ 10.18 (d, J=1.5 Hz, 1H), 9.16 (d, J=1.4 Hz, 1H), 8.56 (s, 1H ), 8.35 (d, J=6.2 Hz, 1H), 7.46 (ddd, J=7.7, 1.7, 1.0 Hz, 1H), 7.39 (t, J= 2.0 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.22-7.18 (m, 1H), 6.91 (dtd, J=7.9, 2 ,9, 1.1 Hz, 1H), 6.64 (d, J=6.3 Hz, 1H), 3.80 (s, 3H), 3.81-3.75 (m, 1H), 3 .42-3.16 (m, 4H), 1.34 (s, 3H). IV-310 443 2.84 IV-311 443 2.84 IV-312 441 1.84 1H NMR (500 MHz, methanol-d4) δ 9.94 (d, J=1.4 Hz, 1H), 8.99 (d, J=1.4 Hz, 1H), 8.61 (s, 1H ), 8.38 (d, J=6.6 Hz, 1H), 7.61 (d, J=2.3 Hz, 2H), 6.85 (d, J=6.6 Hz, 1H), 5.04 (d, J=6.9 Hz, 1H), 4.96 (d, J=1.8 Hz, 1H), 4.18-4.03 (m, 1H), 3.87-3 .71 (m, 2H), 3.58 (ddd, J=13.3, 12.1, 4.7 Hz, 1H), 1.55 (d, J=6.8 Hz, 3H). IV-313 401 2 1H NMR (500 MHz, methanol-d4) δ 10.37 (s, 1H), 9.17 (s, 1H), 8.72 (s, 1H), 8.51 (d, J=6.2 Hz , 1H), 7.88 (s, 2H), 6.96 (d, J=6.4 Hz, 1H), 3.65 (d, J=6.3 Hz, 1H), 3.57-3 .47 (m, 2H), 2.66 (d, J=4.0 Hz, 1H), 2.20 (d, J=11.0 Hz, 1H), 1.57 (d, J=6, 4 Hz, 3H), 1.26 (d, J=6.7 Hz, 3H). IV-314 401 2 1H NMR (500 MHz, methanol-d4) δ 10.34 (s, 1H), 9.15 (d, J=1.4 Hz, 1H), 8.63 (s, 1H), 8.34 (dd , J=6.3, 1.2 Hz, 1H), 7.72 (s, 2H), 6.80 (d, J=6.3 Hz, 1H), 5.15 (s, 1H), 4 .27 (d, J=3.6 Hz, 1H), 3.84 (s, 1H), 3.03 (dd, J=5.3, 2.1 Hz, 1H), 2.85 (s, 1H), 1.36-1.27 (m, 3H), 1.11 (d, J=6.7 Hz, 3H). IV-315 431 2.36 1H NMR (500 MHz, methanol-d4) δ 10.30 (s, 1H), 9.20 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.39 (d , J=6.3 Hz, 1H), 7.64 (s, 2H), 6.81 (d, J=6.4 Hz, 1H), 4.89 (d, J=3.0 Hz, 1H ), 4.21 (dd, J=11.6, 3.9 Hz, 1H), 3.86 (td, J=12.0, 3.3 Hz, 1H), 3.48-3.39 ( m, 1H), 1.14 (d, J=6.8 Hz, 3H), 2H is not observed. IV-316 397.2 2.2 1H NMR (500 MHz, methanol-d4) δ 9.93-9.81 (m, 1H), 8.97-8.87 (m, 1H), 8.60-8.50 (m, 1H), 8.36 (ddd, J=7.5, 4.6, 1.6 Hz, 1H), 7.65-7.52 (m, 2H), 6.80-6.69 (m, 1H), 5.05-4.96 (m, 1H), 4.93 (s, 1H), 4.13-4.00 (m, 1H), 3.86-3.67 (m, 2H), 3. 55-3.42 (m, 1H), 1.51 (d, J=6.8 Hz, 3H). IV-317 416.2 2.83 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.43-9.25 (m, 1H), 8.68 (s, 1H), 8.49 (d, J= 1.8 Hz, 1H), 8.39 (d, J=6.3 Hz, 1H), 6.94 (d, J=6.3 Hz, 1H), 6.40 (dd, J=1, 9, 0.8 Hz, 1H), 4.54 (s, 1H), 4.39-4.05 (m, 1H), 3.50 (dd, J=13.2, 9.8 Hz, 1H ), 3.25-3.08 (m, 1H), 2.22-2.10 (m, 1H), 1.95-1.72 (m, 2H), 1.72-1.58 (m , 1H), 1H is not observed. IV-318 431.2 2.38 1H NMR (500 MHz, methanol-d4) δ 10.30 (s, 1H), 9.23-9.15 (m, 1H), 8.67 (s, 1H), 8.38 (d, J= 6.3 Hz, 1H), 7.98-7.88 (m, 1H), 7.64 (s, 2H), 6.80 (d, J=6.4 Hz, 1H), 4.88 ( d, J=3.0 Hz, 1H), 4.21 (dd, J=11.6, 3.9 Hz, 1H), 3.86 (td, J=12.0, 3.2 Hz, 1H ), 3.44 (s, 1H), 1.14 (d, J=6.7 Hz, 3H), 2H not observed. IV-319 429.1 2.52 1H NMR (500 MHz, methanol-d4) δ 10.27 (s, 1H), 9.18 (dd, J=1.4, 0.7 Hz, 1H), 8.61 (s, 1H), 8 .38 (d, J=6.3 Hz, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.17 (t, J=1.4 Hz, 1H), 6.92 (d, J=1.3 Hz, 1H), 6.79 (d, J=6.3 Hz, 1H), 4.75 (d, J=14.2 Hz, 1H), 4.60 (q , J=3.8 Hz, 1H), 4.54 (d, J=8.9 Hz, 1H), 3.72 (dd, J=14.1, 3.5 Hz, 1H), 3.38 (ddd, J=13.4, 11.3, 3.6 Hz, 1H), 2.42-2.28 (m, 1H), 1.92-1.80 (m, 1H), 1.80 -1.62 (m, 1H), 0.84 (d, J=6.9 Hz, 3H). IV-320 429.1 2.59 1H NMR (500 MHz, methanol-d4) δ 10.31 (d, J=1.5 Hz, 1H), 9.19 (dd, J=1.3, 0.7 Hz, 1H), 8.64 (s, 1H), 8.38 (d, J=6.3 Hz, 1H), 7.82 (t, J=1.2 Hz, 1H), 7.31 (t, J=1.4 Hz , 1H), 7.07 (t, J=1.1 Hz, 1H), 6.85 (d, J=6.3 Hz, 1H), 4.73-4.45 (m, 1H), 3 .94 (td, J=11.2, 4.5 Hz, 1H), 3.47-3.34 (m, 1H), 3.27-3.13 (m, 1H), 2.33-2 .13 (m, 1H), 2.11-1.97 (m, 1H), 1.50 (qd, J=12.9, 4.4 Hz, 1H), 1.35-1.18 (m , 2H), 0.83 (d, J=6.5 Hz, 3H). IV-321 417 2.73 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.57 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.67 (s , 1H), 8.40 (d, J=6.3 Hz, 1H), 6.92 (d, J=6.3 Hz, 1H), 4.59 (s, 1H), 4.24 (s , 1H), 3.58 (dd, J=13.3, 9.7 Hz, 1H), 3.40 (t, J=12.0 Hz, 1H), 3.19 (tt, J=9, 9, 4.0 Hz, 1H), 2.16 (dt, J=13.0, 4.3 Hz, 1H), 1.94 (dtd, J=13.8, 10.5, 3.9 Hz , 1H), 1.86 (dt, J=13.0, 4.1 Hz, 1H), 1.77-1.60 (m, 1H). IV-322 417.2 1.85 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.35 (d , J=6.3 Hz, 1H), 6.84 (d, J=6.3 Hz, 1H), 4.56-4.11 (m, 2H), 3.22 (dd, J=13, 3, 10.4 Hz, 1H), 3.14 (ddd, J=13.6, 11.3, 3.0 Hz, 1H), 2.30-2.19 (m, 1H), 2.02 -1.90 (m, 1H), 1.83-1.73 (m, 1H), 1.73-1.63 (m, 1H), 1.55-1.41 (m, 1H). IV-323 458.1 2.43 1H NMR (500 MHz, methanol-d4) δ 10.24 (s, 1H), 9.22 (d, J=1.4 Hz, 1H), 8.72 (s, 1H), 8.51 (d , J=6.3 Hz, 1H), 7.89 (s, 2H), 6.91 (d, J=6.3 Hz, 1H), 4.94 (d, J=4.6 Hz, 1H ), 3.96-3.79 (m, 1H), 1.55 (d, J=6.8 Hz, 3H), 1.46 (d, J=7.2 Hz, 3H), 1.36 (d, J=7.1 Hz, 3H). IV-324 462.1 2.53 1H NMR (500MHz, methanol-d4) δ 10.21 (s, 1H), 9.21 (s, 1H), 8.62 (s, 1H), 8.35 (d, 1H), 7.68 ( s, 2H), 4.85 (masked, 1H), 4.45 (m, 1H), 4.35 (d, 1H), 3.15-3.00 (m, 2H, 1.30 (d, 3H), 1.24 (d, 3H). IV-325 415.3 2.39 1H NMR (500 MHz, DMSO-d6) δ 14.35 (d, J=93.1 Hz, 2H), 10.22 (s, 1H), 9.38 (d, J=1.3 Hz, 1H ), 9.09 (d, J=1.4 Hz, 1H), 8.77 (s, 1H), 8.44 (d, J=6.3 Hz, 1H), 7.59 (t, J =1.1 Hz, 1H), 6.96 (d, J=6.4 Hz, 1H), 4.95-4.16 (m, 2H), 3.27 (dd, J=13.1, 10.6 Hz, 1H), 3.19 (td, J=13.3, 12.3, 2.8 Hz, 1H), 3.06-2.95 (m, 1H), 2.23-2 .11 (m, 1H), 1.95-1.78 (m, 2H), 1.70-1.56 (m, 1H). IV-326 416.2 2.2 1H NMR (500 MHz, DMSO-d6) δ 10.19 (d, J=2.9 Hz, 1H), 9.37 (d, J=1.2 Hz, 1H), 8.72 (s, 1H ), 8.40 (d, J=6.4 Hz, 1H), 8.33 (s, 1H), 6.95 (dd, J=6.6, 2.1 Hz, 1H), 4.84 -4.20 (m, 2H), 3.45 (t, J=11.8 Hz, 1H), 3.30 (t, J=12.2 Hz, 1H), 3.13-2.99 ( m, 1H), 2.22-2.09 (m, 1H), 2.01-1.83 (m, 2H), 1.72-1.57 (m, 1H). IV-327 444.2 2.27 1H NMR (500 MHz, DMSO-d6) δ 12.69 (s, 1H), 10.22 (s, 1H), 9.35 (s, 1H), 8.71 (s, 1H), 8.37 (d, J=6.2 Hz, 1H), 7.74 (s, 1H), 7.57 (s, 1H), 6.94 (s, 1H), 4.07 (s, 1H), 2 .83 (s, 2H), 2.23 (s, 1H), 1.19 (s, 3H), 1.16-1.03 (m, 3H). IV-328 442.9 2.21 1H NMR (500 MHz, methanol-d4) δ 10.07-10.01 (m, 1H), 8.98 (d, J=1.3 Hz, 1H), 8.60 (s, 1H), 8 .39 (d, J=6.3 Hz, 1H), 7.69 (s, 2H), 6.80 (d, J=6.3 Hz, 1H), 4.92 (d, J=3, 0 Hz, 1H), 4.24 (dd, J=11.7, 3.8 Hz, 1H), 3.89 (td, J=12.0, 3.3 Hz, 2H), 3.53- 3.40 (m, 2H), 1.16 (d, J=6.7 Hz, 3H). IV-329 442.9 2.21 1H NMR (500 MHz, methanol-d4) δ 10.07-10.01 (m, 1H), 8.98 (d, J=1.3 Hz, 1H), 8.60 (s, 1H), 8 .39 (d, J=6.3 Hz, 1H), 7.69 (s, 2H), 6.80 (d, J=6.3 Hz, 1H), 4.92 (d, J=3, 0 Hz, 1H), 4.24 (dd, J=11.7, 3.8 Hz, 1H), 3.89 (td, J=12.0, 3.3 Hz, 2H), 3.53- 3.40 (m, 2H), 1.16 (d, J=6.7 Hz, 3H). IV-330 472.3 2.76 1H NMR (500 MHz, DMSO-d6) δ 10.24-10.04 (m, 1H), 9.39 (s, 1H), 9.02-8.91 (m, 1H), 8.74 ( s, 1H), 8.55 (d, J=6.3 Hz, 1H), 7.86 (s, 2H), 7.12 (dd, J=6.3, 3.1 Hz, 1H), 5.42-5.04 (m, 1H), 4.76 (s, 1H), 3.20 (d, J=24.8 Hz, 1H), 2.16 (d, 1H), 1.25 (d, J=7.0 Hz, 3H), 1.17 (d, J=6.8 Hz, 3H), 1.15-1.11 (m, 3H). 2 C-H missing IV-331 417.3 1.83 1H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.42 (d , J=6.4 Hz, 1H), 4.85-4.52 (m, 1H), 4.52-4.19 (m, 1H), 3.51 (dd, J=13.2, 10 ,1 Hz, 1H), 3.44-3.26 (m, 2H), 2.28-2.15 (m, 1H), 2.05-1.93 (m, 1H), 1.93- 1.84 (m, 1H), 1.75-1.59 (m, 1H). IV-332 392.2 2.24 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 9.14-9.00 (m, 2H), 8 .79 (s, 1H), 8.46 (d, J=6.3 Hz, 1H), 7.00 (d, J=6.3 Hz, 1H), 4.76-4.59 (m, 1H), 4.58-4.47 (m, 1H), 4.46-4.27 (m, 1H), 3.72-3.58 (m, 1H), 3.30-3.22 ( m, 1H), 2.33-2.23 (m, 1H), 2.14 (dtd, J=12.6, 11.1, 4.1 Hz, 1H), 1.99-1.85 ( m, 1H), 1.76-1.61 (m, 1H). IV-333 430.3 2.16 1H NMR (500MHz, methanol-d4) δ 10.27 (s, 1H), 9.19 (s, 1H), 8.63 (s, 1H), 8.34 (d, 1H), 7.78 ( s, 2H), 6.78 (d, 1H), 4.70 (broad s, 1H), 3.94 (m, 1H), 3.23-3.18 (m, 3H), 3.10 ( m, 1H), 1.44 (d, 3H). IV-334 449.3 2.59 1H NMR (500 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.11 (m, 1H), 9.36 (s, 1H), 8.72 (s, 1H), 8.52 (d, 1H), 7.65 (m, 2H), 5.10 (m, 1H), 4.27 (m, 1H), 4.16 (m, 1H), 4.05 (m, 1H) , 3.93 (m, 1H), 3.70 (m, 1H), 1.20 (d, 3H). IV-335 449 2.65 1H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.11 (m, 1H), 9.37 (s, 1H), 8.72 (s, 1H), 8.54 (d, 1H), 7.80-7.60 (m, 2H), 4.72 (m, 1H), 4.48 (m, 2H), 3.90 (m, 1H), 3.60 ( masked, 1H), 2.96 (m, 1H), 1.25 (d, 3H). IV-336 458.3 2.41 1H NMR (500 MHz, methanol-d4) δ 10.25 (d, J=71.8 Hz, 1H), 9.21 (d, J=10.7 Hz, 1H), 8.78-8.60 (m, 1H), 8.46-8.26 (m, 1H), 7.73 (s, 2H), 6.77 (d, J=6.3 Hz, 1H), 4.98 (d, J=57.6 Hz, 1H), 4.30 (t, J=6.7 Hz, 1H), 4.12 (d, J=71.1 Hz, 1H), 3.26 (qd, J= 6.7, 4.2 Hz, 1H), 1.30 (t, J=13.3 Hz, 6H), 1.21-1.04 (m, 3H). IV-337 458.3 2.42 1H NMR (500 MHz, methanol-d4) δ 10.13 (s, 1H), 9.11 (s, 1H), 8.60 (s, 1H), 8.38 (dd, J=6.2, 1.3 Hz, 1H), 7.78 (d, J=3.2 Hz, 2H), 6.79 (d, J=6.3 Hz, 1H), 5.58-5.08 (m, 1H), 4.45 (d, J=56.4 Hz, 1H), 3.71 (h, J=5.1, 3.7 Hz, 1H), 1.42 (dd, J=6.7 , 2.4 Hz, 3H), 1.34 (d, J=7.3 Hz, 3H), 1.29-1.14 (m, 3H). IV-338 422.3 1.97 IV-339 422.3 1.96 IV-340 427.2 2.23 1H NMR (500 MHz, DMSO-d6) δ 14.34 (s, 1H), 9.88 (d, J=1.3 Hz, 1H), 9.11 (d, J=1.3 Hz, 1H ), 9.07 (d, J=1.4 Hz, 1H), 8.66 (s, 1H), 8.41 (d, J=6.3 Hz, 1H), 7.59 (t, J =1.1 Hz, 1H), 6.92 (d, J=6.4 Hz, 1H), 4.93-4.53 (m, 1H), 4.53-4.12 (m, 1H) , 3.26 (dd, J=13.1, 10.5 Hz, 1H), 3.17 (ddd, J=14.0, 11.4, 2.9 Hz, 1H), 3.00 (s , 1H), 2.21-2.11 (m, 1H), 1.92-1.75 (m, 2H), 1.69-1.54 (m, 1H). IV-341 372.3 2.09 1H NMR (500 MHz, DMSO-d6) δ 14.34 (s, 1H), 10.26 (d, J=1.5 Hz, 1H), 9.32 (d, J=1.4 Hz, 1H ), 9.07 (d, J=1.3 Hz, 1H), 8.76 (s, 1H), 8.42 (d, J=6.3 Hz, 1H), 7.59 (t, J =1.1 Hz, 1H), 6.95 (d, J=6.4 Hz, 1H), 4.71 (s, 1H), 4.54-4.19 (m, 1H), 3.26 (dd, J=13.1, 10.5 Hz, 1H), 3.21-3.11 (m, 1H), 3.01 (d, J=3.9 Hz, 1H), 2.16 ( dd, J=12.7, 3.6 Hz, 1H), 1.93-1.75 (m, 2H), 1.69-1.54 (m, 1H). IV-342 442.2 2 1H NMR (500 MHz, DMSO-d6) δ 9.89 (d, J=1.3 Hz, 1H), 9.58 (s, 1H), 9.12 (d, J=1.3 Hz, 1H ), 8.73 (s, 1H), 8.49 (d, J=6.3 Hz, 1H), 8.24 (s, 1H), 7.84 (s, 1H), 6.89 (d , J=6.3 Hz, 1H), 6.51 (s, 1H), 4.63 (s, 1H), 3.80 (s, 1H), 3.61-3.44 (m, 1H) , 1.20 (d, J=6.7 Hz, 3H). IV-343 440.2 1.94 1H NMR (500 MHz, DMSO-d6) δ 9.89 (d, J=1.4 Hz, 1H), 9.68 (s, 1H), 9.37 (s, 1H), 9.13 (d , J=1.3 Hz, 1H), 8.68 (s, 1H), 8.53 (d, J=6.3 Hz, 1H), 7.82 (s, 2H), 7.01 (d , J=6.3 Hz, 1H), 5.01 (s, 1H), 4.78 (d, J=9.4 Hz, 1H), 3.54 (d, J=11.9 Hz, 1H ), 1.21 (d, J=7.0 Hz, 3H). IV-344 442.3 2.02 1H NMR (500 MHz, methanol-d4) δ 9.98 (d, J=1.4 Hz, 1H), 8.94 (d, J=1.3 Hz, 1H), 8.54 (s, 1H ), 8.32 (d, J=6.3 Hz, 1H), 7.77 (s, 2H), 6.78 (d, J=6.4 Hz, 1H), 4.00 (dd, J =11.2, 3.2 Hz, 1H), 3.11-2.95 (m, 2H), 2.74 (dd, J=12.8, 11.1 Hz, 1H), 1.28 ( d, J=6.3 Hz, 3H). IV-345 444.4 2.29 1H NMR (500 MHz, methanol-d4) δ 10.44 (s, 1H), 10.28 (s, 1H), 9.24 (s, 1H), 8.71 (s, 1H), 8.49 (d, J=5.2 Hz, 1H), 7.69 (s, 2H), 7.28 (d, J=5.2 Hz, 1H), 5.11-4.88 (m, 1H) , 4.75-4.43 (m, 1H), 4.29 (s, 1H), 3.15-2.75 (m, 2H), 1.31 (s, 3H), 1.25-1 .01 (m, 3H). IV-346 427.3 2.42 1H NMR (500 MHz, methanol-d4) δ 9.90 (d, J=1.4 Hz, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.48 (s, 1H ), 8.24 (d, J=6.3 Hz, 1H), 7.61 (s, 2H), 6.71 (d, J=6.4 Hz, 1H), 4.59 (s, 1H ), 3.26-3.02 (m, 2H), 2.90-2.81 (m, 1H), 2.18 (dd, J=12.9, 4.0 Hz, 1H), 2, 00-1.85 (m, 1H), 1.87-1.63 (m, 2H), 1.37 (d, J=6.6 Hz, 1H). IV-347 382.3 1.77 1H NMR (500 MHz, methanol-d4) δ 9.91 (s, 1H), 8.97 (s, 1H), 8.62 (s, 1H), 8.48-8.33 (m, 1H) , 7.77 (s, 1H), 7.25 (s, 1H), 6.83 (d, J=6.5 Hz, 1H), 4.61-4.46 (m, 2H), 4, 27-4.14 (m, 1H), 3.70-3.47 (m, 1H), 3.21-3.09 (m, 2H), 2.10-1.85 (m, 1H). IV-348 427.9 1.78 1H NMR (500 MHz, methanol-d4) δ 10.03 (s, 1H), 8.94 (s, 1H), 8.60 (s, 1H), 8.36 (d, J=6.3 Hz , 1H), 7.71 (s, 1H), 7.15 (s, 1H), 6.79 (d, J=6.3 Hz, 1H), 4.42 (s, 1H), 4.00 -3.89 (m, 1H), 3.26-3.11 (m, 2H), 3.07-2.94 (m, 1H). IV-349 410.1 2.02 1H NMR (500 MHz, methanol-d4) δ 9.95 (s, 1H), 8.97 (d, J=1.3 Hz, 1H), 8.64 (s, 1H), 8.35 (d , J=6.3 Hz, 1H), 7.72 (d, J=1.2 Hz, 1H), 7.10 (s, 1H), 6.77 (d, J=6.5 Hz, 1H ), 5.38 (s, 1H), 4.55 (s, 1H), 4.29-4.15 (m, 1H), 3.86 (s, 1H), 3.12-2.97 ( m, 1H), 2.86 (s, 1H), 1.32 (d, J=6.3 Hz, 3H), 1.12-0.94 (m, 3H). IV-350 442.1 1.94 1H NMR (500 MHz, methanol-d4) δ 9.99 (s, 1H), 8.95 (d, J=1.3 Hz, 1H), 8.56 (s, 1H), 8.33 (d , J=6.3 Hz, 1H), 7.70 (s, 2H), 6.76 (d, J=6.4 Hz, 1H), 4.56 (s, 2H), 4.21 (d , J=3.8 Hz, 1H), 3.29-3.24 (m, 1H), 3.01 (td, J=12.6, 3.7 Hz, 1H), 1.14 (d, J=6.8 Hz, 3H). IV-351 442.1 1.94 1H NMR (500 MHz, methanol-d4) δ 10.03-9.93 (m, 1H), 8.95 (d, J=1.3 Hz, 1H), 8.55 (s, 1H), 8 .34 (d, J=6.3 Hz, 1H), 7.72 (s, 2H), 6.77 (d, J=6.4 Hz, 1H), 4.55 (s, 4H), 4 .28 (d, J=3.8 Hz, 1H), 3.06 (dd, J=13.2, 3.9 Hz, 1H), 1.16 (d, J=6.9 Hz, 3H) . IV-352 444.4 2.21 1H NMR (500 MHz, methanol-d4) δ 10.36 (s, 1H), 9.22 (s, 1H), 8.75 (s, 1H), 8.38 (d, J=6.3 Hz , 1H), 7.77-7.70 (m, 1H), 7.33 (d, J=4.4 Hz, 1H), 7.11 (s, 1H), 6.83 (d, J= 6.3 Hz, 1H), 4.56 (s, 1H), 4.24 (s, 1H), 3.56 (d, J=2.6 Hz, 1H), 3.00-2.85 ( m, 1H), 1.33 (q, J=8.6 Hz, 3H), 1.26 (d, J=6.4 Hz, 3H). IV-353 410.3 2.1 1H NMR (500 MHz, methanol-d4) δ 9.85 (d, J=1.4 Hz, 1H), 8.94 (d, J=1.3 Hz, 1H), 8.53 (s, 1H ), 8.29 (d, J=6.3 Hz, 1H), 7.78 (s, 1H), 6.76 (d, J=6.4 Hz, 1H), 4.55 (s, 1H ), 4.29 (dd, J=11.3, 3.4 Hz, 1H), 3.05-2.94 (m, 2H), 1.32 (s, 3H), 1.27 (s, 3H). IV-354 456.3 2.12 1H NMR (500 MHz, methanol-d4) δ 9.94 (s, 1H), 8.92 (s, 1H), 8.51 (s, 1H), 8.27 (d, J=6.3 Hz , 1H), 7.78 (s, 2H), 6.75 (d, J=6.4 Hz, 1H), 4.65-4.46 (m, 3H), 4.25 (dd, J= 11.3, 3.4 Hz, 1H), 3.05-2.88 (m, 2H), 1.31 (s, 3H), 1.27 (s, 3H). IV-355 441.3 2.29 1H NMR (500 MHz, methanol-d4) δ 9.94 (d, J=1.3 Hz, 1H), 8.97 (d, J=1.2 Hz, 1H), 8.58 (s, 1H ), 8.34 (dd, J=6.5, 0.8 Hz, 1H), 7.33 (d, J=0.9 Hz, 1H), 6.88-6.81 (m, 1H) , 4.38 (s, 1H), 3.41-3.33 (m, 1H), 3.12-2.98 (m, 1H), 2.63 (s, 3H), 2.26 (dd , J=13.0, 4.1 Hz, 1H), 1.98 (dt, J=13.5, 3.7 Hz, 1H), 1.94-1.84 (m, 1H), 1, 78 (ddt, J=13.1, 7.9, 3.9 Hz, 1H), 2H not observed. IV-356 437.3 2.25 1H NMR (500 MHz, methanol-d4) δ 10.02 (d, J=1.3 Hz, 1H), 8.96 (d, J=1.3 Hz, 1H), 8.61 (s, 1H ), 8.38 (d, J=6.3 Hz, 1H), 7.62 (s, 1H), 6.86 (d, J=6.4 Hz, 1H), 6.56 (t, J =2.1 Hz, 1H), 4.56 (s, 2H), 3.96 (s, 2H), 2.67 (s, 3H), 2.63-2.45 (m, 2H). IV-357 430.1 2.1 1H NMR (500 MHz, methanol-d4) δ 10.30-10.11 (m, 1H), 9.15 (d, J=1.3 Hz, 1H), 8.59 (s, 1H), 8 .29 (d, J=6.3 Hz, 1H), 7.67 (s, 2H), 6.74 (d, J=6.4 Hz, 1H), 4.19 (d, J=3, 7 Hz, 1H), 3.29-3.21 (m, 1H), 3.00 (td, J=12.7, 3.7 Hz, 1H), 1.13 (d, J=6.8 Hz, 3H), 3H is not observed. IV-358 430.1 2.1 1H NMR (500 MHz, methanol-d4) δ 10.30-10.11 (m, 1H), 9.15 (d, J=1.3 Hz, 1H), 8.59 (s, 1H), 8 .29 (d, J=6.3 Hz, 1H), 7.67 (s, 2H), 6.74 (d, J=6.4 Hz, 1H), 4.19 (d, J=3, 7 Hz, 1H), 3.29-3.21 (m, 1H), 3.00 (td, J=12.7, 3.7 Hz, 1H), 1.13 (d, J=6.8 Hz, 3H), 3H is not observed. IV-359 445.3 2.16 1H NMR (500 MHz, methanol-d4) δ 9.40 (d, 1H), 8.46 (s, 1H), 7.93 (s, 1H), 7.59-7.49 (m, 1H) , 6.85 (s, 1H), 6.80 (s, 1H), 6.16-6.12 (m, 1H), 3.07 (m, 2H), 2.83 (m, 2H), 2.39 (m, 1H), 2.27 (m, 1H), 2.11 (m, 1H), 1.37-1.19 (m, 3H). IV-360 428 2.42 1H NMR (500 MHz, methanol-d4) δ 9.91 (d, J=1.3 Hz, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.49 (s, 1H ), 8.24 (d, J=6.3 Hz, 1H), 7.61 (s, 2H), 6.71 (d, J=6.4 Hz, 1H), 4.59 (s, 1H ), 4.38 (s, 1H), 3.22-3.06 (m, 2H), 2.86 (tt, J=10.9, 3.9 Hz, 1H), 2.23-2, 15 (m, 1H), 1.92 (dp, J=13.4, 3.3 Hz, 1H), 1.85-1.64 (m, 2H). IV-361 427 2.42 1H NMR (500 MHz, methanol-d4) δ 9.92 (d, J=1.5 Hz, 1H), 8.91 (d, J=1.3 Hz, 1H), 8.49 (s, 1H ), 8.25 (d, J=6.3 Hz, 1H), 7.61 (s, 2H), 6.72 (d, J=6.4 Hz, 1H), 4.59 (s, 1H ), 4.38 (s, 1H), 3.22-3.06 (m, 2H), 2.86 (tt, J=10.9, 4.0 Hz, 1H), 2.23-2, 15 (m, 1H), 1.97-1.88 (m, 1H), 1.84-1.64 (m, 2H). IV-362 425 2.23 1H NMR (500 MHz, methanol-d4) δ 9.96 (d, J=1.3 Hz, 1H), 8.92 (d, J=1.3 Hz, 1H), 8.54 (s, 1H ), 8.27 (d, J=6.3 Hz, 1H), 7.65 (d, J=1.1 Hz, 1H), 6.96 (s, 1H), 6.75 (d, J =6.4 Hz, 1H), 4.74-4.61 (m, 1H), 4.56-4.36 (m, 1H), 3.24-3.13 (m, 2H), 2, 98-2.83 (m, 1H), 2.25-2.13 (m, 1H), 1.99-1.80 (m, 2H), 1.80-1.67 (m, 1H). IV-363 425 2.23 1H NMR (500 MHz, methanol-d4) δ 9.96 (d, J=1.3 Hz, 1H), 8.92 (d, J=1.3 Hz, 1H), 8.54 (s, 1H ), 8.27 (d, J=6.3 Hz, 1H), 7.65 (d, J=1.1 Hz, 1H), 6.96 (s, 1H), 6.75 (d, J =6.4 Hz, 1H), 4.74-4.61 (m, 1H), 4.56-4.36 (m, 1H), 3.24-3.13 (m, 2H), 2, 98-2.83 (m, 1H), 2.25-2.13 (m, 1H), 1.99-1.80 (m, 2H), 1.80-1.67 (m, 1H). IV-364 442 2.01 1H NMR (500 MHz, methanol-d4) δ 9.85 (s, 1H), 8.89 (s, 1H), 8.47 (s, 1H), 8.25 (d, J=6.3 Hz , 1H), 7.77 (s, 2H), 6.72 (d, J=6.3 Hz, 1H), 4.56 (s, 1H), 4.35 (s, 1H), 3.99 (dd, J=11.1, 3.2 Hz, 1H), 3.10-2.89 (m, 2H), 2.71 (t, J=11.9 Hz, 1H), 1.27 ( d, J=6.3 Hz, 3H). IV-365 440 2 1H NMR (500 MHz, methanol-d4) δ 9.85 (s, 1H), 8.89 (s, 1H), 8.47 (s, 1H), 8.25 (d, J=6.3 Hz , 1H), 7.77 (s, 2H), 6.72 (d, J=6.3 Hz, 1H), 4.56 (s, 1H), 4.35 (s, 1H), 3.99 (dd, J=11.1, 3.2 Hz, 1H), 3.10-2.89 (m, 2H), 2.71 (t, J=11.9 Hz, 1H), 1.27 ( d, J=6.3 Hz, 3H). IV-366 450.1 2.24 IV-367 450.1 2.25 IV-368 450.1 2.25 IV-369 444.1 2.28 1H NMR (500 MHz, methanol-d4) δ 10.33 (d, J=74.1 Hz, 1H), 9.24 (s, 1H), 8.71 (s, 1H), 8.51 (d , J=5.2 Hz, 1H), 7.72 (s, 2H), 7.30 (d, J=5.2 Hz, 1H), 5.02 (d, J=46.1 Hz, 1H ), 4.59 (s, 1H), 4.40 (s, 1H), 3.23-3.09 (m, 1H), 3.00 (s, 1H), 1.36 (d, J= 6.3 Hz, 3H), 1.28-1.02 (m, 3H). IV-370 444.1 2.28 1H NMR (500 MHz, methanol-d4) δ 10.33 (d, J=74.1 Hz, 1H), 9.24 (s, 1H), 8.71 (s, 1H), 8.51 (d , J=5.2 Hz, 1H), 7.72 (s, 2H), 7.30 (d, J=5.2 Hz, 1H), 5.02 (d, J=46.1 Hz, 1H ), 4.59 (s, 1H), 4.40 (s, 1H), 3.23-3.09 (m, 1H), 3.00 (s, 1H), 1.36 (d, J= 6.3 Hz, 3H), 1.28-1.02 (m, 3H). IV-371 428.2 1.67 1H NMR (500 MHz, DMSO-d6) δ 12.8 (m, 1H), 9.91 (s, 1H), 9.1 (s, 1H), 8.60 (s, 1H), 8.39 (d, 1H), 7.70 (s, 2H), 6.90 (d, 1H), 4.30 (br s, 2H), 3.81 (m, 1H), 3.10 (m, 2H ), 3.02 (m, 1H), 2.85 (m, 1H). IV-372 456.2 1.99 IV-373 456.3 2.06 1H NMR (500 MHz, methanol-d4) δ 10.05 (s, 1H), 8.96 (d, J=1.3 Hz, 1H), 8.62 (s, 1H), 8.35 (d , J=6.4 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.10 (s, 1H), 6.78 (d, J=6.4 Hz, 1H ), 5.36 (s, 1H), 4.50 (s, 1H), 4.23 (d, J=3.7 Hz, 1H), 3.87 (s, 1H), 3.11-2 .99 (m, 1H), 2.87 (s, 1H), 1.33 (s, 3H), 1.05 (s, 3H). IV-374 441 2.28 1H NMR (500 MHz, methanol-d4) δ 9.98 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.28 (d, J=6.3 Hz , 1H), 6.84-6.70 (m, 2H), 4.72-4.58 (m, 1H), 4.51-4.39 (m, 1H), 3.22-3.09 (m, 2H), 2.88-2.70 (m, 1H), 2.35 (s, 3H), 2.22-2.11 (m, 1H), 1.99-1.89 (m , 1H), 1.89-1.77 (m, 1H), 1.77-1.63 (m, 1H). IV-375 441 2.28 1H NMR (500 MHz, methanol-d4) δ 9.98 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.28 (d, J=6.3 Hz , 1H), 6.84-6.70 (m, 2H), 4.72-4.58 (m, 1H), 4.51-4.39 (m, 1H), 3.22-3.09 (m, 2H), 2.88-2.70 (m, 1H), 2.35 (s, 3H), 2.22-2.11 (m, 1H), 1.99-1.89 (m , 1H), 1.89-1.77 (m, 1H), 1.77-1.63 (m, 1H). IV-376 456 2.04 1H NMR (500 MHz, methanol-d4) δ 10.04 (s, 1H), 8.95 (d, J=1.3 Hz, 1H), 8.71-8.53 (m, 1H), 8 .34 (d, J=6.3 Hz, 1H), 7.73 (s, 1H), 7.11 (s, 1H), 6.78 (d, J=6.3 Hz, 1H), 5 .37 (s, 1H), 4.24 (dd, J=4.0, 1.1 Hz, 1H), 3.87 (s, 1H), 3.06 (ddd, J=10.2, 6 ,2, 3.6 Hz, 1H), 2.87 (s, 1H), 1.43-1.18 (m, 3H), 1.05 (s, 3H). IV-377 454 2.03 1H NMR (500 MHz, methanol-d4) δ 9.98 (s, 1H), 8.93 (d, J=1.3 Hz, 1H), 8.57 (d, J=16.6 Hz, 1H ), 8.31 (d, J=6.3 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H), 7.10 (s, 1H), 6.75 (d, J =6.4 Hz, 1H), 5.34 (s, 1H), 4.55 (s, 1H), 4.23 (d, J=4.0 Hz, 1H), 3.85 (s, 1H ), 3.05 (ddt, J=9.1, 6.4, 3.2 Hz, 1H), 2.86 (s, 1H), 1.33 (d, J=6.5 Hz, 3H) , 1.04 (s, 3H). IV-378 416.3 2.41 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.36 (s, 1H), 8.70 (s, 1H), 8.40 (d, 1H), 7.76 (s, 1H), 6.93 (d, 1H), 4.80-4.40 (m, 2H), 3.30 (masked, 2H), 3.00 (m, 1H), 2.18 ( m, 1H), 1.86 (m, 2H), 1.66 (m, 1H). IV-379 429.4 2.61 IV-380 431.4 2.26 1H NMR (500 MHz, methanol-d4) δ 10.24 (s, 1H), 9.20 (d, J=1.4 Hz, 1H), 8.98 (d, J=1.4 Hz, 1H ), 8.67 (s, 1H), 8.40 (d, J=6.3 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 6.87 (d, J =6.4 Hz, 1H), 4.94 (dd, J=11.1, 2.8 Hz, 1H), 4.46 (s, 1H), 4.04-3.88 (m, 1H) , 3.21 (dd, J=13.0, 11.0 Hz, 1H), 2.92 (dd, J=13.2, 10.7 Hz, 1H), 1.39 (d, J=6 ,2 Hz, 3H). IV-381 431.4 2.22 1H NMR (500 MHz, methanol-d4) δ 10.34 (s, 1H), 9.21 (d, J=1.4 Hz, 1H), 8.93 (d, J=1.3 Hz, 1H ), 8.73 (s, 1H), 8.44 (d, J=6.3 Hz, 1H), 7.48 (d, J=1.2 Hz, 1H), 6.85 (d, J =6.3 Hz, 1H), 5.34-5.25 (m, 1H), 4.64 (d, J=12.2 Hz, 1H), 4.20-4.02 (m, 1H) , 3.88 (dd, J=13.9, 4.2 Hz, 2H), 3.27 (dd, J=13.1, 8.8 Hz, 1H), 1.33 (d, J=6 ,2 Hz, 3H). IV-382 410.3 2.12 IV-383 456.3 2.14 IV-384 469.3 2.52 1H NMR (500 MHz, methanol-d4) δ 9.83 (d, J=1.4 Hz, 1H), 8.99 (d, J=1.3 Hz, 1H), 8.59 (s, 1H ), 8.32 (d, J=6.7 Hz, 1H), 7.37 (d, J=0.9 Hz, 1H), 6.91 (d, J=6.7 Hz, 1H), 4.78 (s, 1H), 4.44 (s, 1H), 3.44 (dd, J=13.2, 10.7 Hz, 1H), 3.38-3.32 (m, 2H) , 3.10 (tt, J=11.3, 10.5, 3.9 Hz, 1H), 2.33-2.23 (m, 1H), 2.07-1.97 (m, 1H) , 1.97-1.86 (m, 1H), 1.86-1.73 (m, 1H), 1.43 (d, J=7.0 Hz, 6H). IV-385 467.3 2.52 1H NMR (500 MHz, methanol-d4) δ 10.05 (d, J=1.3 Hz, 1H), 8.97 (d, J=1.3 Hz, 1H), 8.62 (s, 1H ), 8.39 (d, J=6.3 Hz, 1H), 7.66 (s, 1H), 6.87 (d, J=6.3 Hz, 1H), 6.68-6.56 (m, 1H), 4.57 (s, 2H), 4.03-3.89 (m, 2H), 3.38 (p, J=7.0 Hz, 1H), 2.61-2, 52 (m, 2H), 1.47 (d, J=7.1 Hz, 6H). IV-386 431.4 2.18 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.26 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.69 (s , 1H), 8.32 (d, J=6.3 Hz, 1H), 7.62 (s, 2H), 6.87 (d, J=6.4 Hz, 1H), 4.91 (s , 1H), 3.54 (s, 1H), 2.09-1.83 (m, 3H), 1.59 (s, 1H). IV-387 439.3 2.52 1H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 9.93 (s, 1H), 9.10 (d, 1H), 8.60 (s, 1H), 8.37 (d, 1H), 7.66 (m, 1H), 7.51 (m, 1H), 6.87 (s, 1H), 5.00-4.00 (br m, 2H), 3.09 (m, 1H), 3.07 (m, 1H), 1.88-1.64 (m, 3H), 1.57 (m, 1H), 0.99 (m, 3H). IV-388 429.4 2.67 1H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.24 (s, 1H), 9.36 (d, 1H), 8.70 (s, 1H), 8.39 (d, 1H), 7.57 (m, 2H), 6.93 (s, 1H), 5.30-4.00 (br m, 2H), 3.15 (m, 1H), 2.95 (m, 1H), 2.00-1.84 (m, 3H), 1.64 (m, 1H), 0.99 (m, 3H). IV-389 430.3 2.55 IV-390 470.3 2.34 IV-391 468.4 2.78 IV-392 454.3 2.13 1H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 1H), 9.85 (s, 1H), 9.09 (d, J=1.3 Hz, 1H), 8.57 (s , 1H), 8.39 (s, 1H), 7.66 (s, 2H), 6.84 (s, 1H), 6.50 (s, 1H), 2.26-2.12 (m, 1H), 2.07 (s, 6H), 1.36-1.21 (m, 1H), 1.21-1.07 (m, 2H). IV-393 454.3 2.48 IV-394 506.4 2.03 1H NMR (500 MHz, methanol-d4) δ 10.34 (s, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.65 (s, 1H), 8.29 (d , J=6.4 Hz, 1H), 7.56 (s, 1H), 6.80 (d, J=6.4 Hz, 1H), 4.59 (s, 1H), 3.95 (s , 1H), 3.80 (td, J=5.5, 2.8 Hz, 1H), 3.72 (s, 1H), 3.61 (dd, J=13.2, 8.7 Hz, 1H), 3.40 (dd, J=8.7, 4.4 Hz, 1H), 3.07 (d, J=2.4 Hz, 6H), 2.17-2.04 (m, 2H ). IV-395 506.3 2.05 1H NMR (500 MHz, methanol-d4) δ 10.31 (s, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.66 (s, 1H), 8.34 (dd , J=6.3, 1.0 Hz, 1H), 7.61 (d, J=2.5 Hz, 2H), 6.80 (d, J=6.2 Hz, 1H), 4.61 (s, 1H), 3.53-3.42 (m, 1H), 3.17 (s, 3H), 3.15 (s, 3H), 2.95 (dd, J=9.2, 3 ,2 Hz, 3H), 2.39-2.25 (m, 1H), 1.75 (q, J=11.3 Hz, 1H). IV-396 445.3 2.46 1H NMR (500 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.21 (s, 1H), 9.36 (dd, J=5.0, 1.3 Hz, 1H), 8 .93 (d, J=76.8 Hz, 1H), 8.70 (s, 1H), 8.38 (dd, J=27.7, 6.3 Hz, 1H), 7.62 (d, J=1.0 Hz, 1H), 6.98 (dd, J=42.7, 6.4 Hz, 1H), 3.61 (dtd, J=13.2, 6.6, 3.9 Hz , 1H), 3.40 (s, 3H), 3.13 (qd, J=7.3, 4.2 Hz, 1H), 2.95-2.87 (m, 1H), 2.77 ( tt, J=12.0, 3.9 Hz, 2H), 2.44 (d, J=12.2 Hz, 1H), 1.90-1.77 (m, 1H), 1.59-1 .48 (m, 1H). IV-397 362.3 1.69 1H NMR (500 MHz, DMSO-d6) δ 12.7 (s, 1H), 9.69 (m, 1H), 9.22 (d, 1H), 8.58 (s, 1H), 8.39 -8.34 (m, 1H), 8.14 (m, 1H), 7.90-7.60 (m, 2H), 6.88 (m, 1H), 4.80 (br s, 1H) , 4.1 (m, 1H), 3.25-3.10 (m, 3H), 2.94 (m, 1H), 1.02 (d, 3H) IV-398 376.3 1.78 IV-399 506.1 2.03 1H NMR (500 MHz, methanol-d4) δ 10.30 (s, 1H), 9.17 (d, J=1.4 Hz, 1H), 8.65 (s, 1H), 8.33 (d , J=6.3 Hz, 1H), 7.60 (s, 2H), 6.79 (d, J=6.3 Hz, 1H), 3.53-3.41 (m, 1H), 3 .17 (d, J=1.0 Hz, 3H), 3.15 (d, J=1.0 Hz, 3H), 3.00-2.92 (m, 1H), 2.84 (d, J=11.7 Hz, 1H), 2.35-2.27 (m, 1H), 1.74 (q, J=11.9 Hz, 1H), 1.29 (s, 1H), 1, 26 (d, J=6.5 Hz, 1H), 1H is not observed. IV-400 506.2 2.03 IV-401 470 2.33 1H NMR (500 MHz, methanol-d4) δ 9.95 (d, J=1.3 Hz, 1H), 8.94 (d, J=1.3 Hz, 1H), 8.53 (s, 1H ), 8.31 (d, J=6.3 Hz, 1H), 7.65 (s, 2H), 6.72 (d, J=6.4 Hz, 1H), 4.73-4.59 (m, 1H), 4.39-4.19 (m, 1H), 3.70 (d, J=3.9 Hz, 1H), 3.48-3.37 (m, 1H), 2, 84 (dd, J=13.0, 7.5 Hz, 1H), 2.34 (td, J=12.2, 3.6 Hz, 1H), 1.28 (d, J=6.8 Hz , 3H), 1.26 (d, J=6.5 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). IV-402 468 2.33 IV-403 456.3 2.16 IV-404 456.3 2.16 1H NMR (500 MHz, methanol-d4) δ 10.04 (s, 1H), 9.00-8.94 (m, 1H), 8.58 (s, 1H), 8.44 (d, J= 5.2 Hz, 1H), 7.74 (s, 2H), 7.21 (d, J=5.2 Hz, 1H), 4.90 (s, 1H), 4.69-4.44 ( m, 1H), 4.30 (s, 1H), 3.02 (s, 1H), 2.78 (s, 1H), 1.29 (s, 3H), 1.14 (s, 3H). IV-405 431.1 2.25 1H NMR (500 MHz, methanol-d4) δ 10.32 (d, 1H), 9.22-9.14 (m, 1H), 8.68 (s, 1H), 8.37 (d, 1H) , 7.71 (d, 1H), 7.18 (d, 1H), 6.81 (d, 1H), 4.71 (dd, 1H), 4.58 (s, 1H), 4.46 ( s, 1H), 3.89 (m, 1H), 3.27-3.12 (m, 1H), 2.87 (dd, 1H), 1.35 (d, 3H). IV-406 431.1 2.25 IV-407 410.1 2.11 1H NMR (500 MHz, methanol-d4) δ 9.95 (s, 1H), 9.00 (d, J=1.3 Hz, 1H), 8.61 (s, 1H), 8.44 (d , J=5.2 Hz, 1H), 7.71 (s, 2H), 7.21 (d, J=5.2 Hz, 1H), 4.95 (s, 1H), 4.58 (s , 1H), 4.30 (s, 1H), 3.02 (s, 1H), 2.79 (s, 1H), 1.30 (s, 3H), 1.12 (s, 3H). IV-408 410.1 2.1 IV-409 449.3 2.61 1H NMR (500 MHz, methanol-d4) δ 10.33 (s, 1H), 9.19 (d, J=1.4 Hz, 1H), 8.67 (s, 1H), 8.32 (d , J=6.3 Hz, 1H), 6.94 (s, 1H), 6.81 (d, J=6.4 Hz, 1H), 4.71-4.35 (m, 2H), 2 .82 (s, 1H), 2.16 (d, J=12.9 Hz, 1H), 1.98-1.78 (m, 2H), 1.71 (d, J=12.5 Hz, 1H), 2H is not observed. IV-410 430.3 1.88 1H NMR (500 MHz, methanol-d4) δ 10.33 (s, 1H), 9.23-9.17 (m, 1H), 8.68 (s, 1H), 8.40 (d, J= 6.2 Hz, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 6.74 (d, J=6.3 Hz, 1H), 4.90 (dd, J= 6.6, 3.8 Hz, 1H), 4.43 (s, 2H), 4.24 (s, 1H), 4.14-4.02 (m, 1H). IV-411 402.4 2.03 IV-412 402.4 2.06 IV-413 441 2.51 IV-414 441 2.51 IV-415 445.4 2.57 1H NMR (500 MHz, methanol-d4) δ 10.33 (s, 1H), 9.23-9.17 (m, 1H), 8.68 (s, 1H), 8.40 (d, J= 6.2 Hz, 1H), 7.71 (s, 1H), 7.64 (s, 1H), 6.74 (d, J=6.3 Hz, 1H), 4.90 (dd, J= 6.6, 3.8 Hz, 1H), 4.43 (s, 2H), 4.24 (s, 1H), 4.14-4.02 (m, 1H). IV-416 445.4 2.57 1H NMR (500 MHz, methanol-d4) δ 10.15 (s, 1H), 9.26 (d, J=1.3 Hz, 1H), 8.74 (s, 1H), 8.39 (d , J=6.8 Hz, 1H), 7.60 (s, 2H), 6.99 (s, 1H), 5.01 (d, J=1.6 Hz, 1H), 3.98-3 .83 (m, 1H), 3.26-3.13 (m, 1H), 1.55 (d, J=6.7 Hz, 3H), 1.26 (d, J=6.1 Hz, 3H). IV-417 431.4 2.39 1H NMR (500 MHz, methanol-d4) δ 10.30 (s, 1H), 9.25-9.20 (m, 1H), 8.70 (s, 1H), 8.50 (d, J= 5.2 Hz, 1H), 7.63 (s, 2H), 7.31 (d, J=5.2 Hz, 1H), 4.95-4.86 (m, 2H), 4.48 ( d, J=13.6 Hz, 1H), 4.25-4.14 (m, 1H), 3.92-3.78 (m, 1H), 3.45 (s, 1H), 1.15 (d, J=6.6 Hz, 3H). IV-418 431.4 2.45 1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.22 (s, 1H), 8.72-8.66 (m, 1H), 8.56-8.48 ( m, 1H), 7.63-7.53 (m, 1H), 7.35-7.24 (m, 1H), 5.21-5.08 (m, 1H), 4.92 (s, 1H), 4.45-4.30 (m, 1H), 3.74 (ddd, J=31.0, 11.4, 3.7 Hz, 2H), 3.53 (dt, J=14, 7, 7.3 Hz, 1H), 1.57-1.43 (m, 3H). IV-419 429.2 2.61 IV-420 429.2 2.61 1H NMR (500 MHz, methanol-d4) δ 10.27 (s, 1H), 9.18 (d, J=1.3 Hz, 1H), 8.61 (s, 1H), 8.29 (d , J=6.3 Hz, 1H), 7.57 (s, 2H), 6.77 (d, J=6.4 Hz, 1H), 3.26-3.14 (m, 1H), 3 ,13-3.05 (m, 1H), 2.22-2.06 (m, 1H), 2.04-1.90 (m, 4H), 1.73 (qt, J=13.0, 4.4 Hz, 1H), 1.10 (d, J=6.9 Hz, 3H). IV-421 462.5 2.5 IV-422 448.5 2.36 IV-423 349 3.08 1H NMR (400 MHz, DMSO-d6) δ 10.26 (dd, J=1.5, 0.8 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.36 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 3.75 (s, 4H), 1.75 -1.67 (m, 2H), 1.67-1.54 (m, 4H). IV-424 363.1 3.29 1H NMR (400 MHz, DMSO-d6) δ 10.25 (dt, J=1.7, 0.8 Hz, 1H), 9.42-9.22 (m, 1H), 8.69 (s, 1H), 8.35 (d, J=6.3 Hz, 1H), 6.86 (d, J=6.4 Hz, 1H), 4.36 (s, 2H), 3.11-2, 98 (m, 1H), 2.81-2.61 (m, 1H), 1.92-1.70 (m, 2H), 1.63 (ddd, J=10.6, 8.6, 5 ,1 Hz, 1H), 1.56-1.40 (m, 1H), 1.26 (qd, J=12.0, 3.9 Hz, 1H), 0.96 (d, J=6, 6 Hz, 3H). IV-425 408.1 1.97 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.71 (s, 1H), 8.41 (d , J=6.2 Hz, 1H), 7.64-7.33 (m, 1H), 6.96 (d, J=53.3 Hz, 2H), 4.50 (d, J=53, 8 Hz, 1H), 4.02 (s, 1H), 3.93-3.46 (m, 6H), 2.95 (s, 1H). IV-426 351.1 2.45 1H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J=1.4 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.72 (s, 1H ), 8.44 (d, J=6.3 Hz, 1H), 6.87 (d, J=6.3 Hz, 1H), 3.74 (s, 8H). IV-427 365 2.48 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.41-9.29 (m, 1H), 8.69 (s, 1H), 8.37 (d, J= 6.2 Hz, 1H), 6.78 (d, J=6.3 Hz, 1H), 4.20-3.70 (m, 6H), 3.70-3.62 (m, 2H), 1.94 (p, J=6.1 Hz, 2H). IV-428 335 2.86 1H NMR (400 MHz, DMSO-d6) δ 10.41 (d, J=1.4 Hz, 1H), 9.42-9.30 (m, 1H), 8.67 (s, 1H), 8 .33 (d, J=6.1 Hz, 1H), 6.51 (d, J=6.1 Hz, 1H), 3.69 (s, 2H), 3.47-3.36 (m, 2H), 2.03 (s, 4H). IV-429 363.1 3.2 1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.40-9.25 (m, 1H), 8.66 (s, 1H), 8.33 (d, J= 6.3 Hz, 1H), 6.69 (d, J=6.3 Hz, 1H), 3.89 (s, 2H), 3.61 (s, 2H), 1.88-1.72 ( m, 4H), 1.53 (dt, J=5.9, 2.8 Hz, 4H). IV-430 431.4 2.84 1H NMR (500 MHz, methanol-d4) δ 10.27 (s, 1H), 9.27-9.18 (m, 1H), 8.70 (s, 1H), 8.33 (d, J= 6.6 Hz, 1H), 7.78 (s, 1H), 7.66 (d, J=2.1 Hz, 1H), 6.87 (d, J=6.6 Hz, 1H), 6 .33-6.24 (m, 1H), 4.49 (s, 1H), 4.08-3.88 (m, 2H), 3.63-3.40 (m, 1H), 2.56 -2.43 (m, 1H), 2.42-2.19 (m, 1H). IV-431 376.3 2.14 1H NMR (400 MHz, DMSO-d6) δ 10.38-10.27 (m, 1H), 9.48-9.40 (m, 1H), 8.91 (d, J=5.4 Hz, 1H), 8.88 (s, 1H), 8.64 (s, 1H), 8.30 (d, J=0.7 Hz, 1H), 7.73 (d, J=5.4 Hz, 1H), 5.00 (t, J=5.3 Hz, 1H), 4.26 (t, J=5.4 Hz, 2H), 3.81 (dq, J=11.0, 5.4 Hz, 2H). IV-432 392 2.03 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.64 (d, J=3.3 Hz, 1H ), 8.31 (d, J=6.1 Hz, 1H), 7.36 (s, 1H), 6.85 (s, 1H), 6.48 (d, J=6.1 Hz, 1H ), 3.99-3.74 (m, 1H), 3.61 (s, 1H), 3.57-3.35 (m, 1H), 3.29-3.03 (m, 1H), 2.80-2.58 (m, 1H), 2.37-2.07 (m, 3H), 1.74 (d, J=11.7 Hz, 1H). IV-433 351.04 2.1 1H NMR (400 MHz, DMSO-d6) δ 10.39 (d, J=7.2 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.66 (s, 1H ), 8.36-8.30 (m, 1H), 6.50 (dt, J=6.7, 3.7 Hz, 1H), 5.12 (s, 1H), 4.48 (d, J=5.7 Hz, 1H), 3.68 (q, J=13.8, 11.5 Hz, 2H), 3.54 (d, J=16.7 Hz, 2H), 2.10 ( s, 1H), 1.99 (d, J=10.4 Hz, 1H). IV-434 365.05 2.22 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.33 (d, J=1.3 Hz, 1H), 8.62 (s, 1H), 8.28 (d , J=6.1 Hz, 1H), 6.45 (d, J=6.1 Hz, 1H), 4.78 (s, 1H), 3.69 (d, J=53.0 Hz, 1H ), 3.46 (ddd, J=16.9, 11.3, 5.9 Hz, 4H), 3.20 (s, 1H), 2.10 (s, 1H), 1.84 (s, 1H). no exchanging proton observed IV-435 379 2.32 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.65 (s, 1H), 8.30 (d , J=6.0 Hz, 1H), 6.47 (d, J=6.1 Hz, 1H), 4.52 (t, J=5.1 Hz, 1H), 3.83 (s, 1H ), 3.53 (q, J=6.2 Hz, 3H), 3.38 (s, 1H), 3.10 (dt, J=63.4, 9.4 Hz, 1H), 2.41 (s, 1H), 2.19 (s, 1H), 1.66 (dq, J=13.5, 8.3, 6.7 Hz, 3H). IV-436 365.2 2.37 1H NMR (400 MHz, DMSO-d6) δ 10.32 (d, J=34.3 Hz, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.69 (s, 1H ), 8.33 (s, 1H), 6.57 (d, J=62.8 Hz, 1H), 4.87 (d, J=39.1 Hz, 1H), 4.38 (s, 1H ), 3.97 (s, 1H), 3.70 (s, 1H), 3.51 (s, 3H), 2.17-1.92 (m, 3H). IV-437 364.9 2.3 1H NMR (400 MHz, DMSO-d6) δ 10.24 (dd, J=1.5, 0.8 Hz, 1H), 9.35 (d, J=1.2 Hz, 1H), 8.66 (s, 1H), 8.34 (d, J=6.3 Hz, 1H), 6.81 (d, J=6.4 Hz, 1H), 4.92 (d, J=4.3 Hz , 1H), 4.03 (d, J=52.5 Hz, 2H), 3.60 (dq, J=8.0, 4.0 Hz, 1H), 3.41 (s, 1H), 3 .21 (dd, J=12.9, 8.0 Hz, 1H), 2.02-1.75 (m, 1H), 1.60-1.42 (m, 2H). 1 proton masked by solvent peak IV-438 393.15 2.66 IV-439 379.35 2.44 1H NMR (400 MHz, DMSO-d6) δ 10.29 (dd, J=1.5, 0.8 Hz, 1H), 9.40 (d, J=1.4 Hz, 1H), 8.72 (s, 1H), 8.40 (d, J=6.4 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 4.64 (t, J=5.2 Hz , 1H), 4.38 (s, 1H), 3.41 (t, J=5.7 Hz, 2H), 3.33 (s, 1H), 3.17 (s, 1H), 2.96 (dd, J=13.1, 10.3 Hz, 1H), 1.92-1.63 (m, 3H), 1.60-1.33 (m, 2H). IV-440 379 2.55 1H NMR (400 MHz, DMSO-d6) δ 10.27 (dd, J=1.4, 0.7 Hz, 1H), 9.35 (d, J=1.4 Hz, 1H), 8.68 (s, 1H), 8.33 (d, J=6.4 Hz, 1H), 6.81 (d, J=6.5 Hz, 1H), 4.78 (t, J=5.7 Hz , 1H), 4.52 (s, 1H), 3.72-3.57 (m, 2H), 3.10-2.99 (m, 1H), 1.91 (d, J=12.5 Hz, 1H), 1.77 (d, J=13.2 Hz, 1H), 1.63 (s, 3H), 1.62 (s, 1H), 1.73-1.41 (m, 1H ). IV-441 365.4 2.19 IV-442 393.2 2.46 1H NMR (400 MHz, DMSO-d6) δ 10.25 (dd, J=1.5, 0.8 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.67 (s, 1H), 8.35 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 4.47 (s, 2H), 4.39 (t, J=5.1 Hz, 1H), 3.49 (td, J=6.6, 5.1 Hz, 2H), 3.08-2.96 (m, 2H), 1.80 ( d, J=11.9 Hz, 3H), 1.41 (q, J=6.5 Hz, 2H), 1.24-1.09 (m, 2H). IV-443 378.7 2.32 1H NMR (400 MHz, DMSO-d6) δ 10.26 (dd, J=1.4, 0.8 Hz, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.68 (s, 1H), 8.36 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 4.52 (t, J=5.3 Hz , 1H), 3.30 (d, J=5.3 Hz, 3H), 3.09-2.98 (m, 2H), 1.84-1.71 (m, 4H), 1.26- 1.12 (m, 2H). IV-444 392.55 2.56 1H NMR (400 MHz, DMSO-d6) δ 10.25 (dt, J=1.5, 0.8 Hz, 1H), 9.36 (dd, J=1.4, 0.6 Hz, 1H) , 8.67 (s, 1H), 8.35 (d, J=6.3 Hz, 1H), 6.84 (d, J=6.4 Hz, 1H), 4.48-4.08 ( m, 2H), 3.53 (qt, J=6.4, 4.4 Hz, 2H), 3.12 (ddd, J=13.8, 11.4, 3.0 Hz, 1H), 2 .86 (dd, J=13.1, 10.3 Hz, 1H), 1.95-1.59 (m, 3H), 1.57-1.21 (m, 4H), 0.99-0 .90 (m, 1H). IV-445 393.1 2.58 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.35 (q, J=0.6 Hz, 1H), 8.67 (d, J=17.1 Hz, 1H ), 8.33 (d, J=6.2 Hz, 1H), 6.69 (d, J=6.3 Hz, 1H), 4.70 (d, J=51.9 Hz, 1H), 4.30-4.07 (m, 1H), 3.86-3.64 (m, 1H), 3.61-3.45 (m, 1H), 3.44-3.36 (m, 1H ), 3.30 (d, J=6.3 Hz, 1H), 3.20 (d, J=13.6 Hz, 1H), 2.06-1.54 (m, 5H), 1.39 -1.17 (m, 2H). IV-446 381.1 2.08 1H NMR (400 MHz, DMSO-d6) δ 10.25 (dd, J=1.6, 0.8 Hz, 1H), 9.37 (d, J=1.4 Hz, 1H), 8.72 (s, 1H), 8.44 (d, J=6.3 Hz, 1H), 6.86 (d, J=6.4 Hz, 1H), 4.88-4.80 (m, 1H) , 4.41 (s, 1H), 4.30 (s, 1H), 4.00 (dd, J=11.7, 2.8 Hz, 1H), 3.59 (td, J=11.2 , 2.4 Hz, 1H), 3.57-3.47 (m, 3H), 3.18-3.06 (m, 1H), 2.88 (d, J=13.0 Hz, 1H) . IV-447 379.05 2.29 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.66 (s, 1H), 8.32 (d , J=6.3 Hz, 1H), 6.67 (s, 1H), 4.61 (d, J=3.8 Hz, 1H), 3.83 (d, J=59.4 Hz, 3H ), 3.56 (d, J=30.1 Hz, 3H), 1.99 (dt, J=8.3, 5.7 Hz, 1H), 1.84-1.38 (m, 4H) . IV-448 416.2 2.53 IV-449 402.1 2.46 IV-450 445.1 2.53 1H NMR (500 MHz, methanol-d4) δ 10.30 (s, 1H), 9.19 (d, J=1.3 Hz, 1H), 8.66 (s, 1H), 8.36 (d , J=6.3 Hz, 1H), 7.63 (s, 2H), 6.81 (s, 1H), 5.18-4.46 (m, 2H), 4.40-3.70 ( m, 2H), 3.11-2.83 (m, 1H), 1.39 (d, J=6.1 Hz, 3H), 1.10 (d, J=6.7 Hz, 3H) IV-451 445.1 2.53 1H NMR (500 MHz, methanol-d4) δ 10.46-10.08 (m, 1H), 9.19 (d, J=2.5 Hz, 1H), 8.74-8.59 (m, 1H), 8.36 (dd, J=6.9, 3.2 Hz, 1H), 7.63 (s, 2H), 6.81 (s, 1H), 5.17-4.58 (m , 2H), 4.48-3.72 (m, 2H), 3.12-2.79 (m, 1H), 1.39 (d, J=6.1 Hz, 3H), 1.10 ( d, J=6.8 Hz, 3H). IV-452 429.4 2.68 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.23 (s, 1H), 9.35 (s, 1H), 8.65 (s, 1H), 8.38 (d, 1H), 7.43 (s, 1H), 6.90 (d, 1H), 4.56 (s, 2H), 3.12 (m, 1H), 2.97 (m, 1H) , 2.62 (m, 1H), 2.19 (s, 3H), 1.98 (m, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.62 ( m, 1H). IV-453 406.4 2.27 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.37 (s, 1H), 8.71 (s, 1H), 8.40 (d, J=6.3 Hz , 1H), 7.45 (s, 1H), 6.99 (s, 1H), 6.89 (d, J=6.1 Hz, 1H), 5.63-5.21 (m, 1H) , 5.01-4.33 (m, 2H), 4.18-3.76 (m, 1H), 1.94-1.75 (m, 2H), 1.67 (d, J=13, 2 Hz, 1H), 1.47 (d, J=13.5 Hz, 1H), 1.13 (d, J=6.8 Hz, 3H). IV-454 412.4 1.9 1H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.07 (s, 1H), 9.30 (d, 1H), 8.65 (s, 1H), 8.39 (s, 1H), 7.62 (m, 2H), 7.06 (t, 1H), 6.91 (s, 1H), 5.07-4.39 (m, 1H), 3.90 ( m, 1H), 3.11 (m, 3H), 2.82-2.74 (m, 1H), 1.01 (d, 3H). IV-455 412.4 1.93 1H NMR (500 MHz, DMSO-d6) δ 12.66 (s, 1H), 10.19-9.99 (m, 1H), 9.32 (d, 1H), 8.84-8.67 ( m, 1H), 8.37 (s, 1H), 7.91-7.72 (m, 2H), 7.06 (t, 1H), 6.71-6.51 (m, 1H), 5 .93-4.64 (m, 1H), 3.78 (m, 0.5H), 3.12 (m, 3.5H), 2.83 (m, 1H), 0.90 (m, 3H ). IV-456 401 2.18 1H NMR (500 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.40 (s, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.62 (s, 1H), 6.97 (d, J=14.6 Hz, 1H), 6.52 (q, J=5.7, 4.4 Hz, 1H) , 4.14-3.47 (m, 5H), 2.43-2.30 (m, 1H), 2.22-2.08 (m, 1H). IV-457 401 2.42 1H NMR (500 MHz, DMSO-d6) δ 12.62 (br s, 1H), 10.39 (s, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8, 34 (s, 1H), 7.61 (s, 1H), 6.54 (s, 1H), 6.21 (d, J=9.8 Hz, 1H), 4.36-3.43 (m , 5H), 2.47-2.37 (m, 1H), 2.25-2.12 (m, 1H). IV-458 444.2 2.26 1H NMR (500 MHz, methanol-d4) δ 10.19(s, 1H), 9.08 (s, 1H), 8.52 (m, 1H), 8.22 (m, 1H), 7.55 (s, 1H), 6.69 (m, 1H), 4.40 (s, 2H), 3.80 (dd, 1H), 2.90 (m, 1H), 2.66 (m, 1H) , 2.23 (s, 3H), 1.16 (d, 3H). IV-459 444.2 2.26 1H NMR (500 MHz, methanol-d4) δ 10.19(s, 1H), 9.08 (s, 1H), 8.52 (m, 1H), 8.22 (m, 1H), 7.55 (s, 1H), 6.69 (m, 1H), 4.40 (s, 2H), 3.80 (dd, 2H), 2.90 (m, 1H), 2.66 (m, 1H) , 2.23 (s, 3H), 1.16 (d, 3H). IV-460 430.2 2.14 1H NMR (500 MHz, methanol-d4) δ 10.27 (s, 1H), 9.20 (d, 1H), 8.63 (m, 1H), 8.36 (d, 1H), 7.79 (s, 2H), 6.83 (d, 1H), 4.60 (s, 2H), 4.11-4.08 (m, 1H), 3.11 (m, 2H), 2.81 ( m, 1H), 1.32 (d, 3H). IV-461 430.1 2.14 1H NMR (500 MHz, methanol-d4) δ 10.27 (s, 1H), 9.20 (d, 1H), 8.63 (m, 1H), 8.36 (d, 1H), 7.79 (s, 2H), 6.83 (d, 1H), 4.60 (s, 2H), 4.11-4.08 (m, 1H), 3.11 (m, 2H), 2.81 ( m, 1H), 1.32 (d, 3H). IV-462 426.2 2.01 1H NMR (500 MHz, DMSO-d6) δ 12.44-12.32 (m, 1H), 10.05 (s, 1H), 9.30 (s, 1H), 8.62 (s, 1H) , 8.37 (d, 1H), 7.62-7.44 (m, 1H), 7.06 (t, 1H), 6.89 (d, 1H), 3.72 (m, 1H), 2.87 (m, 3H), 2.64 (m, 2H), 2.25 (s, 3H), 1.13 (d, 3H). IV-463 426.2 2.01 1H NMR (500 MHz, DMSO-d6) δ 12.44-12.32 (m, 1H), 10.05 (s, 1H), 9.30 (s, 1H), 8.62 (s, 1H) , 8.37 (d, 1H), 7.62-7.44 (m, 1H), 7.06 (t, 1H), 6.89 (d, 1H), 3.72 (m, 1H), 2.87 (m, 3H), 2.64 (m, 2H), 2.25 (s, 3H), 1.13 (d, 3H). IV-464 420.2 2.44 1H NMR (400 MHz, DMSO-d6) δ 9.26 (dd, J=1.6, 0.8 Hz, 1H), 8.15 (d, J=1.3 Hz, 1H), 7.62 (s, 1H), 7.29 (d, J=6.4 Hz, 1H), 5.76 (d, J=6.4 Hz, 1H), 1.85-1.57 (m, 2H) , 0.89-0.52 (m, 3H), 0.20 (d, J=6.9 Hz, 3H), 0.07 (d, J=5.6 Hz, 3H).
3 peaks are not very well resolved: 4.45, 3.74, 2.84 are all broad singlets, probably due to the NH or CH located after the N in the piperidine ring. IV-465 458.2 2.47 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.22 (s, 1H), 9.35 (s, 1H), 8.69 (s, 1H), 8.38 (d, 1H), 6.90 (d, 1H), 4.67 (br s, 2H), 3.76 (m, 1H), 2.97 (m, 1H), 2.64 (m, 1H ), 2.53 (masked, 1H), 2.24 (s, 6H), 1.12 (d, 3H). IV-466 481.4 2.73 1H NMR (500 MHz, methanol-d4) δ 10.31 (s, 1H), 9.27-9.20 (m, 1H), 8.68 (s, 1H), 8.41 (d, J= 6.4 Hz, 1H), 7.67 (s, 2H), 6.92 (d, J=6.4 Hz, 1H), 6.57 (t, J=75.1 Hz, 1H), 5 .05-4.86 (m, 1H), 4.71-4.46 (m, 1H), 4.35 (tt, J=10.4, 4.7 Hz, 1H), 3.16-2 .98 (m, 3H), 2.57-2.46 (m, 1H), 1.99-1.88 (m, 1H). IV-467 458.2 2.47 1H NMR (500 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.22 (s, 1H), 9.35 (s, 1H), 8.69 (s, 1H), 8.38 (d, 1H), 6.90 (d, 1H), 4.67 (br s, 2H), 3.76 (m, 1H), 2.97 (m, 1H), 2.64 (m, 1H ), 2.53 (masked, 1H), 2.24 (s, 6H), 1.12 (d, 3H). IV-468 411.1 2.38 1H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.04 (s, 1H), 9.29 (s, 1H), 8.60 (s, 1H), 8.38 (d, 1H), 7.43 (s, 1H), 7.30-7.05 (t, 1H), 6.87 (d, 1H), 4.47 (s, 2H), 3.31 ( m, 1H), 3.09 (m, 1H), 2.97 (m, 1H), 2.20 (s, 3H), 1.98 (m, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.62 (m, 1H). IV-469 411.1 2.38 1H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.04 (s, 1H), 9.29 (s, 1H), 8.60 (s, 1H), 8.38 (d, 1H), 7.43 (s, 1H), 7.30-7.05 (t, 1H), 6.87 (d, 1H), 4.47 (s, 2H), 3.31 ( m, 1H), 3.09 (m, 1H), 2.97 (m, 1H), 2.20 (s, 3H), 1.98 (m, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.62 (m, 1H). IV-470 429.1 2.64 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.23 (s, 1H), 9.35 (s, 1H), 8.65 (s, 1H), 8.38 (d, 1H), 7.43 (s, 1H), 6.90 (d, 1H), 4.56 (s, 2H), 3.12 (m, 1H), 2.97 (m, 1H) , 2.62 (m, 1H), 2.19 (s, 3H), 1.98 (m, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.62 ( m, 1H). IV-471 429.1 2.64 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.23 (s, 1H), 9.35 (s, 1H), 8.65 (s, 1H), 8.38 (d, 1H), 7.43 (s, 1H), 6.90 (d, 1H), 4.56 (s, 2H), 3.12 (m, 1H), 2.97 (m, 1H) , 2.62 (m, 1H), 2.19 (s, 3H), 1.98 (m, 1H), 1.86 (m, 1H), 1.72 (m, 1H), 1.62 ( m, 1H). IV-472 481.4 2.63 1H NMR (500 MHz, methanol-d4) δ 10.29 (s, 1H), 9.24 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8.36 (d , J=6.5 Hz, 1H), 7.65 (s, 2H), 6.89 (d, J=6.6 Hz, 1H), 6.50 (t, J=75.3 Hz, 1H ), 5.13-4.26 (m, 3H), 3.52 (d, J=1.7 Hz, 1H), 3.32-3.22 (m, 2H), 2.40-2, 30 (m, 1H), 2.16-2.07 (m, 1H). IV-473 433.1 2.77 1H NMR (500 MHz, methanol-d4) δ 10.23-10.06 (m, 1H), 9.08 (dd, J=1.4, 0.7 Hz, 1H), 8.51 (s, 1H), 8.20 (d, J=6.3 Hz, 1H), 7.41-7.30 (m, 1H), 6.65 (d, J=6.4 Hz, 1H), 4, 41 (d, J=86.5 Hz, 2H), 3.15-3.00 (m, 2H), 2.71 (tt, J=11.0, 3.9 Hz, 1H), 2.04 (dt, J=12.2, 3.7 Hz, 1H), 1.82 (dp, J=13.5, 3.4 Hz, 1H), 1.79-1.67 (m, 1H), 1.61 (dddt, J=11.8, 9.3, 7.8, 3.9 Hz, 1H). IV-474 498.1 2.66 1H NMR (500 MHz, DMSO-d6) δ 13.61 (s, 1H), 10.18 (s, 1H), 9.34 (s, 1H), 8.65 (s, 1H), 8.40 (d, 1H), 8.01 (s, 1H), 6.85 (s, 1H), 5.07-4.14 (br m, 2H), 3.88 (m, 1H), 2.90 (m, 2H), 2.79-2.65 (m, 1H), 1.13 (d, 3H). IV-475 498.1 2.66 1H NMR (500 MHz, DMSO-d6) δ 13.61 (s, 1H), 10.18 (s, 1H), 9.34 (s, 1H), 8.65 (s, 1H), 8.40 (d, 1H), 8.01 (s, 1H), 6.85 (s, 1H), 5.07-4.14 (br m, 2H), 3.88 (m, 1H), 2.90 (m, 2H), 2.79-2.65 (m, 1H), 1.13 (d, 3H). IV-476 443.1 2.7 1H NMR (500 MHz, DMSO-d6) δ 12.0 (s, 1H), 10.22 (s, 1H), 9.35 (s, 1H), 8.64 (s, 1H), 8.34 (d, 1H), 6.89 (d, 1H), 5.07-4.14 (br m, 2H), 3.17-3.02 (m, 2H), 2.61 (m, 1H) , 2.18 (s, 6H), 1.95 (m, 1H), 1.84 (m, 2H), 1.58 (m, 1H). IV-477 443.2 2.7 1H NMR (500 MHz, DMSO-d6) δ 12.0 (s, 1H), 10.22 (s, 1H), 9.35 (s, 1H), 8.64 (s, 1H), 8.34 (d, 1H), 6.89 (d, 1H), 5.07-4.14 (br m, 2H), 3.17-3.02 (m, 2H), 2.61 (m, 1H) , 2.18 (s, 6H), 1.95 (m, 1H), 1.84 (m, 2H), 1.58 (m, 1H). IV-478 416 2.07 1H NMR (500 MHz, DMSO-d6) δ 10.37 (br d, J=20.3 Hz, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.37 ( br s, 1H), 7.15 (s, 1H), 6.97 (d, J=0.9 Hz, 1H), 6.58 (d, J=6.1 Hz, 1H), 5.02 (br s, 1H), 4.18-3.51 (m, 6H), 2.42 (br s, 2H). IV-479 436.4 2.12 1H NMR (400 MHz, DMSO-d6) δ 10.34-10.14 (m, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8 .37 (d, J=6.3 Hz, 1H), 7.94 (t, J=5.6 Hz, 1H), 6.89 (d, J=6.4 Hz, 1H), 4.65 (t, J=5.5 Hz, 1H), 4.42 (s, 2H), 3.40 (p, J=5.9 Hz, 2H), 3.23-2.97 (m, 4H) , 2.45-2.31 (m, 1H), 1.90 (d, J=12.3 Hz, 1H), 1.76 (dtd, J=24.0, 12.2, 10.9, 3.9 Hz, 2H), 1.48 (d, J=12.9 Hz, 1H). IV-480 405.3 2.12 1H NMR (400 MHz, DMSO-d6) δ 10.23 (d, J=1.4 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.75 (s, 1H ), 8.43 (d, J=6.3 Hz, 1H), 6.91 (d, J=6.3 Hz, 1H), 6.61 (s, 1H), 4.54 (d, J =55.7 Hz, 2H), 3.72 (tt, J=12.9, 3.7 Hz, 2H), 3.46 (ddd, J=9.4, 8.3, 1.2 Hz, 1H), 3.07-2.86 (m, 4H). IV-481 420.1 2.37 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.37 (s, 1H), 8.71 (s, 1H), 8.38 (d, J=6.4 Hz , 1H), 7.44 (s, 1H), 6.99 (d, J=6.3 Hz, 1H), 6.87 (d, J=6.4 Hz, 1H), 2.89-2 .68 (m, 1H), 2.22-2.01 (m, 2H), 1.41 (d, J=13.4 Hz, 1H), 1.14 (d, J=6.9 Hz, 3H), 0.98 (d, J=6.7 Hz, 3H); 3, the proton signal is absent; the corresponding CHs located after N of piperidine are often significantly broadened. IV-482 441.3 2.54 1H NMR (400 MHz, DMSO-d6) δ 10.26 (d, J=1.4 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.74 (s, 1H ), 8.41 (d, J=6.3 Hz, 1H), 6.81 (d, J=6.3 Hz, 1H), 4.61 (s, 1H), 4.22 (s, 1H ), 3.29-3.16 (m, 3H), 3.15-3.04 (m, 1H), 3.04 (s, 3H), 2.19 (s, 1H), 2.01 ( s, 1H), 1.76 (s, 1H), 1.64-1.44 (m, 2H). IV-483 427.3 2.42 1H NMR (400 MHz, DMSO-d6) δ 10.24 (dd, J=1.5, 0.8 Hz, 1H), 9.38 (d, J=1.3 Hz, 1H), 8.71 (s, 1H), 8.46 (d, J=6.3 Hz, 1H), 6.96 (d, J=6.3 Hz, 1H), 4.84 (s, 1H), 4.36 (s, 1H), 3.39-3.33 (m, 2H), 3.27-3.13 (m, 1H), 3.09 (s, 3H), 2.22 (d, J=13 ,9 Hz, 1H), 2.04-1.75 (m, 2H), 1.56 (d, J=12.8 Hz, 1H). IV-484 415.3 2.44 1H NMR (500 MHz, methanol-d4) δ 10.32 (s, 1H), 9.21 (s, 1H), 8.67 (s, 1H), 8.45 (d, 1H), 7.62 (s, 1H), 7.21 (d, 1H), 6.92 (s, 1H), 4.90 (masked, 1H), 4.73 (m, 1H), 3.18 (m, 2H) , 2.89 (m, 1H), 2.19 (m, 1H), 1.93-1.88 (m, 2H), 1.75 (m, 1H). IV-485 429.4 2.71 1H NMR (500 MHz, methanol-d4) δ 10.34 (s, 1H), 9.23 (s, 1H), 8.68 (s, 1H), 8.48 (d, 1H), 7.54 (s, 2H), 7.21 (d, 1H), 5.20 (m, 1H), 4.73 (m, 1H), 3.18 (m, 1H), 3.09 (m, 1H) , 2.15 (m, 1H), 1.97 (m, 2H), 1.176 (m, 1H), 1.22 (m, 1H), 1.10 (d, 3H). IV-486 394.1 2.04 IV-487 378.2 2.15 IV-488 392.1 2.39 IV-489 380.2 2.05 1H NMR (400 MHz, DMSO-d6) δ 10.23 (d, J=5.7 Hz, 1H), 9.36 (s, 1H), 8.74 (s, 1H), 8.43 (d , J=6.2 Hz, 1H), 6.85 (dd, J=9.4, 6.3 Hz, 1H), 4.46-4.17 (m, 4H), 4.05-3, 97 (m, 1H), 3.58 (td, J=11.6, 2.8 Hz, 1H), 3.41 (dtd, J=10.8, 5.7, 2.6 Hz, 1H) , 3.18-3.04 (m, 1H), 2.83 (dd, J=13.1, 10.4 Hz, 1H), 2.70 (d, J=5.7 Hz, 2H). IV-490 447.1 2.22 1H NMR (400 MHz, DMSO-d6) δ 10.24 (dd, J=1.5, 0.8 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.36 (d, J=6.3 Hz, 1H), 7.72 (s, 1H), 6.89 (d, J=6.4 Hz, 1H), 4.88 -3.69 (m, 2H), 3.28-3.05 (m, 6H), 2.84 (dt, J=10.7, 5.1 Hz, 1H), 2.75-2.63 (m, 1H), 2.43 (tt, J=9.8, 3.6 Hz, 1H), 2.01-1.88 (m, 1H), 1.82 (dt, J=13.1 , 3.9 Hz, 1H), 1.70-1.57 (m, 1H), 1.48 (q, J=11.9 Hz, 1H). IV-491 433.1 2.73 1H NMR (500 MHz, methanol-d4) δ 10.21-10.13 (m, 1H), 9.07 (dd, J=1.3, 0.7 Hz, 1H), 8.50 (s, 1H), 8.19 (d, J=6.4 Hz, 1H), 7.38 (dd, J=2.4, 0.6 Hz, 1H), 6.64 (d, J=6.4 Hz, 1H), 4.63-4.16 (m, 2H), 3.15-2.97 (m, 2H), 2.70 (tt, J=11.0, 3.9 Hz, 1H) , 2.09-1.99 (m, 1H), 1.82 (dp, J=13.3, 3.3 Hz, 1H), 1.78-1.67 (m, 1H), 1.61 (dtt, J=13.2, 11.7, 3.9 Hz, 1H). IV-492 433.1 2.73 1H NMR (500 MHz, methanol-d4) δ 10.35-10.28 (m, 1H), 9.19 (t, J=1.8 Hz, 1H), 8.67-8.59 (m, 1H), 8.37-8.24 (m, 1H), 7.50 (d, J=2.3 Hz, 1H), 6.82-6.69 (m, 1H), 4.75-4 .29 (m, 2H), 3.27-3.12 (m, 2H), 2.82 (tq, J=10.6, 3.3 Hz, 1H), 2.16 (ddd, J=12 ,3, 4.4, 2.4 Hz, 1H), 2.00-1.90 (m, 1H), 1.90-1.79 (m, 1H), 1.79-1.65 (m , 1H). IV-493 416 2.32 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.42-9.33 (m, 1H), 8.71 (s, 1H), 8.43 (d, J= 6.3 Hz, 1H), 8.28 (d, J=1.0 Hz, 1H), 7.77 (d, J=1.0 Hz, 1H), 6.97 (d, J=6, 3 Hz, 1H), 4.75 (tt, J=9.3, 4.4 Hz, 1H), 3.75 (dd, J=13.1, 9.7 Hz, 1H), 3.41- 3.34 (m, 1H), 3.29 (d, J=6.2 Hz, 1H), 2.27 (qdt, J=13.0, 9.9, 4.5 Hz, 2H), 1 .93 (dq, J=12.4, 4.1 Hz, 1H), 1.72 (dtt, J=14.9, 9.9, 4.5 Hz, 1H). IV-494 401 2.37 1H NMR (500 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.41 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.35 (d, J=5.7 Hz, 1H), 7.68 (s, 1H), 7.48 (s, 1H), 6.55 (s, 1H), 3.95-3.80 (m, 1H), 3.76-3.43 (m, 3H), 2.42 (br s, 1H), 2.07 (br s, 1H). IV-495 393.1 3.01 1H NMR (500 MHz, DMSO-d6) δ 10.23 (dd, J=1.4, 0.8 Hz, 1H), 9.35 (dd, J=1.4, 0.6 Hz, 1H) , 8.66 (s, 1H), 8.35 (d, J=6.3 Hz, 1H), 6.81 (d, J=6.4 Hz, 1H), 4.26 (s, 2H) , 3.29 (d, J=6.0 Hz, 2H), 3.25 (s, 3H), 3.22-3.15 (m, 1H), 3.01 (dd, J=13.1 , 9.7 Hz, 1H), 1.95-1.66 (m, 3H), 1.61-1.27 (m, 2H). IV-496 405.1 2.82 1H NMR (500 MHz, DMSO-d6) δ 10.23 (d, J=1.2 Hz, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.66 (s, 1H ), 8.35 (d, J=6.3 Hz, 1H), 6.87 (d, J=6.3 Hz, 1H), 3.92-3.81 (m, 1H), 3.77 -3.58 (m, 3H), 3.30 (m, 2H, not observed), 3.45 (dd, J=99.2, 8.6 Hz, 2H), 1.86-1.52 ( m, 6H). IV-497 377.1 2.55 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.67 (s, 1H), 8.36 (d , J=6.0 Hz, 1H), 6.54 (d, J=6.1 Hz, 1H), 4.61 (t, J=5.2 Hz, 1H), 4.01-3.87 (m, 1H), 3.80 (td, J=8.3, 4.7 Hz, 4H), 3.36 (d, J=5.2 Hz, 1H), 3.12 (s, 1H) , 2.16 (dq, J=12.4, 7.8 Hz, 1H), 1.88 (t, J=7.3 Hz, 1H). IV-498 406.3 2.29 IV-499 406.3 2.28 IV-500 420.1 2.44 IV-501 420.1 2.43 IV-502 446.1 2.9 1H NMR (400 MHz, methanol-d4) δ 10.26-10.16 (m, 1H), 9.30-9.21 (m, 1H), 8.67 (d, J=1.0 Hz, 1H), 8.37 (dd, J=6.6, 1.2 Hz, 1H), 6.87 (d, J=6.6 Hz, 1H), 4.86-4.70 (m, 1H ), 4.51 (s, 1H), 4.32-4.19 (m, 1H), 3.19 (q, J=11.4, 10.5 Hz, 2H), 2.31 (dtt, J=20.4, 10.2, 5.6 Hz, 1H), 2.20-1.93 (m, 2H), 1.83-1.59 (m, 2H). IV-503 446.1 2.96 1H NMR (400 MHz, methanol-d4) δ 10.32 (dd, J=1.5, 0.8 Hz, 1H), 9.30-9.18 (m, 1H), 8.70 (s, 1H), 8.40 (d, J=6.5 Hz, 1H), 6.85 (d, J=6.5 Hz, 1H), 4.87 (s, 1H), 4.49 (s, 1H), 4.24 (qd, J=8.0, 5.0 Hz, 1H), 3.22-3.07 (m, 2H), 2.23 (dt, J=11.3, 4, 1 Hz, 1H), 2.10 (t, J=10.9 Hz, 1H), 2.06-1.93 (m, 1H), 1.90-1.56 (m, 2H). IV-504 406.1 2.31 1H NMR (500 MHz, DMSO-d6) δ 10.24 (d, J=1.3 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.74 (s, 1H ), 8.42 (d, J=6.3 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 3.87-3.75 (m, 2H), 3.58 (td, J=11.1, 2.2 Hz, 1H), 3.22 (t, J=10.5 Hz, 1H), 3.13 (t, J=11.7 Hz, 1H), 2 .80 (dd, J=78.4, 11.5 Hz, 2H), 2.69-2.58 (m, 2H), 2.30-2.13 (m, 3H). IV-505 419.1 2.92 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.71 (s, 1H), 8.35 (d , J=6.3 Hz, 1H), 6.92 (s, 1H), 3.73 (s, 4H), 3.60 (dddd, J=45.4, 11.3, 7.0, 3 ,8 Hz, 4H), 1.63 (d, J=2.8 Hz, 4H), 1.52-1.30 (m, 4H). IV-506 448.2 3.22 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.67 (s, 1H), 8.43 (d , J=6.3 Hz, 1H), 6.96 (d, J=6.4 Hz, 1H), 4.70 (d, J=1.6 Hz, 1H), 3.82-3.60 (m, 2H), 3.23-3.00 (m, 2H), 2.51 (p, J=1.8 Hz, 3H), 2.19 (td, J=11.4, 3.3 Hz, 1H), 0.99 (s, 9H). IV-507 419.1 2.89 1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.74-8.57 (m, 1H), 8 .33 (d, J=6.0 Hz, 1H), 6.65-6.37 (m, 1H), 4.07-3.79 (m, 4H), 3.72-3.46 (m , 2H), 3.31 (s, 2H), 2.15 (d, J=46.4 Hz, 2H), 1.66 (dd, J=22.4, 12.8 Hz, 3H), 1 .54 (s, 1H), 1.43-1.23 (m, 2H). IV-508 391.4 2.61 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.36 (s, 1H), 8.67 (s, 1H), 8.34 (d, J=6.0 Hz , 1H), 6.51 (s, 1H), 4.72 (d, J=7.6 Hz, 2H), 4.47-4.34 (m, 2H), 3.67-3.62 ( m, 1H), 3.58-3.52 (m, 1H), 3.49-3.40 (m, 1H), 3.25 (d, J=10.2 Hz, 1H), 3.14 -2.99 (m, 1H), 2.87-2.71 (m, 1H), 2.26-2.13 (m, 1H), 1.77-1.60 (m, 1H). IV-509 407.4 3.25 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.67 (s, 1H), 8.36 (d , J=6.3 Hz, 1H), 6.69 (s, 1H), 4.29-4.17 (m, 1H), 3.86-3.64 (m, 1H), 3.65- 3.37 (m, 1H), 3.29 (s, 3H+m, 3H), 3.26 (s, 2H), 1.83-1.69 (m, 2H), 1.67-1, 56 (m, 1H), 1.37-1.24 (m, 2H). IV-510 448.4 2.89 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.36 (d , J=6.3 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 4.47 (m, 4H, broad), 3.59 (t, J=4.6 Hz , 4H), 3.29 (s, 1H), 3.05 (d, J=2.2 Hz, 1H), 2.42-2.28 (m, 4H), 2.17 (d, J= 7.3 Hz, 2H), 1.85 (d, J=13.2 Hz, 2H), 1.14 (q, J=12.2, 10.2 Hz, 2H). IV-511 391.3 2.61 1H NMR (500 MHz, DMSO-d6) δ 10.24 (d, J=0.7 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.69 (s, 1H ), 8.37 (d, J=6.2 Hz, 1H), 6.89 (d, J=6.3 Hz, 1H), 4.40 (s, 4H), 3.70 (s, 4H ), 2.01-1.79 (m, 4H). IV-512 393.3 3 1H NMR (500 MHz, DMSO-d6) δ 10.25 (d, J=1.3 Hz, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.68 (s, 1H ), 8.36 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 4.49 (s, 2H), 3.25 (s, 3H ), 3.23 (d, J=6.3 Hz, 2H), 3.05 (td, J=12.7, 2.8 Hz, 2H), 2.00-1.90 (m, 1H) , 1.79 (dd, J=13.3, 3.5 Hz, 2H), 1.31-1.13 (m, 2H). IV-513 374.05 2.58 1H NMR (400 MHz, DMSO-d6) δ 10.24 (t, J=1.1 Hz, 1H), 9.37 (d, J=1.4 Hz, 1H), 8.72 (s, 1H ), 8.42 (d, J=6.3 Hz, 1H), 6.91 (d, J=6.4 Hz, 1H), 4.06 (s, 2H), 3.58 (s, 1H ), 3.32-3.19 (m, 2H), 2.11-1.97 (m, 2H), 1.81 (ddt, J=13.7, 9.1, 4.4 Hz, 2H ). IV-514 388.05 2.75 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.35 (s, 1H), 8.65 (s, 1H), 8.32 (d, J=6.0 Hz , 1H), 6.47 (s, 1H), 3.80 (s, 1H), 3.53 (s, 1H), 3.06 (s, 1H), 2.68 (s, 2H), 2 .38 (s, 2H), 2.14 (s, 2H), 1.80 (s, 1H). 1 proton peak is masked by solvent peaks IV-515 404.1 2.19 1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 9.15-9.10 (m, 1H), 8.43 (s, 1H), 8.12 (d, J= 6.3 Hz, 1H), 7.39 (s, 1H), 6.58 (d, J=6.3 Hz, 1H), 4.16 (s, 1H), 3.25-3.11 ( m, 2H), 2.93 (s, 1H), 2.67 (d, J=9.9 Hz, 1H), 2.52-2.38 (m, 2H), 1.78-1.69 (m, 1H), 1.27 (d, J=10.3 Hz, 1H), 0.75 (s, 1H). IV-516 373.9 2.57 1H NMR (400 MHz, DMSO-d6) δ 10.34 (dd, J=1.5, 0.8 Hz, 1H), 9.48 (q, J=0.6 Hz, 1H), 8.85 (s, 1H), 8.55 (d, J=6.3 Hz, 1H), 7.09 (d, J=6.3 Hz, 1H), 4.33-4.24 (m, 1H) , 4.05 (d, J=13.6 Hz, 2H), 3.82-3.68 (m, 1H), 3.29 (dq, J=6.6, 3.4 Hz, 1H), 2.19 (s, 1H), 2.23-2.01 (m, 2H), 1.92-1.73 (m, 1H). IV-517 363.25 3.29 1H NMR (400 MHz, DMSO-d6) δ 10.25 (t, J=1.1 Hz, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.68 (s, 1H ), 8.35 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 4.47 (s, 2H), 3.03 (td, J =12.8, 2.5 Hz, 2H), 1.81-1.71 (m, 1H), 1.74 (s, 2H), 1.14 (dddd, J=16.3, 14.0 , 11.4, 3.9 Hz, 2H), 0.95 (d, J=6.2 Hz, 3H). IV-518 363.33 3.27 1H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J=1.2 Hz, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.68 (s, 1H ), 8.36 (d, J=6.3 Hz, 1H), 6.82 (d, J=6.5 Hz, 1H), 4.81 (s, 1H), 4.34 (s, 1H ), 3.13-3.01 (m, 1H), 1.79 (d, J=13.8 Hz, 1H), 1.77-1.60 (m, 4H), 1.51-1, 43 (m, 1H), 1.24 (d, J=6.8 Hz, 3H). IV-519 377.34 3.43 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.28 (d, J=1.3 Hz, 1H), 8.60 (s, 1H), 8.26 (d , J=6.3 Hz, 1H), 6.75 (d, J=6.4 Hz, 1H), 4.33 (s, 2H), 2.93 (t, J=11.3 Hz, 1H ), 1.71 (s, 2H), 1.48 (d, J=7.4 Hz, 1H), 1.47-1.34 (m, 2H), 1.02 (d, J=6, 9 Hz, 3H), 0.97-0.84 (m, 3H). IV-520 393.19 2.62 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.66 (s, 1H), 8.31 (d , J=5.9 Hz, 1H), 6.50 (dd, J=15.2, 6.3 Hz, 1H), 4.45 (s, 1H), 4.00-3.76 (m, 1H), 3.55 (dt, J=39.5, 10.1 Hz, 2H), 2.37 (s, 1H), 1.97 (d, J=35.9 Hz, 3H), 1, 20 (d, J=3.8 Hz, 6H). IV-521 360.2 2.44 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.71 (s, 1H), 8.42 (d , J=6.1 Hz, 1H), 6.60 (d, J=6.1 Hz, 1H), 3.68 (t, J=6.7 Hz, 5H), 2.45 (d, J =6.6 Hz, 1H), 2.37 (d, J=7.2 Hz, 1H). IV-522 405.3 2.81 1H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.33 (d, J=6.0 Hz , 1H), 6.66-6.32 (m, 1H), 3.64 (dt, J=57.6, 36.9 Hz, 6H), 1.98 (s, 2H), 1.60 ( d, J=5.1 Hz, 4H), 0.95 (d, J=6.5 Hz, 2H). IV-523 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.36 (d, J=1.5 Hz, 1H), 8.71 (d, J=2.1 Hz, 1H ), 8.37 (dd, J=6.2, 1.5 Hz, 1H), 6.96 (d, J=6.3 Hz, 1H), 4.37-4.16 (m, 4H) , 4.00 (s, 2H), 3.65 (s, 2H), 2.08-1.87 (m, 2H), 1.58 (tt, J=4.3, 1.8 Hz, 2H ). IV-524 419 2.62 1H NMR (500 MHz, DMSO-d6) δ 12.29 (br s, 1H), 10.40 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8, 36 (d, J=6.0 Hz, 1H), 7.66 (s, 1H), 6.55 (d, J=6.0 Hz, 1H), 4.19-3.32 (m, 5H ), 2.41 (brs, 1H), 2.08 (brs, 1H). IV-525 445.3 2.5 1H NMR (500 MHz, DMSO-d6) δ 14.51 (s, 2H), 10.20 (s, 1H), 9.39 (d, J=1.3 Hz, 1H), 9.15 (d , J=3.5 Hz, 1H), 8.81 (s, 1H), 8.51 (s, 1H), 7.66 (s, 1H), 6.92 (s, 1H), 5.09 -5.02 (m, 1H), 5.38-4.65 (m, 1H), 4.60-3.99 (m, 1H), 3.99-3.85 (m, 1H), 3 .08-2.92 (m, 1H), 1.36 (d, J=6.1 Hz, 3H), 1.02 (d, J=6.7 Hz, 3H). IV-526 420.45 2.45 1H NMR (400 MHz, DMSO-d6) δ 10.27-10.21 (m, 1H), 9.35 (d, J=1.2 Hz, 1H), 8.68 (s, 1H), 8 .36 (d, J=6.3 Hz, 1H), 7.94 (t, J=5.8 Hz, 1H), 6.82 (d, J=6.3 Hz, 1H), 4.30 (s, 2H), 3.13 (ddd, J=13.8, 11.2, 2.9 Hz, 1H), 3.04 (t, J=6.5 Hz, 2H), 2.87 ( dd, J=13.2, 10.2 Hz, 1H), 1.85 (s, 3H), 1.78 (dq, J=17.2, 4.0 Hz, 1H), 1.66 (ddd , J=10.3, 6.7, 3.6 Hz, 1H), 1.53-1.39 (m, 1H), 1.37-1.24 (m, 1H), 0.97 (d , J=6.3 Hz, 1H). IV-527 421.45 2.32 1H NMR (400 MHz, DMSO-d6) δ 10.03 (d, J=1.6 Hz, 1H), 9.12 (d, J=1.4 Hz, 1H), 8.47 (s, 1H ), 8.14 (dd, J=6.3, 1.3 Hz, 1H), 6.58 (d, J=6.4 Hz, 1H), 5.87 (t, J=5.9 Hz , 1H), 5.20 (s, 2H), 2.89 (t, J=11.7 Hz, 1H), 2.81-2.68 (m, 2H), 2.61 (t, J= 11.8 Hz, 2H), 1.62-1.50 (m, 2H), 1.22 (t, J=12.3 Hz, 2H), 1.14-0.76 (m, 2H). IV-528 392.09 2.17 IV-529 406.35 2.35 1H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J=1.3 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.69 (s, 1H ), 8.37 (d, J=6.3 Hz, 1H), 7.32 (s, 1H), 6.84-6.77 (m, 2H), 3.17 (t, J=11, 3 Hz, 1H), 2.92 (dd, J=13.0, 10.0 Hz, 1H), 2.19-1.99 (m, 3H), 1.99-1.70 (m, 3H ), 1.53-1.22 (m, 3H). IV-530 406.3 2.32 1H NMR (400 MHz, DMSO-d6) δ 10.23 (t, J=1.1 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.70 (s, 1H ), 8.38 (d, J=6.3 Hz, 1H), 7.93 (d, J=7.2 Hz, 1H), 6.81 (d, J=6.4 Hz, 1H), 3.74-3.69 (m, 1H), 3.17 (dd, J=12.9, 8.9 Hz, 1H), 1.93-1.81 (m, 1H), 1.85 ( s, 2H), 1.80 (s, 3H), 1.57 (d, J=11.0 Hz, 2H), 0.96 (d, J=6.2 Hz, 1H). 1 proton peak is masked by solvent peaks IV-531 379.1 2.76 1H NMR (400 MHz, DMSO-d6) δ 10.24 (dd, J=1.5, 0.8 Hz, 1H), 9.37 (d, J=1.2 Hz, 1H), 8.74 (s, 1H), 8.41 (d, J=6.3 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 3.79-3.70 (m, 4H) , 3.64 (s, 2H), 1.21 (s, 6H). IV-532 365 2.65 1H NMR (400 MHz, DMSO-d6) δ 9.99 (dt, J=1.5, 0.9 Hz, 1H), 9.12 (d, J=1.3 Hz, 1H), 8.46 (s, 1H), 8.19 (d, J=6.3 Hz, 1H), 6.59 (d, J=6.3 Hz, 1H), 4.28 (s, 1H), 3.90 (d, J=13.6 Hz, 1H), 3.76 (dd, J=11.5, 3.8 Hz, 1H), 3.55 (d, J=11.5 Hz, 1H), 3 .43 (dd, J=11.6, 3.2 Hz, 1H), 3.29 (td, J=11.9, 3.1 Hz, 1H), 3.09-2.97 (m, 1H ), 1.04 (d, J=6.8 Hz, 3H). IV-533 404.1 2.23 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8.35 (d, J=6.0 Hz , 1H), 7.88 (s, 1H), 6.53 (s, 1H), 4.04-3.33 (m, 6H), 2.35-1.82 (m, 4H). IV-534 404.1 2.11 1H NMR (400 MHz, DMSO-d6) δ 10.46-10.33 (m, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.66 (d, J=11, 0 Hz, 1H), 8.36 (s, 1H), 7.70 (s, 1H), 6.53 (s, 1H), 3.76 (d, J=30.5 Hz, 2H), 3 .51 (d, J=27.2 Hz, 2H), 2.40-2.23 (m, 2H), 2.09 (d, J=6.2 Hz, 2H), 1.14-0, 90 (m, 2H). IV-535 430.1 3.02 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 9.15 (s, 1H), 8.94 (s , 1H), 8.79 (s, 1H), 8.46 (d, J=6.3 Hz, 1H), 7.04 (d, J=6.3 Hz, 1H), 6.63 (s , 1H), 4.55 (s, 1H), 3.95 (s, 1H), 3.27 (d, J=0.8 Hz, 4H). IV-536 428.05 2.31 1H NMR (400 MHz, DMSO-d6) δ 10.25 (t, J=1.1 Hz, 1H), 9.37 (d, J=1.4 Hz, 1H), 8.75 (s, 1H ), 8.45 (d, J=6.3 Hz, 1H), 7.03 (s, 2H), 6.88 (d, J=6.4 Hz, 1H), 5.02 (s, 1H ), 4.38 (s, 1H), 3.19-3.09 (m, 1H), 3.04 (ddd, J=18.4, 10.8, 5.3 Hz, 2H), 2, 23 (d, J=11.7 Hz, 1H), 1.88 (s, 1H), 1.80 (qd, J=12.1, 4.1 Hz, 1H), 1.57 (s, 1H ). IV-537 406.1 2.2 IV-538 444.4 2.31 1H NMR (500 MHz, methanol-d4) δ 10.35 (s, 1H), 9.21 (s, 1H), 8.73 (s, 1H), 8.37 (d, J=6.3 Hz , 1H), 7.74 (s, 1H), 7.11 (s, 1H), 6.81 (d, J=6.1 Hz, 1H), 5.41 (s, 1H), 4.24 (d, J=3.7 Hz, 1H), 3.06 (s, 1H), 2.88 (s, 1H), 1.33 (d, J=6.2 Hz, 3H), 1.05 (s, 3H). IV-539 406.1 2.4 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.34 (d, J=1.2 Hz, 1H), 8.70 (s, 1H), 8.42-8 .10 (m, 1H), 7.24 (s, 1H), 6.99-6.73 (m, NH2), 4.08 (d, J=130.3 Hz, 2H), 3.51 ( d, J=22.7 Hz, 1H), 3.35-3.31 (m, 2H), 2.13 (ddd, J=13.3, 6.7, 3.7 Hz, 2H), 1 .81-1.44 (m, 2H), 1.13 (s, 3H). IV-540 401 2.49 IV-541 401 2.5 IV-542 418.1 2.37 1H NMR (500 MHz, DMSO-d6) δ 10.23 (d, J=1.3 Hz, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.69 (s, 1H ), 8.34 (d, J=6.4 Hz, 1H), 7.74 (s, 1H), 6.93 (d, J=6.4 Hz, NH), 4.36 (s, 2H ), 3.29-3.04 (m, 4H), 1.99-1.74 (m, 4H), 1.59 (td, J=11.4, 3.9 Hz, 2H). IV-543 419.2 2.98 1H NMR (500 MHz, DMSO-d6) δ 10.25 (d, J=1.2 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.66 (s, 1H ), 8.38 (d, J=6.4 Hz, 1H), 6.87 (d, J=6.4 Hz, 1H), 3.84 (t, J=7.8 Hz, 1H), 3.75 (dd, J=8.4, 3.9 Hz, 1H), 3.69-3.58 (m, 1H), 3.15 (d, J=11.2 Hz, 1H), 2 .99 (dd, J=13.2, 9.9 Hz, 1H), 2.51, 3H not observed), 2.18-1.95 (m, 2H), 1.84-1.70 (m , 2H), 1.70-1.56 (m, 1H), 1.54-1.32 (m, 3H). IV-544 419.2 3.02 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.37 (s, 1H), 8.67 (s, 1H), 8.37 (d, J=6.3 Hz , 1H), 6.86 (d, J=6.4 Hz, 1H), 3.94 (t, J=7.8 Hz, 1H), 3.74 (td, J=8.3, 3, 4 Hz, 1H), 3.62 (dd, J=8.4, 6.8 Hz, 1H), 3.43 (t, J=8.1 Hz, 1H), 3.19 (t, J= 12.0 Hz, 1H), 3.06-2.96 (m, 1H), 2.51 (2H not observed), 2.12-1.95 (m, 2H), 1.94-1.71 (m, 2H), 1.62-1.35 (m, 3H), 1.22 (d, J=6.5 Hz, 1H). IV-545 415.3 2.68 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.24 (s, 1H), 9.51-9.25 (m, 1H), 8.69 (s, 1H) , 8.38 (d, J=6.3 Hz, 1H), 7.58 (d, J=69.0 Hz, 2H), 6.94 (d, J=6.3 Hz, 1H), 4 .89-4.04 (m, 2H), 3.23-3.03 (m, 2H), 2.74 (tt, J=10.9, 3.9 Hz, 1H), 2.15-2 .02 (m, 1H), 1.83 (dt, J=13.2, 3.5 Hz, 1H), 1.78-1.53 (m, 2H). IV-546 415.3 2.67 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.24 (s, 1H), 9.53-9.28 (m, 1H), 8.69 (s, 1H) , 8.38 (d, J=6.3 Hz, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 6.94 (d, J=6.4 Hz, 1H) , 5.08-4.06 (m, 2H), 3.12 (ddd, J=17.8, 12.3, 9.7 Hz, 2H), 2.74 (tt, J=10.8, 3.9 Hz, 1H), 2.14-2.03 (m, 1H), 1.89-1.78 (m, 1H), 1.78-1.54 (m, 2H). IV-547 416.1 2.4 1H NMR (500 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.72 (s, 1H), 8.63 (s , 1H), 8.42 (d, J=6.3 Hz, 1H), 8.01 (s, 1H), 6.95 (d, J=6.3 Hz, 1H), 4.64 (s , 1H), 4.54 (tt, J=9.5, 4.7 Hz, 1H), 4.31 (s, 1H), 3.65 (dd, J=13.1, 9.7 Hz, 1H), 3.28 (d, J=0.9 Hz, 1H), 2.21 (td, J=9.7, 4.5 Hz, 2H), 1.91 (dt, J=13.6 , 3.9 Hz, 1H), 1.68 (dh, J=15.1, 4.7 Hz, 1H). IV-548 438.3 2.88 1H NMR (500 MHz, methanol-d4) δ 10.2 (s, 1H), 9.36 (s, 1H), 8.80 (s, 1H), 8.40 (d, 1H), 8.04 (s, 1H), 7.08 (d, 1H), 6.62 (s, 1H), 4.73 (m, 1H), 4.12 (m, 2H), 2.63 (m, 1H) , 2.01 (m, 1H), 1.45-1.30 (m, 1H). IV-549 444.4 2.31 IV-550 412.25 2.73 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.32 (s, 1H), 8.65 (s, 1H), 8.56-8.49 (m, 2H) , 8.34 (d, J=6.0 Hz, 1H), 7.42-7.35 (m, 2H), 6.54 (d, J=6.0 Hz, 1H), 4.24 ( s, 1H), 3.93 (s, 1H), 3.52 (d, J=66.1 Hz, 3H), 2.15 (s, 1H), 0.92 (d, J=6.6 Hz, 1H). IV-551 420.2 2.32 1H NMR (400 MHz, DMSO-d6) δ 10.36 (d, J=8.3 Hz, 1H), 9.38 (s, 1H), 8.77-8.64 (m, 1H), 8 .42 (d, J=5.9 Hz, 1H), 6.62 (dd, J=9.1, 6.0 Hz, 1H), 4.36 (s, 3H), 4.10-3, 98 (m, 1H), 4.01-3.86 (m, 1H), 3.45 (dq, J=35.9, 10.5 Hz, 2H), 2.93 (d, J=12, 3 Hz, 3H), 0.96 (d, J=6.2 Hz, 1H). IV-552 412.25 2.9 1H NMR (400 MHz, DMSO-d6) δ 10.40 (d, J=7.5 Hz, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.56 (ddd , J=4.8, 1.8, 0.9 Hz, 1H), 8.35 (s, 1H), 7.80 (td, J=7.7, 1.9 Hz, 1H), 7, 44 (d, J=7.9 Hz, 1H), 7.30 (ddd, J=7.6, 4.8, 1.2 Hz, 1H), 6.57 (d, J=5.8 Hz , 1H), 4.21 (s, 1H), 4.00-3.55 (m, 2H), 2.48-2.41 (m, 2H), 2.29 (s, 1H), 0, 99-0.90 (m, 1H). IV-553 420.25 2.5 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 2H), 9.36 (d, J=1.3 Hz, 2H), 8.68 (d, J=10.5 Hz, 2H ), 8.34 (d, J=6.1 Hz, 2H), 6.57-6.48 (m, 2H), 4.04 (s, 1H), 3.72 (s, 1H), 3 .23 (d, J=7.2 Hz, 1H), 2.99 (s, 3H), 2.27 (s, 2H), 1.90 (d, J=10.3 Hz, 2H). IV-554 432.26 2.65 1H NMR (400 MHz, DMSO-d6) δ 10.36 (d, J=9.1 Hz, 1H), 9.34 (s, 1H), 8.66 (d, J=2.0 Hz, 1H ), 8.32 (t, J=5.0 Hz, 1H), 6.49 (s, 1H), 3.94 (d, J=11.2 Hz, 1H), 3.84 (d, J =9.2 Hz, 1H), 3.61 (ddd, J=35.2, 21.6, 9.1 Hz, 2H), 3.35 (d, J=11.8 Hz, 2H), 2 .85 (s, 3H), 2.43 (dd, J=13.5, 7.1 Hz, 1H), 1.98 (dt, J=12.6, 7.1 Hz, 1H), 1, 94-1.79 (m, 4H). IV-555 363.23 3.35 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 9.36 (s, 1H), 8.66 (s, 1H), 8.32 (d, J=6.1 Hz , 1H), 6.54-6.45 (m, 1H), 3.86-3.77 (m, 1H), 3.55 (d, J=9.0 Hz, 1H), 3.40 ( dd, J=18.7, 8.9 Hz, 1H), 3.16 (d, J=10.0 Hz, 1H), 2.44 (s, 2H), 1.00 (d, J=6 ,4 Hz, 6H). IV-556 411.25 3.42 1H NMR (400 MHz, DMSO-d6) δ 10.32 (d, J=7.2 Hz, 1H), 9.27 (s, 1H), 8.60 (s, 1H), 8.27 (s , 1H), 7.35-7.24 (m, 4H), 7.19 (s, 1H), 6.47 (d, J=19.0 Hz, 1H), 4.19 (s, 1H) , 3.89 (d, J=24.4 Hz, 1H), 3.61 (s, 1H), 3.51 (s, 2H), 3.35 (d, J=11.1 Hz, 1H) , 2.08 (d, J=10.1 Hz, 1H). IV-557 432.26 2.53 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.34 (d, J=1.3 Hz, 1H), 8.63 (s, 1H), 8.30 (d , J=6.1 Hz, 1H), 6.47 (s, 1H), 3.79 (s, 1H), 3.53 (d, J=7.5 Hz, 1H), 3.49-3 .36 (m, 2H), 3.29 (dd, J=7.5, 2.1 Hz, 2H), 3.12 (s, 1H), 2.68 (s, 1H), 2.26 ( t, J=8.4 Hz, 2H), 2.13 (s, 1H), 1.97 (tt, J=8.3, 4.3 Hz, 2H), 1.77 (d, J=5 ,4 Hz, 1H). 1 proton masked by solvent peak IV-558 484.1 2.57 1H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 1H), 10.17 (t, J=1.1 Hz, 1H), 9.47-9.21 (m, 1H), 8 .69 (s, 1H), 8.46 (d, J=6.2 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 7.06 (d, J= 6.3 Hz, 1H), 4.76 (s, 1H), 3.95 (dt, J=11.2, 3.9 Hz, 1H), 3.70 (s, 1H), 3.11 ( dt, J=10.5, 7.9 Hz, 2H), 3.02 (t, J=12.0 Hz, 1H). IV-559 441.26 3.46 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.36 (s, 1H), 8.67 (s, 1H), 8.35 (d, J=6.1 Hz , 1H), 7.36-7.25 (m, 2H), 7.02-6.90 (m, 3H), 6.54 (d, J=6.1 Hz, 1H), 4.12 ( s, 1H), 4.02 (d, J=11.5 Hz, 1H), 3.89 (s, 1H), 3.70 (s, 1H), 3.60 (s, 1H), 3, 50 (s, 1H), 2.88 (s, 1H), 2.26 (s, 1H), 1.97 (s, 1H). IV-560 419.3 2.02 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 10.34 (d, J=19.5 Hz, 1H), 9.37 (s, 1H), 8.71 (s , 1H), 8.54 (s, 1H), 8.41 (s, 1H), 6.61 (s, 1H), 3.99-3.87 (m, 2H), 3.75 (s, 2H), 3.65 (d, J=14.0 Hz, 1H), 2.25 (s, 1H). IV-561 425.31 3.58 1H NMR (400 MHz, DMSO-d6) δ 10.34 (d, J=36.2 Hz, 1H), 9.37 (s, 1H), 8.67 (s, 1H), 8.36 (d , J=25.9 Hz, 1H), 7.35-7.23 (m, 5H), 6.59 (d, J=41.0 Hz, 1H), 4.65 (s, 1H), 3 .71 (d, J=33.3 Hz, 1H), 3.44 (s, 1H), 3.13 (d, J=13.0 Hz, 1H), 2.83 (s, 1H), 2 .71 (s, 1H), 1.96-1.83 (m, 4H). IV-562 419 2.73 1H NMR (500 MHz, DMSO-d6) δ 12.29 (br s, 1H), 10.40 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8, 36 (d, J=6.0 Hz, 1H), 7.66 (s, 1H), 6.55 (d, J=6.0 Hz, 1H), 4.19-3.32 (m, 5H ), 2.41 (brs, 1H), 2.08 (brs, 1H). IV-563 419 2.74 1H NMR (500 MHz, DMSO-d6) δ 12.29 (br s, 1H), 10.40 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8, 36 (d, J=6.0 Hz, 1H), 7.66 (s, 1H), 6.55 (d, J=6.0 Hz, 1H), 4.19-3.32 (m, 5H ), 2.41 (brs, 1H), 2.08 (brs, 1H). IV-564 401.25 2.38 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.36 (s, 1H), 8.70 (s, 1H), 8.40 (d, J=6.0 Hz , 1H), 7.80 (t, J=1.2 Hz, 1H), 7.33 (s, 1H), 6.96 (s, 1H), 6.60 (d, J=6.1 Hz , 1H), 5.11 (s, 1H), 4.24 (s, 1H), 4.02-3.75 (m, 2H), 3.65 (d, J=37.0 Hz, 2H) , 2.59 (s, 1H). IV-565 434.26 2.31 1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.35 (d, J=1.2 Hz, 1H), 8.67 (s, 1H), 8.35 (d , J=6.0 Hz, 1H), 6.55 (d, J=6.1 Hz, 1H), 5.76 (s, 1H), 4.21 (d, J=17.0 Hz, 1H ), 4.14 (d, J=17.0 Hz, 1H), 3.99 (d, J=12.0 Hz, 1H), 3.88 (s, 1H), 3.77-3.61 (m, 1H), 3.57 (s, 2H), 2.93 (s, 3H), 2.38 (s, 1H), 2.17 (s, 1H). IV-566 421.3 2.31 1H NMR (400 MHz, DMSO-d6) δ 10.25 (d, J=12.8 Hz, 1H), 9.35 (d, J=1.4 Hz, 1H), 8.67 (s, 1H ), 8.35 (d, J=6.2 Hz, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 6.72 (s, 1H), 5.76 (s , 1H), 3.98 (d, J=20.8 Hz, 2H), 3.67 (s, 2H), 3.04 (s, 2H), 2.85 (s, 2H), 2.66 (s, 1H), 1.94 (dd, J=8.4, 3.3 Hz, 2H). IV-567 478.3 2.83 1H NMR (500 MHz, DMSO-d6) δ 12.67 (s, 1H), 10.12-10.00 (m, 1H), 9.40 (m, 1H), 8.73 (m, 1H) , 7.72-7.56 (m, 2H), 7.11-7.03 (m, 1H), 4.94-4.60 (m, 1H), 4.30-4.03 (m, 2H), 2.94 (m, 1H), 2.80-2.71 (m, 1H), 2.62 (m, 1H), 1.15 (m, 3H), 0.97-0.90 (m, 3H). IV-568 419.1 2.15 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.66 (s, 1H), 8.44 (d , J=6.3 Hz, 1H), 7.88 (s, NH), 6.88 (d, J=6.4 Hz, 1H), 3.36 (td, J=13.3, 12, 5, 5.6 Hz, 2H), 3.22-3.08 (m, 2H), 3.06-2.88 (m, 3H), 2.69 (d, J=9.3 Hz, 1H ), 2.50 (d, J=1.9 Hz, 2H), 2.34-2.24 (m, 1H). IV-569 434.3 2.87 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.36 (s, 1H), 8.69 (d, J=22.1 Hz, 1H), 8.35 (t , J=5.8 Hz, 1H), 6.54 (dd, J=24.7, 6.2 Hz, 1H), 3.99 (d, J=9.8 Hz, 1H), 3.79 -3.55 (m, 5H), 3.26 (t, J=11.1 Hz, 3H), 2.91-2.77 (m, 1H), 2.61-2.56 (m, 1H ), 2.50-2.39 (m, 3H), 0.96 (t, J=6.6 Hz, 3H). IV-570 425.21 2.36 1H NMR (400 MHz, DMSO-d6) δ 10.34 (d, J=1.2 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.70 (s, 1H ), 8.42 (d, J=6.1 Hz, 1H), 6.63 (s, 1H), 3.92 (d, J=5.7 Hz, 3H), 3.60 (s, 2H ), 3.52 (s, 1H), 3.29-3.20 (m, 2H), 2.42-2.28 (m, 1H), 2.03 (ddd, J=19.7, 12 ,6, 6.3 Hz, 1H). IV-571 418.3 2.66 1H NMR (400 MHz, DMSO-d6) δ 10.23 (t, J=1.0 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.76 (s, 1H ), 8.45 (d, J=6.2 Hz, 1H), 6.96 (d, J=6.3 Hz, 1H), 4.51-4.42 (m, 2H), 4.34 (s, 1H), 4.23 (d, J=17.5 Hz, 1H), 3.63 (dd, J=13.6, 7.6 Hz, 1H), 3.58-3.50 ( m, 1H), 1.83 (t, J=12.5 Hz, 2H), 1.68 (d, J=13.3 Hz, 1H), 1.50 (tdd, J=12.9, 9 .5, 3.7 Hz, 1H), 1.36-1.21 (m, 1H), 1.26 (s, 1H), 0.99-0.90 (m, 1H). IV-572 469 3.03 IV-573 431 2.32 IV-574 429 2.72 IV-575 415 2.66 IV-576 441 2.86 IV-577 444.3 2.33 1H NMR (500 MHz, methanol-d4) δ 10.17 (s, 1H), 9.21 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.71 (s, 2H), 4.67 (m, 1H), 4.38 (m, 1H), 4.24 (m, 1H), 3.16 (m, 1H) , 2.93 (m, 1H), 1.34 (d, 3H), 1.14 (d, 3H). IV-578 473.3 2.59 1H NMR (500 MHz, DMSO-d6) δ 12.80 (s, 1H), 10.31 (s, 1H), 9.32 (s, 1H), 8.63 (s, 1H), 7.60 (s, 2H), 7.02 (s, 1H), 5.66 (s, 1H), 4.80-4.20 (br m, 2H), 3.30 (masked, 3H), 2.89 (m, 3H), 2.52 (s, 1H), 1.34 (d, 3H), 1.14 (d, 3H). IV-579 420.3 2.37 IV-580 405.35 2.83 1H NMR (400 MHz, DMSO-d6) δ 10.42 (d, J=5.3 Hz, 1H), 9.40 (s, 1H), 8.70 (s, 1H), 8.35 (dd , J=6.1, 1.4 Hz, 1H), 6.52 (d, J=6.3 Hz, 1H), 4.02 (s, 1H), 3.93-3.69 (m, 4H), 3.64-3.43 (m, 3H), 2.26 (s, 4H), 2.07 (dd, J=11.9, 4.8 Hz, 1H), 1.78-1 .64 (m, 1H). IV-581 392.1 2.25 1H NMR (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.67 (s, 1H), 8.34 (d , J=6.1 Hz, 1H), 7.42 (s, NH), 7.07 (s, NH), 6.50 (d, J=6.1 Hz, 1H), 3.99 (dd , J=131.5, 10.7 Hz, 1H), 3.74 (d, J=35.5 Hz, 1H), 3.61-3.39 (m, 1H), 3.23 (d, J=10.3 Hz, 1H), 2.48-2.37 (m, 1H), 1.97 (d, J=8.7 Hz, 1H), 1.35 (s, 3H). IV-582 428.1 2.39 1H NMR (500 MHz, DMSO-d6) δ 10.20 (d, J=1.2 Hz, 1H), 9.38 (d, J=1.3 Hz, 1H), 8.76 (s, 1H ), 8.49 (d, J=6.3 Hz, 1H), 7.64 (s, NH), 7.16 (s, NH), 7.08 (d, J=6.3 Hz, 1H ), 3.55 (dd, J=32.3, 13.9 Hz, 1H), 3.21 (t, J=12.6 Hz, 1H), 2.77-2.61 (m, 1H) , 2.45-2.16 (m, 3H). IV-583 443.3 2.63 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.20 (m, 1H), 9.31 (m, 1H), 8.70 (m, 1H), 7.77 -7.44 (m, 3H), 6.97 (m, 1H),4.80-4.45 (m, 1H), 4.45-4.10 (m, 2H), 2.98 (m , 1H), 2.71 (m, 1H), 2.51 (masked, 1H), 1.19 (m, 3H), 0.99 (m, 3H). IV-584 433.1 2.42 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.71 (s, 1H), 8.40 (d , J=6.3 Hz, 1H), 6.87 (d, J=6.3 Hz, 1H), 6.37 (s, NH), 3.64-3.51 (m, 1H), 3 .48-3.38 (m, 2H), 3.26 (t, J=8.3 Hz, 3H), 3.14 (d, J=12.2 Hz, 1H), 3.01 (t, J=12.3 Hz, 1H), 2.50 (2H not observed), 1.90-1.76 (m, 4H), 1.56 (s, 1H). IV-585 364.1 2.51 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.71 (s, 1H), 8.41 (d , J=6.3 Hz, 1H), 6.87 (d, J=6.3 Hz, 1H), 3.75 (s, 4H), 2.46-2.40 (m, 4H), 2 .25 (s, 3H). IV-586 409.2 2.74 1H NMR (500 MHz, DMSO-d6) δ 10.25 (dd, J=1.5, 0.7 Hz, 1H), 9.37 (d, J=1.2 Hz, 1H), 8.73 (s, 1H), 8.41 (d, J=6.3 Hz, 1H), 6.84 (d, J=6.3 Hz, 1H), 4.05 (t, J=5.1 Hz , 2H), 3.88-3.65 (m, 2H), 3.57-3.40 (m, 2H), 3.37 (dd, J=13.2, 7.5 Hz, 2H), 3.26 (s, 3H), 1.18 (d, J=6.3 Hz, 3H). IV-587 409.1 2.81 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.74 (s, 1H), 8.43 (d , J=6.2 Hz, 1H), 6.89 (d, J=6.3 Hz, 1H), 3.80-3.61 (m, 2H), 3.48 (dd, J=4, 8, 3.8 Hz, 2H), 3.32 (s, 3H), 3.31-3.26 (m, 2H), 2.76 (dt, J=65.6, 11.9 Hz, 2H ), 1.22 (d, J=6.2 Hz, 3H). IV-588 395.1 2.61 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.73 (s, 1H), 8.44 (d , J=6.2 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 4.28 (s, 2H), 4.07-3.92 (m, 1H), 3 .68 (ddd, J=10.5, 7.7, 4.8 Hz, 1H), 3.59 (td, J=11.6, 2.9 Hz, 1H), 3.52-3.44 (m, 2H), 3.32 (s, 3H), 3.21-3.06 (m, 1H), 2.93 (dd, J=13.1, 10.7 Hz, 1H). IV-589 415.1 2.71 IV-590 491.1 2.01 IV-591 491.1 2.01 IV-592 491.1 2.05 IV-593 474.3 2.72 1H NMR (500 MHz, methanol-d4) δ 10.30 (s, 1H), 9.20 (s, 1H), 8.67 (s, 1H), 7.74 (s, 2H), 6.08 (s, 1H), 5.00-4.80 (masked, 2H), 4.39 (m, 1H), 4.06 (s, 3H), 3.15 (m, 1H), 2.90 ( m, 1H), 1.35 (d, 3H), 1.14 (d, 3H). IV-594 395.1 3.13 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.65 (s, 1H), 8.32 (d , J=6.1 Hz, 1H), 6.50 (d, J=5.9 Hz, 1H), 3.88 (d, J=43.5 Hz, 1H), 3.64 (s, 1H ), 3.55 (s, 1H), 3.42 (s, 1H), 2.72-2.60 (m, 3H), 2.22 (s, 1H), 2.13 (s, 3H) , 1.83 (s, 1H). IV-595 393.1 1.98 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.67 (s, 1H), 8.38 (d , J=6.3 Hz, 1H), 7.49-7.33 (NH), 7.29-7.14 (NH), 6.84 (d, J=6.4 Hz, 1H), 4 .09 (d, J=77.0 Hz, 2H), 3.42-3.31 (m, 2H), 2.99 (dt, J=12.7, 3.8 Hz, 1H), 2, 82-2.65 (m, 2H). IV-596 407.1 2.11 1H NMR (500 MHz, DMSO-d6) δ 10.21 (d, J=1.4 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.68 (d, J =0.9 Hz, 1H), 8.41 (dd, J=6.3, 0.7 Hz, 1H), 7.59-7.39 (NH), 7.27-7.16 (NH) , 6.90 (d, J=6.3 Hz, 1H), 4.32 (s, 2H), 3.30-3.21 (m, 2H), 2.98 (dt, J=11.7 , 3.2 Hz, 1H), 2.62 (dd, J=9.9, 3.5 Hz, 1H), 2.24 (s, 3H), 2.21 (dd, J=11.4, 3.3 Hz, 1H). IV-597 362.9 3.29 1H NMR (400 MHz, DMSO-d6) δ 10.24 (t, J=1.1 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.67 (s, 1H ), 8.35 (d, J=6.3 Hz, 1H), 6.81 (d, J=6.4 Hz, 1H), 4.81 (s, 1H), 4.34 (d, J =13.4 Hz, 1H), 3.07 (td, J=13.1, 2.9 Hz, 1H), 1.83-1.62 (m, 3H), 1.62 (s, 1H) , 1.46 (dd, J=12.5, 4.6 Hz, 1H), 1.24 (d, J=6.8 Hz, 3H). 1 proton peak is masked by solvent peaks IV-598 378.1 2.06 1H NMR (500 MHz, DMSO-d6) δ 10.39 (d, J=1.3 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.68 (s, 1H ), 8.35 (d, J=6.0 Hz, 1H), 7.55 (s, 1H), 7.04 (s, NH), 6.53 (s, NH), 3.97-3 .37 (m, 4H), 3.19-3.06 (m, 1H), 2.27 (dt, J=13.1, 6.2 Hz, 1H), 2.14 (s, 1H). IV-599 1H NMR (500 MHz, DMSO-d6) δ 10.23 (d, J=1.3 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.70 (s, 1H ), 8.46 (d, J=6.3 Hz, 1H), 7.40 (d, J=18.8 Hz, NH2), 6.91 (d, J=6.4 Hz, 1H), 4.34 (d, J=95.6 Hz, 2H), 4.11-3.98 (m, 2H), 3.70 (td, J=11.2, 2.9 Hz, 1H), 3 .32-3.31 (m, 1H), 3.27-3.15 (m, 1H). IV-600 416.1 2.46 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.35 (d, J=1.2 Hz, 1H), 8.70 (s, 1H), 8.42 (d , J=6.3 Hz, 1H), 8.26 (d, J=1.1 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 6.96 (d, J =6.4 Hz, 1H), 4.73 (dq, J=9.2, 4.7, 4.3 Hz, 1H), 4.32 (s, 1H), 3.74 (dd, J= 13.0, 9.7 Hz, 1H), 3.40-3.32 (m, 1H), 2.33-2.18 (m, 3H), 1.97-1.87 (m, 1H) , 1.70 (s, 1H). IV-601 449 2.87 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.70 (s, 1H), 8.42 (d , J=6.3 Hz, 1H), 8.26 (d, J=1.1 Hz, 1H), 7.75 (d, J=1.0 Hz, 1H), 6.96 (d, J =6.4 Hz, 1H), 4.73 (tt, J=9.3, 4.5 Hz, 1H), 3.74 (dd, J=13.1, 9.7 Hz, 1H), 3 ,40-3.30 (m, 4H), 3.27 (s, 6H), 2.29-2.19 (m, 2H), 1.92 (dt, J=13.5, 4.1 Hz , 1H), 1.72 (td, J=10.2, 5.2 Hz, 1H). IV-602 433.1 2.07 1H NMR (500 MHz, DMSO-d6) δ 10.38 (dd, J=1.3, 0.7 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.75 -8.61 (m, 1H), 8.35 (d, J=6.1 Hz, 1H), 7.80 (d, J=2.1 Hz, 1H), 6.64-6.51 ( m, 1H), 4.00 (d, J=73.3 Hz, 1H), 3.78-3.58 (m, 2H), 3.41 (d, J=10.0 Hz, 2H), 3.21 (s, 2H), 3.08 (s, 2H), 2.77-2.66 (m, 2H), 2.30 (s, 1H), 1.92 (d, J=17, 4 Hz, 1H). IV-603 411 2.13 1H NMR (500 MHz, methanol-d4) δ 10.40 (s, 1H), 9.10 (dd, J=1.4, 0.8 Hz, 1H), 8.56 (d, J=1, 7 Hz, 1H), 8.19 (d, J=6.2 Hz, 1H), 6.38 (dd, J=6.2, 4.5 Hz, 1H), 3.98 (d, J= 91.0 Hz, 1H), 3.71 (s, 1H), 3.45 (s, 2H), 2.95 (d, J=6.4 Hz, 2H), 2.82 (s, 1H) , 2.63 (s, 3H), 2.35 (s, 1H), 1.92 (s, 1H). IV-604 427.1 2.33 1H NMR (500 MHz, methanol-d4) δ 10.40 (s, 1H), 9.10 (dd, J=1.4, 0.8 Hz, 1H), 8.56 (d, J=1, 7 Hz, 1H), 8.19 (d, J=6.2 Hz, 1H), 6.38 (dd, J=6.2, 4.5 Hz, 1H), 3.98 (d, J= 91.0 Hz, 1H), 3.71 (s, 1H), 3.45 (s, 2H), 2.95 (d, J=6.4 Hz, 2H), 2.82 (s, 1H) , 2.63 (s, 3H), 2.35 (s, 1H), 1.92 (s, 1H). IV-605 406.1 2.23 1H NMR (500 MHz, DMSO-d6) δ 10.26 (dt, J=1.6, 0.8 Hz, 1H), 9.36 (dd, J=1.4, 0.7 Hz, 1H) , 8.69 (s, 1H), 8.36 (d, J=6.3 Hz, 1H), 7.29-7.25 (m, 1H), 6.85 (d, J=6.4 Hz, 1H), 6.77 (s, 1H), 4.46 (s, 2H), 3.10-3.01 (m, 2H), 2.04 (d, J=2.9 Hz, 3H ), 1.83-1.76 (m, 2H), 1.25-1.13 (m, 2H). IV-606 416 2.16 IV-607 426.1 2.01 1H NMR (500 MHz, methanol-d4) δ 10.47 (s, 1H), 9.20 (d, J=1.3 Hz, 1H), 8.68-8.63 (m, 1H), 8 .29 (d, J=6.1 Hz, 1H), 6.50-6.44 (m, 1H), 4.88-4.79 (m, 1H), 4.10 (d, J=111 .6 Hz, 1H), 3.88 (s, 1H), 3.70 (s, 1H), 3.65 (s, 1H), 3.54 (s, 2H), 3.14 (s, 3H ), 3.02 (s, 1H), 2.48 (s, 1H), 2.04 (dd, J=17.6, 9.7 Hz, 1H). IV-608 405.2 2.79 1H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.37 (d, J=1.2 Hz, 1H), 8.69 (s, 1H), 8.34 (d , J=6.1 Hz, 1H), 6.52 (s, 1H), 3.83 (d, J=32.9 Hz, 2H), 3.63 (d, J=47.1 Hz, 2H ), 3.43 (t, J=7.6 Hz, 2H), 2.51 (4H not observed), 2.25-2.00 (m, 2H), 1.65 (s, 2H). IV-609 405.2 2.83 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 9.37 (d, J=1.2 Hz, 1H), 8.68 (s, 1H), 8.33 (s , 1H), 6.51 (d, J=6.1 Hz, 1H), 3.98-3.75 (m, 3H), 3.63 (d, J=40.6 Hz, 2H), 3 .45-3.38 (m, 1H), 2.26-2.14 (m, 4H), 1.90-1.72 (m, 2H), 1.71-1.57 (m, 2H) . IV-610 377.1 3.53 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.36 (d, J=1.4 Hz, 1H), 8.61 (s, 1H), 8.32 (s , 1H), 6.47 (d, J=40.3 Hz, 1H), 3.70-3.58 (m, 1H), 3.08-2.94 (m, 1H), 2.46- 2.36 (m, 2H), 2.16-2.00 (m, 1H), 1.65 (d, J=52.4 Hz, 6H), 1.11 (d, J=6.4 Hz , 3H). IV-611 392.1 2.13 1H NMR (500 MHz, DMSO-d6) δ 10.26 (d, J=1.2 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.70 (s, 1H ), 8.39 (d, J=6.3 Hz, 1H), 7.33 (NH), 6.88 (d, J=6.4 Hz, 1H), 6.82 (NH), 4, 62-4.39 (m, 2H), 3.11 (t, J=12.2 Hz, 2H), 2.53-2.52 (m, 1H), 1.85 (d, J=13, 3 Hz, 2H), 1.65-1.51 (m, 2H). IV-612 393.1 2.07 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.69 (d, J=22.1 Hz, 1H ), 8.35 (t, J=5.8 Hz, 1H), 6.54 (dd, J=24.7, 6.1 Hz, 1H), 3.75-3.56 (m, 4H) , 0.96 (t, J=6.6 Hz, 4H). IV-613 395.1 2.32 1H NMR (500 MHz, DMSO-d6) δ 10.23 (d, J=1.2 Hz, 1H), 9.37 (d, J=1.6 Hz, 1H), 8.72 (s, 1H ), 8.43 (d, J=6.3 Hz, 1H), 6.94-6.74 (m, 1H), 4.86 (t, J=5.6 Hz, 1H), 3.88 -3.69 (m, 2H), 3.61-3.47 (m, 4H), 3.18 (d, J=5.2 Hz, 1H), 1.28 (dd, J=20.6 , 6.7 Hz, 3H). IV-614 392.3 2.22 1H NMR (500 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.36 (d, J=1.2 Hz, 1H), 8.67 (s, 1H), 8.34 (d , J=6.0 Hz, 1H), 7.52 (s, 1H), 6.94 (s, 1H), 3.59-3.49 (m, 1H), 2.86-2.77 ( m, 1H), 2.51 (2H, not observed), 2.33 (dd, J=12.9, 7.7 Hz, 1H), 2.19-2.08 (m, 1H), 1, 32 (d, J=71.8 Hz, 3H). IV-615 392.3 2.13 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.35 (d, J=1.4 Hz, 1H), 8.66 (s, 1H), 8.31 (d , J=6.1 Hz, 1H), 6.48 (d, J=7.5 Hz, 1H), 4.43 (t, J=5.1 Hz, 1H), 4.04-3.76 (m, 1H), 3.74-3.33 (m, 4H), 3.09 (t, J=9.4 Hz, 0.5H), 3.00 (t, J=9.4 Hz, 0.5H), 2.32 (br s, 1H), 2.19 (br s, 1H), 1.66 (br s, 1H), 1.51, (br s, 4H). Note: Rotary isomer signals are evident. IV-616 393 2.54 1H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.35 (d, J=1.4 Hz, 1H), 8.66 (s, 1H), 8.31 (d , J=6.1 Hz, 1H), 6.48 (d, J=7.5 Hz, 1H), 4.43 (t, J=5.1 Hz, 1H), 4.04-3.76 (m, 1H), 3.74-3.33 (m, 4H), 3.09 (t, J=9.4 Hz, 0.5H), 3.00 (t, J=9.4 Hz, 0.5H), 2.32 (br s, 1H), 2.19 (br s, 1H), 1.66 (br s, 1H), 1.51, (br s, 4H). Note: Rotary isomer signals are evident. IV-617 394.1 2.17 IV-618 408.1 2.08 1H NMR (500 MHz, DMSO-d6) δ 10.24 (dd, J=1.4, 0.8 Hz, 1H), 9.36 (dd, J=1.2, 0.6 Hz, 1H) , 8.72 (s, 1H), 8.44 (d, J=6.2 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 4.70 (t, J= 5.5 Hz, 1H), 4.18 (d, J=5.6 Hz, 2H), 3.80 (s, 4H), 3.64 (s, 2H), 3.55 (d, J= 5.7 Hz, 2H). IV-619 422.2 2.71 IV-620 403.1 2.51 1H NMR (500 MHz, DMSO-d6) δ 10.25 (dt, J=1.6, 0.8 Hz, 1H), 9.38-9.34 (m, 1H), 8.71 (s, 1H), 8.41 (d, J=6.3 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 3.83-3.71 (m, 4H), 2, 75 (td, J=6.6, 1.0 Hz, 2H), 2.67 (td, J=6.5, 1.0 Hz, 2H), 2.58 (t, J=5.2 Hz , 4H). IV-621 431.3 2.11 1H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.22 (s, 1H), 9.35 (s, 1H), 8.69 (s, 1H), 8.38 (d, J=6.3 Hz, 1H), 7.56 (s, 2H), 6.94 (d, J=6.4 Hz, 1H), 4.80 (d, J=5.5 Hz , 1H), 4.40 (br s, 2H), 3.73 (tt, J=9.4, 4.4 Hz, 1H), 3.30-3.27 (m, 2H), 2.58 (td, J=9.9, 4.4 Hz, 1H), 1.99 (dd, J=13.0, 4.0 Hz, 1H), 1.52-1.45 (m, 1H). IV-622 431.3 2.1 1H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.22 (s, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.38 (d, J=6.3 Hz, 1H), 7.56 (br d, J=67.6 Hz, 2H), 6.94 (d, J=6.3 Hz, 1H), 4.80 ( d, J=5.6 Hz, 1H), 4.42 (br s, 2H), 3.76-3.70 (m, 1H), 3.28-3.25 (m, 2H), 2, 58 (td, J=9.3, 4.2 Hz, 1H), 1.99 (dd, J=13.1, 3.9 Hz, 1H), 1.53-1.45 (m, 1H) . IV-623 431.3 2.15 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.70 (s, 1H), 8.38 (d , J=6.3 Hz, 1H), 7.40 (NH), 6.90 (d, J=6.5 Hz, 1H+NH), 4.42 (s, 2H), 3.24-2 .99 (m, 2H), 2.37 (td, J=3.6, 1.4 Hz, 1H), 1.94 (d, J=11.7 Hz, 1H), 1.86-1, 63 (m, 2H), 1.50 (t, J=12.3 Hz, 1H). IV-624 431.3 2.15 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.70 (s, 1H), 8.38 (d , J=6.3 Hz, 1H), 7.40 (NH), 6.90 (d, J=6.5 Hz, 1H+NH), 4.42 (s, 2H), 3.24-2 .99 (m, 2H), 2.37 (td, J=3.6, 1.4 Hz, 1H), 1.94 (d, J=11.7 Hz, 1H), 1.86-1, 63 (m, 2H), 1.50 (t, J=12.3 Hz, 1H). IV-625 392.1 2.2 IV-626 392.1 2.2 1H NMR (500 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.70 (s, 1H), 8.38 (d , J=6.3 Hz, 1H), 7.40 (NH), 6.90 (d, J=6.5 Hz, 1H+NH), 4.42 (s, 2H), 3.24-2 .99 (m, 2H), 2.37 (td, J=3.6, 1.4 Hz, 1H), 1.94 (d, J=11.7 Hz, 1H), 1.86-1, 63 (m, 2H), 1.50 (t, J=12.3 Hz, 1H). IV-627 458.2 2.48 IV-628 469 2.91 1H NMR (500 MHz, DMSO-d6) δ 13.54 (br s, 1H), 10.37 (m, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8, 36 (d, J=6.0 Hz, 1H), 8.01 (s, 1H), 6.55 (d, J=6.1 Hz, 1H), 4.34-3.43 (m, 5H ), 2.43 (br s, 1H), 2.22-2.03 (m, 1H). IV-629 469 2.91 1H NMR (500 MHz, DMSO-d6) δ 13.54 (br s, 1H), 10.37 (m, 1H), 9.35 (s, 1H), 8.67 (s, 1H), 8, 36 (d, J=6.0 Hz, 1H), 8.01 (s, 1H), 6.55 (d, J=6.1 Hz, 1H), 4.34-3.43 (m, 5H ), 2.43 (br s, 1H), 2.22-2.03 (m, 1H). IV-630 455 2.85 1H NMR (500 MHz, DMSO-d6) δ 10.39-10.33 (m, 1H), 9.38 (d, J=9.5 Hz, 1H), 8.72 (d, J=8, 5 Hz, 1H), 8.38 (s, 1H), 7.48 (s, 1H), 6.61 (d, J=6.3 Hz, 1H), 3.85-3.26 (m, 4H), 2.44 (brs, 1H), 2.17-2.03 (m, 1H), 1.35 (s, 3H), 0.84 (s, 2H), 0.70 (s, 2H ), the peak of water obscures some signals. IV-631 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8.38 (d , J=6.3 Hz, 1H), 7.44 (s, NH), 6.96 (s, NH), 6.88 (d, J=6.4 Hz, 1H), 3.09 (s , 1H), 2.55-2.52 (m, 2H), 2.41-2.31 (m, 1H), 1.92-1.65 (m, 4H), 1.23 (d, J =6.8 Hz, 3H). IV-632 491.1 1.98 IV-633 491.2 1.98 1H NMR (500 MHz, methanol-d4) δ 10.33 (s, 1H), 9.20 (s, 1H), 8.68 (s, 1H), 8.41 (d, J=6.3 Hz , 1H), 7.65 (s, 2H), 6.90 (d, J=6.4 Hz, 1H), 5.09-4.92 (m, 1H), 3.25-3.14 ( m, 1H), 3.14-3.04 (m, 1H), 2.99-2.88 (m, 1H), 2.41-2.31 (m, 1H), 2.30-2, 16 (m, 2H), 1.96-1.82 (m, 1H), 1.67 (d, J=12.8 Hz, 3H), 1.63 (d, J=12.9 Hz, 3H ). IV-634 415.1 2.54 1H NMR (500 MHz, methanol-d4) δ 10.31 (dd, J=1.5, 0.8 Hz, 1H), 9.30-9.21 (m, 1H), 8.97 (d, J=5.6 Hz, 1H), 8.87 (s, 1H), 8.77 (d, J=2.8 Hz, 1H), 7.87 (d, J=5.6 Hz, 1H) , 6.67 (d, J=2.8 Hz, 1H), 3.72-3.61 (m, 1H), 3.47-3.33 (m, 2H), 3.33-3.21 (m, 1H), 3.11 (ddd, J=12.8, 11.0, 3.6 Hz, 1H), 2.33-2.24 (m, 1H), 2.10-1.99 (m, 1H), 2.00-1.84 (m, 2H). IV-635 415 2.54 1H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 10.38 (d, J=13.3 Hz, 1H), 9.36 (d, J=1.3 Hz, 1H ), 8.66 (s, 1H), 8.32 (d, J=5.6 Hz, 1H), 7.58 (brs, 1H), 7.40 (brs, 1H), 6.50 (d , J=6.0 Hz, 1H), 3.92-3.81 (m, 1H), 3.67-3.50 (m, 2H), 3.49-3.34 (m, 1H), 2.63-2.55 (m, 3H), 2.15 (brs, 1H), 1.82-1.70 (m, 1H). IV-636 488.4 2.27 1H NMR (500 MHz, methanol-d4) δ 10.24 (s, 1H), 9.20 (d, J=1.5 Hz, 1H), 8.69 (s, 1H), 8.45 (d , J=6.3 Hz, 1H), 7.86 (s, 2H), 7.41 (s, 2H), 6.89 (d, J=6.2 Hz, 1H), 5.01 (s , 2H), 3.87-3.63 (m, 2H), 3.53-3.34 (m, 4H), 3.20-3.05 (m, 1H), 1.61 (d, J =6.3 Hz, 3H), 1.47 (d, J=7.0 Hz, 3H). IV-637 499.3 2.84 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.69 (m, 1H), 9.34 (s, 1H), 9.01 (m, 1H), 8.71 (s, 1H), 7.84 (s, 2H), 4.69 (m, 1H), 4.10 (m, 3H), 3.30 (masked, 3H), 2.99 (m, 1H) , 2.50 (masked, 1H), 2.30 (m, 2H), 1.43 (m, 3H), 1.15 (m, 3H). IV-638 445.3 2.52 1H NMR (500 MHz, methanol-d4) δ 10.35 (s, 1H), 9.20 (d, J=1.4 Hz, 1H), 8.74 (s, 1H), 8.40 (d , J=6.3 Hz, 1H), 7.71 (d, J=1.3 Hz, 1H), 7.05 (s, 1H), 6.80 (d, J=6.3 Hz, 1H ), 5.49 (s, 1H), 4.88 (s, 1H), 4.47 (s, 1H), 3.91 (s, 1H), 3.03 (s, 1H), 1.41 (d, J=6.1 Hz, 3H), 1.13-0.96 (m, 3H). IV-639 445.2 2.52 1H NMR (500 MHz, methanol-d4) δ 10.33 (s, 1H), 9.24-9.12 (m, 1H), 8.72 (s, 1H), 8.38 (d, J= 6.3 Hz, 1H), 7.71 (d, J=1.3 Hz, 1H), 7.11-6.98 (m, 1H), 6.79 (d, J=6.2 Hz, 1H), 5.33 (s, 1H), 4.91-4.86 (m, 1H), 4.47 (s, 1H), 3.90 (s, 1H), 3.02 (s, 1H ), 1.41 (d, J=6.1 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H). IV-640 504.4 2.26 IV-641 416.45 2.09 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 10.36 (s, 1H), 9.37-9.32 (m, 1H), 8.65 (s, 1H) , 8.33 (d, J=5.9 Hz, 1H), 6.52 (d, J=7.4 Hz, 1H), 4.06 (s, 1H), 3.83 (s, 2H) , 3.65 (s, 3H), 2.43 (d, J=23.1 Hz, 2H), 2.32 (s, 2H). IV-642 402.05 2.05 1H NMR (400 MHz, DMSO-d6) δ 13.82 (s, 1H), 10.34 (d, J=17.5 Hz, 1H), 9.35 (s, 1H), 8.64 (d , J=9.6 Hz, 1H), 8.34 (d, J=6.0 Hz, 1H), 8.28 (s, 1H), 6.54 (s, 1H), 4.11 (s , 1H), 3.95-3.51 (m, 3H), 2.49-2.05 (m, 3H). IV-643 391.15 3.6 1H NMR (400 MHz, DMSO-d6) δ 10.31-10.20 (m, 1H), 9.36 (s, 1H), 8.71-8.64 (m, 1H), 8.38- 8.26 (m, 1H), 6.89-6.72 (m, 1H), 3.85 (s, 1H), 2.10 (s, 1H), 1.95-1.50 (m, 1H), 1.48-1.30 (m, 1H), 1.29-1.13 (m, 2H), 1.17-1.00 (m, 3H), 1.01 (q, J= 3.5, 2.7 Hz, 2H), 1.01-0.88 (m, 4H), 0.76-0.63 (m, 1H). IV-644 402.95 3.69 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.34 (d, J=1.3 Hz, 1H), 8.65 (s, 1H), 8.29 (d , J=6.1 Hz, 1H), 6.52-6.43 (m, 1H), 3.91 (dd, J=22.3, 12.6 Hz, 1H), 3.60-3, 50 (m, 1H), 3.23-2.98 (m, 1H), 2.14 (s, 2H), 1.78 (s, 4H), 1.62 (s, 3H), 1.53 (s, 2H), 1.23 (s, 2H). IV-645 434.1 2.17 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 9.33 (d, J=1.3 Hz, 1H), 8.64 (d, J=10.0 Hz, 1H ), 8.29 (d, J=6.1 Hz, 1H), 6.48 (dd, J=24.3, 6.2 Hz, 1H), 4.57 (d, J=4.1 Hz , 1H), 3.93 (dt, J=44.1, 9.3 Hz, 1H), 3.71-3.34 (m, 3H), 3.28-2.89 (m, 1H), 2.89-2.70 (m, 1H), 2.17 (td, J=24.1, 20.4, 13.8 Hz, 3H), 1.86 (t, J=10.0 Hz, 1H), 1.75 (d, J=11.4 Hz, 3H), 1.42 (d, J=11.9 Hz, 2H). 1 proton masked by solvent peak IV-646 411.85 2.59 1H NMR (400 MHz, DMSO-d6) δ 10.37 (d, J=8.6 Hz, 1H), 9.35 (s, 1H), 8.72-8.60 (m, 3H), 8 .50 (dd, J=4.8, 1.6 Hz, 1H), 8.36 (d, J=5.6 Hz, 1H), 7.83 (dt, J=7.9, 2.0 Hz, 1H), 7.45-7.37 (m, 1H), 6.56 (d, J=6.1 Hz, 1H), 4.28 (s, 1H), 3.98 (d, J =9.7 Hz, 1H), 3.69 (d, J=9.7 Hz, 1H), 3.61 (s, 1H), 3.58-3.40 (m, 1H), 2.21 (s, 1H). IV-647 430.6 1.72 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 9.33 (s, 1H), 8.64 (s, 1H), 8.30 (d, J=6.1 Hz , 1H), 6.50 (dd, J=14.1, 6.1 Hz, 1H), 5.27 (s, 1H), 4.04-3.72 (m, 1H), 3.66 ( s, 1H), 3.55 (s, 1H), 3.39-3.14 (m, 5H), 2.33 (d, J=14.2 Hz, 1H), 2.13 (s, 1H ), 1.13 (dd, J=6.5, 2.4 Hz, 1H). IV-648 535.3 2.14 1H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 10.32 (m, 1H), 9.34 (m, 1H), 8.66 (m, 1H), 7.70 -7.48 (m, 2H), 5.97 (m, 1H), 5.01-4.71 (m, 1H), 4.05 (m, 2H), 3.45 (m, 6H), 2.85 (m, 1H), 2.50 (masked, 2H), 1.16 (m, 3H), 0.91 (m, 3H). IV-649 444.3 2.2 1H NMR (500 MHz, methanol-d4) δ 10.17 (s, 1H), 9.21 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.71 (s, 2H), 4.67 (m, 1H), 4.38 (m, 1H), 4.24 (m, 1H), 3.16 (m, 1H) , 2.93 (m, 1H), 1.34 (d, 3H), 1.14 (d, 3H). IV-650 444.3 2.2 1H NMR (500 MHz, methanol-d4) δ 10.17 (s, 1H), 9.21 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.28 (s, 1H), 7.71 (s, 2H), 4.67 (m, 1H), 4.38 (m, 1H), 4.24 (m, 1H), 3.16 (m, 1H) , 2.93 (m, 1H), 1.34 (d, 3H), 1.14 (d, 3H). IV-651 464.2 2.48 1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.19 (s, 1H), 9.68-9.43 (m, 1H), 9.38 (s, 1H) , 9.18-8.94 (m, 1H), 8.80 (s, 1H), 8.54 (d, J=6.2 Hz, 1H), 8.12 (s, 1H), 7, 08 (d, J=6.3 Hz, 1H), 5.21-4.51 (m, 2H), 4.50-4.36 (m, 1H), 3.75-3.63 (m, 2H), 3.20-3.06 (m, 1H), 1.36 (d, J=6.4 Hz, 3H). IV-652 464.2 2.48 IV-653 483.1 3.08 1H NMR (400 MHz, DMSO-d6) δ 13.54 (d, J=2.0 Hz, 1H), 10.18 (s, 1H), 9.34 (d, J=1.3 Hz, 1H ), 8.73 (s, 1H), 8.39 (d, J=6.3 Hz, 1H), 6.95 (d, J=6.4 Hz, 1H), 6.64 (d, J =1.9 Hz, 1H), 4.59 (s, 2H), 3.26-3.06 (m, 2H), 2.98 (tt, J=10.8, 3.8 Hz, 1H) , 2.15 (d, J=12.4 Hz, 1H), 1.97-1.74 (m, 2H), 1.61 (q, J=13.0, 12.4 Hz, 1H). IV-654 497.1 2.98 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.35 (d, J=1.2 Hz, 1H), 8.70 (s, 1H), 8.38 (d , J=6.3 Hz, 1H), 7.74 (d, J=1.4 Hz, 1H), 6.94 (d, J=6.3 Hz, 1H), 4.59 (s, 2H ), 3.69 (s, 3H), 3.25 (d, J=12.6 Hz, 1H masked with water), 3.22-2.94 (m, 2H), 2.18-1.99 ( m, 1H), 1.87 (dd, J=12.2, 9.2 Hz, 2H), 1.63 (q, J=13.6, 12.8 Hz, 1H). IV-655 429.2 2.75 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.68 (s, 1H), 8.39 (d , J=6.3 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 6.95 (d, J=6.4 Hz, 1H), 6.17 (d, J =1.9 Hz, 1H), 4.54 (s, 2H), 3.81 (s, 3H), 3.13 (dt, J=23.2, 12.4 Hz, 2H), 3.02 -2.87 (m, 1H), 2.15-1.96 (m, 1H), 1.93-1.55 (m, 3H). IV-656 417.1 2.44 1H NMR (400 MHz, DMSO-d6) δ 10.19 (d, J=1.4 Hz, 1H), 9.35 (d, J=1.1 Hz, 1H), 9.16 (s, 1H ), 8.66 (s, 1H), 8.38 (d, J=6.3 Hz, 1H), 6.91 (d, J=6.4 Hz, 1H), 4.53 (s, 1H ), 4.14 (s, 1H), 3.71 (dd, J=13.4, 9.0 Hz, 1H), 3.48 (t, J=11.4 Hz, 1H), 3.43 -3.33 (m, 1H masked with water), 2.32-2.12 (m, 1H), 2.07-1.93 (m, 1H), 1.90-1.79 (m, 1H) , 1.77-1.57 (m, 1H). IV-657 431.05 2.51 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.21 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.69 (s , 1H), 8.43 (d, J=6.2 Hz, 1H), 7.46 (s, 1H), 6.94 (d, J=6.3 Hz, 1H), 4.65 (d , J=10.2 Hz, 1H), 4.42 (s, 2H), 4.09-4.01 (m, 1H), 3.75 (td, J=11.6, 2.7 Hz, 1H), 3.31-3.19 (m, 1H), 2.08 (d, J=0.7 Hz, 3H), 1.27 (dd, J=6.6, 5.5 Hz, 1H ). IV-658 468.15 2.57 1H NMR (400 MHz, DMSO-d6) δ 10.23 (d, J=1.4 Hz, 1H), 9.36 (s, 1H), 8.71 (d, J=1.2 Hz, 1H ), 8.41 (dd, J=6.3, 1.2 Hz, 1H), 6.84 (d, J=6.3 Hz, 1H), 3.43-3.34 (m, 4H) , 3.25 (t, J=7.6 Hz, 4H), 3.08 (s, 1H), 2.34-2.20 (m, 2H), 1.95 (s, 1H), 1, 86 (ddd, J=14.5, 8.7, 3.8 Hz, 2H), 1.57 (d, J=12.8 Hz, 1H). IV-659 498.11 2.86 IV-660 432.16 2.04 1H NMR (400 MHz, DMSO-d6) δ 11.22 (s, 1H), 10.26-10.20 (m, 1H), 9.36 (d, J=1.3 Hz, 1H), 8 .75 (s, 1H), 8.40 (d, J=6.3 Hz, 1H), 6.92 (d, J=6.4 Hz, 1H), 3.31 (s, 1H), 3 ,37-3.26 (m, 1H), 3.21 (t, J=11.8 Hz, 1H), 2.77-2.65 (m, 1H), 2.12-2.02 (m , 1H), 1.95-1.74 (m, 2H), 1.57 (d, J=12.3 Hz, 1H), 1.04-0.90 (m, 2H). IV-661 432.16 2.02 1H NMR (400 MHz, DMSO-d6) δ 13.65 (s, 1H), 10.20 (s, 1H), 9.35 (d, J=1.3 Hz, 1H), 8.69 (s , 1H), 8.43 (d, J=6.2 Hz, 1H), 6.93 (d, J=6.3 Hz, 1H), 4.69-4.61 (m, 1H), 4 .33 (s, 1H), 4.06 (ddd, J=11.5, 3.6, 1.9 Hz, 1H), 3.76 (td, J=11.4, 2.8 Hz, 1H ), 3.51 (q, J=12.0, 9.9 Hz, 1H), 3.32-3.23 (m, 1H), 2.34 (s, 3H), 0.99-0, 90 (m, 1H). IV-662 473.28 2.47 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.35 (d, J=1.2 Hz, 1H), 8.65 (s, 1H), 8.36 (d , J=6.3 Hz, 1H), 6.89 (d, J=6.4 Hz, 1H), 6.01 (s, 1H), 4.77 (t, J=5.3 Hz, 1H ), 3.69 (s, 2H), 3.62 (td, J=7.0, 5.3 Hz, 2H), 3.32 (s, 5H), 3.21-3.06 (m, 1H), 2.74 (t, J=6.9 Hz, 2H), 2.05 (d, J=12.6 Hz, 1H), 1.87-1.68 (m, 1H), 1, 61 (s, 1H), 0.99-0.90 (m, 1H). IV-663 432.1 2.42 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.36 (d, J=1.3 Hz, 1H), 8.67 (d, J=3.5 Hz, 1H ), 8.37 (dd, J=6.4, 0.7 Hz, 1H), 7.58-7.53 (m, 1H), 7.08 (s, 1H), 6.88 (dd, J=6.4, 3.3 Hz, 1H), 3.45 (t, J=8.7 Hz, 1H), 3.17 (t, J=11.7 Hz, 1H), 3.13- 2.92 (m, 3H), 2.34-1.94 (m, 4H), 1.78 (t, J=11.3 Hz, 1H), 1.62-1.14 (m, 3H) . IV-664 483.3 3.48 1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.36 (s, 1H), 8.71 (s, 1H), 8.41 (d, J=6.3 Hz , 1H), 8.18-8.01 (m, 1H), 6.98 (d, J=6.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 4 .79-4.60 (m, 1H), 4.59-4.47 (m, 1H), 4.47-4.18 (m, 1H), 3.67 (dd, J=12.9, 9.9 Hz, 1H), 3.31 (ddd, J=13.7, 11.1, 3.0 Hz, 1H), 2.28-2.15 (m, 2H), 1.98-1 .86 (m, 1H), 1.76-1.60 (m, 1H). IV-665 415.3 2.92 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.40 (d, J=6.4 Hz , 1H), 7.84 (d, J=2.2 Hz, 1H), 7.49 (d, J=1.8, 0.7 Hz, 1H), 6.96 (d, J=6, 5 Hz, 1H), 6.27 (t, J=2.1 Hz, 1H), 4.81-4.51 (m, 1H), 4.50-4.21 (m, 2H), 3, 57 (dd, J=13.0, 10.0 Hz, 1H), 3.27 (ddd, J=13.8, 11.3, 3.0 Hz, 1H), 2.26-2.14 ( m, 2H), 1.98-1.85 (m, 1H), 1.76-1.59 (m, 1H). IV-666 512.3 2.75 1H NMR (500 MHz, methanol-d4) δ 10.29 (s, 1H), 9.23 (d, J=1.3 Hz, 1H), 8.75 (s, 1H), 8.51 (d , J=6.2 Hz, 1H), 7.54 (d, J=0.7 Hz, 1H), 6.96 (d, J=6.3 Hz, 1H), 4.92-4.86 (m, 1H), 3.62 (ddd, J=10.8, 6.5, 3.8 Hz, 1H), 3.33 (d, J=1.7 Hz, 1H), 1.56 ( d, J=6.6 Hz, 3H), 1.28 (d, J=7.1 Hz, 3H). IV-667 444.3 2.5 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.36 (s, 1H), 8.72 (s, 1H), 8.41 (d, J=6.2 Hz , 1H), 7.38 (s, 1H), 6.97 (d, J=6.4 Hz, 1H), 6.31 (s, 1H), 4.01 (d, J=11.8 Hz , 1H), 3.88 (s, 3H), 2.98-2.92 (m, 2H), 2.73-2.67 (m, 2H), 2.53-2.50 (m, 1H ), 1.14 (d, J=5.8 Hz, 3H). IV-668 415.1 2.54 1H NMR (500 MHz, DMSO-d6) δ 12.6 (s, 1H), 10.45 (s, 1H), 9.34 (s, 1H), 8.64 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 6.41 (s, 1H), 4.15-3.80 (m, 1H), 3.73-3.65 (m, 1H), 3.45 (m, 2H), 2.38 (m, 3H), 2.03 (m, 1H), 1.24 (m, 1H), 0.98 (m, 1H). IV-669 458.2 2.46 1H NMR (500 MHz, DMSO-d6) δ 12.6 (s, 1H), 10.32 (s, 1H), 9.34 (s, 1H), 8.67 (s, 1H), 7.61 (m, 2H), 6.80 (m, 1H), 4.95-4.60 (m, 1H), 4.25-3.80 (m, 2H), 2.85 (m, 1H), 2.70 (m, 1H), 2.37 (s, 3H), 1.24 (m, 3H), 0.98 (m, 3H). IV-670 458.2 2.46 1H NMR (500 MHz, DMSO-d6) δ 12.6 (s, 1H), 10.32 (s, 1H), 9.34 (s, 1H), 8.67 (s, 1H), 7.61 (m, 2H), 6.80 (m, 1H), 4.95-4.60 (m, 1H), 4.25-3.80 (m, 2H), 2.85 (m, 1H), 2.70 (m, 1H), 2.37 (s, 3H), 1.24 (m, 3H), 0.98 (m, 3H). IV-671 433.1 2.46 1H NMR (500 MHz, methanol-d4) δ 10.33 (s, 1H), 9.40 (s, 1H), 9.20 (d, J=1.4 Hz, 1H), 8.67 (s , 1H), 8.37 (d, J=6.3 Hz, 1H), 6.85 (d, J=6.4 Hz, 1H), 4.74 (s, 1H), 4.33 (s , 1H), 3.72 (dd, J=13.3, 9.5 Hz, 1H), 3.61 (dd, J=8.9, 5.1 Hz, 1H), 3.52-3, 42 (m, 1H), 2.38 (dd, J=13.1, 4.4 Hz, 1H), 2.16-2.05 (m, 1H), 1.98 (dt, J=8, 6, 4.4 Hz, 1H), 1.89-1.75 (m, 1H). IV-672 444.1 2.16 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.36 (s, 1H), 8.71 (s, 1H), 8.40 (d, J=6.3 Hz , 1H), 7.57 (s, 1H), 6.95 (d, J=6.4 Hz, 1H), 6.91 (s, 1H), 3.91 (dt, J=11.3, 3.3 Hz, 1H), 3.69 (s, 3H), 3.00-2.86 (m, 2H), 2.67-2.60 (m, 2H), 2.53-2.50 (m, 1H), 1.13 (d, J=6.2 Hz, 3H). IV-673 512.2 2.52 1H NMR (500 MHz, methanol-d4) δ 10.27 (s, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.67 (d, J=5.9 Hz, 1H ), 8.33 (d, J=6.3 Hz, 1H), 7.27 (s, 1H), 6.88-6.74 (m, 1H), 5.31 (s, 1H), 4 .52 (s, 1H), 4.24 (d, J=3.9 Hz, 1H), 3.89 (s, 1H), 3.04 (ddd, J=10.0, 6.1, 3 ,2 Hz, 1H), 2.86 (s, 1H), 1.31 (d, J=6.2 Hz, 3H), 1.13-0.94 (m, 3H). IV-674 512.1 2.52 1H NMR (500 MHz, methanol-d4) δ 10.27 (s, 1H), 9.18 (d, J=1.4 Hz, 1H), 8.67 (d, J=5.9 Hz, 1H ), 8.33 (d, J=6.3 Hz, 1H), 7.27 (s, 1H), 6.88-6.74 (m, 1H), 5.31 (s, 1H), 4 .52 (s, 1H), 4.24 (d, J=3.9 Hz, 1H), 3.89 (s, 1H), 3.04 (ddd, J=10.0, 6.1, 3 ,2 Hz, 1H), 2.86 (s, 1H), 1.31 (d, J=6.2 Hz, 3H), 1.13-0.94 (m, 3H). IV-675 432.2 3.17 1H NMR (500 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.37 (s, 1H), 8.68 (s, 1H), 8.40 (d, J=6.4 Hz , 1H), 7.77 (d, J=3.3 Hz, 1H), 7.66 (d, J=3.3 Hz, 1H), 6.97 (d, J=6.5 Hz, 1H ), 4.88-4.51 (m, 2H), 3.51 (dd, J=13.1, 10.1 Hz, 1H), 3.41-3.27 (m, 2H), 2, 30-2.17 (m, 1H), 2.04-1.82 (m, 2H), 1.76-1.61 (m, 1H). IV-676 471 2.15 1H NMR (500 MHz, methanol-d4) δ 10.32 (s, 1H), 9.22 (s, 1H), 8.69 (s, 1H), 8.37 (d, 1H), 7.80 (m, 1H), 7.50 (m, 1H), 6.80 (m, 1H), 6.58 (m, 1H), 4.40 (m, 1H), 4.15-4.05 ( m, 1H), 3.72 (m, 1H), 3.50 (m, 3H), 1.24 (m, 3H), 0.98 (m, 3H). IV-677 471.2 2.23 1H NMR (500 MHz, methanol-d4) δ 10.50-10.32 (m, 1H), 9.22 (s, 1H), 8.69 (s, 1H), 8.37 (d, 1H) , 7.77 (m, 1H), 7.50 (m, 1H), 6.80 (m, 1H), 6.63 (m, 1H), 5.10 (m, 1H), 4.30 ( m, 1H), 4.06 (m, 1H), 3.88 (m, 1H), 3.05 (m, 1H), 2.90 (m, 1H), 1.24 (m, 3H), 0.98 (m, 3H). IV-678 416.1 2.58 1H NMR (500 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.40 (d, J=6.2 Hz , 1H), 8.26 (s, 1H), 7.02 (s, 1H), 6.92 (d, J=6.3 Hz, 1H), 4.50 (s, 2H), 3.41 (dd, J=13.2, 9.9 Hz, 1H), 3.34 (d, J=11.2 Hz, 1H), 3.04 (d, J=9.5 Hz, 1H), 2 .13 (d, J=9.8 Hz, 1H), 1.83 (d, J=10.7 Hz, 2H), 1.64 (s, 1H). IV-679 456.3 2.52 1H NMR (400 MHz, methanol-d4) δ 10.31 (s, 1H), 9.20 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8.45 (d , J=6.3 Hz, 1H), 7.86 (s, 2H), 6.91 (d, J=6.3 Hz, 1H), 5.49 (d, J=0.6 Hz, 1H ), 3.22 (s, 1H), 2.29 (d, J=11.4 Hz, 1H), 2.15 (d, J=0.6 Hz, 1H), 1.86 (s, 1H ), 1.42-1.19 (m, 5H). IV-680 415.3 2.62 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.24 (s, 1H), 9.35-9.34 (m, 1H), 8.67 (s, 1H) , 8.35 (d, J=6.3 Hz, 1H), 7.55 (br s, 1H), 7.39 (br s, 1H), 6.87 (d, J=6.4 Hz, 1H), 4.52 (br s, 2H), 3.17-3.10 (m, 2H), 2.86 (tt, J=11.5, 3.9 Hz, 1H), 1.98 ( d, J=15.0 Hz, 2H), 1.52 (qd, J=12.7, 4.1 Hz, 2H). IV-681 484.3 2.51 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.21 (s, 1H), 9.36 (s, 1H), 8.68 (d, J=8.5 Hz , 1H), 8.37 (dd, J=17.0, 6.3 Hz, 1H), 7.57 (d, J=71.2 Hz, 2H), 6.88 (d, J=8, 2 Hz, 1H), 3.51(s, 1H), 3.19-2.56 (m, 7H), 2.45-2.17 (m, 2H), 2.13-1.52 (m , 5H), 1.33 (q, J=12.2 Hz, 1H). IV-682 473.1 2.31 1H NMR (500 MHz, methanol-d4) δ 10.36 (d, J=1.4 Hz, 1H), 9.22 (dd, J=1.4, 0.7 Hz, 1H), 8.69 (d, J=0.9 Hz, 1H), 8.38-8.24 (m, 1H), 7.51 (s, 2H), 6.73 (d, J=6.4 Hz, 1H) , 3.47-3.40 (m, 2H), 3.01 (t, J=12.2 Hz, 1H), 2.32-2.15 (m, 1H), 2.04-1.80 (m, 2H), 1.30 (s, 6H). IV-683 473.1 2.3 1H NMR (500 MHz, methanol-d4) δ 10.35 (d, J=0.9 Hz, 1H), 9.25-9.16 (m, 1H), 8.68 (s, 1H), 8 .31 (d, J=6.3 Hz, 1H), 7.49 (s, 2H), 6.72 (d, J=6.4 Hz, 1H), 3.49-3.37 (m, 2H), 3.00 (t, J=12.2 Hz, 1H), 2.21 (d, J=12.8 Hz, 1H), 1.96 (td, J=12.6, 4.6 Hz, 1H), 1.90-1.78 (m, 1H), 1.27 (s, 6H). IV-684 473.1 2.26 1H NMR (500 MHz, methanol-d4) δ 10.31 (s, 1H), 9.19 (d, J=1.3 Hz, 1H), 8.64 (s, 1H), 8.34 (d , J=6.3 Hz, 1H), 7.63 (s, 2H), 6.79 (d, J=6.4 Hz, 1H), 4.67 (s, 2H), 3.06-2 .78 (m, 3H), 2.33-2.18 (m, 1H), 1.77-1.54 (m, 2H), 1.31 (d, J=5.4 Hz, 7H). IV-685 473.1 2.26 1H NMR (500 MHz, methanol-d4) δ 10.30 (s, 1H), 9.19 (d, J=1.3 Hz, 1H), 8.63 (s, 1H), 8.33 (d , J=6.3 Hz, 1H), 7.62 (s, 2H), 6.78 (d, J=6.4 Hz, 1H), 4.76 (s, 1H), 3.01-2 .78 (m, 3H), 2.31-2.21 (m, 1H), 1.80-1.55 (m, 2H), 1.31 (d, J=5.5 Hz, 6H). IV-686 416.2 2.85 1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.37-9.36 (m, 1H), 8.67 (s, 1H), 8.38 (d, J= 6.3 Hz, 1H), 8.02 (s, 1H), 7.14 (d, J=0.7 Hz, 1H), 6.91 (d, J=6.4 Hz, 1H), 4 .55 (br s, 1H), 4.20 (br s, 1H), 3.59 (dd, J=13.3, 9.6 Hz, 1H), 3.44-3.37 (m, 1H ), 3.18-3.11 (m, 1H), 2.20-2.14 (m, 1H), 1.99-1.82 (m, 2H), 1.69-1.60 (m , 1H). IV-687 458.3 2.47 1H NMR (500 MHz, DMSO-d6) δ 10.25-10.12 (m, 1H), 9.34 (s, 1H), 8.70 (s, 1H), 8.38 (s, 1H) , 7.65 (s, 1H), 7.42 (s, 1H), 6.88 (m, 1H), 4.98-4.75 (m, 1H), 4.25 (m, 0.5H ), 4.02 (m, 1H), 3.83 (s, 3H), 2.90 (m, 1H), 2.80-2.70 (m, 1H), 2.60 (m, 0. 5H), 1.17 (m, 3H), 1.00 (m, 3H); 1 proton peak not observed IV-688 415.3 2.56 1H NMR (500 MHz, DMSO-d6) δ 12.71 (s, 1H), 10.34 (s, 1H), 9.36 (s, 1H), 8.68 (s, 1H), 8.35 (d, J=6.4 Hz, 1H), 7.68 (s, 1H), 7.46 (s, 1H), 6.67-6.42 (m, 1H), 4.44 (d, J=205.3 Hz, 1H), 3.78 (d, J=89.4 Hz, 1H), 3.59-3.39 (m, 1H), 2.36 (d, J=47.5 Hz, 2H), 1.26 (d, J=11.7 Hz, 1H), 1.03-0.84 (m, 3H). IV-689 415.3 2.66 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 10.34 (s, 1H), 9.35 (d, J=1.4 Hz, 1H), 8.67 (s , 1H), 8.35 (d, J=6.0 Hz, 1H), 7.49 (d, J=95.5 Hz, 2H), 6.53 (s, 1H), 4.22 (d , 1H) 3.59 (s, 2H), 2.16-1.92 (m, 1H), 1.34 (d, J=95.4 Hz, 5H). IV-690 461.3 2.72 1H NMR (500 MHz, methanol-d4) δ 10.21 (s, 1H), 9.15 (d, 1H), 8.51 (s, 1H), 7.69 (s, 2H), 7.16 -7.14 (dd, 1H), 6.64-6.62 (dd, 1H), 4.45 (m, 1H), 4.30 (m, 1H), 4.08 (m, 1H), 3.08-3.03 (m, 1H), 2.85-2.78 (m, 1H), 1.31 (m, 3H), 1.02 (m, 3H). IV-691 432.2 3 1H NMR (500 MHz, DMSO-d6) δ 10.14 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 9.01 (d, J=0.8 Hz, 1H ), 8.70 (s, 1H), 8.40 (d, J=6.4 Hz, 1H), 7.85 (s, 1H), 6.99 (d, J=6.5 Hz, 1H ), 4.65-4.34 (m, 2H), 3.39-3.20 (m, 3H), 2.21-2.12 (m, 1H), 1.90-1.74 (m , 2H), 1.72-1.58 (m, 1H). IV-692 390.1 2.07 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.36 (s, 1H), 8.69 (s, 1H), 8.37 (d, J=6.4 Hz , 1H), 6.88 (d, J=6.3 Hz, 1H), 3.31(br s, 4H) 3.68 (d, J=18.7 Hz, 4H), 1.80 (t , J=5.7 Hz, 4H). IV-693 505.3 2.06 1H NMR (500 MHz, methanol-d4) δ 10.18 (s, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 8.42 (d, J=6.6 Hz , 1H), 7.71 (s, 2H), 7.05 (d, J=6.7 Hz, 1H), 3.30-3.13 (m, 1H), 2.42-2.10 ( m, 3H), 1.81-1.59 (m, 6H), 1.20 (d, J=6.9 Hz, 3H). IV-694 416.3 2.96 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.69 (s, 1H), 8.38 (d , J=6.4 Hz, 1H), 8.32 (d, J=0.9 Hz, 1H), 7.97 (s, 1H), 6.92 (d, J=6.4 Hz, 1H ), 4.68-4.30 (m, 2H), 3.35-3.20 (m, 2H), 2.87-2.77 (m, 1H), 2.16-2.04 (m , 1H), 1.90-1.74 (m, 2H), 1.72-1.56 (m, 1H). IV-695 417.3 2.43 1H NMR (500 MHz, methanol-d4) δ 10.44 (d, J=5.2 Hz, 1H), 9.18 (s, 1H), 8.64 (d, J=3.8 Hz, 1H ), 8.34-8.21 (m, 1H), 7.40 (s, 2H), 6.50 (s, 1H), 4.93 (s, 1H), 4.56 (s, 1H) , 3.91 (d, J=9.2 Hz, 1H), 3.77-3.58 (m, 1H), 2.43 (s, 1H), 2.32 (d, J=16.0 Hz, 1H), 1.30 (d, J=6.7 Hz, 1H). IV-696 404.1 2.37 1H NMR (500 MHz, methanol-d4) δ 10.33 (s, 1H), 9.20 (d, J=1.3 Hz, 1H), 8.62 (s, 1H), 8.34-8 .25 (m, 1H), 6.77-6.69 (m, 1H), 4.24 (s, 2H), 3.81 (dt, J=20.2, 8.7 Hz, 2H), 3.72 (t, J=8.3 Hz, 1H), 3.64 (q, J=8.8 Hz, 1H), 3.28 (ddd, J=13.7, 10.8, 3, 3 Hz, 1H), 2.97 (tt, J=23.1, 10.4 Hz, 1H), 2.73 (h, J=8.0 Hz, 1H), 1.98-1.81 ( m, 3H), 1.68-1.56 (m, 1H), 1.33 (ddd, J=14.9, 11.5, 7.3 Hz, 1H). IV-697 505.3 2.16 1H NMR (500 MHz, methanol-d4) δ 10.18 (s, 1H), 9.28 (s, 1H), 8.75 (s, 1H), 8.42 (d, J=6.6 Hz , 1H), 7.71 (s, 2H), 7.05 (d, J=6.7 Hz, 1H), 3.30-3.13 (m, 1H), 2.42-2.10 ( m, 3H), 1.81-1.59 (m, 6H), 1.20 (d, J=6.9 Hz, 3H). IV-698 468 2.48 1H NMR (500 MHz, DMSO-d6) δ 10.35 (dt, J=1.5, 0.8 Hz, 1H), 9.37 (d, J=1.3 Hz, 1H), 8.64 (s, 1H), 8.38 (d, J=5.9 Hz, 1H), 6.41 (d, J=6.0 Hz, 1H), 3.93 (s, 4H), 3.15 (s, 4H), 2.89 (s, 3H), 1.92 (t, J=5.5 Hz, 4H). IV-699 395.1 1.67 1H NMR (400 MHz, DMSO-d6) δ 10.46 (d, J=1.5 Hz, 1H), 9.22 (d, J=1.3 Hz, 1H), 8.66 (s, 1H ), 8.42 (d, J=6.1 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.86 (s, 1H), 6.53 (s, 1H ), 4.18-3.47 (m, 6H), 2.05 (s, 3H), 1.49 (s, 6H). IV-767 447.2 1.37 (300MHz, DMSO-d6) 12.27 (s,1H), 10.20 (s,1H), 9.36 (s,1H), 8.67 (s,1H), 8.38 (d, J =6.2Hz,1H), 7.64 (s,1H), 6.92 (d, J=6.3Hz,1H), 4.55 (s,2H), 2.84 (d, J=12 ,9Hz,1H), 2.67 (q, J=13.7,13.0Hz,2H), 2.05 (d, J=12.6Hz,1H), 1.73 (s,1H), 1 .39 (q, J=12.4Hz,1H), 1.01 (d, J=6.4Hz,3H).

Example 107: 2-(1H-Pyrazol-4-yl)-4-[2-[2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl]pyrimidin-4-yl]morpholine, V- 15

[001544] 5-(4-Chloropyrimidin-2-yl)-2-(trifluoromethyl)imidazo[2,1-b]thiazole (11 mg, 0.036 mmol), 2-(1H-pyrazol-4-yl)morpholine ( 10 mg, 0.065 mmol) and DIPEA (30 μL, 0.172 mmol) were dissolved in NMP (1 mL) and heated in a sealed tube at 80°C for 18 h. The reaction mixture was cooled to ambient temperature and immediately purified using preparative HPLC reverse phase [Waters Sunfire C18, 10 µM, 100 Å column, gradient mode 10% - 95% B (solvent A: 0.05% TFA in water; solvent B: CH ₃ CN) for 16 min at 25 ml /min]. Fractions were collected and freeze-dried to yield 2-(1H-pyrazol-4-yl)-4-[2-[2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl]pyrimidin-4-yl] morpholine (trifluoroacetate) V-15 (7.8 mg, 40%) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.10 (d, J=1.6 Hz, 1H), 8.35 (d, J=6.3 Hz, 1H), 8.14 (s , 1H), 7.69 (s, 2H), 6.87 (d, J=6.4 Hz, 1H), 4.58 (dd, J=10.7, 2.6 Hz, 1H), 4 .05-4.03 (m, 1H), 3.70 (td, J=11.5, 2.6 Hz, 1H), 3.21-3.13 (m, 2H), 2.52-2 .48 (m, 2H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -55.75, -74.34.; ESVI-MS m/z 422.1 (M+1) ⁺ .

[001545] The following compounds were prepared using a methodology similar to that described in Example 107:

5-[4-[3-Dimethylphosphoryl-5-(1H-pyrazol-4-yl)-1-piperidyl]pyrimidin-2-yl]-2-(trifluoromethyl)imidazo[2,1-b]thiazole (racemic cis -diastereoisomer), V-5;

5-[4-[3-Dimethylphosphoryl-5-(1H-pyrazol-4-yl)-1-piperidyl]pyrimidin-2-yl]-2-

(trifluoromethyl)imidazo[2,1-b]thiazole (racemic trans-diastereoisomer), V-6;

5-[4-[3-(1H-Pyrazol-4-yl)pyrrolidin-1-yl]pyrimidin-2-yl]-2-(trifluoromethyl)imidazo[2,1-b]thiazole, V-7;

1-[2-[2-(Trifluoromethyl)imidazo[2,1-b]thiazol-5-yl]pyrimidin-4-yl]-1,4-diazepan-5-one, V-8;

Dimethyl((1-(2-(2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone, V-9 ;

(3S)-1-[2-[2-(Trifluoromethyl)imidazo[2,1-b]thiazol-5-yl]pyrimidin-4-yl]piperidin-3-carboxamide, V-10;

5-[4-[2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-2-(trifluoromethyl)imidazo[2,1-b]thiazole , V-13;

N-[[1-[2-[2-(Difluoromethyl)imidazo[2,1-b]thiazol-5-yl]pyrimidin-4-yl]-4,4-difluoro-5-methyl-3-piperidyl] methyl]methanesulfonamide, V-14

Example 108: N-((-1-(2-(2-(Difluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)-4,4-difluoro-5-methylpiperidin- 3-yl)methyl)methanesulfonamide and N-((-1-(2-(2-(difluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)-4,4-difluoro -5-methylpiperidin-3-yl)methyl)methanesulfonamide, V-1 and V-2

[001546] Racemic mixture of N-[[1-[2-[2-(difluoromethyl)imidazo[2,1-b]thiazol-5-yl]pyrimidin-4-yl]-4,4-difluoro-5-methyl -3-piperidyl]methyl]methanesulfonamide (prepared using a similar methodology to that described in Example 121) was separated by chiral supercritical liquid chromatography [column: Chiralpak AS-H; mobile phase: CO2:methanol (+ 20 mM ammonia) 70:30] and isolated individual compounds, V-1 (8.4 mg, 77%, 99.1% ee) and V-2 (7.5 mg, 69%, 99.5% ee) as white solids.

Example 109: 2-(1H-Pyrazol-4-yl)-4-(2-(2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)morpholine, V- 3 and 2-(1H-pyrazol-4-yl)-4-(2-(2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)morpholine, V-4

[001547] Racemic mixture of 2-(1H-pyrazol-4-yl)-4-(2-(2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)morpholine ( prepared using a similar methodology to that described in Example 121) separated by chiral supercritical liquid chromatography [column: Lux Cellulose-2; Mobile phase: CO ₂ :isopropanol (+ 20 mM ammonia) 30:70] and isolated individual compounds V-3 (16.8 mg, 38%, 96.9% ee) and V-4 (14.5 mg, 32%, 98.9% ee).

Example 110: 5-[4-[2,5-Dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-2-(trifluoromethyl)imidazo[2,1- b]thiazole, V-11 and V-12

[001548] Racemic mixture of 5-[4-[2,5-dimethyl-3-(1H-pyrazol-4-yl)piperazin-1-yl]pyrimidin-2-yl]-2-(trifluoromethyl)imidazo[2, 1-b]thiazole (obtained using a procedure similar to that used in Example 1) was separated using chiral supercritical liquid chromatography [column: Chiralpak AD-H; Mobile phase: CO ₂ :methanol (+ 20 mM ammonia) 70:30] and isolated individual compounds enantiomers V-11 (6.0 mg, 41%, 99.5% ee) and V-12 (7.9 mg , 51%, 99.1% ee).

Example 111: Imino(methyl)((1-(2-(2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-λ6 -sulfanone, V-18 and V-19

[001549] 5-(4-Chloropyrimidin-2-yl)-2-(trifluoromethyl)imidazo[2,1-b]thiazole (25 mg, 0.082 mmol), 3-((methylsulfinyl)methyl)piperidine (62 mg, 0.123 mmol) and DIPEA (57 µl, 0.328 mmol) were dissolved in NMP (0.82 ml) and heated in a sealed tube at 100°C for 16 h. The reaction mixture was cooled to ambient temperature and immediately purified using preparative HPLC with reverse phase [Waters Sunfire C18, 10 µM, 100 Å column, gradient mode 10% - 95% B (solvent A: 0.05% TFA in water; solvent B: CH ₃ CN) for 16 min at 25 ml/ min]. Fractions were collected and freeze-dried to yield 5-(4-(3-((methylsulfinyl)methyl)piperidin-1-yl)pyrimidin-2-yl)-2-(trifluoromethyl)imidazo[2,1-b]thiazole (in form of separated racemic diastereoisomers). Each diastereoisomer (15 mg, 0.035 mmol), ammonium carbamate (10.9 mg, 0.140 mmol) and (diacetoxyiodo)benzene (33.8 mg, 0.105 mmol) were combined in a round bottom flask, then MeOH/DCM (1:1 mixture) was added 0.7 ml). The reaction mixture was stirred at ambient temperature for 3 hours. The crude mixture was then purified by preparative reverse phase HPLC [Waters Sunfire C18, 10 µM, 100 Å column, 10% - 95% B gradient (solvent A: 0. 1% ammonium hydroxide in water; solvent B: CH ₃ CN) for 16 min at 25 ml/min] to obtain imino(methyl)((1-(2-(2-(trifluoromethyl)imidazo[2,1-b ]thiazol-5-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)-λ6-sulfanone, V-18 and V-19.

[001550] The following compounds were prepared using a methodology similar to that described in Example 111:

((2,5-Dimethyl-1-(2-(2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)piperidin-3-yl)methyl)(imino) (methyl)-λ6-sulfanone, V-16 and V-17.

Table 8: Analysis data for compounds of formula V

[001551] The purity and retention time of the compounds of the present invention were determined using HPLC.

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). Mobile phases were acetonitrile and water/acetonitrile (95:5 with 10 mM ammonium formate, pH9). Study duration 5 min

V-No. LCMS (ES+) LCMS (rt, min) ¹ HNMR V-1 493.8 2.77 1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.35 (d, 1H), 8.12 (s, 1H), 7.52 (t, 1H), 6.86 (d, 1H), 4.98 (br s, 1H), 4.47 (br s, 1H), 3.45 (dd, 1H), 3.02-2.97 (m, 1H), 2, 97 (s, 3H), 2.87-2.79 (m, 2H), 2.21-2.15 (m, 2H), 1.05 (d, 3H). V-2 493.9 2.76 1H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.35 (d, 1H), 8.12 (s, 1H), 7.52 (t, 1H), 6.85 (d, 1H), 4.95 (br s, 1H), 4.43 (br s, 1H), 3.45 (dd, 1H), 3.02-2.97 (m, 1H), 2, 97 (s, 3H), 2.87-2.79 (m, 2H), 2.20-2.13 (m, 2H), 1.05 (d, 3H). V-3 422.1 2.50 1H NMR (500 MHz, methanol-d4) δ 9.13 (q, 1H), 8.32 (d, 1H), 8.11 (s, 1H), 7.74 (br s, 2H), 6, 75 (d, 1H), 4.71 (dd, 1H), 4.54 (br s, 1H), 4.31 (br s, 1H), 4.15-4.11 (m, 1H), 3 .84 (td, 1H), 3.30-3.29 (m, 1H), 3.27-3.22 (m, 1H). V-4 422.1 2.50 1H NMR (500 MHz, methanol-d4) δ 9.13 (q, 1H), 8.32 (d, 1H), 8.11 (s, 1H), 7.74 (br d, 2H), 6, 75 (d, 1H), 4.71 (dd, 1H), 4.54 (br s, 1H), 4.31 (br s, 1H), 4.15-4.11 (m, 1H), 3 .84 (td, 1H), 3.30-3.27 (m, 1H), 3.25 (dd, 1H). V-5 496.1 2.16 1H NMR (500 MHz, methanol-d4) δ 9.13-9.08 (m, 1H), 8.32 (dd, J=6.4, 1.5 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H), 7.67 (s, 2H), 6.82 (dd, J=6.4, 1.5 Hz, 1H), 3.21-3.12 (m, 1H ), 3.07 (t, J=12.4 Hz, 1H), 2.94 (tt, J=11.9, 4.2 Hz, 1H), 2.41-2.34 (m, 1H) , 2.23 (dt, J=12.2, 3.5 Hz, 1H), 1.89 (dq, J=12.5, 6.0 Hz, 1H), 1.66 (ddd, J=22 ,6, 12.9, 0.7 Hz, 6H), 1.15 (dd, J=6.8, 2.8 Hz, 2H). V-6 496.0 2.11 1H NMR (500 MHz, methanol-d4) δ 9.11 (t, J=1.4 Hz, 1H), 8.28 (d, J=6.3 Hz, 1H), 8.12 (s, 1H ), 7.57 (s, 2H), 6.74 (d, J=6.4 Hz, 1H), 4.50 (d, J=10.8 Hz, 1H), 4.45-4.38 (m, 1H), 3.69 (dd, J=13.4, 3.8 Hz, 2H), 3.44 (t, J=4.5 Hz, 1H), 2.30 (qt, J= 10.0, 5.0 Hz, 2H), 1.66 (d, J=12.8 Hz, 3H), 1.62 (d, J=12.8 Hz, 3H), 1.18 (d, J=6.5 Hz, 2H). V-7 406.1 2.64 1H NMR (500 MHz, methanol-d4) δ 9.21-9.17 (m, 1H), 8.19 (d, J=6.1 Hz, 1H), 7.78 (s, 1H), 7 .57 (s, 2H), 6.39 (d, J=6.2 Hz, 1H), 4.22 (s, 1H), 3.98 (s, 1H), 3.60 (s, 3H) , 2.52 (s, 1H), 2.17 (s, 1H). V-8 383.0 2.28 1H NMR (400 MHz, DMSO-d6) δ 9.08 (q, J=1.4 Hz, 1H), 8.32 (d, J=6.3 Hz, 1H), 8.12 (s, 1H ), 7.67 (t, J=5.2 Hz, 1H), 6.79 (d, J=6.3 Hz, 1H), 3.88 (s, 4H), 3.26 (d, J =5.6 Hz, 1H), 2.62-2.53 (m, 2H), 2.46 (p, J=1.8 Hz, 1H). V-9 445.1 2.50 1H NMR (400 MHz, DMSO-d6) δ 9.11 (q, J=1.4 Hz, 1H), 8.26 (d, J=6.3 Hz, 1H), 8.05 (s, 1H ), 6.70 (d, J=6.3 Hz, 1H), 4.20 (s, 2H), 3.29 (s, 1H), 3.02 (dd, J=11.3, 0, 9 Hz, 7H), 2.85 (t, J=11.7 Hz, 1H), 1.94-1.85 (m, 1H), 1.75 (q, J=3.9 Hz, 1H) , 1.57-1.44 (m, 2H). V-10 397.1 2.42 1H NMR (400 MHz, DMSO-d6) δ 9.10 (q, J=1.4 Hz, 1H), 8.27 (d, J=6.3 Hz, 1H), 8.07 (s, 1H ), 7.39 (s, 1H), 6.91 (s, 1H), 6.79 (d, J=6.3 Hz, 1H), 4.34 (s, 2H), 3.21-2 .97 (m, 2H), 2.36 (td, J=10.9, 5.4 Hz, 1H), 1.97-1.87 (m, 1H), 1.82-1.63 (m , 2H), 1.45 (ddt, J=16.2, 12.5, 6.5 Hz, 1H). V-11 449.2 2.55 1H NMR (500 MHz, methanol-d4) δ 9.04 (d, J=9.9 Hz, 1H), 8.22 (d, J=6.3 Hz, 1H), 8.04 (s, 1H ), 7.68 (s, 2H), 6.69 (d, J=6.3 Hz, 1H), 5.03 (s, 1H), 4.24 (d, J=3.7 Hz, 1H ), 3.81 (s, 1H), 3.00 (ddd, J=9.5, 6.2, 3.1 Hz, 1H), 2.82 (s, 1H), 1.28 (d, J=6.3 Hz, 3H), 1.08 (d, J=6.8 Hz, 3H). V-12 449.1 2.56 1H NMR (500 MHz, methanol-d4) δ 9.04 (d, J=9.9 Hz, 1H), 8.22 (d, J=6.3 Hz, 1H), 8.04 (s, 1H ), 7.68 (s, 2H), 6.69 (d, J=6.3 Hz, 1H), 5.03 (s, 1H), 4.24 (d, J=3.7 Hz, 1H ), 3.81 (s, 1H), 3.00 (ddd, J=9.5, 6.2, 3.1 Hz, 1H), 2.82 (s, 1H), 1.28 (d, J=6.3 Hz, 3H), 1.08 (d, J=6.8 Hz, 3H). V-13 449.3 2.59 1H NMR (500 MHz, methanol-d4) δ 9.11 (s, 1H), 8.42 (d, J=6.3 Hz, 1H), 8.15 (s, 1H), 7.85 (s , 2H), 6.87 (d, J=6.3 Hz, 1H), 4.88 (d, J=4.2 Hz, 1H), 3.62 (ddd, J=11.0, 6, 4, 3.8 Hz, 1H), 3.19 (s, 1H), 2.67 (d, J=5.4 Hz, 1H), 1.54 (d, J=6.5 Hz, 3H) , 1.31 (d, J=7.1 Hz, 3H). V-14 493.1 2.77 1H NMR (500 MHz, DMSO-d6) δ 8.99 (t, J=2.6 Hz, 1H), 8.35 (d, J=6.3 Hz, 1H), 8.15 (s, 1H ), 7.51 (t, J=53.7 Hz, 1H), 7.37 (t, J=6.7 Hz, 1H), 6.88 (d, J=6.3 Hz, 1H), 3.48-3.44 (m, 1H), 3.03-2.97 (m, 2H), 2.99 (s, 3H), 2.88-2.81 (m, 2H), 2. 22- 2.16 (m, 3H), 1.06 (d, J=6.7 Hz, 3H). V-15 422.1 2.49 1H NMR (500 MHz, DMSO-d6) δ 9.10 (d, J=1.6 Hz, 1H), 8.35 (d, J=6.3 Hz, 1H), 8.14 (s, 1H ), 7.69 (s, 2H), 6.87 (d, J=6.4 Hz, 1H), 4.58 (dd, J=10.7, 2.6 Hz, 1H), 4.05 -4.03 (m, 1H), 3.70 (td, J=11.5, 2.6 Hz, 1H), 3.21-3.13 (m, 2H), 2.52-2.48 (m, 2H). V-16 473.0 2.64 ---- V-17 473.0 2.65 ---- V-18 445.1 2.4 1H NMR (500 MHz, methanol-d4) δ 9.15 (q, J=1.4 Hz, 1H), 8.26 (d, J=6.3 Hz, 1H), 8.12 (s, 1H ), 6.70 (d, J=6.4 Hz, 1H), 4.63 (s, 1H), 4.24 (s, 1H), 3.34-3.13 (m, 4H), 3 .09 (d, J=0.7 Hz, 3H), 2.32 (dtt, J=12.6, 6.3, 3.0 Hz, 1H), 2.12 (dt, J=12.7 , 4.2 Hz, 1H), 1.90-1.80 (m, 1H), 1.75-1.56 (m, 2H). V-19 445.1 2.41 1H NMR (500 MHz, methanol-d4) δ 9.14 (q, J=1.4 Hz, 1H), 8.25 (d, J=6.3 Hz, 1H), 8.12 (s, 1H ), 6.69 (d, J=6.4 Hz, 1H), 4.69 (s, 1H), 4.27 (s, 1H), 3.34-3.21 (m, 2H), 3 ,20-3.13 (m, 2H), 3.10 (s, 3H), 2.37 (dddt, J=13.9, 9.6, 8.0, 4.0 Hz, 1H), 2 .12-2.03 (m, 1H), 1.93-1.81 (m, 1H), 1.76-1.55 (m, 2H).

Example 112: Additional Typical Connections

[001552] Additional compounds of Formula II were prepared using methodologies similar to those described in Examples 1-111 above:

1-(4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, II-731

N-((4-(4-(imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)morpholin-2-yl)methyl)methanesulfonamide, II-732

N-((1-(4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)-5-methylpyridin-2-yl)piperidin-3-yl)methyl)methanesulfonamide, II- 733

3-(2-(4-acetylpiperazin-1-yl)pyridin-4-yl)imidazo[1,2-b]pyridazin-6-carboxylic acid, II-734,

N-(1-(4-(6-(pyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-4-yl)acetamide, II-735

1-(4-(4-(6-(3-aminopyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethane-1- he, II-736

1-(4-(4-(6-(pyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, II-737

1-(4-(4-(6-morpholinoimidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one, II-738

N-(((2R,3S)-1-cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin- 2-yl)methyl)methanesulfonamide, II-752

N-(((2S,3R)-1-cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin- 2-yl)methyl)methanesulfonamide, II-753

N-(((2R,3S)-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl) methyl)methanesulfonamide, II-754

N-(((2S,3R)-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl) methyl)methanesulfonamide, II-755

N-(((2S,3S)-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl) methyl)methanesulfonamide, II-756

dimethyl((5-methyl-1-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl)imino)-λ6-sulfanone , II-757

(2S,6S)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3 -yl)pyrimidin-4-yl)morpholine, II-758

(2R,6S)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3 -yl)pyrimidin-4-yl)morpholine, II-759

(2R,6R)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3 -yl)pyrimidin-4-yl)morpholine, II-760

(2S,6R)-2-(1,3-dimethyl-1H-pyrazol-4-yl)-6-methyl-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3 -yl)pyrimidin-4-yl)morpholine, II-761

2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl )morpholine, II-762

N-(((2R,3R)-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-2-methylpiperidin-3-yl) methyl)methanesulfonamide, II-763

(((3S,5R)-1-(6-(6-(3-fluoroazetidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin- 3-yl)imino)dimethyl-λ6-sulfanone, II-764

(2S,6S)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl )pyrimidin-4-yl)morpholine, II-765

(2R,6R)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl )pyrimidin-4-yl)morpholine, II-766

(2S,6R)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl )pyrimidin-4-yl)morpholine, II-767

(2R,6S)-2-methyl-6-(5-methyl-1H-pyrazol-4-yl)-4-(6-(6-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl )pyrimidin-4-yl)morpholine, II-768

N-(((2S,3S)-1-cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin- 2-yl)methyl)methanesulfonamide, II-769

N-(((2R,3R)-1-cyclopropyl-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-3-methylpiperazin- 2-yl)methyl)methanesulfonamide, II-770

N-(((2S,6R)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6-(trifluoromethyl)morpholine-2 -yl)methyl)methanesulfonamide, II-771

N-(R)-1-((S)-4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)morpholin-2-yl) ethyl)methanesulfonamide, II-772

N-(((3S,5S)-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-5- methylpiperidin-3-yl)methyl)methanesulfonamide, II-773

N-(((3S,5S)-5-cyclopropyl-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)piperidin-3-yl )methyl)methanesulfonamide, II-774

N-((5-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-8,8-difluoro-5-azaspiro[2.5]octan- 7-yl)methyl)methanesulfonamide, II-775

(S)-N-((4-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-6,6-dimethylmorpholin-2-yl) methyl)methanesulfonamide, II-776

N-((3R,5S)-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)methanesulfonamide , II-777

N-(((3R,6S)-1-(6-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyrimidin-4-yl)-4,4-difluoro-6- methylpiperidin-3-yl)methyl)methanesulfonamide, II-778

N-((1-(6-(azetidin-3-yloxy)-4-(6-(difluoromethyl)imidazo[1,2-b]pyridazin-3-yl)pyridin-2-yl)piperidin-3-yl )methyl)methanesulfonamide, II-779

[001553] Additional compounds of Formula III were prepared using methodologies similar to those described in Examples 1-111 above:

3-(2-phenylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine, III-15

2-(4-(pyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl)octahydro-6H-pyrido[1,2-a]pyrazin-6-one, III-16

[001554] Additional compounds of Formula IV were prepared using methodologies similar to those described in Examples 1-111 above:

3-(6-(4-acetylpiperazin-1-yl)-3-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyrazin-6-carboxamide, IV-700

3-(2-(4-acetylpiperazin-1-yl)-5-methoxypyrimidin-4-yl)imidazo[1,2-a]pyrazin-6-carboxamide, IV-701

4-(3-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-1,2,4-thiadiazol-5-yl)-2-(1H-pyrazol-4-yl) morpholine, IV-702

(S)-N-((4-(3-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-1,2,4-thiadiazol-5-yl)morpholine-2- yl)methyl)methanesulfonamide, IV-703

2-(1H-pyrazol-4-yl)-4-(3-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-1,2,4-thiadiazol-5-yl) morpholine, IV-704

(S)-N-((4-(3-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-1,2,4-thiadiazol-5-yl)morpholine-2- yl)methyl)methanesulfonamide, IV-705

3-(4-(3-(4H-1,2,4-triazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyrazine , IV-752

3-(2-((3R,5S)-3-(3-fluoro-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyrazine, IV-754

3-(2-((3S,5R)-3-methyl-5-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo [1,2-a]pyrazine, IV-755

-(2-((3R,5S)-3-methyl-5-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyrazine, IV-756

3-(2-((3R,5R)-3-(3-fluoro-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyrazine, IV-757

3-(2-((3R,5R)-3-methyl-5-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo [1,2-a]pyrazine, IV-758

3-(2-((3S,5S)-3-methyl-5-(3-methyl-1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-4-yl)-6-(trifluoromethyl)imidazo [1,2-a]pyrazine, IV-759

(2R,6R)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl )pyrimidin-4-yl)morpholine, IV-760

(2S,6S)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl )pyrimidin-4-yl)morpholine, IV-761

(2R,6S)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl )pyrimidin-4-yl)morpholine, IV-762

(2S,6R)-2-methyl-6-(3-methyl-1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl )pyrimidin-4-yl)morpholine, IV-763

3-(4-((3R,5S)-3-(3-fluoro-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyrazine, IV-764

3-(2-((3S,5R)-3-(3-fluoro-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyrazine, IV-765

3-(2-((3R,5R)-3-(3-fluoro-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyrazine, IV-766

3-(2-((3S,5S)-3-(3-fluoro-1H-pyrazol-4-yl)-5-methylpiperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[ 1,2-a]pyrazine, IV-767

3-(4-((3S,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine, IV-768

3-(4-((3R,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine, IV-769

3-(4-((3R,5R)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine, IV-770

3-(4-((3S,5S)-3-methyl-5-(1H-pyrazol-4-yl)piperidin-1-yl)pyrimidin-2-yl)-6-(trifluoromethyl)imidazo[1,2 -a]pyrazine, IV-771

(((3S,5R)-1-(2-(6-(difluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino) dimethyl-λ6-sulfanone, IV-772

(((3S,5R)-1-(2-(6-chloroimidazo[1,2-a]pyrazin-3-yl)pyrimidin-4-yl)-5-methylpiperidin-3-yl)imino)dimethyl-λ6 -sulfanone, IV-773

(3S,5R)-5-(3-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4 -yl)piperidin-3-ol, IV-774

(3R,5S)-5-(3-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4 -yl)piperidin-3-ol, IV-775

(3R,5R)-5-(3-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4 -yl)piperidin-3-ol, IV-776

(3S,5S)-5-(3-methyl-1H-pyrazol-4-yl)-1-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)pyrimidin-4 -yl)piperidin-3-ol, IV-777

cyclopropyl((2R,3S,6S)-3,6-dimethyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3 -yl)pyrimidin-4-yl)piperazin-1-yl)methanone, IV-778

((2R,3S,6S)-3,6-dimethyl-2-(1H-pyrazol-4-yl)-4-(2-(6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3- yl)pyrimidin-4-yl)piperazin-1-yl)(isoxazol-4-yl)methanone, IV-779

[001555] Additional compound of Formula V was prepared using similar methodologies to those described in Examples 1-111 above:

2-(1H-pyrazol-4-yl)-4-(2-(2-(trifluoromethyl)imidazo[2,1-b]thiazol-5-yl)pyrimidin-4-yl)morpholine, V-20

Example 113: GCN2 Enzyme Inhibition Study

[001556] Screening for the ability of compounds to inhibit GCN2 kinase activity was performed 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.

[001557] 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).

[001558] 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 percent inhibition data using a nonlinear tight coupling algorithm. All analysis data were processed using Screener ^® software (Genedata, Switzerland).

Table 9: Enzyme activity of compounds of formula II

[001559] +++ for Ki<10 nM; ++ for Ki in the range of 10 nM-1 µM; + for Ki>1 µM; ---- No data

Compound of formula II GCN2(Ki) II-1 ++ II-2 +++ II-3 +++ II-4 ++ II-5 ++ II-6 ++ II-7 + II-8 ++ II-9 ++ II-10 ++ II-11 ++ II-12 ++ II-13 +++ II-14 ++ II-15 ++ II-16 ++ II-17 ++ II-18 +++ II-19 ++ II-20 ++ II-21 ++ II-22 ++ II-23 ++ II-24 ++ II-25 ++ II-26 ++ II-27 ++ II-28 ++ II-29 ++ II-30 ++ II-31 +++ II-32 +++ II-33 +++ II-34 +++ II-35 ++ II-36 +++ II-37 ++ II-38 ++ II-39 ++ II-40 +++ II-41 ++ II-42 ++ II-43 + II-44 ++ II-45 +++ II-46 ++ II-47 ++ II-48 ++ II-49 ++ II-50 ++ II-51 ++ II-52 ++ II-53 +++ II-54 ++ II-55 +++ II-56 ++ II-57 +++ II-58 +++ II-59 +++ II-60 +++ II-61 +++ II-62 ++ II-63 +++ II-64 +++ II-65 +++ II-66 +++ II-67 +++ II-68 +++ II-69 +++ II-70 ++ II-71 +++ II-72 +++ II-73 ++ II-74 +++ II-75 +++ II-76 ++ II-77 ++ II-78 +++ II-79 ++ II-80 +++ II-81 ++ II-82 ++ II-83 +++ II-84 +++ II-85 +++ II-86 +++ II-87 +++ II-88 ++ II-89 +++ II-90 ++ II-91 +++ II-92 +++ II-93 +++ II-94 +++ II-95 ++ II-96 +++ II-97 ++ II-98 ++ II-99 +++ II-100 ++ II-101 +++ II-102 ++ II-103 +++ II-104 ++ II-105 +++ II-106 +++ II-107 ++ II-108 ++ II-109 ++ II-110 +++ II-111 +++ II-112 +++ II-113 ++ II-114 ++ II-115 ++ II-116 +++ II-117 ++ II-118 ++ II-119 +++ II-120 +++ II-121 +++ II-122 +++ II-123 ++ II-124 +++ II-125 +++ II-126 ++ II-127 ++ II-128 ++ II-129 +++ II-130 ++ II-131 +++ II-132 +++ II-133 +++ II-134 ++ II-135 ++ II-136 +++ II-137 ++ II-138 ++ II-139 ++ II-140 ++ II-141 +++ II-142 +++ II-143 +++ II-144 ++ II-145 ++ II-146 ++ II-147 ++ II-148 +++ II-149 +++ II-150 ++ II-151 ++ II-152 ++ II-153 +++ II-154 +++ II-155 ++ II-156 ++ II-157 +++ II-158 ++ II-159 ++ II-160 ++ II-161 ++ II-162 ++ II-163 ++ II-164 ++ II-165 ++ II-166 ++ II-167 ++ II-168 ++ II-169 ++ II-170 ++ II-171 ++ II-172 ++ II-173 ++ II-174 ++ II-175 ++ II-176 ++ II-177 +++ II-178 ++ II-179 ++ II-180 ++ II-181 + II-182 ++ II-183 ++ II-184 ++ II-185 ++ II-186 ++ II-187 ++ II-188 ++ II-189 ++ II-190 ++ II-191 ++ II-192 ++ II-193 ++ II-194 ++ II-195 ++ II-196 ++ II-197 +++ II-198 ++ II-199 ++ II-200 ++ II-201 ++ II-202 +++ II-203 ++ II-204 ++ II-205 ++ II-206 ++ II-207 ++ II-208 ++ II-209 ++ II-210 ++ II-211 ++ II-212 ++ II-213 +++ II-214 ++ II-215 ++ II-216 ++ II-217 ++ II-218 ++ II-219 +++ II-220 + II-221 +++ II-222 ++ II-223 ++ II-224 ++ II-225 +++ II-226 ++ II-227 ++ II-228 ++ II-229 +++ II-230 +++ II-231 ++ II-232 ++ II-233 +++ II-234 ++ II-235 ++ II-236 ++ II-237 +++ II-238 ++ II-239 +++ II-240 +++ II-241 + II-242 ++ II-243 ++ II-244 ++ II-245 ++ II-246 ++ II-247 +++ II-248 ++ II-249 ++ II-250 ++ II-251 ++ II-252 ++ II-253 ++ II-254 ++ II-255 ++ II-256 ++ II-257 ++ II-258 +++ II-259 +++ II-260 ++ II-261 ++ II-262 +++ II-263 ++ II-264 ++ II-265 ++ II-266 +++ II-267 ++ II-268 +++ II-269 ++ II-270 +++ II-271 ++ II-272 ++ II-273 ++ II-274 ++ II-275 ++ II-276 ++ II-277 +++ II-278 +++ II-279 ++ II-280 ++ II-281 +++ II-282 ++ II-283 ++ II-284 ++ II-285 ++ II-286 ++ II-287 ++ II-288 ++ II-289 ++ II-290 ++ II-291 +++ II-292 ++ II-293 ++ II-294 ++ II-295 + II-296 + II-297 ++ II-298 ++ II-299 ++ II-300 +++ II-301 ++ II-302 ++ II-303 ++ II-304 +++ II-305 ++ II-306 ++ II-307 ++ II-308 ++ II-309 + II-310 ++ II-311 +++ II-312 +++ II-313 +++ II-314 ++ II-315 ++ II-316 +++ II-317 ++ II-318 ++ II-319 ++ II-320 ++ II-321 ++ II-322 ++ II-323 ++ II-324 ++ II-325 ++ II-326 ++ II-327 ++ II-328 ++ II-329 +++ II-330 ++ II-331 +++ II-332 ++ II-333 ++ II-334 ++ II-335 ++ II-336 + II-337 ++ II-338 ++ II-339 ++ II-340 ++ II-341 ++ II-342 ++ II-343 ++ II-344 +++ II-345 +++ II-346 ++ II-347 +++ II-348 ++ II-349 ++ II-350 +++ II-351 ++ II-352 ++ II-353 ++ II-354 ++ II-355 ++ II-356 ++ II-357 ++ II-358 ++ II-359 ++ II-360 ++ II-361 +++ II-362 ++ II-363 ++ II-364 +++ II-365 ++ II-366 +++ II-367 ++ II-368 ++ II-369 ++ II-370 ++ II-371 +++ II-372 + II-373 +++ II-374 ++ II-375 +++ II-376 ++ II-377 ++ II-378 ++ II-379 ++ II-380 + II-381 +++ II-382 ++ II-383 ++ II-384 +++ II-385 +++ II-386 +++ II-387 ++ II-388 ++ II-389 ++ II-390 +++ II-391 +++ II-392 ++ II-393 ++ II-394 ++ II-395 ++ II-396 ++ II-397 +++ II-398 ++ II-399 ++ II-400 ++ II-401 ++ II-402 ++ II-403 +++ II-404 ++ II-405 ++ II-406 + II-407 ++ II-408 ++ II-409 ++ II-410 ++ II-411 ++ II-412 ++ II-413 + II-414 ++ II-415 ++ II-416 +++ II-417 ++ II-418 ++ II-419 ++ II-420 ++ II-421 ++ II-422 ++ II-423 ++ II-424 +++ II-425 ++ II-426 ++ II-427 +++ II-428 ++ II-429 ++ II-430 ++ II-431 +++ II-432 +++ II-433 +++ II-434 ++ II-435 ++ II-436 ++ II-437 +++ II-438 ++ II-439 ++ II-440 ++ II-441 ++ II-442 ++ II-443 +++ II-444 +++ II-445 ++ II-446 ++ II-447 ++ II-448 +++ II-449 +++ II-450 ++ II-451 ++ II-452 ++ II-453 ++ II-454 ++ II-455 ++ II-456 ++ II-457 ++ II-458 +++ II-459 + II-460 ++ II-461 +++ II-462 +++ II-463 +++ II-464 ++ II-465 ++ II-466 +++ II-467 +++ II-468 ++ II-469 ++ II-470 ++ II-471 ++ II-472 +++ II-473 ++ II-474 ++ II-475 ++ II-476 ++ II-477 ++ II-478 ++ II-479 +++ II-480 ++ II-481 ++ II-482 +++ II-483 ++ II-484 ++ II-485 +++ II-486 ++ II-487 ++ II-488 ++ II-489 + II-490 +++ II-491 +++ II-492 ++ II-493 ++ II-494 +++ II-495 +++ II-496 ++ II-497 ++ II-498 ++ II-499 ++ II-500 ++ II-501 ++ II-502 ++ II-503 ++ II-504 ++ II-505 ++ II-506 ++ II-507 +++ II-508 ++ II-509 +++ II-510 ++ II-511 +++ II-512 ++ II-513 ++ II-514 ++ II-515 +++ II-516 ++ II-517 ++ II-518 ++ II-519 ++ II-520 ++ II-521 ++ II-522 ++ II-523 +++ II-524 +++ II-525 +++ II-526 +++ II-527 +++ II-528 +++ II-529 ++ II-530 ++ II-531 ++ II-532 ++ II-533 ++ II-534 ++ II-535 ++ II-536 ++ II-537 +++ II-538 +++ II-539 ++ II-540 ++ II-541 +++ II-542 +++ II-543 ++ II-544 +++ II-545 ++ II-546 +++ II-547 ++ II-548 + II-549 ++ II-550 +++ II-551 ++ II-552 ++ II-553 ++ II-554 ++ II-555 ++ II-556 ++ II-557 ++ II-558 +++ II-559 ++ II-560 +++ II-561 ++ II-562 +++ II-563 ++ II-564 ++ II-565 ++ II-566 +++ II-567 ++ II-568 +++ II-569 ++ II-570 ++ II-571 ++ II-572 ++ II-573 ++ II-574 ++ II-575 ++ II-576 +++ II-577 +++ II-578 +++ II-579 ++ II-580 ++ II-581 ++ II-582 + II-583 + II-584 ++ II-585 +++ II-586 ++ II-587 +++ II-588 ++ II-589 ++ II-590 + II-591 +++ II-592 +++ II-593 +++ II-594 ++ II-595 ++ II-596 ++ II-597 ++ II-598 ++ II-599 ++ II-600 + II-601 +++ II-602 +++ II-603 ++ II-604 ++ II-605 ++ II-606 +++ II-607 +++ II-608 ++ II-609 +++ II-610 ++ II-611 ++ II-612 +++ II-613 ++ II-614 ++ II-615 ++ II-616 ++ II-617 ++ II-618 +++ II-619 ++ II-620 ++ II-621 ++ II-622 ++ II-623 +++ II-624 ++ II-625 ++ II-626 +++ II-627 ++ II-628 ++ II-629 ++ II-630 ++ II-631 +++ II-632 ++ II-633 ++ II-634 ++ II-635 ++ II-636 ++ II-637 ++ II-638 ++ II-639 ++ II-640 ++ II-641 ++ II-642 +++ II-643 +++ II-644 ++ II-645 ++ II-646 ++ II-647 ++ II-648 +++ II-649 ++ II-650 +++ II-651 ++ II-652 ++ II-653 ++ II-654 ++ II-655 --- II-656 --- II-657 --- II-658 --- II-659 --- II-660 --- II-661 --- II-662 --- II-663 --- II-664 --- II-665 --- II-666 --- II-667 --- II-668 --- II-669 --- II-670 --- II-671 --- II-672 --- II-673 --- II-674 --- II-675 --- II-676 ++ II-677 --- II-678 --- II-679 --- II-680 --- II-681 --- II-682 --- II-683 --- II-684 --- II-685 --- II-686 --- II-687 --- II-688 --- II-689 --- II-690 --- II-691 ++ II-692 ++ II-693 ++ II-694 ++ II-695 +++ II-696 ++ II-697 + II-698 +++ II-699 ++ II-700 +++ II-701 ++ II-702 ++ II-703 +++ II-704 ++ II-705 +++ II-706 ++ II-707 ++ II-708 + II-709 ++ II-710 ++ II-711 ++ II-712 + II-713 ++ II-714 --- II-715 ++ II-716 +++ II-717 +++ II-718 ++ II-719 ++ II-720 ++ II-721 ++ II-722 ++ II-723 ++ II-724 ++ II-725 +++ II-726 ++ II-727 ++ II-728 ++ II-729 +++ II-730 ++ II-731 + II-732 + II-733 + II-734 + II-735 + II-736 + II-737 + II-738 + II-739 ++ II-740 +++ II-741 +++ II-742 ++ II-743 ++ II-744 ++ II-745 ++ II-746 ++ II-747 ++ II-748 ++ II-749 ++ II-750 +++

Table 10: Enzyme activity of compounds of formula II

[001560] +++ for IC ₅₀ <10 nM; ++ for IC ₅₀ in the range of 10 nM-1 µM; + for IC ₅₀ >1 µM

Compound II GCN2 IC ₅₀ II-752 +++ II-753 ++ II-754 + II-755 + II-756 + II-757 ++ II-758 + II-759 ++ II-760 ++ II-761 + II-762 ++ II-763 +++ II-764 ++ II-765 ++ II-766 ++ II-767 ++ II-768 +++ II-769 ++ II-770 ++ II-771 ++ II-772 ++

Table 11: Enzyme activity of compounds of formula III

[001561] +++ for Ki<10 nM; ++ for Ki in the range of 10 nM-1 µM; + for Ki >1 µM; ---- No data

Compound III GCN2(Ki) III-1 ++ III-2 +++ III-3 ++ III-4 +++ III-5 ++ III-6 +++ III-7 +++ III-8 ++ III-9 ++ III-10 +++ III-11 +++ III-12 +++ III-13 +++ III-14 ++ III-15 + III-16 +

Table 12: Enzyme activity of compounds of formula IV

[001562] +++ for Ki<10 nM; ++ for Ki in the range of 10 nM-100 nM; + for Ki 100 nM-1 µM; * for Ki >1 µM; ---- No data

Compound of formula IV GCN2(Ki) IV-1 + IV-2 + IV-3 +++ IV-4 +++ IV-5 ++ IV-6 +++ IV-7 ++ IV-8 +++ IV-9 +++ IV-10 +++ IV-11 ++ IV-12 +++ IV-13 ++ IV-14 +++ IV-15 ++ IV-16 ++ IV-17 + IV-18 +++ IV-19 +++ IV-20 ++ IV-21 + IV-22 + IV-23 + IV-24 + IV-25 + IV-26 + IV-27 ++ IV-28 ++ IV-29 + IV-30 + IV-31 + IV-32 + IV-33 + IV-34 + IV-35 + IV-36 + IV-37 + IV-38 ++ IV-39 + IV-40 ++ IV-41 + IV-42 ++ IV-43 + IV-44 + IV-45 + IV-46 + IV-47 + IV-48 + IV-49 + IV-50 ++ IV-51 + IV-52 + IV-53 ++ IV-54 ++ IV-55 ++ IV-56 + IV-57 + IV-58 ++ IV-59 +++ IV-60 +++ IV-61 + IV-62 + IV-63 + IV-64 + IV-65 + IV-66 + IV-67 + IV-68 + IV-69 + IV-70 + IV-71 + IV-72 + IV-73 + IV-74 + IV-75 + IV-76 + IV-77 + IV-78 + IV-79 + IV-80 + IV-81 + IV-82 + IV-83 + IV-84 + IV-85 + IV-86 + IV-87 + IV-88 + IV-89 + IV-90 + IV-91 + IV-92 + IV-93 + IV-94 + IV-95 + IV-96 ++ IV-97 ++ IV-98 + IV-99 + IV-100 + IV-101 + IV-102 + IV-103 + IV-104 + IV-105 + IV-106 ++ IV-107 ++ IV-108 ++ IV-109 ++ IV-110 + IV-111 + IV-112 + IV-113 + IV-114 + IV-115 + IV-116 + IV-117 + IV-118 + IV-119 + IV-120 + IV-121 + IV-122 + IV-123 + IV-124 + IV-125 + IV-126 + IV-127 + IV-128 + IV-129 + IV-130 + IV-131 + IV-132 + IV-133 + IV-134 + IV-135 + IV-136 + IV-137 + IV-138 + IV-139 + IV-140 + IV-141 + IV-142 + IV-143 + IV-144 + IV-145 + IV-146 + IV-147 + IV-148 + IV-149 + IV-150 + IV-151 + IV-152 + IV-153 + IV-154 + IV-155 + IV-156 + IV-157 + IV-158 + IV-159 + IV-160 + IV-161 + IV-162 + IV-163 + IV-164 + IV-165 + IV-166 + IV-167 + IV-168 + IV-169 + IV-170 + IV-171 + IV-172 + IV-173 + IV-174 + IV-175 + IV-176 + IV-177 + IV-178 + IV-179 + IV-180 + IV-181 + IV-182 ++ IV-183 + IV-184 ++ IV-185 ++ IV-186 +++ IV-187 ++ IV-188 + IV-189 ++ IV-190 + IV-191 ++ IV-192 +++ IV-193 +++ IV-194 +++ IV-195 ++ IV-196 ++ IV-197 + IV-198 ++ IV-199 ++ IV-200 +++ IV-201 +++ IV-202 ++ IV-203 ++ IV-204 ++ IV-205 ++ IV-206 ++ IV-207 +++ IV-208 ++ IV-209 +++ IV-210 +++ IV-211 +++ IV-212 + IV-213 ++ IV-214 +++ IV-215 ++ IV-216 +++ IV-217 +++ IV-218 ++ IV-219 ++ IV-220 ++ IV-221 ++ IV-222 +++ IV-223 + IV-224 +++ IV-225 ++ IV-226 ++ IV-227 + IV-228 ++ IV-229 + IV-230 +++ IV-231 + IV-232 ++ IV-233 ++ IV-234 ++ IV-235 +++ IV-236 ++ IV-237 + IV-238 ++ IV-239 + IV-240 + IV-241 + IV-242 ++ IV-243 ++ IV-244 + IV-245 + IV-246 + IV-247 +++ IV-248 ++ IV-249 + IV-250 + IV-251 + IV-252 + IV-253 ++ IV-254 ++ IV-255 ++ IV-256 + IV-257 ++ IV-258 + IV-259 + IV-260 ++ IV-261 ++ IV-262 + IV-263 + IV-264 +++ IV-265 + IV-266 ++ IV-267 + IV-268 + IV-269 ++ IV-270 + IV-271 + IV-272 + IV-273 + IV-274 ++ IV-275 + IV-276 + IV-277 ++ IV-278 +++ IV-279 +++ IV-280 +++ IV-281 ++ IV-282 +++ IV-283 + IV-284 + IV-285 ++ IV-286 ++ IV-287 ++ IV-288 +++ IV-289 + IV-290 +++ IV-291 + IV-292 +++ IV-293 ++ IV-294 ++ IV-295 + IV-296 +++ IV-297 + IV-298 + IV-299 ++ IV-300 + IV-301 + IV-302 + IV-303 + IV-304 +++ IV-305 +++ IV-306 +++ IV-307 + IV-308 + IV-309 ++ IV-310 ++ IV-311 +++ IV-312 ++ IV-313 + IV-314 +++ IV-315 ++ IV-316 + IV-317 ++ IV-318 +++ IV-319 + IV-320 + IV-321 + IV-322 + IV-323 +++ IV-324 ++ IV-325 ++ IV-326 + IV-327 ++ IV-328 +++ IV-329 ++ IV-330 ++ IV-331 + IV-332 + IV-333 ++ IV-334 + IV-335 ++ IV-336 + IV-337 +++ IV-338 + IV-339 + IV-340 +++ IV-341 ++ IV-342 + IV-343 +++ IV-344 ++ IV-345 ++ IV-346 +++ IV-347 + IV-348 ++ IV-349 ++ IV-350 + IV-351 +++ IV-352 ++ IV-353 + IV-354 ++ IV-355 +++ IV-356 +++ IV-357 + IV-358 +++ IV-359 +++ IV-360 +++ IV-361 +++ IV-362 ++ IV-363 +++ IV-364 ++ IV-365 +++ IV-366 + IV-367 + IV-368 + IV-369 +++ IV-370 + IV-371 ++ IV-372 ++ IV-373 +++ IV-374 ++ IV-375 +++ IV-376 +++ IV-377 + IV-378 +++ IV-379 +++ IV-380 +++ IV-381 ++ IV-382 ++ IV-383 ++ IV-384 ++ IV-385 ++ IV-386 ++ IV-387 +++ IV-388 +++ IV-389 +++ IV-390 +++ IV-391 + IV-392 +++ IV-393 + IV-394 + IV-395 ++ IV-396 +++ IV-397 + IV-398 ++ IV-399 +++ IV-400 ++ IV-401 ++ IV-402 +++ IV-403 +++ IV-404 + IV-405 +++ IV-406 ++ IV-407 +++ IV-408 + IV-409 +++ IV-410 ++ IV-411 ++ IV-412 + IV-413 ++ IV-414 +++ IV-415 +++ IV-416 +++ IV-417 +++ IV-418 ++ IV-419 + IV-420 +++ IV-421 ++ IV-422 + IV-423 + IV-424 + IV-425 + IV-426 + IV-427 + IV-428 + IV-429 + IV-430 +++ IV-431 + IV-432 + IV-433 + IV-434 + IV-435 + IV-436 + IV-437 + IV-438 + IV-439 + IV-440 + IV-441 + IV-442 + IV-443 + IV-444 + IV-445 + IV-446 + IV-447 + IV-448 + IV-449 + IV-450 + IV-451 +++ IV-452 +++ IV-453 +++ IV-454 ++ IV-455 + IV-456 + IV-457 + IV-458 + IV-459 ++ IV-460 + IV-461 ++ IV-462 + IV-463 + IV-464 +++ IV-465 ++ IV-466 +++ IV-467 + IV-468 ++ IV-469 ++ IV-470 +++ IV-471 ++ IV-472 ++ IV-473 +++ IV-474 +++ IV-475 ++ IV-476 +++ IV-477 ++ IV-478 + IV-479 + IV-480 + IV-481 ++ IV-482 + IV-483 + IV-484 ++ IV-485 +++ IV-486 + IV-487 + IV-488 + IV-489 + IV-490 + IV-491 +++ IV-492 +++ IV-493 ++ IV-494 ++ IV-495 + IV-496 + IV-497 + IV-498 + IV-499 +++ IV-500 + IV-501 +++ IV-502 + IV-503 + IV-504 + IV-505 + IV-506 + IV-507 + IV-508 + IV-509 + IV-510 + IV-511 + IV-512 + IV-513 + IV-514 + IV-515 + IV-516 + IV-517 + IV-518 ++ IV-519 ++ IV-520 + IV-521 + IV-522 + IV-523 + IV-524 +++ IV-525 +++ IV-526 + IV-527 + IV-528 + IV-529 + IV-530 + IV-531 + IV-532 + IV-533 + IV-534 + IV-535 ++ IV-536 + IV-537 + IV-538 +++ IV-539 + IV-540 +++ IV-541 ++ IV-542 + IV-543 + IV-544 + IV-545 +++ IV-546 +++ IV-547 + IV-548 +++ IV-549 + IV-550 + IV-551 + IV-552 + IV-553 + IV-554 + IV-555 + IV-556 + IV-557 + IV-558 ++ IV-559 + IV-560 + IV-561 + IV-562 +++ IV-563 +++ IV-564 + IV-565 + IV-566 + IV-567 ++ IV-568 + IV-569 + IV-570 + IV-571 + IV-572 +++ IV-573 ++ IV-574 ++ IV-575 ++ IV-576 ++ IV-577 +++ IV-578 +++ IV-579 + IV-580 ++ IV-581 + IV-582 ++ IV-583 +++ IV-584 + IV-585 + IV-586 + IV-587 + IV-588 + IV-589 ++ IV-590 + IV-591 + IV-592 +++ IV-593 +++ IV-594 ++ IV-595 + IV-596 + IV-597 ++ IV-598 + IV-599 + IV-600 + IV-601 +++ IV-602 + IV-603 + IV-604 + IV-605 + IV-606 + IV-607 + IV-608 + IV-609 + IV-610 + IV-611 + IV-612 + IV-613 + IV-614 + IV-615 ++ IV-616 ++ IV-617 + IV-618 + IV-619 + IV-620 + IV-621 +++ IV-622 +++ IV-623 +++ IV-624 ++ IV-625 + IV-626 +++ IV-627 +++ IV-628 ++ IV-629 +++ IV-630 ++ IV-631 ++ IV-632 ++ IV-633 ++ IV-634 + IV-635 ++ IV-636 +++ IV-637 +++ IV-638 + IV-639 +++ IV-640 +++ IV-641 + IV-642 + IV-643 + IV-644 + IV-645 + IV-646 ++ IV-647 + IV-648 +++ IV-649 + IV-650 +++ IV-651 +++ IV-652 ++ IV-653 + IV-654 + IV-655 + IV-656 + IV-657 + IV-658 + IV-659 + IV-660 + IV-661 + IV-662 + IV-663 + IV-664 + IV-665 + IV-666 ++ IV-667 + IV-668 ++ IV-669 + IV-670 +++ IV-671 + IV-672 + IV-673 +++ IV-674 + IV-675 ++ IV-676 + IV-677 ++ IV-678 ++ IV-679 +++ IV-680 ++ IV-681 ++ IV-682 ++ IV-683 ++ IV-684 +++ IV-685 +++ IV-686 + IV-687 + IV-688 ++ IV-689 ++ IV-690 +++ IV-691 ++ IV-692 + IV-693 ++ IV-694 + IV-695 ++ IV-696 + IV-697 + IV-698 + IV-699 + IV-700 + IV-701 + IV-702 + IV-703 + IV-704 + IV-705 + IV-706 +++ IV-707 ++ IV-708 ++ IV-709 + IV-710 + IV-711 + IV-712 + IV-713 + IV-714 + IV-715 + IV-716 + IV-717 + IV-718 + IV-719 + IV-720 + IV-721 + IV-722 + IV-723 + IV-724 * IV-725 * IV-726 * IV-727 * IV-728 * IV-729 * IV-730 * IV-731 * IV-732 * IV-733 * IV-734 * IV-735 * IV-736 * IV-737 * IV-738 * IV-739 * IV-740 * IV-741 * IV-742 * IV-743 * IV-744 * IV-745 * IV-746 * IV-747 * IV-748 * IV-749 * IV-750 * IV-751 *

Table 13: Enzyme activity of compounds of formula IV

[001563] +++ for IC ₅₀ <10 nM; ++ for IC ₅₀ in the range of 10 nM-1 µM; + for IC ₅₀ >1 µM

Compound IV GCN2 IC ₅₀ IV-754 ++ IV-755 ++ IV-756 ++ IV-757 ++ IV-758 ++ IV-759 ++ IV-760 ++ IV-761 ++ IV-762 ++ IV-763 +++ IV-764 ++ IV-765 ++ IV-766 ++ IV-767 +++ IV-768 ++ IV-769 ++ IV-770 ++ IV-771 +++ IV-772 ++ IV-773 ++ IV-774 ++ IV-775 ++ IV-776 +++ IV-777 ++ IV-778 ++ IV-779 ++

Table 14: Enzyme activity of compounds of formula V

[001564] +++ for Ki <10 nM; ++ for Ki in the range of 10 nM-100 nM; + for Ki 100 nM-1 µM; --- No data

Compound V GCN2(Ki) V-1 +++ V-2 + V-3 +++ V-4 ++ V-5 ++ V-6 + V-7 ++ V-8 + V-9 + V-10 +++ V-11 +++ V-12 + V-13 +++ V-14 ++ V-15 +++ V-16 + V-17 ++ V-18 + V-19 + V-20 +++

Example 114: GCN2 Inhibition Study in Cells

[001565] 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.

[001566] 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.

[001567] 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 15: Cellular activity of compounds of formula II (biomarker assay)

[001568] +++ for IC ₅₀ <0.5 µM; ++ for IC ₅₀ in the range 0.5 µM -5 µM range; + for IC ₅₀ >5 µM; ---- No data

Compound of formula II Biomarker GCN2(IC ₅₀ ) II-1 ++ II-2 ++ II-3 ++ II-4 ++ II-5 + II-6 ++ II-7 + II-8 ++ II-9 ++ II-10 + II-11 + II-12 ++ II-13 ++ II-14 + II-15 + II-16 + II-17 ++ II-18 +++ II-19 ++ II-20 + II-21 + II-22 + II-23 --- II-24 + II-25 + II-26 + II-27 + II-28 +++ II-29 + II-30 ++ II-31 +++ II-32 +++ II-33 +++ II-34 +++ II-35 ++ II-36 +++ II-37 ++ II-38 + II-39 ++ II-40 +++ II-41 ++ II-42 + II-43 --- II-44 ++ II-45 +++ II-46 + II-47 ++ II-48 + II-49 ++ II-50 ++ II-51 ++ II-52 + II-53 ++ II-54 ++ II-55 +++ II-56 ++ II-57 ++ II-58 +++ II-59 +++ II-60 +++ II-61 ++ II-62 + II-63 + II-64 +++ II-65 ++ II-66 ++ II-67 +++ II-68 ++ II-69 +++ II-70 + II-71 ++ II-72 +++ II-73 + II-74 ++ II-75 +++ II-76 + II-77 + II-78 +++ II-79 + II-80 ++ II-81 + II-82 ++ II-83 ++ II-84 ++ II-85 ++ II-86 ++ II-87 ++ II-88 ++ II-89 ++ II-90 ++ II-91 --- II-92 ++ II-93 +++ II-94 +++ II-95 ++ II-96 ++ II-97 + II-98 ++ II-99 ++ II-100 ++ II-101 ++ II-102 + II-103 +++ II-104 + II-105 ++ II-106 ++ II-107 +++ II-108 ++ II-109 ++ II-110 +++ II-111 ++ II-112 ++ II-113 ++ II-114 + II-115 ++ II-116 ++ II-117 ++ II-118 ++ II-119 +++ II-120 + II-121 +++ II-122 ++ II-123 ++ II-124 ++ II-125 +++ II-126 + II-127 ++ II-128 ++ II-129 ++ II-130 + II-131 +++ II-132 ++ II-133 ++ II-134 ++ II-135 ++ II-136 +++ II-137 + II-138 ++ II-139 ++ II-140 + II-141 ++ II-142 ++ II-143 +++ II-144 ++ II-145 ++ II-146 ++ II-147 +++ II-148 +++ II-149 +++ II-150 ++ II-151 ++ II-152 + II-153 +++ II-154 +++ II-155 ++ II-156 ++ II-157 +++ II-158 ++ II-159 ++ II-160 ++ II-161 + II-162 ++ II-163 ++ II-164 ++ II-165 --- II-166 --- II-167 + II-168 ++ II-169 + II-170 ++ II-171 ++ II-172 ++ II-173 ++ II-174 + II-175 ++ II-176 ++ II-177 +++ II-178 ++ II-179 ++ II-180 + II-181 + II-182 + II-183 ++ II-184 ++ II-185 + II-186 ++ II-187 + II-188 ++ II-189 ++ II-190 + II-191 + II-192 + II-193 + II-194 + II-195 + II-196 + II-197 +++ II-198 + II-199 + II-200 + II-201 + II-202 +++ II-203 + II-204 + II-205 ++ II-206 + II-207 + II-208 + II-209 + II-210 + II-211 ++ II-212 ++ II-213 ++ II-214 ++ II-215 ++ II-216 + II-217 ++ II-218 ++ II-219 +++ II-220 --- II-221 +++ II-222 ++ II-223 + II-224 ++ II-225 +++ II-226 ++ II-227 + II-228 + II-229 +++ II-230 +++ II-231 ++ II-232 ++ II-233 +++ II-234 ++ II-235 ++ II-236 --- II-237 ++ II-238 ++ II-239 ++ II-240 +++ II-241 + II-242 + II-243 ++ II-244 + II-245 + II-246 + II-247 +++ II-248 ++ II-249 ++ II-250 + II-251 + II-252 + II-253 + II-254 + II-255 + II-256 + II-257 ++ II-258 +++ II-259 +++ II-260 ++ II-261 ++ II-262 +++ II-263 ++ II-264 + II-265 + II-266 +++ II-267 ++ II-268 +++ II-269 --- II-270 ++ II-271 ++ II-272 + II-273 ++ II-274 + II-275 ++ II-276 ++ II-277 ++ II-278 +++ II-279 + II-280 + II-281 +++ II-282 + II-283 + II-284 + II-285 + II-286 + II-287 + II-288 + II-289 ++ II-290 ++ II-291 +++ II-292 ++ II-293 ++ II-294 + II-295 + II-296 + II-297 ++ II-298 ++ II-299 ++ II-300 +++ II-301 ++ II-302 ++ II-303 ++ II-304 +++ II-305 + II-306 ++ II-307 ++ II-308 + II-309 + II-310 ++ II-311 +++ II-312 +++ II-313 +++ II-314 + II-315 + II-316 +++ II-317 ++ II-318 ++ II-319 + II-320 + II-321 + II-322 + II-323 ++ II-324 + II-325 ++ II-326 + II-327 + II-328 ++ II-329 +++ II-330 ++ II-331 +++ II-332 + II-333 ++ II-334 ++ II-335 + II-336 + II-337 + II-338 + II-339 ++ II-340 +++ II-341 + II-342 ++ II-343 + II-344 +++ II-345 +++ II-346 + II-347 +++ II-348 ++ II-349 ++ II-350 +++ II-351 + II-352 + II-353 + II-354 + II-355 + II-356 + II-357 + II-358 + II-359 + II-360 ++ II-361 +++ II-362 ++ II-363 + II-364 +++ II-365 + II-366 +++ II-367 ++ II-368 + II-369 + II-370 ++ II-371 --- II-372 + II-373 ++ II-374 ++ II-375 +++ II-376 ++ II-377 +++ II-378 ++ II-379 ++ II-380 + II-381 +++ II-382 ++ II-383 ++ II-384 +++ II-385 +++ II-386 +++ II-387 ++ II-388 ++ II-389 ++ II-390 +++ II-391 +++ II-392 ++ II-393 + II-394 ++ II-395 + II-396 ++ II-397 +++ II-398 ++ II-399 + II-400 + II-401 + II-402 + II-403 +++ II-404 ++ II-405 ++ II-406 + II-407 + II-408 ++ II-409 + II-410 ++ II-411 ++ II-412 ++ II-413 + II-414 + II-415 + II-416 +++ II-417 ++ II-418 ++ II-419 ++ II-420 ++ II-421 ++ II-422 +++ II-423 + II-424 +++ II-425 ++ II-426 ++ II-427 +++ II-428 + II-429 + II-430 ++ II-431 +++ II-432 +++ II-433 +++ II-434 + II-435 + II-436 ++ II-437 +++ II-438 ++ II-439 ++ II-440 ++ II-441 ++ II-442 + II-443 +++ II-444 +++ II-445 + II-446 + II-447 ++ II-448 +++ II-449 +++ II-450 ++ II-451 ++ II-452 ++ II-453 + II-454 + II-455 ++ II-456 +++ II-457 ++ II-458 +++ II-459 + II-460 + II-461 ++ II-462 +++ II-463 +++ II-464 --- II-465 ++ II-466 +++ II-467 --- II-468 --- II-469 ++ II-470 ++ II-471 + II-472 +++ II-473 + II-474 ++ II-475 +++ II-476 ++ II-477 ++ II-478 ++ II-479 +++ II-480 + II-481 ++ II-482 +++ II-483 + II-484 ++ II-485 +++ II-486 ++ II-487 +++ II-488 + II-489 + II-490 +++ II-491 +++ II-492 ++ II-493 ++ II-494 --- II-495 +++ II-496 + II-497 ++ II-498 + II-499 ++ II-500 + II-501 --- II-502 +++ II-503 ++ II-504 + II-505 + II-506 + II-507 --- II-508 --- II-509 +++ II-510 ++ II-511 +++ II-512 --- II-513 --- II-514 --- II-515 --- II-516 ++ II-517 --- II-518 + II-519 ++ II-520 ++ II-521 ++ II-522 ++ II-523 +++ II-524 --- II-525 +++ II-526 +++ II-527 +++ II-528 +++ II-529 ++ II-530 --- II-531 --- II-532 --- II-533 --- II-534 --- II-535 ++ II-536 --- II-537 +++ II-538 +++ II-539 --- II-540 ++ II-541 +++ II-542 +++ II-543 ++ II-544 +++ II-545 ++ II-546 +++ II-547 ++ II-548 + II-549 --- II-550 --- II-551 --- II-552 --- II-553 --- II-554 --- II-555 --- II-556 --- II-557 --- II-558 --- II-559 --- II-560 --- II-561 --- II-562 --- II-563 --- II-564 --- II-565 --- II-566 --- II-567 --- II-568 --- II-569 --- II-570 --- II-571 --- II-572 --- II-573 --- II-574 --- II-575 --- II-576 --- II-577 --- II-578 --- II-579 --- II-580 --- II-581 --- II-582 --- II-583 --- II-584 --- II-585 --- II-586 --- II-587 --- II-588 --- II-589 --- II-590 --- II-591 --- II-592 --- II-593 +++ II-594 --- II-595 --- II-596 --- II-597 --- II-598 --- II-599 --- II-600 --- II-601 --- II-602 +++ II-603 --- II-604 --- II-605 --- II-606 --- II-607 +++ II-608 --- II-609 --- II-610 --- II-611 --- II-612 --- II-613 --- II-614 --- II-615 --- II-616 --- II-617 --- II-618 +++ II-619 --- II-620 --- II-621 --- II-622 --- II-623 --- II-624 --- II-625 --- II-626 --- II-627 --- II-628 --- II-629 --- II-630 --- II-631 +++ II-632 --- II-633 --- II-634 --- II-635 --- II-636 --- II-637 --- II-638 --- II-639 --- II-640 --- II-641 --- II-642 --- II-643 --- II-644 --- II-645 --- II-646 --- II-647 --- II-648 --- II-649 --- II-650 +++ II-651 --- II-652 ++ II-653 --- II-654 --- II-655 --- II-656 --- II-657 --- II-658 --- II-659 --- II-660 --- II-661 --- II-662 --- II-663 --- II-664 --- II-665 --- II-666 --- II-667 --- II-668 --- II-669 --- II-670 --- II-671 --- II-672 --- II-673 --- II-674 --- II-675 --- II-676 + II-677 --- II-678 --- II-679 --- II-680 --- II-681 --- II-682 --- II-683 --- II-684 --- II-685 --- II-686 --- II-687 --- II-688 --- II-689 --- II-690 --- II-691 --- II-692 ++ II-693 ++ II-694 --- II-695 ++ II-696 + II-697 --- II-698 ++ II-699 + II-700 +++ II-701 + II-702 --- II-703 --- II-704 + II-705 +++ II-706 ++ II-707 + II-708 --- II-709 ++ II-710 ++ II-711 ++ II-712 --- II-713 --- II-714 --- II-715 ++ II-716 +++ II-717 +++ II-718 --- II-719 ++ II-720 ++ II-721 ++ II-722 --- II-723 ++ II-724 ++ II-725 +++ II-726 + II-727 + II-728 + II-729 ++ II-730 ++ II-731 + II-732 + II-733 + II-734 --- II-735 + II-736 + II-737 + II-738 + II-739 +++ II-740 +++ II-741 +++ II-752 +++ II-753 ++ II-757 +++ II-759 + II-762 ++ II-763 +++ II-765 + II-766 + II-767 +++ II-768 +++ II-769 ++ II-770 ++

Table 16: Cellular activity of compounds of formula III (biomarker assay)

[001569] +++ for IC ₅₀ <0.5 µM; ++ for IC ₅₀ in the range 0.5 µM -5 µM; + for IC ₅₀ >5 µM; --- No data

Compound III Biomarker GCN2(IC ₅₀ ) III-1 + III-2 +++ III-3 + III-4 +++ III-5 + III-6 ++ III-7 ++ III-8 ++ III-9 + III-10 +++ III-11 +++ III-12 +++ III-13 --- III-14 --- III-15 --- III-16 +

Table 17: Cellular activity of compounds of formula IV (biomarker assay)

[001570] +++ for IC ₅₀ <0.5 µM; ++ for IC ₅₀ in the range 0.5 µM -5 µM; + for IC ₅₀ >5 µM; --- No data.

Compound of formula IV- Biomarker GCN2(IC ₅₀ ) IV-1 --- IV-2 + IV-3 +++ IV-4 ++ IV-5 ++ IV-6 +++ IV-7 ++ IV-8 ++ IV-9 +++ IV-10 +++ IV-11 ++ IV-12 +++ IV-13 +++ IV-14 +++ IV-15 ++ IV-16 ++ IV-17 + IV-18 ++ IV-19 +++ IV-20 ++ IV-21 + IV-22 + IV-23 + IV-24 + IV-25 + IV-26 + IV-27 ++ IV-28 ++ IV-29 + IV-30 + IV-31 --- IV-32 ++ IV-33 + IV-34 + IV-35 + IV-36 + IV-37 + IV-38 + IV-39 + IV-40 +++ IV-41 + IV-42 ++ IV-43 + IV-44 + IV-45 + IV-46 + IV-47 --- IV-48 + IV-49 + IV-50 ++ IV-51 + IV-52 + IV-53 ++ IV-54 ++ IV-55 ++ IV-56 + IV-57 + IV-58 ++ IV-59 +++ IV-60 ++ IV-61 + IV-62 + IV-63 + IV-64 + IV-65 + IV-66 --- IV-67 + IV-68 + IV-69 + IV-70 + IV-71 + IV-72 + IV-73 + IV-74 + IV-75 + IV-76 + IV-77 + IV-78 + IV-79 --- IV-80 --- IV-81 + IV-82 + IV-83 + IV-84 --- IV-85 + IV-86 + IV-87 + IV-88 + IV-89 + IV-90 + IV-91 + IV-92 + IV-93 + IV-94 + IV-95 + IV-96 ++ IV-97 + IV-98 + IV-99 + IV-100 + IV-101 + IV-102 + IV-103 + IV-104 + IV-105 + IV-106 ++ IV-107 --- IV-108 ++ IV-109 ++ IV-110 + IV-111 + IV-112 + IV-113 + IV-114 + IV-115 + IV-116 + IV-117 + IV-118 + IV-119 + IV-120 + IV-121 + IV-122 + IV-123 + IV-124 + IV-125 + IV-126 + IV-127 --- IV-128 + IV-129 + IV-130 + IV-131 + IV-132 + IV-133 --- IV-134 + IV-135 + IV-136 + IV-137 + IV-138 + IV-139 + IV-140 + IV-141 + IV-142 + IV-143 + IV-144 ++ IV-145 + IV-146 + IV-147 + IV-148 + IV-149 --- IV-150 + IV-151 --- IV-152 + IV-153 --- IV-154 + IV-155 + IV-156 + IV-157 + IV-158 --- IV-159 + IV-160 + IV-161 + IV-162 + IV-163 --- IV-164 + IV-165 + IV-166 + IV-167 + IV-168 + IV-169 + IV-170 + IV-171 + IV-172 + IV-173 --- IV-174 + IV-175 + IV-176 + IV-177 + IV-178 + IV-179 + IV-180 + IV-181 + IV-182 ++ IV-183 + IV-184 +++ IV-185 --- IV-186 --- IV-187 --- IV-188 --- IV-189 ++ IV-190 --- IV-191 ++ IV-192 ++ IV-193 +++ IV-194 +++ IV-195 ++ IV-196 --- IV-197 --- IV-198 --- IV-199 ++ IV-200 ++ IV-201 +++ IV-202 ++ IV-203 --- IV-204 + IV-205 --- IV-206 ++ IV-207 +++ IV-208 --- IV-209 ++ IV-210 ++ IV-211 ++ IV-212 --- IV-213 ++ IV-214 +++ IV-215 +++ IV-216 ++ IV-217 +++ IV-218 --- IV-219 --- IV-220 --- IV-221 --- IV-222 +++ IV-223 --- IV-224 +++ IV-225 ++ IV-226 --- IV-227 --- IV-228 ++ IV-229 --- IV-230 ++ IV-231 --- IV-232 --- IV-233 --- IV-234 + IV-235 --- IV-236 --- IV-237 --- IV-238 --- IV-239 --- IV-240 --- IV-241 --- IV-242 --- IV-243 --- IV-244 --- IV-245 + IV-246 --- IV-247 +++ IV-248 --- IV-249 --- IV-250 --- IV-251 --- IV-252 --- IV-253 --- IV-254 --- IV-255 --- IV-256 --- IV-257 --- IV-258 --- IV-259 --- IV-260 --- IV-261 --- IV-262 --- IV-263 --- IV-264 --- IV-265 --- IV-266 --- IV-267 --- IV-268 --- IV-269 --- IV-270 --- IV-271 --- IV-272 --- IV-273 --- IV-274 --- IV-275 --- IV-276 --- IV-277 --- IV-278 --- IV-279 +++ IV-280 +++ IV-281 --- IV-282 --- IV-283 --- IV-284 --- IV-285 --- IV-286 --- IV-287 --- IV-288 +++ IV-289 --- IV-290 --- IV-291 --- IV-292 --- IV-293 --- IV-294 --- IV-295 --- IV-296 --- IV-297 --- IV-298 --- IV-299 --- IV-300 --- IV-301 --- IV-302 --- IV-303 --- IV-304 --- IV-305 ++ IV-306 --- IV-307 --- IV-308 --- IV-309 --- IV-310 --- IV-311 +++ IV-312 --- IV-313 --- IV-314 --- IV-315 --- IV-316 --- IV-317 --- IV-318 +++ IV-319 --- IV-320 --- IV-321 --- IV-322 --- IV-323 ++ IV-324 --- IV-325 --- IV-326 --- IV-327 --- IV-328 --- IV-329 --- IV-330 --- IV-331 --- IV-332 --- IV-333 --- IV-334 --- IV-335 --- IV-336 --- IV-337 --- IV-338 --- IV-339 --- IV-340 ++ IV-341 + IV-342 --- IV-343 +++ IV-344 ++ IV-345 ++ IV-346 +++ IV-347 + IV-348 --- IV-349 ++ IV-350 ++ IV-351 +++ IV-352 --- IV-353 ++ IV-354 + IV-355 ++ IV-356 --- IV-357 + IV-358 ++ IV-359 +++ IV-360 +++ IV-361 +++ IV-362 ++ IV-363 +++ IV-364 ++ IV-365 ++ IV-366 + IV-367 --- IV-368 + IV-369 ++ IV-370 --- IV-371 ++ IV-372 ++ IV-373 ++ IV-374 ++ IV-375 +++ IV-376 ++ IV-377 ++ IV-378 +++ IV-379 ++ IV-380 --- IV-381 --- IV-382 --- IV-383 --- IV-384 ++ IV-385 ++ IV-386 ++ IV-387 +++ IV-388 +++ IV-389 ++ IV-390 --- IV-391 ++ IV-392 +++ IV-393 --- IV-394 + IV-395 --- IV-396 ++ IV-397 + IV-398 + IV-399 ++ IV-400 + IV-401 ++ IV-402 +++ IV-403 +++ IV-404 ++ IV-405 +++ IV-406 + IV-407 ++ IV-408 + IV-409 ++ IV-410 + IV-411 ++ IV-412 --- IV-413 ++ IV-414 +++ IV-415 +++ IV-416 ++ IV-417 --- IV-418 ++ IV-419 ++ IV-420 +++ IV-421 ++ IV-422 + IV-423 + IV-424 + IV-425 + IV-426 + IV-427 + IV-428 --- IV-429 --- IV-430 --- IV-431 --- IV-432 --- IV-433 --- IV-434 --- IV-435 ++ IV-436 + IV-437 + IV-438 --- IV-439 + IV-440 --- IV-441 --- IV-442 + IV-443 + IV-444 + IV-445 --- IV-446 --- IV-447 + IV-448 --- IV-449 + IV-450 ++ IV-451 +++ IV-452 ++ IV-453 --- IV-454 ++ IV-455 --- IV-456 --- IV-457 --- IV-458 + IV-459 ++ IV-460 ++ IV-461 ++ IV-462 + IV-463 + IV-464 --- IV-465 ++ IV-466 ++ IV-467 + IV-468 ++ IV-469 + IV-470 + IV-471 + IV-472 ++ IV-473 --- IV-474 +++ IV-475 --- IV-476 --- IV-477 --- IV-478 --- IV-479 --- IV-480 + IV-481 --- IV-482 --- IV-483 --- IV-484 --- IV-485 +++ IV-486 --- IV-487 --- IV-488 + IV-489 --- IV-490 --- IV-491 +++ IV-492 +++ IV-493 + IV-494 ++ IV-495 + IV-496 --- IV-497 --- IV-498 --- IV-499 ++ IV-500 --- IV-501 ++ IV-502 --- IV-503 --- IV-504 --- IV-505 --- IV-506 --- IV-507 --- IV-508 --- IV-509 --- IV-510 --- IV-511 --- IV-512 --- IV-513 --- IV-514 --- IV-515 --- IV-516 --- IV-517 --- IV-518 --- IV-519 --- IV-520 --- IV-521 --- IV-522 --- IV-523 --- IV-524 +++ IV-525 ++ IV-526 --- IV-527 --- IV-528 --- IV-529 --- IV-530 --- IV-531 --- IV-532 --- IV-533 --- IV-534 --- IV-535 ++ IV-536 --- IV-537 --- IV-538 ++ IV-539 --- IV-540 ++ IV-541 --- IV-542 --- IV-543 --- IV-544 --- IV-545 ++ IV-546 +++ IV-547 --- IV-548 ++ IV-549 --- IV-550 --- IV-551 --- IV-552 --- IV-553 --- IV-554 --- IV-555 --- IV-556 --- IV-557 --- IV-558 + IV-559 --- IV-560 --- IV-561 --- IV-562 +++ IV-563 ++ IV-564 --- IV-565 --- IV-566 --- IV-567 ++ IV-568 --- IV-569 --- IV-570 --- IV-571 --- IV-572 ++ IV-573 ++ IV-574 + IV-575 ++ IV-576 ++ IV-577 ++ IV-578 ++ IV-579 --- IV-580 + IV-581 --- IV-582 ++ IV-583 ++ IV-584 --- IV-585 --- IV-586 --- IV-587 --- IV-588 --- IV-589 ++ IV-590 + IV-591 + IV-592 + IV-593 ++ IV-594 --- IV-595 --- IV-596 --- IV-597 --- IV-598 --- IV-599 --- IV-600 --- IV-601 +++ IV-602 --- IV-603 --- IV-604 --- IV-605 --- IV-606 --- IV-607 --- IV-608 ++ IV-609 + IV-610 --- IV-611 --- IV-612 --- IV-613 --- IV-614 + IV-615 ++ IV-616 --- IV-617 --- IV-618 --- IV-619 --- IV-620 --- IV-621 ++ IV-622 ++ IV-623 +++ IV-624 ++ IV-625 --- IV-626 ++ IV-627 ++ IV-628 ++ IV-629 ++ IV-630 + IV-631 ++ IV-632 + IV-633 + IV-634 --- IV-635 ++ IV-636 ++ IV-637 ++ IV-638 + IV-639 +++ IV-640 ++ IV-641 --- IV-642 --- IV-643 --- IV-644 --- IV-645 --- IV-646 --- IV-647 --- IV-648 ++ IV-649 + IV-650 ++ IV-651 +++ IV-652 ++ IV-653 --- IV-654 --- IV-655 --- IV-656 --- IV-657 --- IV-658 --- IV-659 --- IV-660 --- IV-661 --- IV-662 --- IV-663 --- IV-664 --- IV-665 --- IV-666 --- IV-667 --- IV-668 ++ IV-669 + IV-670 ++ IV-671 --- IV-672 --- IV-673 ++ IV-674 --- IV-675 + IV-676 ++ IV-677 ++ IV-678 ++ IV-679 ++ IV-680 ++ IV-681 --- IV-682 ++ IV-683 ++ IV-684 +++ IV-685 +++ IV-686 ++ IV-687 ++ IV-688 ++ IV-689 + IV-690 ++ IV-691 ++ IV-692 + IV-693 + IV-694 + IV-695 + IV-696 + IV-697 --- IV-698 --- IV-699 --- IV-700 --- IV-701 --- IV-702 + IV-703 + IV-704 + IV-705 + IV-712 + IV-716 + IV-724 + IV-733 + IV-741 + IV-743 + IV-754 +++ IV-757 +++ IV-758 +++ IV-763 +++ IV-764 +++ IV-765 +++ IV-766 +++ IV-767 +++ IV-769 +++ IV-770 +++ IV-771 +++ IV-772 ++ IV-774 + IV-775 + IV-776 ++ IV-777 ++

Table 18: Cellular activity of compounds of formula V (biomarker assay)

[001571] +++ for IC ₅₀ <0.5 µM; ++ for IC ₅₀ in the range 0.5 µM -5 µM; + for IC ₅₀ >5 µM; ---- No data

Compound V Biomarker GCN2 (IC ₅₀ ) V-1 ++ V-2 ---- V-3 +++ V-4 ++ V-5 + V-6 ---- V-7 ++ V-8 ---- V-9 ---- V-10 +++ V-11 +++ V-12 ++ V-13 +++ V-14 ++ V-15 +++ V-16 + V-17 ++ V-18 + V-19 + V-20 +++

Example 115: GCN2 Inhibition Study by Human IL-2

[001572] 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.

[001573] 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 19. EC ₅₀ values based on IL-2 secretion by T cells

[001574] +++ for EC ₅₀ <100 nM; ++ for EC ₅₀ in the range of 100 µM - 500 nM; + for EC ₅₀ >500 nM

Connection No. IL2/T cell EC ₅₀ (nM) II-752 +++, +++ II-755 ++ II-768 + II-771 ++ II-772 ++ II-773 +++ II-774 +++ II-775 ++ II-776 ++ II-777 ++ II-778 + II-779 + IV-763 ++ IV-767 ++ IV-776 +

[001575] 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 (65)

1. Compound of formula I or a pharmaceutically acceptable salt thereof, wherein 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; ring B represents ; ring C represents ; each of R ¹ independently means fluorine, methyl, ethyl, -OH, methoxy, –CH ₂ OH, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , -CF ₃ , , , , , , , , , , , , , , , , , , , , , , , , , , , , , -COOH, , -CD ₃ , , -CN, , , , , , , , , , , , -CHF ₂ , -PO(CH ₃ ) ₂ , or ; each of R ² independently means –Cl, –CHF ₂ , -CH ₂ CH ₃ , , -CF ₃ , -CF ₂ CH ₃ , -CH ₃ , , -CN, or ; R ³ is hydrogen; R ⁴ is hydrogen; 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. A compound according to claim 1, wherein ring A is a 5-7 membered saturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 3. The compound according to claim 1, in which ring A is: , , , , , , , , , , , or . 4. The compound according to claim 1, in which ring A is: or . 5. The compound according to claim 1, in which ring A is: , , , , , or . 6. The compound according to claim 1, in which ring A is: , , or . 7. The compound according to claim 1, in which ring A is . 8. The compound according to claim 1 of one of the formulas X-a, X-b or X-c: or a pharmaceutically acceptable salt thereof. 9. Connection according to any one of paragraphs. 1-8, in which each of R ¹ independently represents fluorine, methyl, ethyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , -CF ₃ , , , , , , , , , , , , , , , , , , , , -CD ₃ , , , , , , , -CHF ₂ or -PO(CH ₃ ) ₂ . 10. Connection according to any one of paragraphs. 1-8, in which each of R ¹ independently represents fluorine, methyl, , , , , , , , , , , , , , , , , -CF ₃ , , , , , , , , , , , , , , , , , -CD ₃ , , , , , , or -CHF ₂ . 11. Connection according to any one of paragraphs. 1-8, in which each of R ¹ independently represents fluorine, methyl, , , , , , -CF ₃ , , , , -CD ₃ , or -CHF ₂ . 12. Connection according to any one of paragraphs. 1-11, in which each of R ² independently represents –Cl, -CH ₂ CH ₃ , , -CH ₃ , , -CN, or . 13. Connection according to any one of paragraphs. 1-11, in which each of R ² independently represents -CHF ₂ , -CF ₃ or -CF ₂ CH ₃ . 14. Connection according to any one of paragraphs. 1-13, in which m is 1, 2, 3, 4 or 5. 15. Connection according to any one of paragraphs. 1-13, in which m is 3. 16. Connection according to any one of paragraphs. 1-13, in which n is 1. 17. The compound according to claim 1, wherein ring B is . 18. A connection selected from the group consisting of: or a pharmaceutically acceptable salt thereof. 19. 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. 1-18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent. 20. Use of a compound according to any one of paragraphs. 1-18 or a pharmaceutically acceptable salt thereof for inhibiting GCN2 in a biological sample. 21. Use of a compound according to any one of paragraphs. 1-18 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a GCN2-mediated disorder, disease or condition. 22. The use of claim 21, 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. 23. Use according to claim 22, 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. 24. Use according to claim 22, wherein the autoimmune pathological condition is rheumatoid arthritis, systemic lupus, multiple sclerosis, psoriasis, Sjögren's syndrome or organ transplant rejection. 25. Use according to claim 22, wherein the metabolic pathological condition is diabetes. 26. Use according to claim 22, wherein the degenerative disease is osteoarthritis. 27. Use according to claim 22, wherein the inflammatory pathological condition is asthma, inflammatory bowel disease or giant cell arteritis. 28. Use according to claim 22, wherein the cardiovascular disease is ischemic damage. 29. Use according to claim 22, 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. 30. Use according to claim 22, 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. 31. The use of claim 21, wherein the GCN2-mediated disorder, disease or condition is cancer and the method further comprises administering a second agent for treating the cancer.