BR122021006373B1 - POLYCYCLIC TLR7/8 ANTAGONISTS, THEIR USES, AND PHARMACEUTICAL COMPOSITION - Google Patents

Abstract

The present invention relates to compounds of Formula I and pharmaceutically acceptable compositions thereof useful as TLR7/8 antagonists. In Formula (I), Ring A is aryl or heteroaryl; Ring B is aryl or heteroaryl; and X is C(R4)2, O, NR4, S, S(R4), or S(R4)2.

Description

Split from BR112018011556-8, deposited on 12/16/2016. RELATED REQUESTS

[0001] This application claims the benefit of Provisional Application US 62/268,765, filed on December 17, 2015, and Provisional Application US 62/353,603, filed on June 23, 2016. The content of the aforementioned applications is hereby incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

[0002] The present invention provides compounds of Formula (I) as Toll-like receptor 7/8 (TLR7/8) antagonists and their use in the treatment of immune disorders, and other diseases related to the overexpression of TLR7/8.

BACKGROUND OF THE INVENTION

[0003] Toll-like receptors (TLR) currently comprising a gene family of 10 receptors with different specificities are part of the cellular pathogen pattern recognition system, which has evolved for defense against a variety of infections (bacteria, viruses, fungi). Activation of TLRs leads to cytokine responses, for example with release of interferons and activation of specified immune cells. The functional expression of selected TLRs in tissues is highly different. Part of the receptors are located on the cell surface, such as TLR4 (stimulated by E. coli lipopolysaccharide LPS), for example, on epithelial cells, or TLR3, 7, 8 and 9 located on endosomal membranes in specified immune cells. The latter are all activated by nucleic acids, but recognize several types of them. For example, TLR9 is activated by single-stranded DNA containing CpG subsequences, TLR7 and 8 are activated by single-stranded RNA, and TLR3 is activated by double-stranded RNA.

[0004] TLRs have been implicated in several autoimmune and inflammatory diseases, with the clearest example being the role played by TLR7 in the pathogenesis of systemic lupus erythematosus (Barrat and Coffman, Immunol Rev, 223:271-283, 2008). Additionally, a TLR8 polymorphism has been associated with rheumatoid arthritis (Enevold et al., J Rheumatol, 37:905-10, 2010). Although several inhibitors of TLR7, TLR8, and TLR9 have been described, additional TLR inhibitors are desirable. In particular, polynucleotides having inhibitory motifs for one or more of TLR7, TLR8 and TLR9 are necessary to precisely inhibit an immune response in an individual (for example, a patient having an autoimmune disease or an inflammatory disease).

[0005] Strong efforts have been underway around the world for several years in an attempt to exploit the strong immune activation induced by TLR7, 8 or 9 agonists for the treatment of cancer. Cancer immunotherapy, however, has experienced a long history of failures. In recent years, however, knowledge about cancer immune surveillance and the function of immune cell subsets has thus been dramatically improved. TLR7 or TLR9 agonists are in clinical development for cancer monotherapies or combination therapies, or as vaccine adjuvants. The TLR agonist method for cancer immunotherapy is different from previous efforts using, for example, monovalent vaccinations, cytokines, or interferons. TLR agonist-mediated immune activation is pleiotropic through specified immune cells (primarily dendritic cells and B cells, subsequently other cells), which generate an innate and adaptive immune response. Furthermore, not just one interferon is induced, but rather the many different isoforms together, and not only type I (alpha, beta) but also (indirectly) type II (gamma, NK cells).

SUMMARY OF THE INVENTION

[0006] In one aspect, the invention provides compounds of Formula (I): and pharmaceutically acceptable derivatives, solvates, salts, hydrates and stereoisomers thereof.

[0007] In another aspect, the invention provides compounds of Formula (I) that are dual antagonists of TLR7 and TLR8. In another aspect, the invention provides compounds of Formula (I) which are suitable for the treatment and/or prevention of TLR7/8 related disorders. In another aspect, the invention provides compounds that are capable of modulating, especially inhibiting the activity or function of TLR7/8 in disease states in mammals, especially in humans.

[0008] According to another aspect of the invention, methods for treating and/or preventing autoimmune disorders are provided.

[0009] According to another aspect, the present invention provides compounds of Formula (I) that are selective for TLR7 or TLR8.

[0010] According to another aspect, the present invention provides compounds of Formula (I) that are selective for TLR7 and TLR8.

DETAILED DESCRIPTION OF CERTAIN MODALITIES 1. General Description of Compounds of the Invention

[0011] In certain aspects, the present invention provides TLR7/8 antagonists. In some embodiments, such compounds include those of the Formulas described herein, or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

2. Compounds and Definitions

[0012] Compounds of this invention include those generally described above, and are also illustrated by the classes, subclasses, and species described here. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of this invention, chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of which is hereby incorporated by reference.

[0013] The term "aliphatic" or "aliphatic group", as used herein, means a substituted or unsubstituted straight-chain (i.e., unbranched) or branched hydrocarbon chain that is completely saturated or that contains one or more hydrocarbon units. unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more unsaturation units but is not aromatic (also referred to as "carbocycle", "cycloaliphatic" or "cycloalkyl"), which has a single point of binding to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1 to 6 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1 to 5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 to 4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1 to 3 aliphatic carbon atoms, and in still other embodiments, aliphatic groups contain 1 to 2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a C3-C6 monocyclic hydrocarbon that is completely saturated, or that contains one or more unsaturation units, but that is non-aromatic, that has a single point of attachment to the rest of the molecule. Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl groups and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0014] The term "lower alkyl" refers to a linear or branched C1-4 alkyl group. Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0015] The term "lower haloalkyl" refers to a linear or branched C1-4 alkyl group that is substituted with one or more halogen atoms.

[0016] The term "heteroatom" means one or more oxygen, sulfur, nitrogen or phosphorus (including, any oxidized form of nitrogen, sulfur or phosphorus; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

[0017] The term "unsubstituted", as used herein, means that a portion has one or more unsaturation units.

[0018] When used herein, the term "linear or branched, saturated or unsaturated, C1-8 (or C1-6) bivalent hydrocarbon chain" refers to bivalent alkylene, alkenylene, and alkynylene chains that are linear or branched as defined here.

[0019] The term "alkylene" refers to a divalent alkyl group. An "alkylenon chain" is a polymethylene group, i.e. -(CH2)n-, in which n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0020] The term "alkenylene" refers to 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 are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0021] The term "halogen" means F, Cl, Br, or I.

[0022] The term "aryl", used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of five to fourteen members of ring, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" is used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracil and the like, which optionally include one or more substituents. Also included within the scope of the term "aryl", as used herein, is 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. .

[0023] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, for example, "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π shared electrons in a cyclic arrangement; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. 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 pteridinyl. 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, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, , tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group is optionally mono- or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any such terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, in which the alkyl and heteroaryl moieties are independently optionally substituted.

[0024] When used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a 5- to 7-membered monocyclic or 7 to 10 bicyclic heterocyclic moiety. stable members that are either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used with reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl ), or +NR (as in N-substituted pyrrolidinyl).

[0025] A heterocyclic ring can be attached to its pendant group on any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl , thiazepinil, morpholinyl and quinuclidinil. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group is optionally mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently optionally substituted.

[0026] When used here, the term "partially unsaturated" refers to a ring portion that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

[0027] As described here, certain compounds of the invention contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogens that are either explicit or implicit in the structure (e.g., refers to at least ; refers to at least Unless otherwise indicated, an "optionally substituted" group has a suitable substituent at each substitutable position in the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent is either the same or different in each position. Combinations of substituents considered by this invention are preferably those that result in the formation of stable or chemically viable compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to provide for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes described. here.

[0028] Suitable monovalent substituents on a replaceable carbon atom of an "optionally substituted" group are independently deuterium; halogen; -(CH2)o-4R°; -(CH2)o—4OR°; - O(CH2)o-4Ro, -O-(CH2)o—4C(O)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CH2)o—4Ph, which are optionally substituted with R°; -(CH2)o- 4O(CH2)o—iPh which is optionally substituted with R°; -CH=CHPh, which is optionally substituted with R°; -(CH2)o—4O(CH2)o—i-pyridyl which is optionally substituted with R°; -NO2; -CN; -N3; -(CH2)o—4N(R°)2; -(CH2)o-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)o-4N(R°)C(O)NR°2; - N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; - N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; - C(S)R°; -(CH2)O-4C(0)OR°; -(CH2)o—4C(O)SR°; -(CH2)o—4C(O)OSiR°3; - (CH2)o—4θC(O)R°; -OC(O)(CH2)o-4SR°, SC(S)SR°; -(CH2)o-4SC(O)R°; - (CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)0- 4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°;-(CH2)O-4SSR°; -(CH2)O-4S(0)2R°; -(CH2)O-4S(0)20R°; - (CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -N(R°)S(O)2NR°2; - N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; - OP(O)R°2; -OP(O)(OR°)2; SiR°3; -(C1-4 linear or branched alkylene)O-N(R°)2; or -(C1-4 linear or branched alkylene)C(O)O- N(R°)2, wherein each R° is optionally substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph,- O (CH2)0-1Ph, -CH2-(5- to 6-membered heteroaryl ring), or a saturated, partially unsaturated, or aryl 5- to 6-membered ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or , notwithstanding the above definition, two independent occurrences of R°, taken together with their intermediate atom(s), form a mono- or bicyclic, 3- to 12-membered ring, saturated, partially unsaturated, or aryl having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which is optionally substituted as defined below.

[0029] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intermediate atoms), are independently deuterium, halogen, -(CH2)o-2RΦ, -(haloRΦ), -(CH2 )o-2OH, -(CH2)o-2θRΦ, - (CH2)O-2CH(OR*)2; -O(haloR*), -CN, -N3, -(CH2)o-2C(O)RΦ, -(CH2)o-2 C(O)OH, -(CH2)0-2C(O)OR* , -(CH2)0-2SR*, -(CH2)0-2SH, -(CH2)0-2NH2, -(CH2)0-2NHR*, -(CH2)0-2NR*2, -NO2, -SiR *3, -OSiR*3, -C(O)SR*, - (C1-4 linear or branched alkylene)C(O)OR*, or -SSR* where each R* is unsubstituted or where preceded by " halo" is substituted only with one or more halogens, and is independently selected from aliphatic Ci-4, -CH2Ph, -O(CH2)o—iPh, or a 5- to 6-membered saturated, partially unsaturated ring, or aryl having 0 to 4 independently selected heteroatoms of nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

[0030] Suitable divalent substituents on a saturated Carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O—, or -S(C(R*2))2-3S-, where each independent occurrence of R* is selected from hydrogen, aliphatic Ci-6 which is substituted as defined below, or an unsubstituted 5- to 6-membered ring, saturated, partially unsaturated, or aryl having 0 to 4 independently selected heteroatoms of nitrogen, oxygen , or sulfur. Suitable divalent substituents that are attached to vicinal substitutable carbons of an "optionally substituted" group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, aliphatic Ci-6- which is optionally substituted as defined below, or an unsubstituted 5 to 6 membered, saturated, partially unsaturated, or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0031] Suitable substituents on the aliphatic group of R* include halogen, -RΦ, -(haloR*), -OH, -OR*, -O(haloRΦ), -CN, -C(O)OH, -C( O)ORΦ, -NH2, -NHR*, -NRΦ2, or -NO2, where each RΦ is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently Ci-4 aliphatic, - CH2Ph, -O(CH2)0-iPh, or a saturated, partially unsaturated, or aryl 5- to 6-membered ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0032] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -Rt, -NRt2, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C (O)CH2C(O)Rt, -S(O)2Rt, -S^NR^, - C(S)NRt2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each Rt is independently hydrogen, C1-6 aliphatic which is optionally substituted as defined below, unsubstituted -OPh, or an unsubstituted 5 to 6 membered ring, saturated, partially unsaturated, or aryl having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of Rt, taken together with their intermediate atom(s) form an unsubstituted mono- or bicyclic ring, from 3 to 12 members, saturated, partially unsaturated, or aryl having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0033] Suitable substituents on the aliphatic group of Rt are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, - C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, where each R* is unsubstituted or where preceded by "halo" is replaced only with one or more halogens, and is independently C1-4 aliphatic, -CH2Ph, -O(CH2)0-1Ph, or a saturated, partially unsaturated, or aryl 5- to 6-membered ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] In certain embodiments, the terms "optionally substituted," "optionally substituted alkyl," "optionally substituted "optionally substituted alkenyl," "optionally substituted alkynyl," "optionally substituted carbocyclic," "optionally substituted aryl," " optionally substituted heteroaryl," "optionally substituted heterocyclic," and any other optionally substituted group as used herein, refers to groups that are substituted or unsubstituted by independent substitution of one, two, or three, or more of the hydrogen atoms on them with typical substituents, including but not limited to: - F, -Cl, -Br, -I, deuterium, - OH, protected hydroxy, alkoxy, oxo, thio-oxo, - NO2, -CN, CF3, N3 , -NH2, protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -NH cycloalkyl, -NH -aryl, -NH -heteroaryl, -NH -heterocyclic, -dialkylamino, -diarylamino, -diheteroarylamino , - O- alkyl, -O- alkenyl, -O- alkynyl, -O- cycloalkyl, -O- aryl, -O-heteroaryl, -O-heterocyclic, -C(O)- alkyl, -C(O)- alkenyl, -C(O)- alkynyl, -C(O)- carbocyclyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl, - CONH2, -CONH- alkyl, -CONH- alkenyl, -CONH- alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH- heterocyclyl, -OCO2-alkyl, -OCO2-alkenyl, -OCO2-alkynyl, -OCO2- carbocyclyl, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocyclyl, - OCONH2, -OCONH-alkyl, -OCONH-alkenyl, -OCONH-alkynyl, - OCONH-carbocyclyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH - heterocyclyl, -NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)- alkynyl, -NHC(O)- carbocyclyl, -NHC(O)-aryl, -NHC(O)-heteroaryl , -NHC(O)- heterocyclyl, -NHCO2-alkyl, -NHCO2- alkenyl, -NHCO2-alkynyl, -NHCO2-carbocyclyl, -NHCO2-aryl, -NHCO2- heteroaryl, -NHCO2- heterocyclyl, -NHC(O)NH2 , -NHC(O)NH- alkyl, -NHC(O)NH- alkenyl, -NHC(O)NH-alkenyl, -NHC(O)NH- carbocyclyl, -NHC(O)NH-aryl, - NHC(O )NH-heteroaryl, -NHC(O)NH-heterocyclyl, NHC(S)NH2, - NHC(S)NH-alkyl, -NHC(S)NH- alkenyl, -NHC(S)NH- alkynyl, - NHC( S)NH- carbocyclyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, - NHC(S)NH-heterocyclyl, -NHC(NH)NH2, -NHC(NH)NH- alkyl, - NHC(NH)NH- -alkenyl, -NHC(NH)NH- alkenyl, -NHC(NH)NH- carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, - NHC(NH) NH-heterocyclyl, -NHC(NH)- alkyl, -NHC(NH)-alkenyl, - NHC(NH)-alkenyl, -NHC(NH)-carbocyclyl, -NHC(NH)-aryl, - NHC(NH)- heteroaryl, -NHC(NH)-heterocyclyl, -C(NH)NH-alkyl, -C(NH)NH-alkenyl, -C(NH)NH- alkynyl, -C(NH)NH- carbocyclyl, -C(NH )NH-aryl, -C(NH)NH- heteroaryl, -C(NH)NH-heterocyclyl, -S(O)- alkyl, -S(O)- alkenyl, -S(O)-alkynyl, -S( O)-carbocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclyl-SO2NH2, -SO2NH-alkyl, -SO2NH-alkenyl, -SO2NH-alkynyl, -SO2NH-carbocyclyl , -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocyclyl, - NHSO2- alkyl, -NHSO2-alkenyl, -NHSO2- alkynyl, - NHSO2-carbocyclyl, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2- heterocyclyl , - CH2NH2, -CH2SO2CH3, - mono-, di-, or tri-alkyl silyl, - alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic, - heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S- heteroaryl, -S-heterocyclyl , or methylthiomethyl.

[0035] When used herein, the term "pharmaceutically acceptable salt" refers to those salts that fall within the scope of safe medical diagnosis, suitable for use in contact with the tissues of humans and smaller animals without undue toxicity, irritation, allergic response and similar, and are measured with a reasonable risk/benefit 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, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic or organic bases and acids. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group 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 using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include salts of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate , hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0036] Salts derived from suitable bases include alkaline metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4 salts. Alkaline or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0037] Unless otherwise stated, structures represented herein are also understood to include all isomeric (e.g., enantiomeric, diastereomeric and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, double bond isomers Z and E, and conformational Z and E. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds fall within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention fall within the scope of the invention.

[0038] Additionally, unless otherwise stated, structures represented here are also understood to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by carbon enriched by 13C or 14C, fall within the scope of this invention. In some embodiments, the group comprises one or more deuterium atoms.

[0039] A compound of Formula I is also intended to include isotope-labeled forms thereof. An isotope-labeled form of a compound of Formula I is identical to that compound apart from the fact that one or more atoms of the compound have been replaced by an atom or atoms having an atomic mass or atom mass number that is generally of occurrence. Natural. Examples of isotopes that are readily commercially available and that can be incorporated into a compound of Formula I by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2H, 3H, 13C , 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36CI, respectively. A compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt thereof containing one or more of the aforementioned isotopes and/or other isotopes of other atoms is intended to be part of the present invention. An isotope-labeled compound of Formula I can be used in several beneficial ways. For example, an isotope-labeled compound of Formula I in which, for example, a radioisotope, such as 3H or 14C, has been incorporated, is suitable for drug and/or substrate tissue distribution assays. These radioisotopes, i.e. tritium (3H) and carbon-14 (14C), are particularly preferred due to simple preparation and excellent detectability. Incorporation of heavier isotopes, e.g., deuterium (2H), into a compound of Formula I has therapeutic advantages due to the greater metabolic stability of this isotope-labeled compound. Greater metabolic stability translates directly to increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. An isotope-labeled compound of Formula I can generally be prepared by carrying out the procedures described in the synthetic schemes and related description, example part, and preparation part in the present text, substituting a non-isotope-labeled reagent for a non-isotope-labeled reagent. readily available isotope.

[0040] Deuterium (2H) can also be incorporated into a compound of Formula I for the purpose of manipulating the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies for covalent bond formation following this isotopic exchange. Heavier isotope exchange generally results in a reduction in the ground state energy for the chemical bond and thereby causes a reduction in the rate-limiting rate at which bond breaking occurs. If bond breaking occurs in, or in the vicinity of, a saddle point region along the coordinate of a multiple product reaction, product distribution relationships may be altered substantially. For explanation: if deuterium is bonded to a carbon atom in a non-exchangeable position, rate differences of kM/kD= 2-7 are typical. If this rate difference is successfully applied to a compound of Formula I that is susceptible to oxidation, the in vivo profile of this compound can be drastically modified and results in improved pharmacokinetic properties.

[0041] When discovering and developing therapeutic agents, the person skilled in the art is able to optimize pharmacokinetic parameters, while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information on the course of oxidative metabolism of this type, which in turn allows the rational design of deuterated Formula I compounds with improved stability, through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profiles of compounds of Formula I are thereby obtained, and can be expressed quantitatively in terms of increases in in vivo half-life (t/2), concentration at maximum therapeutic effect (Cmax), area under the dose curve response (AUC), and F; and in terms of reduced clearance, dose and material costs.

[0042] The following are intended to illustrate the above: a compound of Formula I that has multiple potential sites of attack for oxidative metabolism, e.g., benzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogs in which various combinations of hydrogen atoms are replaced by deuterium atoms, so that some, most, or all of these hydrogen atoms have been replaced by deuterium atoms. Half-life determinations enable favorable and accurate determination of the extent to which resistance to oxidative metabolism has improved. In this way, it was determined that the half-life of the parent compound can be extended by up to 100%, as a result of deuterium-hydrogen exchange of this type.

[0043] Deuterium-hydrogen exchange in a compound of Formula I can also be used to obtain a favorable modification of the metabolite spectrum of the starting compound in order to decrease or eliminate unwanted toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (C-H) bond cleavage, it can be reasonably assumed that the deuterated analogue will greatly decrease or eliminate production of the unwanted metabolite, even if the particular oxidation is not a rate determination step. Other information on the state of the art with respect to deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 39923997, 1990, Reider et al., J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985, Gillette et al, Biochemistry 33(10) 29272937, 1994, and Jarman et al. Carcinogenesis 16(4), 683-688, 1993.

[0044] When used here, the term "modulator" is defined as a compound that binds to and/or inhibits the target with measurable affinity. In certain embodiments, a modulator has an IC50 and/or binding constant less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than than about 10 nM.

[0045] The terms "measurable affinity" and "measurably inhibit," as used herein, mean a measurable change in TLR7/8 activity between a sample comprising a compound of the present invention, or composition thereof, and TLR7/8, and an equivalent sample comprising TLR7/8, in the absence of said compound, or composition thereof.

[0046] Combinations of substituents and variables considered by this invention are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds that possess sufficient stability to permit manufacture and that maintain the integrity of the compound for a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic administration or prophylaxis to an individual).

[0047] Citation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable, such as any single group or combination of listed groups. Citation of a modality for a variable herein includes that modality as any single modality or in combination with any other modalities or portions thereof.

3. Description of Exemplary Compounds

[0048] According to one aspect, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein: ring A is aryl or heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; ring B is aryl or heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally replaced; R1 is absent, -H, -CHF2, -CF3, -OMe, or -CN; each R2 is independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N( R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; each R3 is independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N( R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; X is C(R4)2, O, NR4, S, S(R4), or S(R4)2; each R4 is independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N( R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; each R5 is independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N( R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; each R is independently hydrogen, C1-6 aliphatic, C3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally replaced; or two R groups on the same atom are taken together with the atom to which they are bonded to form a C3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally replaced; k is 0 or 1; n is 0, 1, or 2; p is 0, 1, or 2; r is 0, 1, or 2; et is 0, 1, or 2.

[0049] In certain embodiments, when , and X is CH2; then R4 is not H, methyl, or hydroxyl.

[0050] In certain embodiments, when , and X is O, then R4 is not -C(O)N(R)2.

[0051] In certain embodiments, R1 is absent.

[0052] In certain embodiments, R1 is -H.

[0053] In certain embodiments, R1 is -CHF2.

[0054] In certain embodiments, R1 is -CF3.

[0055] In certain embodiments, R1 is -OMe.

[0056] In certain embodiments, R1 is -CN.

[0057] In certain embodiments, ring A is C6 aryl or a 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally replaced.

[0058] In certain embodiments, ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; each of which is optionally replaced.

[0059] In certain embodiments, ring A is phenyl, pyridyl or pyrimidinyl; each of which is optionally replaced.

[0060] In certain embodiments, ring A is

[0061] In certain embodiments, ring A is

[0062] In certain embodiments, ring B is C6 aryl or a 5- to 6-membered monocyclic heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally replaced.

[0063] In certain embodiments, ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole or thiazole; each of which is optionally replaced.

[0064] In certain embodiments, ring B is

[0065] In certain embodiments, ring B is

[0065] In certain embodiments, each R2 is independently -H.

[0066] In certain embodiments, each R2 is independently C1-6 aliphatic, C3-10 aryl, a 3 to 8 membered saturated or partially unsaturated carbocyclic ring, a 3 to 7 membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally replaced.

[0067] In certain embodiments, each R2 is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of which is optionally replaced.

[0068] In certain embodiments, each R2 is independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3,3,0]bicyclooctanyl, [4,3,0 ]bicyclononanyl, [4,4,0]bicyclodecanyl, [2,2,2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl , benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetra- hydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H- indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, is oxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; -1,2,5- oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl , pyrazolidinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrido-oxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, , tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thieno-oxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally replaced.

[0069] In certain embodiments, each R2 is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N (R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0070] In certain embodiments, each R3 is independently -H.

[0071] In certain embodiments, each R3 is independently C1-6 aliphatic, C3-10 aryl, a 3 to 8 membered saturated or partially unsaturated carbocyclic ring, a 3 to 7 membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally replaced.

[0072] In certain embodiments, each R3 is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of which is optionally replaced.

[0073] In certain embodiments, each R3 is independently methyl.

[0074] In certain embodiments, each R3 is independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3,3,0]bicyclooctanyl, [4,3,0 ]bicyclononanyl, [4,4,0]bicyclodecanyl, [2,2,2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl ,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetra- hydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, is oxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; , phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido-oxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrrolidinyl, , pyrrolinyl, 2 H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1, 2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1, 2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally replaced.

[0075] In certain embodiments, each R3 is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N (R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0076] In certain embodiments, X is C(R4)2 or O.

[0077] In certain embodiments, X is C(R4)2. In certain embodiments, X is CH2.

[0078] In certain embodiments, X is O.

[0079] In certain embodiments, each R4 is independently -H.

[0080] In certain embodiments, each R4 is independently C1-6 aliphatic, C3-10 aryl, a 3 to 8 membered saturated or partially unsaturated carbocyclic ring, a 3 to 7 membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally replaced.

[0081] In certain embodiments, each R4 is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of which is optionally replaced.

[0082] In certain embodiments, each R4 is independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3,3,0]bicyclooctanyl, [4,3,0 ]bicyclononanyl, [4,4,0]bicyclodecanyl, [2,2,2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl ,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro [2,3-b] tetra- hydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, is oxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; , phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido-oxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrrolidinyl, pyrrolinyl, 2 H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3- thiadiazolyl, 1, 2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thieno-oxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2, 4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl, or xanthenyl; each of which is optionally replaced.

[0083] In certain embodiments, each R4 is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N (R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0084] In certain embodiments, each R4 is independently -H, C1-6 aliphatic, -OR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; each of which is optionally replaced.

[0085] In certain embodiments, each R4 is independently -H, C1-6 aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of which is optionally replaced.

[0086] In certain embodiments, each R4 is independently

[0087] In certain embodiments, each R4 Independently

[0088] In certain embodiments, each R5 is independently -H.

[0089] In certain embodiments, each R 5 is independently C1-6 aliphatic, C3-10 aryl, a 3 to 8 membered saturated or partially unsaturated carbocyclic ring, a 3 to 7 membered heterocyclic ring having 1 to 4 independently selected heteroatoms of nitrogen, oxygen, or sulfur, or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 independently selected heteroatoms of nitrogen, oxygen, or sulfur; each of which is optionally replaced.

[0090] In certain embodiments, each R5 is independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of which is optionally replaced.

[0091] In certain embodiments, each R5 is independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3,3,0]bicyclooctanyl, [4,3,0 ]bicyclononanyl, [4,4,0]bicyclodecanyl, [2,2,2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl , benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetra- hydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isoindolyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isothiazolyl, is oxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; -1,2,5-oxadiazolyl, 1,3,4- oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenantridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl , pyrazolidinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrido-oxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H- quinolizinyl, quinoxalinyl, quinuclidinyl, there, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thieno-oxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl or xanthenyl; each of which is optionally replaced.

[0092] In certain embodiments, each R5 is independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N (R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0093] In certain embodiments, each R5 is independently methyl, cyclopropyl, -F, or -CF3.

[0094] In certain embodiments, each R5 is independently -F, or –CF3.

[0095] In certain embodiments, each of X, ring A, ring B, R1, R2, R3, R4, R5, k, m, n, p, r, and t, is as defined above and described in embodiments, classes and subclasses above and here, alone or in combination.

[0096] In certain embodiments, the present invention provides a compound of Formula Ia, or a pharmaceutically acceptable salt thereof, wherein each of and here, singly or in combination.

[0097] In certain embodiments, the present invention provides a compound of Formula Ib, or a pharmaceutically acceptable salt thereof, wherein each of and here, singly or in combination.

[0098] In certain embodiments, the present invention provides a compound of Formula Ic, or a pharmaceutically acceptable salt thereof, wherein each of and here, singly or in combination.

[0099] In certain embodiments, the present invention provides a compound of Formula Id, or a pharmaceutically acceptable salt thereof, wherein each of and here, singly or in combination.

[00100] In certain embodiments, the present invention provides a compound of Formula Ie, or a pharmaceutically acceptable salt thereof, wherein each of and here, singly or in combination.

[00101] In certain embodiments, the present invention provides a compound of Formula If, or a pharmaceutically acceptable salt thereof, wherein each of and here, singly or in combination.

[00102] In certain embodiments, the present invention provides a compound of Formula Ig, or a pharmaceutically acceptable salt thereof, wherein each of or in combination.

[00103] In certain embodiments, the present invention provides a compound of Formula Ih, or a pharmaceutically acceptable salt thereof, wherein each of X, R1, R2, R3, R4, R5, k, n, p, r, and t is as defined above and described in embodiments, classes and subclasses above and herein alone or in combination.

[00104] In certain embodiments, the present invention provides a compound of Formula Ij, or a pharmaceutically acceptable salt thereof, wherein each of X, R2, R3, R4, R5, n, p, r, et, is as defined above and described in embodiments, classes and subclasses above and herein, alone or in combination .

[00105] In certain embodiments, the present invention provides a compound of Formula Im, or a pharmaceutically acceptable salt thereof, wherein each of X, R2, R3, R4, R5, n, p, r, et, is as defined above and described in embodiments, classes and subclasses above and herein, alone or in combination .

[00106] In certain embodiments, the present invention provides a compound of Formula In, or a pharmaceutically acceptable salt thereof, wherein each of X, R1, R2, R3, R4, R5, k, n, p, r, and t is as defined above and described in embodiments, classes and subclasses above and herein alone or in combination.

[00107] In certain embodiments, the present invention provides a compound of Formula Ip, or a pharmaceutically acceptable salt thereof, wherein each of X, R2, R3, R4, R5, n, p, r, et, is as defined above and described in embodiments, classes and subclasses above and herein, alone or in combination .

[00108] In certain embodiments, the invention provides a compound selected from Table 1:

[00109] In some embodiments, the present invention provides a compound selected from those depicted above, or a pharmaceutically acceptable salt thereof.

[00110] Various structural representations can show a heteroatom without a bonded group, radical, charge or counterion. Those skilled in the art are aware that such representations are intended to indicate that the heteroatom is bonded to hydrogen (for example, 5.0%/OH). is understood to be

[00111] In certain embodiments, the compounds of the invention were synthesized according to the schemes provided in the examples below.

4. Uses, Formulation and Administration Pharmaceutically Acceptable Compositions

[00112] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that it is effective to measurably inhibit TLR7/8, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that it is effective to measurably inhibit TLR7/8, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such a composition.

[00113] The term "patient" or "individual", as used herein, means an animal, preferably a mammal, and most preferably a human.

[00114] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle, which does not destroy the pharmacological activity of the compound with the which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that are used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as serum albumin. human, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, disodium hydrogen phosphate potassium, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[00115] A "pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of delivering, directly or indirectly, a compound of this invention of this invention or an inhibitory active metabolite or residue thereof.

[00116] Compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or through an implanted reservoir. The term "parenteral" when used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, 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 this invention include aqueous or oleaginous suspension. These suspensions are formulated in accordance with 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 or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that are used are water, Ringer's solution and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[00117] For this purpose, any bland fixed oil employed includes synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oily solutions or suspensions also contain a long-chain alcohol dispersant or diluent, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifying or bioavailability enhancing agents that are commonly used in the manufacture of solid, liquid, or other pharmaceutically acceptable dosage forms, should also be used for the purposes of formulation.

[00118] Pharmaceutically acceptable compositions of this invention are orally administered in any orally acceptable dosage form. Examples of dosage forms are capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dry corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents are also optionally added.

[00119] Alternatively, pharmaceutically acceptable compositions of this invention are administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00120] Pharmaceutically acceptable compositions of this invention are also administered topically, especially when the treatment target includes areas or organs easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs.

[00121] Topical application to the lower intestinal tract can be carried out in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically transdermal patches are also used.

[00122] For topical applications, pharmaceutically acceptable compositions provided are formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Exemplary carriers for topical administration of compounds thereof are mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, pharmaceutically acceptable compositions provided may be formulated into a suitable lotion or cream, containing the active components 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 wax esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00123] Pharmaceutically acceptable compositions of this invention are optionally administered by aerosol or nasal inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, adsorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing agents or conventional dispersants.

[00124] More preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[00125] The amount of compounds of the present invention that are optionally combined with the carrier materials to produce a composition in a unit dosage form will vary, depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated such that a dosage between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.

[00126] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, length of administration, excretion rate, drug combination, and the diagnosis of the treating physician, and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend on the particular compound comprised in the composition.

Uses of Pharmaceutically Acceptable Compounds and Compositions

[00127] The present invention also relates to a method for treating an individual who is suffering from a TLR7/8 related disorder, comprising administering to said individual an effective amount of a compound of Formula I and related Formulas.

[00128] The compounds of the present invention are useful as anticancer agents for cancers that are responsive to TLR7 activation. In certain embodiments, cancers include, but are not limited to, cancers of the breast, bladder, brain, and central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidneys, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, testicles, stomach, skin, ureter, vagina and vulva; inherited cancers, retinoblastoma and Wilms tumor; leukemia, lymphoma, non-Hodgkin's disease, chronic and acute myeloid leukemia, acute lymphoblastic leukemia, Hodgkin's disease, multiple myeloma and T-cell lymphoma; myelodysplastic syndrome, plasma cell neoplasia, paraneoplastic syndromes, cancers of unknown primary site and AIDS-related malignancies.

[00129] In certain embodiments, the compounds of the invention are used to treat skin or kidney cancers. Sensitivity of a given cancer to TLR7 activation can be assessed, but not limited to measuring a decrease in primary or metastatic tumor burden (minor, partial or complete regression), changes in blood count, altered hormone or cytokine concentrations in the blood, inhibition new increase in tumor burden, stabilization of disease in the patient, evaluation of biomarkers or surrogate markers relevant to the disease, prolonged overall survival of a patient, prolonged time to progression of a patient's disease, prolonged progression-free survival of a patient, prolonged disease-free survival of a patient, improved quality of life of a patient, or modulation of disease co-morbidity (e.g. proem not limited to pain, cachexia, mobilization, hospitalization, altered blood count, weight loss, healing of injury, fever).

[00130] The compounds according to the present invention may also be useful as immune response modifiers, which can modulate the immune response in various ways, making them useful in the treatment of a variety of disorders.

[00131] Provided herein are methods of inhibiting an immune response comprising administering to the individual an effective amount of a TLR7 and/or TLR8 inhibitor (e.g., TLR inhibitor), using the compounds as described herein. In some variations, the TLR inhibitor inhibits a TLR7-dependent immune response. In some variations, the TLR inhibitor inhibits a TLR8-dependent immune response. In some variations, the TLR inhibitor inhibits both a TLR7-dependent and a TLR8-dependent immune response. In some variations, the TLR inhibitor inhibits a TLR7-dependent, a TLR8-dependent, and a TLR-dependent immune response. Unless otherwise mentioned, the term TLR inhibitor refers to any of the TLR inhibitors described herein. In some preferred embodiments, the subject is a human patient.

[00132] Methods of immunoregulation are provided by the present invention, and include those that suppress and/or inhibit an immune response, including, but not limited to, an immune response. The present invention also provides methods for ameliorating symptoms associated with unwanted immune activation, including, but not limited to, symptoms associated with autoimmunity. Immune suppression and/or inhibition in accordance with the methods described herein can be practiced on individuals including those who are suffering from a disorder associated with an unwanted activation of an immune response. The present invention also provides methods for inhibiting a TLR7 and/or TLR8-induced response (e.g., in vitro or in vivo). In some variations, the cell is contacted with the TLR inhibitor in an amount effective to inhibit a cell response that contributes to an immune response.

[00133] Inhibition of TLR7 and/or TLR8 is useful for the treatment and/or prevention of a variety of diseases or disorders that are responsive to cytokines. Conditions for which TLR7 and/or TLR8 inhibitors can be used as treatments include, but are not limited to, autoimmune diseases and inflammatory disorders. Provided herein are methods of treating or preventing a disease or disorder in an individual comprising administering to the individual an effective amount of a TLR7 and/or TLR8 inhibitor. Furthermore, methods for ameliorating symptoms associated with a disease or disorder are provided comprising administering an effective amount of a TLR7 and/or TLR8 inhibitor to an individual having the disease or disorder. Methods are also provided herein for preventing or delaying the development of a disease or disorder, comprising administering an effective amount of an inhibitor of one or more of TLR7 and/or TLR8 to an individual having the disease or disorder. In certain embodiments, the inhibitor is a compound as described herein.

[00134] Provided herein are methods of inhibiting an immune response in an individual, the method comprising administering to the individual at least one TLR inhibitor as described herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is associated with an autoimmune disease. In other aspects, wherein inhibition of the immune response improves one or more symptoms of the autoimmune disease. In still other aspects, in which the immune response treats the autoimmune disease. In still other aspects, in which inhibition of the immune response prevents or delays the development of autoimmune disease. In some variations, the TLR inhibitor inhibits a TLR7-dependent immune response. In some variations, the TLR inhibitor inhibits a TLR8-dependent immune response. In some variations, the TLR inhibitor inhibits both a TLR7-dependent and a TLR8-dependent immune response. In some aspects, at least one TLR inhibitor is administered in an amount effective to inhibit an immune response in the individual.

[00135] Also provided here are methods of treating or preventing an autoimmune disease in an individual, comprising administering to the individual an effective amount of a TLR7 and/or TLR8 inhibitor. In some aspects, the autoimmune disease is characterized by joint pain, antinuclear antibody positivity, malar, or discoid rash. In some aspects, the autoimmune disease is associated with the skin, muscle tissue, and/or connective tissue. In some embodiments, the autoimmune disease is not evidenced in the individual by symptoms of the skin, muscle tissue, and/or connective tissue. In some embodiments, the autoimmune disease is systemic. Autoimmune diseases include, but are not limited to, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic-onset arthritis , irritable bowel disease (IBD), scleroderma, Sjogren's disease, vitiligo, polymyositis, pemphigus vulgaris, pemphigus foliaceus, inflammatory bowel disease including Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease ( GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases may also include, but are not limited to, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cryopathies.

[00136] In some aspects, the autoimmune disease is selected from the group consisting of arthritis, pancreatitis, mixed connective tissue disease (MCTD), lupus, antiphospholide syndrome (APS), systemic onset arthritis, and irritable bowel syndrome.

[00137] In other aspects, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune skin disease, and multiple sclerosis.

[00138] In other aspects, the autoimmune disease is selected from the group consisting of pancreatitis, glomerulonephritis, pyelitis, sclerosing cholangitis, and type I diabetes. In some aspects, the autoimmune disease is rheumatoid arthritis. In some aspects, the autoimmune disease is autoimmune pancreatitis (AIP). In some ways, the autoimmune disease is glomerulonephritis. In some ways, the autoimmune disease is pyelitis. In some ways, the autoimmune disease is sclerosing cholangitis. In some ways the autoimmune disorder is psoriasis. In some respects, autoimmune disease is a rheumatoid disease or disorder. In some aspects, the rheumatoid disease or disorder is rheumatoid arthritis. In some aspects, the disease is diabetes and/or a diabetic-related disease or disorder. In some aspects, autoimmune disease is associated with RNA-containing immune complexes. In some ways, the autoimmune disease is Sjogren's disease.

[00139] Provided herein are methods of inhibiting an immune response in an individual, the method comprising administering to the individual at least one TLR inhibitor as described herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is associated with an inflammatory disorder. When used herein, the term "inflammatory disorder" encompasses autoimmune diseases as well as inflammatory conditions without a known autoimmune component (e.g., atherosclerosis, asthma, etc.). In other aspects, inhibition of the immune response improves one or more symptoms of the inflammatory disorder. In still other aspects, inhibition of the immune response treats the inflammatory disorder. In still other aspects, inhibition of the immune response prevents or delays the development of the inflammatory disorder. In some aspects, the inflammatory disorder is selected from the group consisting of non-rheumatoid arthritis, renal fibrosis, and hepatic fibrosis. In some respects, the inflammatory disorder is an interface dermatitis. In some other aspects, interface dermatitis is selected from the group consisting of lichen planus, lichenoid eruption, keratosis such as lichen planus, lichen striatus, chronic lichenoid keratosis, erythema multiforme, fixed drug eruption, pityriasis lichenoids, phototoxic dermatitis, dermatitis radiation, viral exanthemas, dermatomyositis, secondary syphilis, lichen sclerosus and atrophic, mycosis fungoides, bullous pemphigoid, lichen aureus, porokeratosis, chronic atrophic acrodermatitis, and regressing melanoma. In some aspects, the inflammatory condition is a skin disorder, such as atopic dermatitis (eczema). In some aspects, the inflammatory disorder is a sterile inflammatory condition, such as drug-induced inflammation of the liver and/or pancreas. In some other respects, inflammatory disease is an inflammatory liver disorder. In some other respects, inflammatory disease is an inflammatory pancreatic disorder.

[00140] Provided herein are methods of inhibiting an immune response in an individual, the method comprising administering to the individual at least one TLR inhibitor as described herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is associated with chronic pathogen stimulation. In some variations, the immune response is associated with HIV infection. In other aspects, in which inhibition of the immune response improves one or more symptoms of the viral disease or disorder resulting from HIV infection. In still other aspects, in which inhibition of the immune response treats the viral disease or disorder resulting from HIV infection. In still other aspects, in which inhibition of the immune response prevents or delays the development of the disease or viral disorder resulting from HIV infection. Other variations provided here relate to immunoinhibitory therapy of individuals who have been exposed to or infected with HIV. Administration of a TLR inhibitor to an individual who has been exposed to or infected with HIV results in suppression of HIV-induced cytokine production. In some aspects, at least one TLR inhibitor is administered in an amount effective to suppress HIV-induced cytokine production in an individual exposed to, or infected with, HIV.

[00141] Provided herein are methods for inhibiting a TLR7 and/or TLR8-dependent immune response in an individual, the method comprising administering to the individual a TLR inhibitor in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is associated with an autoimmune disease. In some ways, the autoimmune disease is rheumatoid arthritis. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of rheumatoid arthritis. In some ways, the autoimmune disease is multiple sclerosis. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of multiple sclerosis. In some ways, the autoimmune disease is lupus. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of lupus. In some ways, the autoimmune disease is pancreatitis. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of pancreatitis. In some ways, the autoimmune disease is diabetes. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of diabetes. In some respects, the disease is Sjogren's disease. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of Sjogren's disease. In some variations, the immune response is associated with an inflammatory disorder. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of an inflammatory disorder. In some variations, the immune response is associated with chronic pathogen stimulation. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of chronic pathogen stimulation. In some variations, the immune response is associated with viral disease resulting from HIV infection. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of viral disease resulting from HIV infection. In any variation, the TLR inhibitor is a polynucleotide comprising an inhibitory motif for one or more of TLR7, TLR8 and TLR9.

[00142] In some embodiments of any of the methods involving administering a TLR inhibitor to an individual (e.g., methods of inhibiting an immune response, treating or preventing an autoimmune disease or inflammatory disorder, etc.) the TLR inhibitor TLR has a therapeutically acceptable safety profile. The TLR inhibitor may, for example, have a therapeutically acceptable histological profile including acceptably low toxicity, if any, of the liver, kidneys, pancreas, or other organs. At the time, polynucleotides were associated with toxicities for certain organs, such as the liver, kidneys and pancreas. In some embodiments, the TLR inhibitor has a safe profile that is unexpected and advantageous. In some embodiments, a safety profile includes assessment of toxicity, histological profile, and/or necrosis (e.g., liver, kidneys, and/or heart). In some embodiments, the TLR inhibitor has a therapeutically acceptable level of toxicity. In some embodiments, the TLR inhibitor has a reduced level of toxicity when compared to another TLR inhibitor. In some embodiments, the TLR inhibitor induces a therapeutically acceptable reduction in body weight when compared to the initial body weight of a treated individual. In some embodiments, the TLR inhibitor induces less than a 5%, 7.5%, 10%, 12.5, or 15% reduction in total body weight. In some embodiments, the TLR inhibitor has a therapeutically acceptable histological profile. In some embodiments, the TLR inhibitor has a better histological profile (e.g., lower severity score), for example, when compared to a reference TLR inhibitor. In some embodiments, the TLR inhibitor has a better histological profile (e.g., lower severity score) after evaluation of the liver, kidneys and/or heart, for example. In some embodiments, the TLR inhibitor has a therapeutically acceptable necrosis score. In some embodiments, the TLR inhibitor has reduced necrosis and/or better (e.g., lower) necrosis score, for example, when compared to a reference TLR inhibitor. In some embodiments, the TLR inhibitor has reduced renal and/or hepatocellular necrosis and/or a better renal and/or hepatocellular necrosis score, for example, when compared to a reference TLR inhibitor.

[00143] Consequently, the invention provides a method of activating TLR7 in an animal, especially a mammal, preferably a human comprising administering an effective amount of a compound of Formula I to the animal. As with all compositions for inhibiting an immune response, the effective amounts and method of administration of the particular TLR inhibitory formulation may vary based on the individual in which the condition is to be treated and other factors apparent to one skilled in the art. An effective amount of a compound will vary depending on factors known in the art, but is expected to be a dose of about 0.1 to 10 mg/kg, 0.5 to 10 mg/kg, 1 to 10 mg/kg , 0.1 to 20 mg/kg, 0.1 to 20 mg/kg, or 1 to 20 mg/kg.

[00144] The invention also provides a method of treating a viral infection in an animal, which comprises administering an effective amount of a compound of Formula I to the animal. An amount effective to treat or inhibit a viral infection is an amount that will cause a reduction in one or more of the manifestations of viral infection, such as viral lesions, viral load, rate of virus production, and mortality, when compared to control animals. untreated. The precise amount will vary according to factors known in the art, but is expected to be a dose as indicated above with respect to TLR7 activation, or a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg.

[00145] In various embodiments, compounds of Formula (I), and related Formulas exhibit an IC50 for binding to TLR7/8 less than about 5 μM, preferably less than about 1 μM, and even more preferably less than about 0.100 μM.

[00146] The method of the invention can be carried out in vitro or in vivo. The susceptibility of a particular cell to treatment with the compounds according to the invention can be particularly determined by in vitro tests, whether in the course of research or clinical application. Typically, a cell culture is combined with a compound according to the invention in various concentrations for a period of time that is sufficient to allow the active agents to inhibit TLR7/8 activity, generally between about one hour and one week. In vitro treatment can be performed using cells cultured from a biopsy sample or cell line.

[00147] The host or patient may belong to any mammalian species, for example, a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for the treatment of human disease.

[00148] For identifying a signal transduction pathway and for detecting interactions between various signal transduction pathways, several scientists have developed suitable models or model systems, for example, cell culture models and transgenic animal models. To determine certain stages in the signal transduction cascade, the interaction of compounds can be used to modulate the signal. The compounds according to the invention can also be used as reagents for testing TLR7/8-dependent signal transduction pathways in animals and/or cell culture models or in the clinical diseases mentioned in this application.

[00149] Furthermore, the subsequent teaching of the present specification with respect to the use of the compounds according to Formula (I) and their derivatives for the production of a medicament for prophylactic or therapeutic treatment and/or monitoring, is considered to be valid and applicable without restrictions to the use of the compound for inhibiting TLR7/8 activity if convenient.

[00150] The invention also relates to the use of compounds according to formula (I) and/or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by TLR7/8 activity. Furthermore, the invention relates to the use of compounds according to formula (I) and/or physiologically acceptable salts thereof for the production of a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by TLR7/8 activity. In certain embodiments, the invention provides the use of a compound according to formula I or physiologically acceptable salts thereof, for the production of a medicament for the prophylactic or therapeutic treatment of a TLR7/8-mediated disorder.

[00151] Compounds of Formula (I) and/or a physiologically acceptable salt thereof can also be used as an intermediate for the preparation of other active drug ingredients. The medicament is preferably prepared in a non-chemical manner, for example, by combining the active ingredient with at least one solid, fluid and/or semi-fluid carrier or excipient, and optionally together with a single or more other active substances in a form appropriate dosage.

[00152] The compounds of Formula (I) according to the invention can be administered before or after the onset of the disease once or several times acting as therapy. The aforementioned compounds and medical products of the inventive use are particularly used for therapeutic treatment. A therapeutically relevant effect alleviates to the same extent one or more symptoms of a disorder, or returns to normal, or partially or completely, one or more physiological or biochemical parameters associated with or causing a disease or pathological condition. Monitoring is considered a type of treatment as long as the compounds are administered at distinct intervals, for example, in order to stimulate the response and eradicate the pathogens and/or symptoms of a disease completely. Identical compound or different compounds can be applied. The methods of the invention can also be used to reduce the likelihood of developing a disorder or even prevent the onset of disorders associated with TLR7/8 activity in advance or to treat the onset and continuation of symptoms.

[00153] Within the meaning of the invention, prophylactic treatment is advisable if the individual has any preconditions for the aforementioned physiological or pathological conditions, such as a family disposition, a genetic defect, or a previously incurred disease.

[00154] The invention also relates to a medicament comprising at least one compound according to the invention and/or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios. In certain embodiments, the invention relates to a medicament comprising at least one compound according to the invention and/or physiologically acceptable salts thereof.

[00155] A "medicine" within the meaning of the invention is any agent in the field of medicine, which comprises one or more compounds of Formula (I) or preparations thereof (for example, a pharmaceutical composition or pharmaceutical formulation) and can be used in the prophylaxis, therapy, monitoring or aftercare of patients suffering from diseases, which are associated with the activity of TLR7/8, in such a way that a pathogenic modification of their general condition or the condition of particular regions of the organism can be established at least temporarily.

[00156] In various embodiments, the active ingredient can be administered alone or in combination with other treatments. A synergistic effect can be obtained by using more than one compound in the pharmaceutical composition, that is, the compound of Formula (I) is combined with at least one other agent as an active ingredient, which is either another compound of Formula (I) or a compound of different structural scaffolding. The active ingredients can be used simultaneously or sequentially.

[00157] The TLR inhibitor of the present invention can be administered in combination with one or more additional therapeutic agents. As described herein, the TLR inhibitor can be combined with a physiologically acceptable carrier. The methods described here can be practiced in combination with other therapies that form the standard of care for the disorder, such as administration of anti-inflammatory agents.

[00158] In some embodiments, a TLR inhibitor as described herein is administered in combination with a corticosteroid. In some embodiments, the corticosteroid is a glucocorticosteroid. In some embodiments, the corticosteroid is a mineralocorticoid. Corticosteroids include, but are not limited to, corticosterone and derivatives, prodrugs, isomers and analogues thereof, cortisone and derivatives, prodrugs, isomers and analogues thereof (i.e., Cortone), aldosterone and derivatives, prodrugs , isomers and analogues thereof, dexamethasone and derivatives, prodrugs, isomers and analogues thereof (i.e. Decadron), prednisone and derivatives, prodrugs, isomers and analogues thereof (i.e. Prelona), fludrocortisones and derivatives , prodrugs, isomers and analogues thereof, hydrocortisone and derivatives, prodrugs, isomers and analogues thereof (i.e., cortisol or Cortef), hydroxycortisone and derivatives, prodrugs, isomers and analogues thereof, betamethasone and derivatives , prodrugs, isomers and analogues thereof (i.e. Celestone), budesonide and derivatives, prodrugs, isomers and analogues thereof (i.e. Entocort EC), methylprednisolone and derivatives, prodrugs, isomers and analogues thereof same (i.e., Medrol), prednisolone and derivatives, prodrugs, isomers, and analogues thereof (i.e., Deltasone, Crtan, Meticorten, Orasone, or Sterapred), triamcinolone and derivatives, prodrugs, isomers, and analogues thereof (i.e. Cenacort or Cenalog), and the like. In some embodiments, the corticosteroid is fludrocortisone or a derivative, prodrug, isomer or analogue thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is hydroxycortisone or a derivative, prodrug, isomer or analogue thereof. In some embodiments, the corticosteroid is hydroxycortisone.

[00159] In some embodiments, the corticosteroid is administered between about any of 0.001 mg to 1 mg, 0.5 mg to 1 mg, 1 mg to 2 mg, 2 mg to 20 mg, 20 mg to 40 mg, 40 to 80 mg, 80 to 120 mg, 120 mg to 200 mg, 200 mg to 500 mg, or 500 mg to 1000 mg per day. In some embodiments, the corticosteroid is administered from about any of 0.1 mg/kg to 0.5 mg/kg, 0.5 mg/kg to 1 mg/kg, 1 mg/kg to 2 mg/kg, 2 mg/kg to 5 mg/kg, 5 mg/kg to 10 mg/kg, 10 mg/kg to 15 mg/kg, 15 mg/kg to 20 mg/kg, 20 mg/kg to 25 mg/kg, 25 mg/kg to 35 mg/kg, or 35 mg/kg to 50 mg/kg per day.

[00160] In some embodiments, the TLR inhibitor used in combination therapy, administered in amounts of the released TLR inhibitor, for example, from about any of 0.1 to 10 mg/kg, 0.5 to 10 mg/kg kg, 1 to 10 mg/kg, 0.1 to 20 mg/kg, 0.1 to 20 mg/kg, or 1 to 20 mg/kg.

[00161] In some embodiments, the TLR inhibitor is administered simultaneously with one or more additional therapeutic agents including, but not limited to, a corticosteroid (simultaneous administration). In some embodiments, the TLR inhibitor is administered sequentially with an additional therapeutic agent including, but not limited to, a corticosteroid (sequential administration). In some embodiments, sequential administration includes administering the TLR inhibitor or additional therapeutic agent in a row within about any of one minute, five minutes, 30 minutes, one hour, five hours, 24 hours, 48 hours, or one week. In some embodiments, the TLR inhibitor is administered by the same administration routine as the additional therapeutic agent. In some embodiments, the TLR inhibitor is administered by a different administration routine than the additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered parenterally (e.g., central venous, intra-arterial, intravenous, intramuscular, intraperitoneal, intradermal, or subcutaneous injection), orally, gastrointestinally, topically, nasopharyngeal, and pulmonary (e.g., inhalation or intranasally). In some embodiments, the additional therapeutic agent is a corticosteroid.

[00162] The described compounds of Formula I can be administered in combination with other known therapeutic agents, including anticancer agents. When used herein, the term "anticancer agent" refers to any agent that is administered to a cancer patient for the purposes of treating cancer.

[00163] The anticancer treatment defined above may be applied as a monotherapy or may involve, in addition to the compounds of Formula I described here, conventional surgery or radiotherapy or medicinal therapy. Such medicinal therapy, e.g., chemotherapy or targeted therapy, may include one or more, but preferably one, of the following antitumor agents: , ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH-3024, VAL-0834; Platinum Compounds: such as carboplatin, cisplatin, eptaplatin, myriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin; DNA altering agents: such as anrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; ansacrine, brostalicin, pixantrone, laromustine1,3; Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin; Microtubule Modifiers: such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin,thesistaxel; Antimetabolites: such as asparaginase3, azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, Nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacitarabine, raltitrexed, sapacitabine, tegafur2,3, trimetrexate; Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levadamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin; Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifen, danazol, deslorelin, epithiostanol, orteronel, enzalutamide1,3; Aromatase Inhibitors: such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane; Small Molecule Kinase Inhibitors: such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, Pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, anib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib4, cabozantinib S-malate1,3, ibrutinib1,3, icotinib4, buparlisibee2, cipatinib4, cobimetinib1,3, idelalisib1,3, fedratinib1, XL-6474; Photosensitizers: such as methoxsalen3; porfimer sodium, talaporfin, temoporfin; Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab2,3; catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab1,2,3, be1.3, racotumomab1, tabalumab1.3, EMD-5257974, nivolumab1,3; Cytokines: such as aldesleukin, interferon alpha2, interferon alpha2a3, interferon alpha2b2,3; celmoleukin, tasonermin, teceleukin, oprelvekin1,3, recombinant interferon beta-1a4; Drug Conjugates: such as denileukin diftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estramustine, gentuzumab, ozogamicin, aflibercept; cintredecin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab stafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab1,3, vintafolide1,3; Vaccines: such as sipuleucel3; vitespeno3, emepepimut-S3, oncoVAX4, risopepimut3, troVax4, MGN-16014, MGN-17034; and Heterogeneous: alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel3, sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazole, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, give, genicin4, picibanil4, reolysin4, retaspimycin hydrochloride1,3, trebananib2,3, virulizin4, carfilzomib1,3, endostatin4, imucotel4, belinostat3, MGN-17034. (1 Prop. INN (Proposed International Nonproprietary Name); 2 Rec. INN (Recommended International Nonproprietary Names); 3 USAN (United States Adopted Name); 4 no INN).

[00164] In some embodiments, combining a TLR inhibitor with one or more additional therapeutic agents reduces the effective amount (including, but not limited to, dosage volume, dosage concentration, and/or total drug dose administered) of the TLR inhibitor and/or the one or more additional therapeutic agents administered to obtain the same result as compared to the effective amount administered when the TLR inhibitor or the additional therapeutic agent is administered alone. In some embodiments, combining a TLR inhibitor with a corticosteroid reduces the effective amount of corticosteroid administered when compared to the corticosteroid administered alone. In some embodiments, combining a TLR inhibitor with additional therapeutic agents reduces the frequency of administrations of the therapeutic agent as compared to administering the additional therapeutic agent alone. In some embodiments, combining a TLR inhibitor with the additional therapeutic agent reduces the total duration of treatment compared to administering the additional therapeutic agent alone. In some embodiments, combining a TLR inhibitor with the additional therapeutic agent reduces side effects associated with administering the additional therapeutic agent alone. In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is fludrocortisone or a derivative, prodrug, isomer or analogue thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, combining an effective amount of the TLR inhibitor with the additional therapeutic agent is more effective compared to an effective amount of the TLR inhibitor or the additional therapeutic agent alone.

[00165] TLR inhibitors may also be useful as a vaccine adjuvant for use in conjunction with any material that modulates the humoral and/or cell-mediated immune response, such as, for example, live viral, bacterial, or parasitic immunogens. ; inactivated viral immunogens, tumor-derived, protozoal, organism-derived, fungal, or bacterial immunogens, toxoids, toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides; and similar. In some aspects, combination therapy including, but not limited to, the combination of a TLR inhibitor and a vaccine is used in the treatment of an autoimmune disease or an inflammatory disorder. In some aspects, combination therapy including, but not limited to, the combination of a TLR inhibitor and a vaccine is used in the treatment of an infectious disease.

[00166] In some embodiments, combination therapy including, but not limited to, the combination of a TLR inhibitor and a corticosteroid is used in the treatment of an autoimmune disease or an inflammatory disorder. In some embodiments, the autoimmune disease is selected from, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, autoimmune skin disease, multiple sclerosis, pancreatitis, glomerulonephritis, pyelitis, sclerosing cholangitis, and type I diabetes. In some embodiments, The autoimmune disease is Sjogren's disease.

[00167] Also provided here are kits comprising a TLR inhibitor as provided herein, and instructions for use in methods of inhibiting a TLR7 and/or TLR8-dependent immune response.

[00168] Kits may comprise one or more containers comprising a TLR inhibitor (or a formulation comprising a TLR inhibitor) as described herein, and a set of instructions, generally written instructions, although electronic storage media (e.g., floppy disk) magnetic or optical disk) containing instructions are also acceptable, with respect to the use and dosage of the TLR inhibitor or formulation for the intended treatment (e.g., suppression of a response to TLR7 and/or TLR8 agonists, suppression of an immune-dependent response of TLR7 and/or TLR8, improvement of one or more symptoms of an autoimmune disease, improvement of a symptom of a chronic inflammatory disease, decreased cytokine production in response to a virus, and/or treatment and/or prevention of one or more symptoms of a disease or disorder mediated by TLR7 and/or TLR8). The instructions included with the kit generally include information such as dosage, dosage schedule, and administration routine for the intended treatment. Containers for the TLR inhibitor (or formulations comprising a TLR inhibitor) can be unit doses, bulk packages (e.g., multidose packages) or subunit doses. The kits may also comprise a container comprising an adjuvant.

[00169] In another aspect, the invention provides a kit consisting of separate packages of an effective amount of a compound according to the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and, optionally, an effective amount of another active ingredient. The kit comprises suitable containers such as boxes, individual vials, pouches or ampoules. The kit may, for example, comprise separate ampoules, each containing an effective amount of a compound according to the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of another active ingredient in dissolved or lyophilized form.

[00170] When used herein, the terms "treatment," "treating," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof. , as described here. In some embodiments, treatment is administered after one or more symptoms have developed. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual before the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic factors or other genetic susceptibility). Treatment is also continued after symptoms have resolved, for example, to prevent or delay their recurrence.

[00171] The compounds and compositions, according to the method of the present invention, are administered using any amount and any administration routine effective for treating or reducing the severity of a disorder provided above. The exact amount required will vary from individual to individual, depending on the species, age, and general condition of the individual, the severity of the invention, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The term "dosage unit form" when used herein refers to a physically discrete unit of agent appropriate for the patient being treated. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of safe medical diagnosis. The specific effective dose level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, body weight, general health, sex, and diet; the administration time, administration routine, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or coincident with the specific compound used, and similar factors, well known in the medical arts.

[00172] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), buccally, as an oral or nasal spray, or the like. , depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention are administered orally or parenterally at dosage levels of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 1 mg/kg to about 50 mg/kg. of the individual's body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[00173] In certain embodiments, a therapeutically effective amount of a compound of Formula (I), and related Formulas and the other active ingredient depends on several factors, including, for example, the age and weight of the animal, the condition of The precise disease requiring treatment, and its severity, the nature of the formulation and the method of administration, are ultimately determined by the physician or veterinarian performing the treatment. However, an effective amount of a compound is generally in the range of 0.1 to 100 mg/kg of recipient (mammal) body weight per day and particularly typically in the range of 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal weighing 70 kg is generally between 70 and 700 mg, where this amount may be administered as an individual dose per day or generally in a series of part doses (such as e.g. , two, three, four, five or six) per day, so that the daily dose is the same. An effective amount of a salt or solvate, or a physiologically functional derivative thereof, can be determined as the fraction of the effective amount of the compound itself.

[00174] In certain embodiments, pharmaceutical formulations can be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit. Such a unit may comprise, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be administered in the form of dosage units comprising a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those comprising a daily dose or part dose, as indicated above, or a corresponding fraction thereof, of an active ingredient. Furthermore, pharmaceutical formulations of this type can be prepared using a process, which is generally known in the pharmaceutical art.

[00175] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms optionally 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, acetate. ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor, and sesame oils), glycerol, alcohol tetrahydrofurfuryl, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

[00176] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions are formulated in accordance with the known art using suitable wetting or suspending agents and suspending agents. The sterile injectable preparation is also a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable solvent or diluent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. Furthermore, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic mono- and diglycerides. Furthermore, fatty acids, such as oleic acid, are used in the preparation of injectables.

[00177] Injectable formulations can be sterilized, for example, by filtration through a bacterial retention 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 medium before of use.

[00178] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the subcutaneous or intramuscular injection compound. This is accomplished by using a liquid suspension of crystalline or amorphous material with poor solubility in water. The rate of absorption of the compound then depends on its rate of dissolution which, in turn, may depend on the crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered form of the compound is accomplished by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming microencapsulation matrices of the compound in biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable deosite formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00179] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or vehicles, such as cocoa butter, polyethylene glycol or a suppository wax, which are solids. at room temperature, but liquids at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00180] Solid dosage forms for administration now include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders 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 glycerol, d) disintegrating agents, such as agar agar , calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) humectants such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as bentonite clay and kaolin, 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 also optionally comprises buffering agents.

[00181] Solid compositions of a similar type are also employed as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They optionally contain opacifying agents, and may also be a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type are also employed as fillers in soft and hard filled gelatin capsules, using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[00182] The active compounds can also be in microencapsulated form with one or more excipients, as mentioned above. Solid dosage forms of tablets, tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release control coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms also comprise, as is normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms optionally also comprise buffering agents. They optionally contain opacifying agents and may also be of a composition that releases the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of inlay compositions that can be used include polymeric substances and waxes.

[00183] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions, with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as falling within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled release of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled either by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00184] According to one embodiment, the invention relates to a method of inhibiting TLR7/8 activity in a biological sample, comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound .

[00185] According to another embodiment, the invention relates to a method of inhibiting TLR7/8, or a mutant thereof, activity in a biological sample in a positive manner, comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[00186] The compounds of the invention are useful in vitro as unique tools for understanding the biological role of TLR7/8, including evaluating the many factors believed to influence, and be influenced by, TLR7/8 production and TLR7 interaction /8. The present compounds are also useful in the development of other compounds that interact with TLR7/8, as the present compounds provide important structure-activity linkage (SAR) information that facilitates such development. Compounds of the present invention that bind to TLR7/8 can be used as reagents to detect TLR7/8 in living cells, fixed cells, in biological fluids, in tissue homogenates, in natural, purified biological materials, etc. For example, by labeling such compounds, one can identify cells expressing TLR7/8. Furthermore, based on their ability to bind to TLR7/8, compounds of the present invention can be used in in situ staining, FACS (fluorescence activated cell sorting), sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE) , ELISA (enzyme-linked immunosorbent assay), etc., enzyme purification, or in purification of cells expressing TLR7/8 within permeabilized cells. The compounds of the invention can also be used as commercial research reagents for various medical research and diagnostic uses. Such uses may include, but are not limited to: use as a calibration standard to quantify the activities of candidate TLR7/8 inhibitors in a variety of functional assays; use as blocking reagents in random compound screening, i.e., in search of new families of TLR7/8 ligands, the compounds can be used to block the recovery of the currently claimed TLR7/8 compounds; use in cocrystallization with TLR7/8, that is, the compounds of the present invention will allow the formation of crystals of the compound bound to TLR7/8, enabling the determination of the compound/enzyme structure by x-ray crystallography; other research and diagnostic applications, in which TLR7/8 is preferably activated or such activation is conveniently calibrated against a known amount of a TLR7/8 inhibitor, etc.; use in assays as probes to determine TLR7/8 expression in cells; and development of assays for the detection of compounds that bind to the same site as the TLR7/8 binding ligands.

[00187] The compounds of the invention can be applied either alone and/or in combination with physical measurements for diagnosis of treatment efficacy. Pharmaceutical compositions containing said compounds and the use of said compounds to treat TLR7/8-mediated conditions is a promising new method for a broad spectrum of therapies that cause a direct and immediate improvement in health status, whether in humans or animals. The novel orally bioavailable and active chemical entities of the invention improve convenience for patients and suitability for physicians.

[00188] The compounds of Formula (I), their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and/or metabolites are characterized by high specificity and stability, low manufacturing costs and convenient handling. These aspects form the basis for a reproducible action, in which the absence of cross-reactivity is included, and for a reliable and safe interaction with the target structure.

[00189] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[00190] Modulating TLR7/8, or a mutant thereof, activity 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 assays.

EXEMPLIFICATION

[00191] As represented in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods represent the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one skilled in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described here.

[00192] The symbols and conventions used in the following process descriptions, schemes, and examples are consistent with those used in contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[00193] Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade).

[00194] All solvents used were commercially available and were used without further purification. Reactions were typically conducted using anhydrous solvents under an inert nitrogen atmosphere. Flash column chromatography was generally performed using Silica gel 60 (particle size 0.035 - 0.070 mm).

[00195] All NMR experiments were recorded either on a Bruker Mercury Plus 400 NMR Spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for proton NMR, or on a Bruker Mercury Plus 300 NMR Spectrometer equipped with a Bruker 300 BBFO probe at 300 MHz for proton NMR, or on a Bruker Avance III 400 NMR Spectrometer equipped with a Bruker PABBO BB-1H/D Z GRD probe at 400 MHz for proton NMR. Most deuterated solvents typically contained 0.03% to 0.05% v/v tetramethylsilane, which was used as the reference signal (set at d 0.00 for both 1H and 13C). In cases where the deuterated solvents did not contain tetramethylsilane, the residual non-deuterated solvent peaks were used as a reference signal, according to published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997).

[00196] LC-MS analysis was performed on one of the following two instruments:

[00197] - SHIMADZU LC-EM machine consisting of a UFLC 20-AD system and LCMS 2020 EM detector. The column used was a Shim-pack XR-ODS, 2.2 μm, 3.0 x 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in acetonitrile) for 2.2 minutes with a 3.6 minute run time. The column temperature was 40°C with the flow rate at 1.0 mL/min. The Diode Arrangement detector was scanned from 200-400 nm. The mass spectrometer was equipped with an electrospray (ES) ion source operated in a positive or negative mode. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.6 s.

[00198] - Agilent 1200 Series mass spectrometers from Agilent Technologies, using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI). Diode Arrangement Detector was scanned from 200-400 nm. The mass spectrometer was scanned between m/z 90-900 with a scan time of 0.6 s. Column: XBridge C8, 3.5 μm, 4.6 x 50 mm; Solvent A: water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow: 2 mL/min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min 5% B or a Waters LC/MS ZMD (ESI).

[00199] HPLC data was obtained from the LC-EM SHIMAZU machine or using Agilent HPLC Series 1100 from Agilent technologies using a column (XBridge C8, 3.5 μm, 4.6 x 50 mm) and two mobile phases (mobile phase A: water + 0.1% TFA; mobile phase B: ACN + 0.1% TFA). The flow rate was 2 mL/min. The gradient method was: 0 min: 5% B; 8 min: 100% B; 8.1 min: 100% B; 8.5 min: 5% B; 10 min 5% B unless otherwise indicated.

[00200] In general, compounds according to Formula (I) and related Formulas of this invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they can be prepared by standard synthetic techniques. In general, the synthetic routes for any individual compound of Formula (I) and related Formulas will depend on the specific substituents of each molecule, such factors being appreciated by those skilled in the art. The following general methods and procedures described below in the examples can be employed to prepare compounds of Formula (I) and related Formulas. Reaction conditions represented in the following schemes, such as temperatures, solvents, or co-reagents, are given as examples only, and are not restrictive. It will be appreciated that where typical or preferred experimental conditions (i.e., reaction temperatures, time, moles of reactants, solvents, etc.) are given, other experimental conditions may also be used, unless otherwise stated. Optimal reaction conditions may vary with the particular reagents or solvents used, but such conditions can be determined by the person skilled in the art using routine optimization procedures. For all methods of protection and deprotection, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter GM Wuts in "Protective Groups in Organic Synthesis", Wiley Interscience, 3rd Edition 1999.Intermediate 1: 8-chloropyrido[2,3-b]pyrazine Method A

[00201] 8-Chloropyrido[2,3-b]pyrazine: To a solution of 4-chloropyridine-2,3-diamine (1.90 g, 13.20 mmols) in THF (100 mL) was added oxaldehyde (1 .00 g, 17.20 mmols) at room temperature. The resulting solution was then stirred for 6 hours at room temperature. When the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to yield 8-chloropyrido[2,3-b ]pyrazine as yellow solid (2.10 g, 91%). MS: m/z = 166.1 [M + H]+.Intermediate 2:4-chloro-1,2-diethyl-1H-pyrrolo[2,3-b]pyridine Method B

[00202] 4-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine: A solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.85 g, 18.68 mmols) in DCM (100 mL) were added benzenesulfonyl chloride (4.95 g, 28.02 mmols), 4-dimethylaminopyridine (228 mg, 1.87 mmol) and triethylamine (5.67 g, 56. 04 mmols) at room temperature. The resulting solution was then stirred for 3 hours at room temperature. When the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to yield 1-(benzenesulfonyl)-4-chloro -1H-pyrrolo[2,3-b]pyridine as white solid (4.98 g, 91%). EM: m/z = 292.9 [M + H]+.Method C

[00203] 4-Chloro-2-ethyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]: At -78°C, to a solution of 1-(benzenesulfonyl)-4-chloro-1H- pyrrolo[2,3-b]pyridine (1.86 g, 6.40 mmols) in THF (35 mL) n-BuLi solution (2.5 M in THF, 5 mL, 12.80 mmols) was added dropwise the drop for a period of 5 minutes. The resulting solution was stirred for one hour at -78°C, and then added with iodoethane (2.20 g, 14.10 mmol) slowly. Then, the reaction mixture was slowly heated from -78°C to 0°C over a period of 3 hours while stirring. When the reaction was carried out, it was stopped abruptly by the addition of saturated NH4Cl solution (20 mL) and the resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 5% gradient) to yield 1-(benzenesulfonyl)-4-chloro-2-ethyl-1H-pyrrole [2,3-b]pyridine as white solid (591 mg, 29%). EM: m/z = 320.8 [M + H]+.Method D

[00204] 4-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine: A solution of 1-(benzenesulfonyl)-4-chloro-2-ethyl-1H-pyrrolo[2,3-b ]pyridine (575 mg, 1.80 mmol) in MeOH (20 mL) was added potassium carbonate (592 mg, 4.30 mmol) at room temperature. The resulting mixture was then stirred for 3.5 hours at 50°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with DCM (50 mL). The insoluble solids in the mixture were filtered and the filtrate was concentrated under reduced pressure to yield 4-chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid (443 mg, crude). EM: m/z = 180.9 [M + H]+.Method E

[00205] 4-Chloro-1,2-diethyl-1H-pyrrolo[2,3-b]pyridine: A solution of 4-chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine (443 mg, raw) in acetonitrile (23 mL) Cs2CO3 (1.40 g, 4.30 mmols) and iodoethane (676 mg, 4.30 mmols) were added at room temperature. The resulting mixture was then stirred for 3.5 hours at 40°C. When the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was diluted with DCM (30 mL). The insoluble solids in the mixture were filtered and the filtrate was concentrated under reduced pressure to yield 4-chloro-1,2-diethyl-1H-pyrrolo[2,3-b]pyridine as yellow oil (333 mg, 89% for two steps ). MS: m/z = 209.0 [M + H]+. Intermediate 3: 4-chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine Method F

[00206] 4-Chloro-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]: At -78°C, to a solution of 1-(benzenesulfonyl)-4-chloro-1H- pyrrolo[2,3-b]pyridine (2.00 g, 6.85 mmols) in tetrahydrofuran (30 mL) was added LDA solution (2 M in THF, 3.4 mL, 6.85 mmols) dropwise. the drop. The resulting solution was stirred for one hour at -78°C, and then iodomethane (0.97 g, 6.85 mmol) was added slowly. The resulting mixture was then stirred for 5 hours at -78°C. When the reaction was done, it was stopped abruptly by H2O (30 mL) and the resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-(benzenesulfonyl)-4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine as brown oil (2.50 g, crude).

[00207] 4-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine: 4-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine was prepared from 4-chloro-2 -methyl-1-(phenylsulfonyl)- 1H-pyrrolo[2,3-b]pyridine using Method D. The crude product was purified by flash chromatography eluting with MeOH in DCM (0% to 10% gradient) to yield 4- chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine as yellow solid (900 mg, 79% for two steps). EM: m/z = 166.9 [M + H]+.Method G

[00208] 4-Chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine: At -10°C, to a solution of 4-chloro-2-methyl-1H-pyrrolo[2,3 -b]pyridine (338 mg, 2.03 mmols) in N,N-dimethylformamide (10 mL) was added sodium hydroxide (240 mg, 6.00 mmols). Then, iodomethane (284 mg, 2.00 mmol) was added and the resulting mixture was stirred for 4 hours at -10°C. When the reaction was done, the reaction mixture was diluted by DCM (100 mL) and the resulting mixture was washed with water (30 mL x 3). The organic phase was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 10% gradient) to yield 4-chloro-1,2-dimethyl-1H-pyrrolo[2,3 - b]pyridine as yellow solid (300 mg, 82%). MS: m/z = 181.0 [M + H]+. Intermediate 4: tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate

[00209] tert-Butyl 5-methylpyridin-3-ylcarbamate: at room temperature, to a solution of 5-methylpyridin-3-amine (9.50 g, 88.0 mmols) in tetrahydrofuran (150 mL) was added NaHMDS solution (2 M in THF, 110 mL, 220.0 mmols) dropwise over a period of 10 minutes. The resulting solution was stirred for one hour at room temperature. Then Boc2O (21.14 g, 92.4 mmols) was added. The reaction mixture was stirred for a further two hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of saturated NH4Cl solution (100 mL). The resulting mixture was extracted with ethyl acetate (150 mL x 3) and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 35% gradient) to give tert-butyl N-(5-methylpyridin-3-yl)carbamate as a solid. yellow (15.18 g, 83%). EM: m/z = 209.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.49 (s, 1 H), 8.38 (d, J = 2.4 Hz, 1 H), 8.05-7.97 (m, 1 H), 7.73 (s, 1 H), 2.24 (s, 3 H), 1.47 (s, 9 H).

[00210] tert-Butyl 5-methylpiperidin-3-ylcarbamate: In a 500 mL pressure tank reactor, tert-butyl N-(5-methylpyridin-3-yl)carbamate (14.22 g, 68.43 mmols ), PtO2 (2.50 g, 11.01 mmol) and Rh/C (5%, 2.50 g, 1.21 mmol) were mixed in AcOH (250 mL) at room temperature. The mixture was hydrogenated at 70°C under 15 atm hydrogen pressure for 24 hours. When the reaction was done, the reaction mixture was cooled to room temperature. The insoluble solids in the reaction mixture were filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (100 mL) and the pH value of the mixture was adjusted to 12 with sodium hydroxide solution (20%). The resulting mixture was extracted with DCM (100 mL x 3) and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield tert-butyl N-(5-methylpiperidin-3-yl)carbamate as light brown solid (14.19, 97%). MS: m/z = 215.2 [M + H]+.

[00211] tert-Butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate: A solution of tert-butyl N-(5-methylpiperidin-3-yl)carbamate (11.70 g, 54.60 mmols) in acetone (200 mL) was added a solution of (2R,3R)-2,3-bis[(4-methoxyphenyl)carbonyloxy]butanedioic acid (28.95 g, 69.19 mmols) in isopropanol (13 mL) in room temperature. The resulting mixture was stirred for 24 hours at room temperature and precipitation occurred. When the reaction was done, the precipitates were collected by filtration to produce a white solid, which was added to a solution of potassium carbonate (29.06 g, 210.27 mmols) in water (15 mL) in portions at 0° W. The resulting mixture was then mixed with dichloromethane (100 ml) at 0°C and stirred for 2.5 hours at room temperature. Then, the mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate as white solid (2.93 g, 25%). MS: m/z = 215.2 [M + H]+.Intermediate 5: 8-chloroquinoxaline-5-carbonitrile

[00212] 4-Chloro-2,3-dinitrobenzoic acid: at room temperature, HNO3 (14.4 mol/L, 16 mL, 0.23 mol) was added to a solution of 4-chloro-2-nitrobenzoic acid ( 19.00 g, 94.52 mmols) in H2SO4 (80 mL) dropwise over a period of 30 minutes. The resulting solution was then stirred for one hour at 130°C. After cooling to room temperature, the reaction mixture was poured into ice water (300 mL). The pH value of the resulting mixture was adjusted to 7 with sodium hydroxide solution (6 M). The mixture was then concentrated under reduced pressure and the insoluble solids in the remaining mixture were filtered. The filtrate pH value was then adjusted to 3 with hydrochloric acid solution (6 M) and precipitation took place. The precipitates were collected by filtration and dried in a vacuum oven to yield 4-chloro-2,3-dinitrobenzoic acid as a light yellow solid (4.8 g, crude). EM: m/z = 247.0 [M + H]+.

[00213] 2,3-Diamino-4-chlorobenzoic acid: To a solution of 4-chloro-2,3-dinitrobenzoic acid (4.80 g, raw) in AcOH (80 mL) was added iron powder (1000 mg , 3.58 mmols) at room temperature. The resulting mixture was stirred for two hours at room temperature. The insoluble solids in the reaction mixture were filtered and the filtrate was concentrated under reduced pressure to yield 2,3-diamino-4-chlorobenzoic acid as black oil (3.12 g, crude). EM: m/z = 186.9 [M + H]+.

[00214] 8-Chloroquinoxaline-5-carboxylic acid: To a solution of 2,3-diamino-4-chlorobenzoic acid (3.12 g, raw) in ethanol (40 mL) was added a solution of oxaldehyde in H2O (40 %, 14.4 mol/L, 20 mL, 0.29 mol) at room temperature. The resulting solution was stirred for two hours at 75°C. After cooling to room temperature, the reaction mixture was diluted with H2O (50 mL) and the resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 8-chloroquinoxaline-5-carboxylic acid as yellow oil (1.70 g, crude). EM: m/z = 208.9 [M + H]+.

[00215] 8-Chloroquinoxaline-5-carboxylic acid: 8-chloroquinoxaline-5-carboxylic acid (1.70 g, raw) was added to thionyl chloride (30 mL, 0.39 mol) at room temperature. The resulting solution was stirred for two hours at 60°C. After the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was diluted with DCM (30 mL). The resulting solution was cooled to 0°C and added by NH4OH solution (28%, 14.8 mol/L, 20 mL, 0.30 mol) dropwise over a period of 5 minutes. The resulting mixture was then stirred for one hour at room temperature. When the reaction was done, the reaction mixture was diluted with 20 mL of H2O and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to give 8-chloroquinoxaline-5-carboxamide as yellow oil (1.20 g, 6 % for 4 steps). MS: m/z = 208.1 [M + H]+.

[00216] 8-Chloroquinoxaline-5-carbonitrile: To a solution of 8-chloroquinoxaline-5-carboxamide (0.78 g, 3.77 mmols) in N,N-dimethylformamide (10 mL) was added POCl3 (4.00 g, 22.88 mmols) at room temperature. The resulting solution was stirred for two hours at 60°C. After cooling to room temperature, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 2% gradient) to give 8-chloroquinoxaline-5-carbonitrile as an off-white solid (555 mg, 78%) . EM: m/z = 189.9 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.24 (s, 2 H), 8.48 (d, J = 8.1 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H). Intermediate 6: 8-bromoquinoxaline-5-carbonitrile 5-Bromo-8-methylquinoxaline: To a solution of 5-methylquinoxaline (9.50 g, 65.97 mmols) in CH3CN (80 mL) was added 1-bromopyrrolidine-2,5-dione (27.00 g, 151 .74 mmols) at room temperature. The resulting solution was stirred for 16 hours at 60°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (500 mL). The insoluble solids in the mixture were filtered off and the filtrate was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 5-bromo-8-methylquinoxaline as brown solid (6.00 g, 41%). EM: m/z = 222.9 [M + H]+.

[00217] 5-Bromo-8-(dibromomethyl)quinoxaline: To a solution of 5-bromo-8-methylquinoxaline (6.00 g, 27.02 mmols) in CCl4 (200 mL) was added NBS (19.23 g , 108.08 mmols) and AIBN (0.71 g, 4.32 mmols) at room temperature. The resulting solution was then stirred for 16 hours at 80°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was diluted with ethyl acetate (500 mL). The insoluble solids in the mixture were filtered, and then the filtrate was washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 5% gradient) to give 5-bromo-8-(dibromomethyl)quinoxaline as a light yellow solid (7. 15 g, 70%). EM: m/z = 378.7 [M + H]+.

[00218] 8-Bromoquinoxaline-5-carbaldehyde: To a solution of 5-bromo-8-(dibromomethyl)quinoxaline (13.50 g, 35.71 mmols) in ethanol (290 mL) was added a solution of AgNO3 (24 .27 g, 142.86 mmols) in water (90 mL) dropwise at room temperature. The resulting mixture was then stirred for one hour at room temperature. When the reaction was done, the reaction mixture was diluted with CH3CN (300 mL) and precipitation occurred. The precipitates were filtered and the filtrate was concentrated under reduced pressure to yield 8-bromoquinoxaline-5-carbaldehyde as a yellow solid (10.00 g, crude). MS: m/z = 236.8 [M + H]+.

[00219] Oxima of (E)-8-bromoquinoxaline-5-carbaldehyde: To a solution of 8-bromoquinoxaline-5-carbaldehyde (10 g, raw) in ethanol (100 mL) NaOAc (6.34 g, 73 .42 mmols) and NH2OH.HCl (3.12 g, 42.65 mmols) at room temperature. The resulting mixture was stirred for 3 hours at 70°C. When the reaction was done, the insoluble solids in the reaction mixture were filtered at 70°C, and then the filtrate was cooled to 0°C and precipitation occurred. The precipitates were collected by filtration and dried in an oven to yield (E)-N-[(8-bromoquinoxalin-5-yl)methylidene]hydroxylamine as yellow solid (2.96 g, 33% for two steps). EM: m/z = 253.9[M + H]+.

[00220] 8-Bromoquinoxaline-5-carbonitrile: A solution of (E)-N-[(8-bromoquinoxalin-5-yl)methylidene]hydroxylamine (3.47 g, 13.82 mmols) in acetonitrile (20 mL ) Cu(OAc)2 (577 mg, 3.18 mmols) and acetic acid (1.24 g, 20.73 mmols) were added at room temperature. The resulting mixture was stirred for 15 hours at 88°C. After cooling to room temperature, the reaction mixture was diluted with acetonitrile (10 mL). The insoluble solids in the mixture were filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 15% gradient) to yield 8-bromoquinoxaline-5-carbonitrile as a yellow solid (1.22 g, 38%). MS: m/z = 235.8 [M + H]+. Intermediate 7: 5-Bromoquinazoline-8-carbonitrile

[00221] 8-Methyl-3H-quinazolin-4-one: 2-amino-3-methylbenzoic acid (125 g, 0.820 mol), formamidine acetate (257 g, 2.46 mol) and formamide (32.5 mL , 0.8200 mol) were mixed in a 2 L R.B equipped with a mechanical stirrer. The reaction mixture was heated at 180°C for 3 hours. Completion of the reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled to RT and diluted with 2N NaOH solution (300 mL). After stirring at the same temperature for 15 min, the reaction mixture was neutralized with 1.5 N HCl solution. The solid precipitate was filtered, washed with ice water and dried under vacuum to yield 8-methyl-3H-quinazolin-4- ona (125 g, 94%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 12.2 (bs, 1H), 8.1 (s, 1H), 8.0 (d, J = 7.8 Hz, 1H), 7.7 (d, J = 7.2 Hz, 1H), 7.4 (t, J = 7.6 Hz, 1H), 2.5 (s, 3H); LC/MS(ESI) 161 (M+H).

[00222] 4-Chloro-8-methylquinazoline: Phosphorus oxychloride (800 mL) was captured in a 2 L round-base flask under nitrogen. To this was added 8-methylquinazolin-4(3H)-one (125 g) in portions. The reaction mixture is refluxed at 120°C for 12 hours. Completion of the reaction was monitored by TLC and LCMS. Upon completion, the reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The resulting residue was dissolved in DCM (500 mL) and slowly stopped in a cooled solution of saturated K2CO3 with constant stirring. Then, the organic layer was separated and washed with brine, dried over sodium sulfate and concentrated in vacuo to provide 4-chloro-8-methylquinazoline (120 g, 86%) as a yellow solid. This was carried to the next step without further purification. EM: m/z = 179/181 [M + H]+.

[00223] 8-Methylquinazoline: To a stirred solution of 4-chloro-8-methylquinazoline (120 g, 0.674 mol) in DCM (700 mL) under nitrogen was added p-toluenesulfonylhydrazide (175.7 g, 0.943 mol) in portions . The reaction mixture was heated at 45°C for 12 hours. Completion of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was cooled to RT, the solvent evaporated to dryness, the resulting residue dissolved in EtOH (500 mL), 5 N NaOH solution (500 mL) added and refluxed for 6 hours. Completion of the reaction was monitored by LCMS. Upon completion, the reaction mixture was cooled to RT and extracted with MTBE (3 x 600 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by chromatography using neutralized silica gel (60 to 120 mesh) and eluted with petroleum ether/ethyl acetate to yield 8-methylquinazoline (60 g, 61%) as a low-melting solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.54 (s, 1H), 9.31 (s, 1H), 7.96 (dd, J = 8.8, 8.1 Hz, 1H) , 7.87-7.84 (m, 1H), 7.64 (d, J =15.2 Hz, 1H), 2.67 (s, 3H).

[00224] 5-Bromo-8-methylquinazoline: To a stirred solution of silver sulfate (151.5 g, 0.486 mol) in concentrated sulfuric acid (700 mL) was added 8-methylquinazoline (50 g, 0.347 mol) in portions at 0°C. Bromine (21.3 mL, 0.382 mol) was added dropwise and the reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS at regular intervals. At the end of 16 hours, LCMS showed 40% starting material, 7% isomer, 10% dibromo compound and 40% product. The reaction mixture was quenched with ice, filtered and basified with ammonium hydroxide solution. The aqueous layer was extracted with MTBE (4 x 500 mL), washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was purified by column chromatography using neutralized silica gel (60-120 mesh) and eluted with petroleum ether/ethyl acetate to yield 5-bromo-8-methylquinazoline (16 g, 20%) as a white solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.59 (s, 1H), 9.39 (s, 1H), 7.92 (d, J = 7.72 Hz, 1H), 7.76 (d, J = 7.72 Hz, 1H), 2.62 (s, 3H); MS: m/z = 223/225 [M + H]+.

[00225] 5-Bromo-8-dibromomethylquinazoline: To a stirred solution of 5-bromo-8-methylquinazoline (53 g, 0.237 mol) in CCl4 (800 mL) under nitrogen, N-bromosuccinimide (94.1 g, 0.522 mol) followed by AIBN (7.8 g, 0.048 mol) at room temperature. The reaction mixture was heated at 90°C for 12 hours. Upon completion, the reaction mixture was cooled to RT, filtered and washed with CCl4. The filtrate was concentrated and recrystallized to yield 5-bromo-8-dibromomethylquinazoline (61 g, 67%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.73 (s, 1H), 9.53 (s, 1H), 8.44 (d, J = 8.04 Hz, 1H), 8.21 (d, J = 8.04 Hz, 1H), 8.02 (s, 1H).

[00226] 5-Bromoquinazoline-8-carbaldehyde: To a stirred solution of 5-bromo-8-dibromomethylquinazoline (110 g, crude mixture) in acetone (1 L) and water (200 mL), silver nitrate (110 g) in portions at 0°C. The reaction mixture was stirred at room temperature for two hours. Completion of the reaction was confirmed by TLC. The reaction mixture was filtered and the filtrate was washed with 10% NaHCO3 solution and extracted with ethyl acetate (3 x 500 mL). The combined organic layer was washed with water and brine. The solvent was dried over sodium sulfate and concentrated in vacuo to provide 5-bromoquinazoline-8-carbaldehyde. This was carried to the next step without further purification. 1H NMR (400 MHz, DMSO-d6, ppm) δ 11.14 (s, 1H), 9.80 (s, 1H), 9.58 (s, 1H), 8.29 (d, J = 12, 3Hz, 2H); MS: m/z = 237/239 [M + H]+.

[00227] 5-Bromoquinazoline-8-carbonitrile: To a stirred solution of 5-bromoquinazoline-8-carbaldehyde (25 g, 0.105 mol) in DMF (125 mL), hydroxylamine (7.3g 0.105 mol) and triethylamine ( 89 mL, 0.633 mol) and T3P (100 mL, 0.158 mol). The reaction mixture was heated to 100°C for 3 hours. The reaction was monitored by 1H NMR. Upon completion, the reaction mixture was cooled to RT and stopped abruptly with ice. The reaction mixture was filtered and the filtrate was basified with sodium bicarbonate and extracted with ethyl acetate (3 x 200 mL). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to yield 5-bromoquinazoline-8-carbonitrile (8 g, 32%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.80 (s, 1H), 9.58 (s, 1H), 8.55 (d, J = 7.9 Hz, 2 H), 8, 27(d, J = 7.8 Hz, 2 H); MS: m/z = 232/234 [M + H]+.Intermediate 8: 5-Bromo-quinoline-8-carbonitrile

[00228] 5-Bromoquinoline-8-carbaldehyde oxime: sodium acetate (1.9 g; 23.3 mmols), 5-bromoquinoline-8-carbaldehyde (5.0 g; 21.2 mmols) and hydrochloride of hydroxylamine (1.6 g; 23.3 mmols) were added to absolute ethanol (50 mL). The beige suspension was heated at 70°C for 3 hours and the reaction mixture was allowed to cool to room temperature. After water (25 mL) was added, the beige suspension was concentrated under reduced pressure to ~30 mL. Water (25 mL), tert-butylmethyl ether (12 mL) and heptane (12 mL) were added to the beige suspension, the mixture was stirred for 5 minutes and concentrated under reduced pressure to ~30 mL. Water (25 mL) was added to the beige suspension, the mixture was cooled to 0°C and a 1N aqueous solution of sodium hydroxide (2 mL) was added. The beige suspension was stirred at 0°C for 10 minutes and filtered. The solid was washed with water and dried under vacuum to provide 5-bromo-quinoline-8-carbaldehyde oxide (5.20 g; 94%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 9.16 (s, 1H), 9.03 (dd, J = 4.2, 1.7 Hz, 1H), 8 .54 (dd, J = 8.6, 1.6 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H) , 7.75 (dd, J = 8.6, 4.2 Hz, 1H); EM: m/z = 251 [M + H]+.

[00229] 5-Bromo-quinoline-8-carbonitrile: A mixture of 5-bromo-quinoline-8-carbaldehyde oxide (5.1 g; 20.3 mmols) and copper(ii) acetate monohydrate (81.1 mg; 0.41 mmol) in anhydrous acetonitrile (40 mL) acetic acid (1.4 mL; 24.4 mmol) was added and the reaction mixture was heated at reflux for 1 day. The brown solution was cooled and water (40 mL) was added. The beige suspension was concentrated under reduced pressure and water (30 mL) was added to the beige suspension. The mixture was cooled to 0°C and a 1N aqueous solution of sodium hydroxide (25 mL) was added. The beige suspension was stirred at 0°C for 10 minutes and filtered. The brown solid was purified by recrystallization from chloroform and hexanes to provide 5-bromo-quinoline-8-carbonitrile (1.22 g; 26%) as a cream solid. 1H NMR (400 MHz, CDCl3) δ 9.13 (dd, J = 4.3, 1.6 Hz, 1H), 8.61 (dd, J = 8.6, 1.6 Hz, 1H), 7 .98 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.66 (dd, J = 8.6, 4.2 Hz, 1H) ; MS: m/z = 234 [M + H]+.Intermediate 9: 5-Bromo-8-trifluoromethyl-quinazoline

[00230] 5-Bromo-8-trifluoromethyl-quinazoline: to a solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (1.0 g; 3.69 mmols) and formamidine hydrochloride (594 mg; 7.38 mmols) in anhydrous acetonitrile (30 mL) were added potassium carbonate (1.8 g; 12.9 mmols) and 4 Â molecular sieves (650 mg). The reaction mixture was heated at reflux overnight. The resulting suspension was cooled, filtered over celite, the solids were washed with acetonitrile and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a PuriFlash column (40 g, 15 μm), eluting with hexane and ethyl acetate to provide 5-bromo-8-trifluoromethyl-quinazoline (222 mg, 22%) as a light yellow solid. MS: m/z = 277 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.81 (s, 1H), 9.56 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H).Intermediate 10:5-bromo-8-methyl-[1,7]naphthyridine

[00231] 5-Bromo-8-methyl-[1,7]naphthyridine: A mixture of 5-bromo-2-methyl-pyridin-3-ylamine (3.00 g; 16.0 mmols), glycerol (4 .7 mL; 64.1 mmols), iron (II) sulfate heptahydrate (892 mg; 3.2 mmols) was added dropwise. The resulting mixture was heated at 120°C overnight. The reaction mixture was treated with ice, a 2N solution of sodium hydroxide, ethyl acetate and dichloromethane. After filtering to remove dark brown solids, the organic layer was separated and washed with brine, dried and concentrated. The crude was purified by silica gel chromatography, eluting with ethyl acetate and hexanes, to provide 5-bromo-8-methyl-[1,7]naphthyridine (470 mg, 13%). MS: m/z = 224 [M + H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (s, 1H), 8.50 (dd, J = 8, 6, 1.6 Hz, 1H), 7.96 (dd, J = 8.5, 4.1 Hz, 1H), 2.95 (s, 3H). Example 1: Synthesis of compound 1 (N-(2-(diethylamino)ethyl)-1-(1,8-naphthyridin-4-yl)piperidine-4-carboxamide) Method H

[00232] Ethyl 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate: In a 25 mL reaction tube, ethyl piperidine-4-carboxylate (157 mg, 1.00 mmol) and DIEA ( 153 mg, 1.18 mmol) was added to a solution of 4-bromo-1,8-naphthyridine (190 mg, 0.91 mmol) in ethanol (10 mL) at room temperature. The tube was sealed and the reaction mixture was heated to 100°C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and the resulting mixture was extracted with DCM (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate as yellow solid (211 mg, 81%).(Note: In Method H, the solvent can also be acetonitrile, dmso or NMP instead of EtOH and the reaction temperature can vary from 95°C to 130°C) Method I

[00233] 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylic acid: To a solution of ethyl 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate (210 mg, 0.74 mmol) in ethanol (9 mL) were added sodium hydroxide (147 mg, 3.67 mmol) and water (3 mL) at room temperature. The resulting mixture was stirred for 3 hours at 50°C. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The pH value of the resulting mixture was adjusted to 5 with HCl solution (3 M). The mixture was extracted with DCM (50 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylic acid as a yellow solid (170 mg, 90%). (Note: In method I, sodium hydroxide can also be replaced by lithium hydroxide, the solvent can also be methanol or a mixture of methanol and THF instead of ethanol, and the reaction temperature can vary from room temperature to 50°C ) Method J

[00234] N-(2-(diethylamino)ethyl)-1-(1,8-naphthyridin-4-yl)piperidine-4-carboxamide. To a solution of 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylic acid (114 mg, 0.44 mmol) in N,N-dimethylformamide (5 mL) was added (2-aminoethyl)diethylamine (103 mg, 0.89 mmol), DIEA (286 mg, 2.21 mmol) and HATU (177 mg, 0.46 mmol) at room temperature. The resulting solution was stirred for 16 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with DCM (50 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column, XBridge BEH130 Prep C18 OBD, 19 x 150 mm, 5 µm, 13 nm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 10% to 50% gradient in 10 min; Detector, UV 254 nm. N-[2-(diethylamino)ethyl]-1-(1,8-naphthyridin-4-yl)piperidine-4-carboxamide as a yellow syrup (29 mg, 17%). Compound 1: HPLC: 94.5% purity, Retention Time = 0.80 min. MS: m/z = 356.2 [M + H]+. 1H NMR (300 MHz, CDCl3, ppm) δ 9.06 (dd, J = 4.2, 2.0 Hz, 1 H), 8.92 (d, J = 5.0 Hz, 1 H), 8 .38 (dd, J = 8.4, 2.0 Hz, 1 H), 7.43 (dd, J = 8.4, 4.2 Hz, 1 H), 6.90 (d, J = 5 .1 Hz, 1 H), 6.64 (s, 1 H), 3.72-3.60 (m, 2 H), 3.54-3.35 (m, 2 H), 3.01- 2.86 (m, 2 H), 2.66 (d, J = 8.1 Hz, 6 H), 2.50-2.30 (m, 1 H), 2.21-2.00 (m , 4 H), 1.20-1.00 (m, 6 H).

[00235] The following compounds were synthesized in a similar way:

[00236] Compound 2 ((4-(diethylamino)piperidin-1-yl)(1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methanone): 8-chloropyrido[ 2,3-b]pyrazine, ethyl piperidine-4-carboxylate and N,N-diethylpiperidin-4-amine. HPLC: 96.5% purity, Retention Time =1.18 min. EM: m/z = 397.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.97 (d, J = 1.7 Hz, 1 H), 8.81 (d, J = 1.7 Hz, 1 H), 8.69 (d, J = 5.4 Hz, 1 H), 7.04 (d, J = 5.5 Hz, 1 H), 4.42 (d, J = 12.3 Hz, 3 H), 4, 05 (d, J = 13.6 Hz, 1H), 3,253.10 (m, 2 H), 3.06-2.93 (m, 2 H), 2.74-2.65 (m, 1 H ), 2.55-2.45 (m, 5 H), 1.85-1.60 (m, 6 H), 1.40-1.10 (m, 2 H), 1.00-0, 90 (m, 6H).

[00237] Compound 414 [2-(2,6-dimethyl-piperidin-1-yl)-ethyl]-amide) (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: from 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 2-(3,5-dimethyl-piperidin-1-yl)-ethylamine HPLC: 95.7% purity, Retention Time. = 2.60 min. MS: m/z = 420 [M + H]+. 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5 , 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.23 (s, 1H), 3.53 (dt, J = 12.9, 3.0 Hz , 2 H), 3.39 (q, J = 5.6 Hz, 2 H), 2.90 (td, J = 11.9, 2.8 Hz, 2 H), 2.79 (d, J = 10.2 Hz, 2 H), 2.48 (t, J = 6.0 Hz, 2 H), 2.35 (tt, J = 11.1, 4.2 Hz, 1H), 2.13 (qd, J = 12.2, 11.2, 3.8 Hz, 2 H), 2.04 (dd, J = 13.2, 3.7 Hz, 2 H), 1.81 - 1.56 (m, 3H), 1.51 (t, J = 10.8 Hz, 2 H), 0.87 (d, J = 6.5 Hz, 6H), 0.56 (q, J = 11.8 Hz, 1H).

[00238] Compound 415 (2-dimethylamino-ethyl)-amide) of (1- (8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo-quinoline-8-carbonitrile , ethyl piperidine-4-carboxylate and (2-aminoethyl)dimethylamine. HPLC: 97.8% purity, Retention Time = 1.84 min. MS: m/z = 352 [M + H]+, 1H NMR ( 400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H ), 6.17 (s, 1H), 3.53 (dt, J = 12.0, 2.8 Hz, 2 H), 3.37 (q, J = 6.1, 4.9 Hz, 2 H), 2.89 (td, J = 12.0, 2.7 Hz, 2 H), 2.49 - 2.40 (m, 2 H), 2.36 (tt, J = 11.2, 4.1 Hz, 1H), 2.25 (s, 6H), 2.14 (qd, J = 12.3, 11.4, 3.8 Hz, 2 H), 2.08 - 1.98 ( m, 2 H).

[00239] Compound 416 [2-(ethyl-methyl-amino)-ethyl]-amide) (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo -quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and (2-aminoethyl)(ethyl)methylamine: > 99% purity, Retention Time = 1.94 min. MS: m/z = 366 [M. + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 3.53 (dt, J = 12.0, 2.7 Hz, 2H), 3.37 (q, J = 5, 3 Hz, 2 H), 2.89 (td, J = 11.9, 2.7 Hz, 2 H), 2.55 - 2.41 (m, 4H), 2.35 (tt, J = 11 .2, 4.2 Hz, 1H), 2.23 (s, 3H), 2.13 (qd, J = 12.2, 11.3, 3.8 Hz, 2 H), 2.08 - 1 .99 (m, 2H), 1.07 (t, J = 7.1 Hz, 3H).

[00240] Compound 419 (2-morpholin-4-yl-ethyl)-amide) of (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo-quinoline -8-carbonitrile, ethyl piperidine-4-carboxylate and 4-(2-aminoethyl)morpholine. HPLC: > 99% purity, Retention Time = 1.92 min. +.1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.6, 1.7 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.06 (d, J = 8 .0 Hz, 1H), 6.08 (s, 1H), 3.73 (t, J = 4.7 Hz, 4H), 3.54 (d, J = 12.2 Hz, 2H), 3 .41 (q, J = 5.6 Hz, 2 H), 2.91 (td, J = 11.9, 2.7 Hz, 2 H), 2.53 (t, J = 6.0 Hz, 2 H), 2.48 (t, J = 4.7 Hz, 4H), 2.36 (tt, J = 11.2, 4.2 Hz, 1H), 2.14 (qd, J = 12, 2, 11.4, 3.8 Hz, 2 H), 2.08 - 1.98 (m, 2 H).

[00241] Compound 420 (2-dimethylamino-1-methyl-ethyl)-amide) of (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo-quinoline -8-carbonitrile, ethyl piperidine-4-carboxylate and 1-dimethylamino-2-propylamine: > 99% purity, Retention Time = 2.06 min. . 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.46 (dd, J = 8.5, 1.7 Hz) , 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 8.5, 4.2 Hz, 1H), 7.06 (d, J = 8, 0 Hz, 1H), 5.96 (s, 1H), 3.96 (dq, J = 9.5, 5.9 Hz, 1H), 3.54 (d, J = 12.2 Hz, 2H ), 2.90 (td, J = 11.9, 2.8 Hz, 2 H), 2.44 - 2.29 (m, 2 H), 2.25 (s, 6H), 2.23 - 2.08 (m, 3H), 2.09 - 1.99 (m, 2H), 1.23 (d, J = 6.4 Hz, 3H).

[00242] (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid) compound 421: From of 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 2-(4-methyl-piperazin-1-yl)-ethylamine: 89.1% purity, Retention Time = 1.83. min. MS: m/z = 407 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8 .45 (dd, J = 8.6, 1.7 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.6, 4.2 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 6.16 (s, 1H), 3.54 (d, J = 12.3 Hz, 2H), 3.40 (q, J = 5.5 Hz, 2 H), 2.91 (td, J = 11.9, 2.7 Hz, 2 H), 2.54 (t, J = 6.0 Hz, 4H) , 2.47 (s, 4H), 2.36 (ddd, J = 11.3, 7.0, 4.2 Hz, 1H), 2.31 (s, 3H), 2.13 (qd, J = 12.1, 11.3, 3.8 Hz, 2 H), 2.07 - 2.01 (m, 2 H).

[00243] Compound 422 (2-pyrrolidin-1-yl-ethyl)-amide) of (1- (8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo-quinoline -8-carbonitrile, ethyl piperidine-4-carboxylate and n-(2-aminoethyl)pyrrolidine: > 99% purity, Retention Time = 2.05 minutes MS: m/z = 378 [M + H] +, 1H NMR (400 MHz, Chloroform- d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J=8.5, 1.8 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8 .0 Hz, 1H), 6.19 (s, 1H), 3.53 (dt, J = 12.1, 2.8 Hz, 2 H), 3.40 (q, J = 5.4 Hz, 2 H), 2.89 (td, J = 12.0, 2.6 Hz, 2 H), 2.67 - 2.59 (m, 2 H), 2.58 - 2.45 (m, 4H ), 2.36 (tt, J = 11.3, 4.1 Hz, 1H), 2.14 (qd, J = 12.3, 11.5, 3.9 Hz, 2H), 2.03 (dd, J = 12.8, 3.1 Hz, 2 H), 1.87 - 1.74 (m, 4H).

[00244] Compound 427 [2-(4,4-difluoro-piperidin-1-yl)-ethyl]-amide) (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 2-(4,4-difluoropiperidin-1-yl)ethylamine HPLC: > 99% purity, Retention Time = 2.23. min. MS: m/z = 428 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8 .44 (dd, J = 8.6, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.07 - 5.96 (m, 1H), 3.54 (ddt, J = 11.9, 4.1, 2.0 Hz, 2 H), 3.41 (q, J = 5.6 Hz, 2 H), 2.90 (td, J = 12.0, 2.6 Hz, 2 H), 2.67 - 2.48 (m, 6H), 2.35 (tt, J = 11.2, 4.1 Hz, 1H), 2.14 (qd, J = 12.3, 11.4, 3.8 Hz , 2H), 2.07 - 1.91 (m, 6H).

[00245] Compound 433 (1-methyl-pyrrolidin-2-ylmethyl)-amide) of (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo-quinoline -8-carbonitrile, ethyl piperidine-4-carboxylate and (1-methylpyrrolidin-2-yl)methanamine: 98.9% purity, Retention Time = 2.01 min. MS: m/z = 378 [M. + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8.6, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.5, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.10 (s, 1H), 3.65 (ddd, J = 13.8, 7.8, 2.5 Hz, 1H), 3.59 - 3.48 (m, 2H), 3.13 (ddd, J = 13.7, 4.2, 2.3 Hz, 1H), 3.07 (t, J = 7.8 Hz, 1H), 2.90 (tt, J = 12.1, 3.6 Hz, 2 H), 2.42 - 2.35 (m, 1H), 2.33 (s, 3H), 2.25 (q, J = 8, 9 Hz, 1H), 2.21 - 2.08 (m, 2H), 2.04 (dd, J = 13.4, 3.8 Hz, 2H), 1.97 - 1.83 (m , 1H), 1.81 - 1.66 (m, 2H), 1.65 - 1.50 (m, 2H).

[00246] Compound 434 (1-cyclopropylmethyl-pyrrolidin-3-yl)-amide) of (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: of 5-bromo-quinoline-8 -carbonitrile, ethyl piperidine-4-carboxylate and 1-(cyclopropylmethyl)pyrrolidin-3-amine: HPLC: 96.6% purity, Retention Time = 2.18 minutes MS: m/z = 404 [M + H. ]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.44 (dd, J = 8.6, 1, 7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.49 (dd, J = 8.6, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.08 (s, 1H), 4.51 (tddd, J = 8.4, 6.3, 3.7, 2.3 Hz, 1H), 3.53 (dt , J = 11.9, 2.6 Hz, 2 H), 3.05 (td, J = 8.8, 3.4 Hz, 1H), 2.88 (td, J = 11.9, 2, 7 Hz, 2 H), 2.80 (dd, J = 10.1, 2.6 Hz, 1H), 2.54 (dd, J = 10.1, 6.4 Hz, 1H), 2.43 - 2.20 (m, 5H), 2.12 (qd, J = 12.0, 11.5, 3.8 Hz, 2 H), 2.06 - 1.97 (m, 2 H), 1 .65 (dtt, J = 11.5, 7.4, 3.2 Hz, 1H), 0.94 - 0.85 (m, 1H), 0.53 (ddd, J = 8.0, 5, 5, 4.2 Hz, 2 H), 0.19 - 0.07 (m, 2 H).

[00247] Compound 435 [1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-amide) ((S)-1-ethyl-pyrrolidine-2-carboxylic acid: From 5 -bromo-quinoline-8-carbonitrile, ethyl piperidine-4-carboxylate and 1-ethyl-l-proline: > 99% purity, Retention Time = 2.21 min. MS: m/z = 392 [M. + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.47 (dd, J = 8.6, 4.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (d, J = 12.0 Hz, 2 H), 3.38 - 3.23 (m, 2 H), 3.19 (td, J = 6.9, 3.4 Hz, 1H), 3.08 (dd, J = 10.3, 4.4 Hz, 1H), 2.86 (tt, J = 11, 9, 2.9 Hz, 2 H), 2.68 (dq, J = 12.1, 7.3 Hz, 1H), 2.52 (dq, J = 12.1, 7.1 Hz, 1H) , 2.34 (ddd, J = 10.5, 9.1, 6.2 Hz, 1H), 2.19 (dtd, J = 12.8, 10.2, 7.8 Hz, 1H), 1 .98 - 1.67 (m, 6H), 1.62 (qd, J = 12.2, 4.2 Hz, 2 H), 1.10 (t, J = 7.2 Hz, 3H).

[00248] Compound 439 (2-azetidin-1-yl-ethyl)-amide) of (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromoquinoline -8-carbonitrile, ethyl piperidine-4-carboxylate and 2-(azetidin-1-yl)ethan-1-amine HPLC: > 99% purity, Retention Time = 1.89 min. 364 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.45 (dd, J = 8 .5, 1.7 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 8.6, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 6.09 (s, 1H), 3.53 (dt, J = 12.3, 2.6 Hz, 2 H), 3.31 - 3.15 (m, 6H), 2.88 (td, J = 11.9, 2.7 Hz, 2 H), 2.55 (dd, J = 6.3, 5.3 Hz, 2 H), 2, 34 (tt, J = 11.2, 4.1 Hz, 1H), 2.22 - 1.98 (m, 6H).

[00249] Compound 440 (2-piperidin-1-yl-ethyl)-amide) of (1-(8-cyano-quinoxalin-5-yl)-piperidine-4-carboxylic acid: of 8-bromo-quinoxaline-5 -carbonitrile, ethyl piperidine-4-carboxylate and 1-(2-aminoethyl)piperidine: > 99% purity, Retention Time = 1.96 min. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.00 (d , J = 8.3 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 6.25 (s, 1H), 4.23 (dt, J = 12.4, 2, 8 Hz, 1H), 3.35 (td, J = 6.0, 4.8 Hz, 2 H), 3.12 (ddd, J = 12.4, 10.2, 3.9 Hz, 2 H ), 2.50 - 2.30 (m, 7H), 2.16 - 1.99 (m, 3H), 1.58 (p, J = 5.5 Hz, 4H), 1.46 (q, J = 6.1 Hz, 2 H).

[00250] Compound 454 (4-[4-(8-cyano-quinoxalin-5-yl)-piperazin-1-yl]-N,N-dimethyl-4-oxo-butyramide): 8-bromo-quinoxaline- 5-carbonitrile,1-boc-piperazine and N,N-dimethylsuccinamic acid. HPLC: > 99% purity, Retention Time = 2.13 min. MS: m/z = 367 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.98 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 3.93 (t, J = 5 .2 Hz, 2 H), 3.87 (t, J = 5.1 Hz, 2 H), 3.69 (t, J = 5.1 Hz, 2 H), 3.58 (t, J = 5.2Hz, 2H), 3.08 (s, 3H), 2.96 (s, 3H), 2.83 - 2.66 (m, 4H).

[00251] Compound 456 (2-diethylamino-ethyl)-amide) of (1-(8-fluoro-pyrido[3,4-b]pyrazin-5-yl)-piperidine-4-carboxylic acid: From 5 -chloro-8-fluoropyrido[3,4-b]pyrazine, ethyl piperidine-4-carboxylate and N,N-diethylethylenediamine: > 99% purity, Retention Time = 1.38 min. = 376 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.80 (d, J = 1.8 Hz , 1H), 8.22 (d, J = 1.3 Hz, 1H), 6.23 (s, 1H), 4.83 - 4.72 (m, 2H), 3.36 - 3.26 (m, 2H), 3.20 - 3.07 (m, 2H), 2.59 - 2.48 (m, 6H), 2.48 - 2.37 (m, 1H), 2.04 - 1.89 (m, 4H), 1.02 (t, J = 7.1 Hz, 6H). Example 2: Synthesis of compound 3 (1-(1-methyl-1H-pyrazolo[3,4- d ]pyrimidin-4-yl)-N-(2-(piperidin-1-yl)ethyl)piperidine-4-carboxamide)

[00252] 1-(1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N-(2-(piperidin-1-yl)ethyl)piperidine-4-carboxamide. At 0°C, to a solution of N-[2-(piperidin-1-yl)ethyl]-1-[1H-pyrazolo[3,4-d]pyrimidin-4-yl]piperidine-4-carboxamide (67 mg, 0.19 mmol) in acetone (5 mL) MeI (53 mg, 0.37 mmol) and Cs2CO3 (100 mg, 0.31 mmol) were added. The resulting solution was stirred for 1.5 hours at 0°C. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with DCM (30 mL x 3) and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 10% to 23% gradient in 10 min; Detector, UV 254. 1-[1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-N-[2-(piperidin-1-yl)ethyl]piperidine-4-carboxamide as a off-white solid (7 mg, 10%).Compound 3: HPLC: 99.1% purity, Retention Time = 0.81 min. MS: m/z = 372.2 [M + H]+. 1H NMR (300 MHz, CDCl3, ppm) δ 8.38 (s, 1 H), 7.95 (s, 1 H), 6.44 (s, 1 H), 4.76 (d, J = 13 .2 Hz, 2 H), 4.04 (s, 3 H), 3.42-3.23 (m, 4 H), 2.60-2.30 (m, 7 H), 2.10- 1.40 (m, 10H).Example 3: Synthesis of compound 4 (N,N-diethyl-1-((1-(pyrido[2,3- b]pyrazin-8-yl)piperidin-4-yl) methyl)piperidin-4-amine)

[00253] (1-(Pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methanol: (1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4 -yl)methanol was prepared from 8-chloropyrido[2,3-b]pyrazine and piperidin-4-ylmethanol using Method H. (1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4- il)methanol was obtained as yellow solid (275 mg, 89%). L Method

[00254] (1-(Pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methyl methanesulfonate: A solution of (1-[pyrido[2,3-b]pyrazin- 8-yl]piperidin-4-yl)methanol (250 mg, 1.02 mmol) and triethylamine (155 mg, 1.53 mmol) in dichloromethane (15 mL) was added methyl sulfonyl chloride (152 mg, 1.33 mmol ) in several batches at room temperature. The resulting solution was stirred for two hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (20 mL). The resulting mixture was extracted with dichloromethane (40 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield (1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methyl methanesulfonate as brown solid (300 mg, 91%). MS: m/z = 323.1 [M + H]+. M Method

[00255] N,N-diethyl-1-((1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl) methyl)piperidin-4-amine: To a solution of (1 -[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methyl methanesulfonate (170 mg, 0.53 mmol) in N,N-dimethylformamide (5 mL) N,N-diethylpiperidin was added -4-amine (330 mg, 2.11 mmols) and DIEA (136 mg, 1.05 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred for 8 hours at 80°C. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with DCM (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column, XBridge BEH130 Prep C18 OBD, 19 x 150 mm 5 µm 13 nm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 10% to 23% gradient in 18 min; Detector, UV 254 nm. N,N-diethyl-1-[(1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methyl]piperidin-4-amine was obtained as a brown solid (47 mg, 23 %).(Note: The reaction temperature in Method M can vary from 80°C to 130°C)

[00256] Compound 4: HPLC: 97.6% purity, Retention Time = 0.73 min. EM: m/z = 383.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.96 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.67 (d , J = 5.4 Hz, 1H), 7.02 (d, J = 5.5 Hz, 1H), 4.39 (d, J = 12.5 Hz, 2 H), 3.11-3, 00 (m, 2H), 2.85 (d, J = 11.1Hz, 2H), 2.49-2.31 (m, 5H), 2.13 (d, J = 6.7Hz , 2 H), 1.88-1.76 (m, 5H), 1.61 (d, J = 12.0 Hz, 2 H), 1.45-1.21 (m, 4H), 0, 95-0.85 (m, 6H).Example 4: Synthesis of compound 5 (N,N-diethyl-1-((1-(quinolin-4-yl)piperidin-4-yl)methyl)piperidin-4- the mine)

[00257] (1-(Quinolin-4-yl)piperidin-4-yl)methyl methanesulfonate: (1-(quinolin-4-yl)piperidin-4-yl)methyl methanesulfonate was prepared from 4-chloroquinoline, piperidin-4 -ylmethanol, and methanesulfonyl chloride using Method H and L. [1-(Quinolin-4-yl)piperidin-4-yl]methyl methanesulfonate was obtained as yellow solid (550 mg, raw). EM: m/z = 321.0 [M + H]+.Method N

[00258] N,N-diethyl-1-((1-(quinolin-4-yl)piperidin-4-yl)methyl) piperidin-4-amine. To a solution of [1-(quinolin-4-yl)piperidin-4-yl]methyl methanesulfonate (450 mg, raw) in acetonitrile (8 mL) was added N,N-diethylpiperidin-4-amine (209 mg, 1 .34 mmol) and Cs2CO3 (651 mg, 2.00 mmols) at room temperature. The resulting mixture was stirred overnight at 80°C. After cooling to room temperature, the reaction mixture was quenched with water (10 mL) and extracted with DCM (40 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 15% to 60% gradient in 8 min; Detector, UV 254 nm. N,N-diethyl-1-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]piperidin-4-amine was obtained as light yellow solid (40 mg, 15% for 3 steps).( Note: in Method N, the solvent can also be DMF instead of acetonitrile and the reaction temperature can vary from 60°C to 130°C)

[00259] Compound 5: HPLC: 99.7% purity, Retention Time = 0.53 min. MS: m/z = 381.3 [M + H]+. 1H NMR (300 MHz, CDCl3, ppm) δ 8.70 (d, J = 5.0 Hz, 1H), 8.08-7.94 (m, 2H), 7.70-7.55 (m , 1H), 7,507.40 (m, 1H), 6.82 (d, J = 5.0 Hz, 1H), 3.62 (d, J = 12.0 Hz, 2H), 2.97 ( d, J = 11.5 Hz, 2 H), 2.81 (dd, J = 12.8, 10.6 Hz, 2 H), 2.78-2.48 (m, 5H), 2.27 (d, J = 7.0 Hz, 2 H), 2.00-1.40 (m, 11H), 1.20-1.00 (m, 6H).Example 5: Synthesis of compound 6 (4- (4-((2-(piperidin-1-yl)ethoxy)methyl)piperidin-1-yl)quinolone) Method O

[00260] 4-(4-((2-(Piperidin-1-yl)ethoxy)methyl)piperidin-1-yl): A solution of [1-(quinolin-4-yl)piperidin-4-yl] methanol (190 mg, 0.78 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (59 mg, 2.48 mmol) at room temperature. The resulting suspension was stirred for 30 minutes at room temperature, and then 1-(2-chloroethyl)piperidine hydrochloride (304 mg, 1.65 mmol) was added. The reaction mixture was stirred for a further 20 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with DCM (50 mL x 3) and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column: XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 41% to 50% gradient in 9 min; Detector, UV 254 nm. 4-(4-[[2-(piperidin-1-yl)ethoxy]methyl]piperidin-1-yl)quinoline as an off-white solid (35 mg, 13%).

[00261] Compound 6: HPLC: 98.9% purity, Retention Time = 1.17 min. EM: m/z = 354.2 [M + H]+. 1H NMR (300 MHz, CDCl3, ppm) δ 8.70 (d, J = 5.0 Hz, 1 H), 8.06-7.96 (m, 2 H), 7.70-7.60 ( m, 1 H), 7,507.40 (m, 1 H), 6.83 (d, J = 5.0 Hz, 1 H), 3.69-3.56 (m, 4 H), 3.41 (d, J = 6.0 Hz, 2 H), 2.90-2.75 (m, 2 H), 2.70-2.30 (m, 6 H), 2.00-1.35 ( m, 11 H). Example 6: Synthesis of compound 7 (yl)piperidin-4-yl)methyl)ethanamine)

[00262] N-(2-Morpholinoethyl)-1-(quinolin-4-yl)piperidine-4-carboxamide: N-(2-morpholinoethyl)-1-(quinolin-4-yl)piperidine-4-carboxamide was prepared from 4-chloroquinoline, ethyl piperidine-4-carboxylate, and 2-morpholinoethanamine using Method H, I, and J. N-[2-(morpholin-4-yl)ethyl]-1-(quinolin-4-yl )piperidine-4-carboxamide was obtained as yellow oil (374 mg, crude). EM: m/z = 369.1 [M + H]+.Method P

[00263] 2-Morpholino-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)- ethanamine: A solution of N-[2-(morpholin-4-yl)ethyl]- 1-(quinolin-4-yl)piperidine-4-carboxamide (374 mg, crude) in tetrahydrofuran (5 mL) was added to BH3-THF (10 mL, 1M, 1.00 mmol) at room temperature. The resulting solution was then stirred for 6 hours at 65°C. After cooling to room temperature, the reaction mixture was quenched with MeOH (2 mL) and extracted with DCM (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0% to 25% gradient) to produce 2-morpholino-N-((1-(quinolin-4-yl)piperidin -4-yl)methyl)ethanamine as light yellow solid (50 mg, 10% for 4 steps).

[00264] Compound 7: HPLC: 98.9% purity, Retention Time = 0.82 min. MS: m/z = 355.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.58 (d, J = 5.2 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz, 1H), 7.91 (dd, J = 8.4, 1.3 Hz, 1H), 7.75-7.65 (m, 1H), 7.57-7.47 (m, 1H), 6.99 (d, J = 5.2 Hz, 1H), 3.80-3.60 (m, 6H), 3.21-2.80 (m, 6H), 2.70-2.40 (m, 2H), 2 .06- 1.91 (m, 3H), 1.77-1.50 (m, 2H), 1.34-1.19 (m, 2H).Example 7: Synthesis of compound 8 (2- morpholino-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)ethanamine) tert-Butyl (1-(quinolin-4-yl)piperidin-4-yl)methylcarbamate: tert-Butyl (1-(quinolin-4-yl)piperidin-4-yl)methylcarbamate was prepared from 4-chloroquinoline and tert- butyl piperidin-4-ylmethylcarbamate using Method H. The crude product was purified by flash chromatography eluting with MeOH in DCM (0% to 15% gradient) to yield tert-butyl N-[[1-(quinolin-4-yl) piperidin-4-yl]methyl]carbamate as light yellow solid (600 mg, 94%). EM: m/z = 342.1 [M + H]+.Q Method

[00265] (1-(Quinolin-4-yl)piperidin-4-yl)methanamine: A solution of tert-butyl N-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]carbamate (557 mg, 1.63 mmol) in MeOH (10 mL) was added concentrated HCl solution (12 M, 1.5 mL) at room temperature. The resulting solution was stirred for 24 hours at room temperature. When the reaction was done, the reaction mixture was concentrated under reduced pressure to yield [1-(quinolin-4-yl)piperidin-4-yl]methanamine dihydrochloride as yellow solid (380 mg, 84%). MS: m/z = 242.1 [M + H]+. (Note: in Method Q, the solvent can also be 1:1 mixture of dioxane/MeOH or dioxane instead of MeOH)

[00266] 2-(Piperidin-1-yl)-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl) acetamide: 2-(piperidin-1-yl)-N-(( 1-(quinolin-4-yl)piperidin-4-yl)methyl)acetamide was prepared from (1-(quinolin-4-yl)piperidin-4-yl)methanamine hydrochloride and 2-(piperidin-1-yl) acid )acetic using Method J. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 40% to 55% gradient in 10 min; Detector, UV 254 nm. 2-(Piperidin-1-yl)-N-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]acetamide was obtained as light yellow solid (152 mg, 72%).

[00267] Compound 8: HPLC: 98.1% purity, Retention Time = 1.46 min. EM: m/z = 367.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.66 (d, J = 4.9 Hz, 1 H), 8.01-7.90 (m, 2 H), 7.83-7, 62 (m, 2 H), 7.58-7.48 (m, 1 H), 6.96 (d, J = 5.0 Hz, 1 H), 3.54 (d, J = 12.1 Hz, 2H),3.19-3.09 (m, 2H), 2.91 (s, 2H), 2.86-2.70 (m, 2H), 2.50-2, 30 (m, 4 H), 1.85-1.62 (m, 3 H), 1.62-1.31 (m, 8 H).

[00268] The following compounds were synthesized in a similar way:

[00269] Compound 388 (2-Piperidin-1-yl- N-(1-pyrido[2,3-b] pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide): From 8-chloro- pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl) piperidine and piperidin-1-yl-acetic acid. HPLC: 98.6% purity, Retention Time = 1.16 min. EM: m/z = 369 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.72 (d , J = 1.7 Hz, 1H), 7.45 (s, 1H), 6.88 (d, J = 5.4 Hz, 1H), 4.45 (d, J = 12.7 Hz, 2 H), 3.28 (t, J = 6.3 Hz, 2 H), 3.08 (td, J = 12.4, 2.3 Hz, 2 H), 2.97 (s, 2 H) , 2.46 (s, 4H), 1,981.79 (m, 3H), 1.64-1.52 (m, 6H), 1.46 (dd, J = 11.2, 5.5 Hz, 2 H).

[00270] Compound 390 (2-Diethylamino-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-yl)-acetamide): From 8-chloro-pyrido[2, 3-b]pyrazine, 4-n-boc-aminopiperidine and 2-(diethylamino)acetic acid hydrochloride. HPLC: > 99% purity, Retention Time = 0.92 min. EM: m/z = 343 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.97 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 5.3 Hz, 1H), 8.74 (d , J = 1.7 Hz, 1H), 7.49 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 5.4 Hz, 1H), 4.34 (dt, J = 13.0, 2.9 Hz, 2H), 4.13 (dddd, J = 15.0, 10.7, 8.6, 4.3 Hz, 1H), 3.26 (ddd, J = 12.9, 11.4, 2.6 Hz, 2 H), 3.04 (s, 2 H), 2.56 (q, J = 7.1 Hz, 4H), 2.13 (dd, J = 13.1, 3.8 Hz, 2 H), 1.77 (qd, J = 11.5, 3.8 Hz, 2 H), 1.03 (t, J = 7.1 Hz, 6H) .

[00271] Compound 391 (3,4-Dimethoxy-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-benzamide): From 8-chloro-pyrido[ 2,3- b]pyrazine, 4-(boc-aminomethyl) piperidine and 3,4-dimethoxybenzoic acid. HPLC: > 99% purity, Retention Time = 1.90 min. EM: m/z = 408 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.72 (d , J = 1.8 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.27 (dd, J = 8.3, 2.1 Hz, 1H), 6.92 -6.83 (m, 2 H), 6.25 (t, J = 6.2 Hz, 1H), 4.45 (d, J = 12.4 Hz, 2 H), 3.94 (s, 3H), 3.93 (s, 3H), 3.45 (t, J = 6.3 Hz, 2 H), 3.08 (td, J = 12.4, 2.4 Hz, 2 H), 2.08-1.97 (m, 1H), 1.96 (d, J = 13.7 Hz, 2 H), 1.65 (qd, J = 12.1, 3.9 Hz, 2 H) .

[00272] Compound 392 ((1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-pyridine-2-carboxylic acid amide): From 8-chloropyrido[2 ,3-b]pyrazine, 4-(boc-aminomethyl) piperidine and 2-picolinic acid. HPLC: 98.7% purity, Retention Time = 1.19 minutes. EM: m/z = 349 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.99 (d, J = 1.8 Hz, 1H), 8.74 (d, J = 5.3 Hz, 1H), 8.62 (d , J = 1.8 Hz, 1H), 8.59 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.80 (td, J = 7.7, 1.7 Hz, 1H), 7.62 (dt, J = 7.9, 1.1 Hz, 1H), 7.34 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 6 .73 (t, J = 6.1 Hz, 1H), 6.58 (d, J = 5.4 Hz, 1H), 4.83 (d, J = 12.8 Hz, 1H), 4.04 (d, J = 13.5 Hz, 1H), 3.33 (td, J = 6.5, 2.6 Hz, 2 H), 3.09 (td, J = 13.5, 2.7 Hz , 1H), 2.84 (td, J = 12.9, 2.9 Hz, 1H), 2.07 (ddt, J = 11.6, 8.3, 4.3 Hz, 1H), 2, 00 (d, J = 15.3 Hz, 1H), 1.83 (d, J = 13.3 Hz, 1H), 1.47 (pd, J = 12.3, 4.2 Hz, 2 H) .

[00273] Compound 394 (2-Dimethylamino-N-(1-pyrido[2,3-b] pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide): 8-chloro-pyrido[2,3- b]pyrazine, 4-(boc-aminomethyl) piperidine and N,N-dimethylglycine. HPLC: > 99% purity, Retention Time = 0.89 min. MS: m/z = 329 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 5.4 Hz, 1H), 8.72 (d , J = 1.7 Hz, 1H), 7.32 (s, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.43 (dt, J = 12.8, 2, 4 Hz, 2 H), 3.28 (t, J = 6.3 Hz, 2 H), 3.06 (td, J = 12.4, 2.4 Hz, 2 H), 2.97 (s , 2 H), 2.30 (s, 6H), 1.97-1.82 (m, 3H), 1.58 (dtd, J = 13.3, 11.7, 3.8 Hz, 2 H ).

[00274] Compound 396 (3-Diethylamino-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-yl)-propionamide): From 8-chloro-pyrido[2, 3- b]pyrazine, 4-(n-boc-amino)piperidine and 3-(diethylamino)propanoic acid hydrochloride. HPLC: 90.1% purity, Retention Time = 1.02 min. MS: m/z = 357 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (s, 1H), 8.97 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 5.3 Hz , 1H), 8.75 (d, J = 1.7 Hz, 1H), 6.90 (d, J = 5.4 Hz, 1H), 4.27 (dt, J = 12.7, 3, 1 Hz, 2 H), 4.17-4.03 (m, 1H), 3.27 (ddd, J = 13.0, 11.1, 2.7 Hz, 2 H), 2.67 (t , J = 5.9 Hz, 2 H), 2.57 (q, J = 7.1 Hz, 4H), 2.38 (t, J = 5.8 Hz, 2 H), 2.13 (dd , J = 12.8, 3.7 Hz, 2 H), 1.73 (qd, J = 11.0, 3.8 Hz, 2 H), 1.06 (t, J = 7.1 Hz, 6H).

[00275] Compound 399 (3,3-Dimethyl-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-butyramide): From 8-chloro-pyrido[ 2,3- b]pyrazine, 4-(boc-aminomethyl) piperidine and 3,3-dimethylbutyric acid. HPLC: 98.9% purity, Retention Time = 2.00 min. MS: m/z = 342 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.72 (d , J = 1.7 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 5.51 (s, 1H), 4.43 (dt, J = 11.0, 3, 3 Hz, 2 H), 3.24 (t, J = 6.2 Hz, 2 H), 3.07 (td, J = 12.4, 2.3 Hz, 2 H), 2.07 (s , 2H), 1.93-1.79 (m, 3H), 1.56 (qd, J = 13.5, 12.9, 3.7 Hz, 3H), 1.05 (s, 9H) .

[00276] Compound 400 (4-Piperidin-1-yl-1-(4-pyrido[2,3-b]pyrazin-8-yl-piperazin-1-yl)-butan-1-one): From 8-chloro-pyrido[2,3- b]pyrazine, 1-boc-piperazine and 4-(piperidin-1-yl)butanoic acid hydrochloride. HPLC: > 99% purity, Retention Time = 1.02 min. MS: m/z = 369 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.00 (d, J = 1.7 Hz, 1H), 8.86 (d, J = 5.3 Hz, 1H), 8.76 (d , J = 1.7 Hz, 1H), 6.87 (d, J = 5.3 Hz, 1H), 3.96-3.79 (m, 5H), 3.83-3.66 (m, 4H), 2.51-2.27 (m, 8H), 1.87 (p, J = 7.3 Hz, 2 H), 1.57 (p, J = 5.6 Hz, 4H), 1 .50-1.37 (m, 2H).

[00277] Compound 402 (2-Azetidin-1-yl-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide): From 8-chloro- pyrido[2,3- b]pyrazine, 4-(boc-aminomethyl) piperidine and 2-(azetidin-1-yl)acetic acid hydrochloride. HPLC: > 99% purity, Retention Time = 0.94 min. EM: m/z = 341 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.3 Hz, 1H), 8.72 (d , J = 1.7 Hz, 1H), 7.19 (s, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.43 (d, J = 12.5 Hz, 2 H), 3.32 (t, J = 7.1 Hz, 4H), 3.26 (t, J = 6.3 Hz, 2 H), 3.12 (s, 2 H), 3.06 ( td, J = 12.4, 2.3 Hz, 2 H), 2.10 (p, J = 7.1 Hz, 2 H), 1.96 - 1.78 (m, 3H), 1.58 (qd, J = 13.3, 3.7 Hz, 2 H).

[00278] Compound 405 (2-Diethylamino-N-methyl-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide): From 8-chloro- pyrido[2,3-b]pyrazine, tert-butyl methyl(piperidin-4-ylmethyl)carbamate and 2-(diethylamino)acetic acid hydrochloride. HPLC: > 99% purity, Retention Time = 1.07 min. MS: m/z = 371 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 5.4 Hz, 1H), 8.72 (d , J = 1.7 Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.41 (d, J = 12.7 Hz, 2 H), 3.34 (d, J = 7.3 Hz, 2 H), 3.28 (s, 2 H), 3.16 (s, 3 H), 3.08 (td, J = 12.3, 2.6 Hz, 2 H) , 2.61 (q, J = 7.4 Hz, 4H), 2.07 (ddtd, J = 14.7, 11.1, 7.6, 4.0 Hz, 1H), 1.84 - 1 .77 (m, 2H), 1.59 (qd, J = 13.0, 12.5, 3.9 Hz, 2H), 1.05 (t, J = 6.9 Hz, 6H).

[00279] Compound 408 (2-(Ethyl-methyl-amino)-N-(1-pyrido[2,3- b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide): From 8- chloropyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and [ethyl(methyl)amino]acetic acid. HPLC: 98.9% purity, Retention Time = 1.35 min. MS: m/z = 343 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 5.3 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.43 (s, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.44 (dt, J = 12.4, 2.4 Hz, 2 H), 3.27 (t, J = 6.3 Hz, 2 H), 3.07 (td, J = 12.5, 2.4 Hz, 2 H), 3.01 (s, 2 H), 2.49 (q, J = 7.2 Hz, 2 H), 2.28 (s, 3H), 1.96 - 1 .81 (m, 3H), 1.58 (qd, J = 13.3, 3.7 Hz, 2H), 1.06 (t, J = 7.1 Hz, 3H).

[00280] Compound 409 (N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-2-piperidin-1-yl-acetamide): From 5-bromo-quinoline- 8-carbonitrile, 4-(boc-aminomethyl)piperidine and piperidin-1-yl-acetic acid. HPLC: 99.0% purity, Retention Time = 2.25 min. MS: m/z = 392 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 2 H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (d, J = 12.5 Hz, 2 H), 3.33 (t, J = 6.5 Hz, 2 H), 2.99 (s, 2 H), 2.86 (td, J = 12.0, 2.3 Hz, 2 H), 2.49 (s, 4H), 1.90 (d, J = 12.7 Hz, 2 H), 1.79 (dtt, J = 14.0, 6.8, 3.9 Hz, 1H), 1.71 - 1.52 (m, 6H), 1, 47 (s, 2 H).

[00281] Compound 410 (N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-2-(ethyl-methyl-amino)-acetamide): From 5-bromo- quinoline-8-carbonitrile, 4-(boc-aminomethyl)piperidine and [ethyl(methyl)amino]acetic acid. HPLC: 95.9% purity, Retention Time = 2.09 min. MS: m/z = 366 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.6, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 2 H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (d, J = 12.3 Hz, 2 H), 3.33 (t, J = 6.5 Hz, 2 H), 3.04 (s, 2 H), 2.86 (td, J = 12.0, 2.3 Hz, 2 H), 2.52 (q, J = 6.7 Hz, 2 H ), 2.32 (s, 3H), 1.91 (d, J = 12.8 Hz, 2 H), 1.79 (ddt, J = 14.2, 6.9, 3.7 Hz, 1H ), 1.62 (qd, J = 12.0, 3.8 Hz, 2H), 1.09 (t, J = 7.1 Hz, 3H).

[00282] Compound 411 (1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-amide) (1-methyl-pyrrolidine-2-carboxylic acid: From 8-chloro -pyrido[2,3-b]pyrazine, 4-(boc-aminomethyl)piperidine and 1-methylpyrrolidine-2-carboxylic acid: 99.7% purity, Retention Time = 1.02 min. /z = 355 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 5, 4 Hz, 1H), 8.72 (d, J = 1.7 Hz, 1H), 7.49 (s, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.44 (d, J = 12.6 Hz, 2 H), 3.25 (td, J = 6.5, 2.3 Hz, 2 H), 3.17 - 2.99 (m, 3H), 2, 91 (dd, J = 10.1.5.3 Hz, 1H), 2.42 - 2.31 (m, 4H), 2.31 - 2.17 (m, 1H), 1.99 - 1, 65 (m, 6H), 1.65 - 1.48 (m, 2H).

[00283] Compound 412 (2-tert-Butoxy-N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide): From 5-bromo-quinoline-8- carbonitrile, 4-(boc-aminomethyl)piperidine and tert-butoxy acetic acid. HPLC: > 99% purity, Retention Time = 3.73 min. MS: m/z = 381 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.81 (s, 1H), 3.92 (s, 2H), 3.50 (d, J = 11.9 Hz , 2 H), 3.34 (t, J = 6.6 Hz, 2 H), 2.85 (td, J = 12.0, 2.3 Hz, 2 H), 1.92 (d, J = 13.4 Hz, 2 H), 1.80 (dtt, J = 14.3, 6.9, 3.8 Hz, 1H), 1.62 (qd, J = 12.0, 3.8 Hz , 2H), 1.25 (s, 9H).

[00284] Compound 417 (2-Azetidin-1-yl-N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide): From 5-bromo-quinoline- 8-carbonitrile, 4-(boc-aminomethyl)piperidine and 2-(azetidin-1-yl)acetic acid hydrochloride. HPLC: > 99% purity, Retention Time = 2.05 min. MS: m/z = 364 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.41 (dd, J = 8.5, 1.7 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.5, 4.2 Hz, 1H), 7.21 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (d, J = 12.1 Hz, 2 H), 3.43 - 3 .20 (m, 6H), 3.14 (s, 2H), 2.85 (td, J = 12.1, 2.3 Hz, 2H), 2.11 (p, J = 7.0 Hz, 2H), 1.91 (d, J = 12.9Hz, 2H), 1.78 (dtt, J = 14.3, 7.0, 3.8Hz, 1H), 1.61 (qd, J = 12.0.3.9 Hz, 2 H).

[00285] Compound 418 ([1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-1-methyl-pyrrolidine-2-carboxylic acid amide): From 5-bromo-quinoline -8-carbonitrile, 4-(boc-aminomethyl)piperidine and 1-methylpyrrolidine-2-carboxylic acid. HPLC: > 99% purity, Retention Time = 2.11 min. MS: m/z = 378 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.40 (dd, J = 8.5, 1.7 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.58 - 7.49 (m, 1H), 7.47 ( dd, J = 8.5, 4.2 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.50 (dt, J = 12.2, 3.2 Hz, 2 H), 3.30 (td, J = 6.6, 2.0 Hz, 2 H), 3.12 (ddd, J = 9.0, 6.6, 1.9 Hz, 1H), 2, 93 (dd, J = 10.2, 5.3 Hz, 1H), 2.85 (tdd, J = 12.0, 4.0, 2.3 Hz, 2 H), 2.45 - 2.33 (m, 4H), 2.26 (ddt, J = 12.7, 9.8, 8.5 Hz, 1H), 1.96 - 1.87 (m, 2H), 1.86 - 1, 69 (m, 4H), 1.67 - 1.53 (m, 2H).Example 8: Synthesis of compound 9 ((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2, 3-b]pyridin-4-yl)-5-methylpiperidin-3-amine) R Method

[00286] tert-Butyl (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate: To a solution of 4-Chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine (200 mg, 1.11 mmol) in N,N-dimethylformamide (10 mL) was added tert-butyl N-[(3R ,5S)-5-methylpiperidin-3-yl]carbamate (237 mg, 1.11 mmol), Pd2(dba)3.CHCl3 (115 mg, 0.11 mmol), DavePhos (87 mg, 0.22 mmol) and K3PO4 (588 mg, 2.77 mmols) at room temperature. The resulting mixture was stirred for two hours at 130°C. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 2% gradient) to yield tert-butyl N-[(3R,5S)-1-[1, 2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl]carbamate as yellow solid (150 mg, 38%). MS: m/z = 359.1 [M + H]+.(Note: The catalyst in Method R may be Pd2(dppf)Cl2.CHCl3) instead of Pd2(dba)3.CHCl3

[00287] (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-amine: (3R,5S)-1 -(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-amine was prepared from tert-butyl(3R,5S)-1-(1,2 - dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-ylcarbamate using Method Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep , 5 um, 19 mm x 250 mm; Mobile phase, methanol in water (with 10 mmol/L NH4HCO3), 3% to 65% gradient in 8 min; Detector, UV 254 nm. (3R,5S)-1-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-amine was obtained as an off-white solid (30 mg, 26% ).

[00288] Compound 9: HPLC: 97.8% purity, Retention Time = 0.91 min. EM: m/z = 259.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 7.91 (d, J = 5.7 Hz, 1H), 6.49 (d, J = 5.7 Hz, 1H), 6.30 (d, J = 1.2Hz, 1H), 4.22-4.12 (m, 1H), 4.00-3.91 (m, 1H), 3.71 (s, 3H), 3.11-3, 00 (m, 1H), 2.63-2.41 (m, 5H), 2.17-2.07 (m, 1H), 2.00-1.80 (m, 1H), 1.10- 0.96 (m, 4H).Example 9: Synthesis of compound 10 ((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5 -methylpiperidin-3-amine)

[00289] (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine: (3R,5S)-5-methyl-1-(pyrido [2,3-b]pyrazin-8-yl)piperidin-3-amine was prepared from tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate and 8-chloropyrido[2,3-b]pyrazine using Method H and Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 3% to 22% gradient in 9 min; Detector, UV 254 nm. (3R,5S)-5-methyl-1-[pyrido[2,3- b]pyrazin-8-yl]piperidin-3-amine was obtained as yellow syrup (20 mg, 10% for two steps).

[00290] Compound 10: HPLC: 94.1% purity, Retention Time = 1.10 min. MS: m/z = 244.0 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.93 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.65 (d, J = 5.6 Hz, 1H), 7.06 (d, J = 5.7 Hz, 1H), 4.78-4.68 (m, 1H), 4.56-4.46 (m, 1H) , 3.12-2.98 (m, 1H), 2.80-2.60 (m, 2H), 2.19-2.08 (m, 1H), 2.081.88 (m, 1H), 1.18-0.89 (m, 4H).

[00291] The following compounds were synthesized in an analogous manner:

[00292] Compound 11 ((3R,5S)-5-methyl-1-(quinolin-4-yl)piperidin-3-amine): tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate and 4- chloroquinoline. HPLC: 99.9% purity, Retention Time = 0.86 min. MS: m/z = 242.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.64 (d, J = 5.2 Hz, 1H), 8.11-8.04 (m, 1H), 8.00-7.93 (m, 1H), 7.78-7.68 (m, 1H), 7.63-7.53 (m, 1H), 7.04 (d, J = 5.2 Hz, 1H), 3.83-3 .74 (m, 1H), 3.643.55 (m, 1H), 3.35-3.20 (m, 1H), 2.60-2.40 (m, 2H), 2.24-2. 07 (m, 2H), 1.13-0.99 (m, 4H).

[00293] Compound 12 (8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile): of 8-chloroquinoxaline-5-carbonitrile and tert-butyl (3R,5S )-5-methylpiperidin-3-ylcarbamate. HPLC: 98.3% purity, Retention Time = 1.20 min. MS: m/z = 268.0 [M + H]+. 1H NMR (300 MHz, CDCl3, ppm) δ 8.96 (s, 1H), 8.91 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.24 (d , J = 8.5 Hz, 1H), 4.50-4.38 (m, 1H), 4.22-4.08 (m, 1H), 3.34-3.15 (m, 1H), 2.80-2.55 (m, 2H), 2.30-1.95 (m, 2H), 1.20-1.00 (m, 4H).Example 10: Synthesis of compound 13(N -((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl)-2-hydroxyacetamide)

[00294] N-((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl)-2-hydroxyacetamide : N-((3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-yl)-2-hydroxyacetamide was prepared of (3R,5S)-1-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-5-methylpiperidin-3-amine and 2-hydroxyacetic acid using Method J. Crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 3% to 75% gradient in 8 min; Detector, UV 254 nm. N-[(3R,5S)-1-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl]-2-hydroxyacetamide was obtained as white solid (30 mg, 17%).

[00295] Compound 13: HPLC: 96.9% purity, Retention Time = 0.67 minute. MS: m/z = 317.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.81 (d, J = 5.4 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.35 (d , J = 5.5 Hz, 1H), 6.20 (s, 1H), 5.42 (s, 1H), 4.00-3.91 (m, 1H), 3,883.74 (m, 4H) , 3.57 (s, 3H), 2.51 (d, J = 11.5 Hz, 1H), 2.47-2.28 (m, 3H), 1.90-1.60 (m, 2 H), 1.28-1.10 (m, 1H), 0.86 (d, J = 6.5 Hz, 3H).

[00296] The following compounds were synthesized in a similar way:

[00297] Compound 14 (2-hydroxy-N-((3R,5S)-5-methyl-1-(quinolin-4-yl)piperidin-3-yl)acetamide): de (3R,5S)-5- methyl-1-(quinolin-4-yl)piperidin-3-amine and 2-hydroxyacetic acid. HPLC: 98.3% purity, Retention Time = 1.04 min. MS: m/z = 300.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.62 (d, J = 5.2 Hz, 1H), 8.15 (dd, J = 8.3, 1.4 Hz, 1H), 7.96 (dd, J = 8.4, 1.2 Hz, 1H), 7.78-7.68 (m, 1H), 7.64-7.54 (m, 1H), 7.05 (d, J = 5.3 Hz, 1H), 4.38-4.26 (m, 1H), 4.01 (s, 2H), 3.90-3.81 (m, 1H), 3.64 (d , J = 12.3 Hz, 1H), 2.70-2.50 (m, 2H), 2.19-2.10 (m, 2H), 1.37-1.25 (m, 1H ), 1.07 (d, J = 6.4 Hz, 3H).

[00298] Compound 15 (2-hydroxy-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)acetamide): A from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-hydroxyacetic acid. HPLC: 95.3% purity, Retention Time = 0.73 min. EM: m/z = 302.0 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1H), 8.80 (d, J = 1.7 Hz, 1H), 8.65 (d, J = 5.7 Hz, 1H), 7.13 (d, J = 5.6 Hz, 1H), 4.72-4.56 (m, 2H), 4.20-4.08 (m, 1H ), 3.99 (s, 2H), 3.05-2.95 (m, 1H), 2.83-2.73 (m, 1H), 2.14-1.94 (m, 2H ), 1.45-1.25 (m, 1H), 1.02 (d, J = 6.6 Hz, 3H).

[00299] Compound 20 ((S)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-hydroxy-3-methylbutanamide): from 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-hydroxy-3-methylbutanoic acid. HPLC: 98.4% purity, Retention Time = 3.24 min. EM: m/z = 368.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.03 (d, J = 1.8 Hz, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.20 (d , J = 8.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 5.32 (d, J = 5.7 Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H), 4.17 (d, J = 11.8 Hz, 1H), 4.053.85 (m, 1H), 3.66 (dd, J = 5.8, 4.0 Hz, 1H), 2.94-2.84 (m, 1H), 2.73-2.63 (m, 1H), 2.03- 1.86 (m, 3H), 1.40-1.20 (m, 1H), 0.95-0.85 (m, 6H), 0.78 (d, J = 6.8 Hz, 3H) .

[00300] Compound 21 (((R)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-hydroxy-3-methylbutanamide): of 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (R)-2-hydroxy-3-methylbutanoic acid HPLC: 97.6% purity, Retention Time = 1.31 min MS: m/z = 368.3 [M + H]+. , 1H), 8.94 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H ), 7.26 (d, J = 8.5 Hz, 1H), 5.34 (d,J= 5.6 Hz, 1H), 4.30-4.15 (m, 2H), 4, 05-3.90 (m, 1H), 3.68 (dd, J = 5.6, 3.9 Hz, 1H), 2.98-2.88 (m, 1H), 2.75-2, 60 (m, 1H), 2.02-1.85 (m, 3H), 1.40-1.20 (m, 1H), 0.96-0.85 (m, 6H), 0.78 ( d, J = 6.8 Hz, 3H).

[00301] Compound 22 ((S)-2-hydroxy-3-methyl-N-((3R,5S)-5-methyl-1- (pyrido[2,3-b]pyrazin-8-yl)piperidin- 3-yl)butanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-hydroxy-acid 3-methylbutanoic acid. HPLC: 96.8% purity, Retention Time = 1.05 min. MS: m/z = 344.0 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.17 (d, J = 5.7 Hz, 1H), 4.71-4.60 (m, 2H), 4.18-4.08 (m, 1H ), 3.87 (s, 1H), 3.05-2.94 (m, 1H), 2.87-2.76 (m, 1H), 2.15-1.95 (m, 3H), 1.50-1.30 (m, 1H), 1.09-0.99 (m, 6H), 0.91 (d, J = 6.8 Hz, 3H).

[00302] Compound 23 ((R)-2-hydroxy-3-methyl-N-((3R,5S)-5-methyl-1- (pyrido[2,3-b]pyrazin-8-yl)piperidin- 3-yl)butanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-hydroxy-acid 3-methylbutanoic acid. HPLC: 96.9% purity, Retention Time = 1.02 min. MS: m/z = 344.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 5.7 Hz, 1H), 4.58-4.72 (m, 2H), 4.20-4.10 (m, 1H ), 3.89 (m, 1H), 3.06-2.96 (m, 1H), 2.86-2.75 (m, 1H), 2.15-1.95 (m, 3H), 1.42-1.30 (m, 1H), 1.10-1.00 (m, 6H), 0.90 (d, J = 6.8 Hz, 3H).

[00303] Compound 32 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(dimethylamino)acetamide): 8-((3R ,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(dimethylamino)acetic acid. HPLC: 96.9% purity, Retention Time = 1.25 min. MS: m/z = 353.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.03 (d, J = 1.7 Hz, 1H), 8.94 (d, J = 1.7 Hz, 1H), 8.19 (d , J = 8.4 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 4.33-4.13 (m, 2H), 4.05-3.88 (m, 1H), 2.97-2.79 (m, 3H), 2.72-2.60 (m, 1H), 2.21 ( s, 6H), 1.98-1.82 (m, 2H), 1.34-1.20 (m, 1H), 0.92 (d, J = 6.2 Hz, 3H).

[00304] Compound 33 (2-(dimethylamino)-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)acetamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-(dimethylamino)acetic acid. HPLC: 99.6% purity, Retention Time = 1.31 min. EM: m/z = 329.0 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 4.74-4.59 (m, 3H), 4.20-4.04 (m, 1H) , 3,102.89 (m, 3H), 2.83-2.73 (m, 1H), 2.34 (s, 6H), 2.16-1.93 (m, 2H), 1,401.28 ( m, 1H), 1.04 (d, J = 6.6 Hz, 3H).

[00305] Compound 36 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3-methyloxetane-3-carboxamide): From 8- chloroquinoxaline-5-carbonitrile, tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate and 3-methyloxane-3-carboxylic acid. HPLC: 99.2% purity, Retention Time = 1.15 min. EM: m/z = 366.0 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.7 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.95-4.85 (m, 2H), 4.41-4.02 (m, 5H ), 2.80-2.55 (m, 2H), 2.12-1.93 (m, 2H), 1.57 (s, 3H), 1.31-1.12 (m, 1H ), 0.98 (d, J = 6.4 Hz, 3H).

[00306] Compound 37 (3-methyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3- b]pyrazin-8-yl)piperidin-3-yl)oxetan-3- carboxamide): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-methyloxane-3-carboxylic acid. HPLC: 99.8% purity, Retention Time = 0.88 min. EM: m/z = 342.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 4.90-4.80 (m, 2H), 4.73- 4.61 (m, 2 H), 4.39 (d, J = 6.1 Hz, 2 H), 4.15-4.03 (m, 1H), 2.91-2.71 (m, 2 H), 2.12 -1.92 (m, 2H), 1.60 (s, 3H), 1.34-1.22 (m, 1H), 1.01 (d, J = 6.6 Hz, 3H).

[00307] Compound 40 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3,3-dimethylbutanamide): of 8-((3R, 5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 3,3-dimethylbutanoic acid. HPLC: 95.2% purity, Retention Time = 3.11 min. EM: m/z = 366.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 1.7 Hz, 1H), 8.93 (d, J = 1.7 Hz, 1H), 8.20 (d , J = 8.4 Hz, 1H), 7.79 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 4.38-4.19 (m, 2H), 3.99-3.84 (m, 1H), 2.79-2.63 (m, 2H), 2.00-1.80 (s, 4H), 1.24 -1.10 (m, 1H), 1.02-0.87 (m, 12H).

[00308] Compound 41 (3,3-dimethyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)butanamide) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3,3-dimethylbutanoic acid. HPLC: 94.8% purity, Retention Time = 0.96 min. EM: m/z = 342.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.00 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.71 (d , J = 5.5 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 4.59 (d, J = 13.1 Hz, 1H), 4.46 (d, J = 12.6 Hz, 1H), 3.94-3.80 (m, 1H), 2.82-2.68 (m, 2H ), 2.00-1.85 (m, 4H), 1.31-1.18 (m, 1H), 1.00-0.80 (m, 12H).

[00309] Compound 97 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-hydroxyacetamide): From 8-((3R, 5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-hydroxyacetic acid. HPLC: 97.5% purity, Retention Time = 1.35 min. EM: m/z = 326.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 9,058.83 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.34 (dd, J = 12.0, 4.3 Hz, 1H), 4.29-4.17 (m, 2 H), 4.02 (s, 2 H), 2.99 -2.87 (m, 1H), 2.72 (t, J = 11.6 Hz, 1H), 2.16-2.00 (m, 2H), 1.42-1.30 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H).

[00310] Compound 108 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(morpholin-4-yl)acetamide): from ( 3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid. HPLC: 98.7% purity, Retention Time = 1.95 min. EM: m/z = 395.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.83 (m, 2 H), 8.10 (d, J = 12.0 Hz, 1H), 7.28 (d, J = 12 .0 Hz, 1H), 4.37-4.13 (m, 3H), 3.78-3.68 (m, 4H), 3.05 (s, 2H), 2.92-2.78 (m, 1H), 2.75-2.65 (m, 1H), 2.58-2.48 (m, 4H), 2.15-1.95 (m, 2H), 1.38- 1.20 (m, 1H), 1.02 (d, J = 12.0 Hz, 3H).

[00311] Compound 109 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide): of 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(4-methylpiperazin-1-yl)acetic acid. HPLC: 99.8% purity, Retention Time = 1.47 min. MS: m/z = 408.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 m, 2 H), 8.10 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8, 4 Hz, 1H), 4.41-4.12 (m, 3H), 3.14-3.01 (m, 2H), 2.86 (dd, J = 11.9, 10.6 Hz, 1H), 2.72 (dd, J = 12.6, 10.8 Hz, 1H), 2.60-2.40 (m, 7H), 2.32 (s, 3H), 2.09 (t , J = 14.0 Hz, 2 H), 1.36-1.24 (m, 1H), 1.04 (d, J = 6.4 Hz, 3H).

[00312] Compound 110 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(morpholin-4- il)acetamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-morpholinoacetic acid. HPLC: 96.5% purity, Retention Time = 1.31 min. MS: m/z = 371.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.7 Hz, 1H), 8.77 (d,J= 1.7 Hz, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.11 (d,J= 5.7 Hz, 1H), 4.70-4.55 (m, 2H), 4.08 (t, J = 11.4 Hz, 1H), 3.74-3.65 (m, 4H), 3.11-2.84 (m, 3H), 2.75 (dd, J = 12.9, 11.1 Hz, 1H) , 2.52-2.49 (m, 4H), 2.08-1.94 (m, 2H), 1.40-1.20 (m, 1H), 0.99 (d, J = 6 .5Hz, 3H).

[00313] Compound 111 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3,3-trifluoropropanamide): de 8-(( 3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 3,3,3-trifluoropropanoic acid. HPLC: 91.5% purity, Retention Time = 1.38 min. MS: m/z = 378.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.93-8.80 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8 .4 Hz, 1H), 4.44-4.30 (m, 1H), 4.29-4.03 (m, 2H), 3.14 (q, J = 10.7 Hz, 2H) , 2.68 (dt, J = 23.6, 11.6 Hz, 2 H), 2.14-1.93 (m, 2 H), 1.21-1.16 (m, 1H), 0 .98 (d, J = 6.4 Hz, 3H).

[00314] Compound 120 (3,3,3-trifluoro-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl] propanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3,3,3-trifluoropropanoic acid. HPLC: 95.3% purity, Retention Time = 1.07 min. MS: m/z = 354.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.11 (d, J = 5.7 Hz, 1H), 4.75-4.56 (m, 2H), 4.15-3.98 (m, 1H ), 3.15 (q, J = 10.7 Hz, 2 H), 2.85-2.65 (m, 2 H), 2.15-1.85 (m, 2 H), 1.22 (td, J = 12.0, 12.0 Hz, 1H), 0.99 (d, J = 6.5 Hz, 3H).

[00315] Compound 130 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1H-imidazol-4-yl)acetamide hydrochloride ): 2-(1H-imidazol-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity, Retention Time = 1.05 min. EM: m/z = 367.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.98-8.85 (m, 3H), 8.11 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7 .32 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 13.3 Hz, 1H), 4.30 (d, J = 12.7 Hz, 1H), 4.23 -4.12 (m, 1H), 3.78 (br s, 2H), 2.85-2.65 (m, 2H), 2.20-1.95 (m, 2H), 1 .27 (td, J = 11.9, 11.9 Hz, 1H), 1.15-0.95 (m, 3H).

[00316] Compound 131 (2-(1H-imidazol-4-yl)-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin- 3-yl]acetamide): from 2-(1H-imidazol-4-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)pipery - din-3-amine. HPLC: 99.2% purity, Retention Time = 0.79 min. MS: m/z = 352.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 5.6 Hz, 1H), 6.96 (s, 1H), 4.72-4.63 (m, 2 H), 4.12-4.00 (m, 1 H), 3.52 (br s, 2 H), 2.90-2.70 (m, 2 H ), 2.15-1.85 (m, 2H), 1.26 (td, J = 12.0, 12.0 Hz, 1H), 1.00 (d, J = 6.6 Hz, 3H ).

[00317] Compound 132 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methyl-1H-imidazol-4-yl )acetamide): 2-(1-methyl-1H-imidazol-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.2% purity, Retention Time = 1.39 min. EM: m/z = 390.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.82 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1 .3Hz, 1H), 7.29 (d, J = 8.4Hz, 1H), 7.01-6.95 (m, 1H), 4.44-4.28 (m, 2H), 4.20-4.08 (m, 1H), 3.71 (s, 3H), 3.48 (br s, 2H), 2.84-2.63 (m, 2H), 2.16 -1.95 (m, 2H), 1.33-1.11 (m, 1H), 1.02 (d, J = 6.5 Hz, 3H).

[00318] Compound 133 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(1-methyl- 1H-imidazol-4-yl)acetamide): from 2-(1-methyl-1H-imidazol-4-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3- b ]pyrazin-8-yl)piperidin-3-amine. HPLC: 95.9% purity, Retention Time = 0.84 min. EM: m/z = 366.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.91 (s, 1H), 8.78 (s, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.53 (s , 1H), 7.13 (d, J = 5.6 Hz, 1H), 6.96 (s, 1H), 4.77-4.57 (m, 2H), 4.133.99 (m, 1H ), 3.69 (s, 3H), 3.47 (s, 2H), 2.90-2.70 (m, 2H), 2.15-1.85 (m, 1H), 1, 26 (td, J = 12.0, 12.0 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H).

[00319] Compound 134 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methoxyacetamide): of 2-methoxyacetic acid and 8-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile.HPLC: 96.7% purity, Retention Time = 1.20 min. MS: m/z = 340.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.82 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8 .4 Hz, 1H), 4.35-4.15 (m, 3H), 3.88 (d, J = 0.6 Hz, 2H), 3.39 (s, 3H), 2.87 ( dd, J = 11.8, 10.4 Hz, 1H), 2.67 (dd, J = 12.4, 10.6 Hz, 1H), 2.04 (d, J = 11.8 Hz, 2 H), 1.30 (td, J = 12.5, 12.5 Hz, 1H), 0.99 (d, J = 6.4 Hz, 3H).

[00320] Compound 140 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methanesulfonamidoacetamide): of 2-(methylsulfonamido)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 93.6% purity, Retention Time = 2.22 min. EM: m/z = 403.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.81 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8 .4 Hz, 1H), 4.38-4.05 (m, 3H), 3.74 (s, 2H), 2.97 (s, 3H), 2.87-2.68 (m, 2 H), 2.16-2.00 (m, 2H), 1.26 (td, J = 11.8, 11.8 Hz, 1H), 0.99 (d, J = 6.4 Hz, 3H).

[00321] Compound 141 (2-methanesulfonamido-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]acetamide): from 2-(methylsulfonamido)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: 98.5% purity, Retention Time = 0.82 min. EM: m/z = 379.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.11 (d, J = 5.7 Hz, 1H), 4.71-4.55 (m, 2H), 4.13-3.99 (m, 1H ), 3.74 (s, 2H), 2.97 (s, 3H), 2.95-2.66 (m, 2H), 2.07 (d, J = 12.9 Hz, 1H) , 2,001.90 (m, 1H), 1.27 (td, J = 12.0, 12.0 Hz, 1H), 0.99 (d, J = 6.5 Hz, 3H).

[00322] Compound 142 (2-(tert-butylamino)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide): 2- (tert-butylamino)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity, Retention Time = 1.38 min. EM: m/z = 381.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.80 (m, 2H), 8.12-8.03 (m, 1H), 7.25 (dd, J = 8.3, 6.2 Hz, 1H), 4.44-4.36 (m, 1H), 4.27 (d, J = 13.1 Hz, 1H), 4.18-4.14 (m, 1H), 3.25 (m, 2H), 2.80 (t, J = 11.3 Hz, 1H), 2.68 (t, J = 11.8 Hz, 1H), 2.16-2.02 ( m, 2H), 1.32-1.21 (m, 1H), 1.13 (s, 9H), 1.03 (d, J = 6.4 Hz, 3H).

[00323] Compound 143 (2-(tert-butylamino)-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl] acetamide): from 2-(tert-butylamino)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: 97.7% purity, Retention Time = 1.04 min. MS: m/z = 357.3 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 5.4 Hz, 1H), 8.74 (d , J = 1.7 Hz, 1H), 7.05 (d, J = 5.5 Hz, 1H), 4.65-4.45 (m, 2H), 4.25-4.11 (m , 1H), 3.25 (s, 2H), 2.86-2.70 (m, 2H), 2.19-2.09 (m, 1H), 2.07-1.93 (m , 1H), 1.25-1.05 (m, 10H), 0.99 (d, J = 6.6 Hz, 3H).

[00324] Compound 144 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-[(2-hydroxyethyl)(methyl)amino]acetamide ): 2-((2-hydroxyethyl)(methyl)amino)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 93.1% purity, Retention Time = 1.09 min. MS: m/z = 383.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.97 (d, J = 1.8 Hz, 1H), 8.89 (d, J = 1.8 Hz, 1H), 8.11 (d , J = 8.4 Hz, 1H), 7.71 (d, J = 6.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 3.28 (d, J = 7.2Hz, 2H), 3.92-4.02 (m, 1H), 3.50-3.54 (m, 2H), 2.83-3.07 (m, 3H), 2.55-2.72 (m, 3H), 2.025 (s, 3H), 1.89-1.98 (m, 3H), 1.88-2.01 (m, 1H), 1.19- 1.31 (m, 2H), 0.93-1.01 (m, 3H).

[00325] Compound 145 (2-[(2-hydroxyethyl)(methyl)amino]-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl] piperidin-3-yl]acetamide): 2-((2-hydroxyethyl)(methyl)amino)acetic acid and (3R,5S)-5-methyl-1- (pyrido[2,3-b]pyrazin-8- il)piperidin-3-amine. HPLC: 90.7% purity, Retention Time = 1.70 min. MS: m/z = 359.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.94 (d, J = 1.5 Hz, 1H), 8.77 (d, J = 1.8 Hz, 1H), 8.69 (d , J = 5.4 Hz, 1H), 7.64 (d, J = 7.2 Hz, 1H), 7.08 (d, J = 5.7 Hz, 1H), 4.43-4.56 (m, 2H), 4.28 (s, 1H), 3.91-3.96 (m, 1H), 3.48 (s, 2H), 2.97-3.03 (m, 1H ), 2.83-2.91 (m, 1H), 2.61-2.72 (m, 2H), 2.49-2.52 (m, 2H), 2.24-2.28 (m, 3H), 1.76-2.01 (m, 2H), 1.21-1.33 (m,1H), 0.94 (d, J = 6.3 Hz, 3H).

[00326] Compound 163 (2-(tert-butoxy)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide): 2- tert-butoxyacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.3% purity, Retention Time = 1.54 min. MS: m/z = 382.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.97-8.85 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.38-4.16 (m, 3H), 3.93 (s, 2H), 2.95 (dd, J = 11.9, 10.5 Hz, 1H ), 2.73 (dd, J = 12.5, 10.6 Hz, 1H), 2.18-2.00 (m, 2H), 1.44-1.33 (m, 1H), 1 .27 (s, 9H), 1.04 (d, J = 6.4 Hz, 3H).

[00327] Compound 164 (2-(tert-butoxy)-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl] acetamide): from 2-tert-butoxyacetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: 97.9% purity, Retention Time = 1.23 min. MS: m/z = 358.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.16 (d, J = 5.6 Hz, 1H), 4.73-4.58 (m, 2 H), 4.17 (tt, J = 11.2 , 4.2 Hz, 1H), 3.93 (s, 2H), 3.09-2.95 (m, 1H), 2.81 (dd, J = 12.8, 11.0 Hz, 1H ), 2.15-1.95 (m, 2H), 1.43 (td, J = 11.8, 11.8 Hz, 1H), 1.28 (s, 9H), 1.05 (d , J = 6.5 Hz, 3H).

[00328] Compound 165 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2,2-difluorocyclopropane-1-carboxamide): From 2,2-difluorocyclopropanecarboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.3% purity, Retention Time = 1.39 min. MS: m/z = 372.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.30 (dd, J = 8.4, 2.4 Hz, 1H), 4.474.27 (m, 2H), 4.25-4.09 (m, 1H ), 2.84-2.64 (m, 2H), 2.59-2.45 (m, 1H), 2.20-1.95 (m, 3H), 1.81-1.73 ( m, 1H), 1.25 (td, J = 12.0, 12.0 Hz, 1H), 1.03 (dd, J = 6.6, 2.4 Hz, 3H).

[00329] Compound 166 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(oxolan-2-ylmethoxy)acetamide): acid 2-(oxolan-2-ylmethoxy)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity, Retention Time = 2.78 min. EM: m/z = 410.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.91 (d, J = 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 4.40 (d, J = 11.9 Hz, 1H), 4.35-4.00 (m , 5H), 3.98-3.79 (m, 2H), 3.64 (dd, J = 10.5, 2.8 Hz, 1H), 3.53-3.43 (m, 1H) , 2.87 (t, J = 11.3 Hz, 1H), 2.71 (t, J = 11.7 Hz, 1H), 2.18-1.89 (m, 5H), 1.72- 1.56 (m, 1H), 1.32 (td, J = 11.9, 11.9 Hz, 1H), 1.05 (d, J = 6.5 Hz, 3H).

[00330] Compound 167 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2,3-dimethylbutanamide): 2,3-dimethylbutanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 98.7% purity, Retention Time = 1.52 min. MS: m/z = 366.3 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.96 (d, J = 1.4 Hz, 1H), 8.83 (d, J = 1.4 Hz, 1H), 8.02 (d , J = 8.3 Hz, 1H), 7.42-7.30 (m, 1H), 5.47 (d, J = 6.9 Hz, 1H), 4.39-4.19 (m, 3H), 2,942.79 (m, 2H), 2.18-1.79 (m, 4H), 1.30-1.16 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H), 1.01-0.89 (m, 9H).

[00331] Compound 168 (2,3-dimethyl-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]butanamide) : 2,3-dimethylbutanoic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: 98.7% purity, Retention Time = 1.21 min. MS: m/z = 342.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.5 Hz, 1H), 8.80 (dd, J = 5.8, 1.8 Hz, 1H), 8.65 (dd, J = 5.6, 1.1 Hz, 1H), 7.16 (d, J = 5.7 Hz, 1H), 4.75-4.60 (m, 2H), 4.11 -3.99 (m, 1H), 2.90-2.70 (m, 2H), 2.12-1.88 (m, 3H), 1.83-1.69 (m, 1H), 1.34-1.19 (m, 1H), 1,140.82 (m, 12H).

[00332] Compound 169 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1H-pyrazol-1-yl)acetamide): of 2-(1H-pyrazol-1-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.4% purity, Retention Time = 1.18 min. EM: m/z = 376.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.93 (d, J = 1.7 Hz, 1H), 8.89 (d, J = 1.7 Hz, 1H), 8,198.06 (m, 1H ), 7.71 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 6.39-6.33 (m, 1H), 4.42 (d, J = 11.7 Hz, 1H), 4.34-4.26 (m, 1H), 4.22-4.11 ( m, 1H), 3.37-3.27 (m, 1H), 3.15-2.95 (m, 1H), 2.852.65 (m, 2H), 2.22-1.98 (m , 2 H), 1.26 (td, J = 12.0, 12.0 Hz, 1H), 1.03 (d, J = 6.4 Hz, 3H).

[00333] Compound 170 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(1H-pyrazol- 1-yl)acetamide): 2-(1H-pyrazol-1-yl)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin -3-amine. HPLC: 98.9% purity, Retention Time = 1.73 min. EM: m/z = 352.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.64 (d, J = 5.6 Hz, 1H), 7.71-7.66 (m, 1H), 7.56-7.51 (m, 1H), 7.13 (d, J = 5.6 Hz, 1H) , 6.34 (t, J = 2.2 Hz, 1H), 4.95-4.80 (m, 2H), 4.75-4.61 (m, 2H), 4.15-3 .99 (m, 1H), 2.94-2.82 (m, 1H), 2.81-2.70 (m, 1H), 2.17-2.06 (m, 1H), 2.05 -1.95 (m, 1H), 1.28 (td, J = 12.0, 12.0 Hz, 1H), 1.01 (d, J = 6.6 Hz, 3H).

[00334] Compound 171 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-methylpyrrolidine-2-carboxamide): 1-methylpyrrolidine acid -2-carboxylic and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 98.5% purity, Retention Time = 1.85 min. MS: m/z = 379.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.38-4.05 (m, 3H), 3.16-3.03 (m, 1H) , 2.91-2.75 (m, 2H), 2.73-2.59 (m, 1H), 2.40-2.26 (m, 4H), 2.211.97 (m, 3H), 1.85-1.71 (m, 3H), 1.33-1.19 (m, 1H), 0.99 (d, J = 6.3 Hz, 3H).

[00335] Compound 172 (Methyl-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]pyrrolidine-2-carboxamide) : 1-methylpyrrolidine-2-carboxylic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: 97.5% purity, Retention Time = 2.22 min. MS: m/z = 355.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.88 (d, J = 1.8 Hz, 1H), 8.76 (t, J = 1.4 Hz, 1H), 8.61 (d, J = 5.6 Hz, 1H), 7.08 (dd, J = 5.7, 1.3 Hz, 1H), 4.66-4.50 (m, 2H), 4.11-3.97 (m, 1H), 3.16-3.00 (m, 1H), 3.01-2.64 (m, 3H), 2.40-1.66 (m, 10H), 1.29 (td , J = 11.8, 11.8 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H).

[00336] Compound 175 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]-3,3-dimethylbutanamide): of 3,3-dimethylbutanoic acid and cis-8 -(3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.1% purity, Retention Time = 2.95 min. MS: m/z = 392.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.46-4.26 (m, 2H), 4.11-4.00 (m, 1H ), 2.91-2.69 (m, 2 H), 2.21-2.09 (m, 1H), 2.06 (s, 2 H), 1.40-1.02 (m, 2 H), 1.01 (s, 9H), 0.63-0.38 (m, 3H), 0.18 (d, J = 3.5 Hz, 2 H).

[00337] Compound 179 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]-2-(dimethylamino)acetamide): 2-(dimethylamino)acetic acid hydrochloride and cis-8-(3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 97.2% purity, Retention Time = 2.42 min. MS: m/z = 379.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1H), 8.84 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.38-4.20 (m, 2H), 4,163.99 (m, 1H), 3, 01-2.80 (m, 4H), 2.29 (s, 6H), 2.23-2.06 (m, 1H), 1.44 (q, J = 11.8 Hz, 1H), 1 .21-1.07 (m, 1H), 0.69-0.38 (m, 3H), 0.27-0.11 (m, 2H).

[00338] Compound 230 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-hydroxycyclopropane-1-carboxamide): 1-hydroxycyclopropane acid -1-carboxylic and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: 98.8% purity, Retention Time = 3.40 min. EM: m/z = 352.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.94-8.80 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8 .4Hz, 1H), 4.35-4.09 (m, 3H), 2.98-2.86 (m, 1H), 2.78-2.62 (m, 1H), 2.15- 1.95 (m, 2H), 1.40-1.15 (m, 3H), 1.00-0.89 (m, 5H).

[00339] Compound 232 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-4-yl)acetamide: de 2-(1-methylpiperidin-4-yl)acetic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile: 95.5% purity, Retention Time = 2.03 min MS: m/z = 407.3 [M + H]+. , 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H ), 5.57 (d, J = 7.3 Hz, 1H), 4.38-4.14 (m, 3H), 2.95-2.69 (m, 4H), 2.30 (s, 3H), 2.19-1.93 (m, 6H), 1.89-1.68 (m, 3H), 1.47-1.09 (m, 3H), 0.98 (d, J = 6.6Hz, 3H).

[00340] Compound 233 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1,4-dimethylpiperidin-4-yl)acetamide ): 2-(1,4-dimethylpiperidin-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.7% purity, Retention Time = 2.95 min. EM: m/z = 421.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8 .4 Hz, 1H), 4.38-4.30 (m, 2H), 4.15 (t, J = 11.9 Hz, 1H), 2.832.55 (m, 4H), 2.46 ( s, 2H), 2.33 (s, 3H), 2.22-1.95 (m, 4H), 1.72-1.67 (m, 2H), 1.56-1.48 ( m, 2H), 1.21 (td, J = 12.1, 12.1Hz, 1H), 1.08 (s, 3H), 1.01 (d, J = 6.3Hz, 3H) .

[00341] Compound 234 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-[1-(2,2-difluoroethyl)piperidin- 4-yl]acetamide): from 2-(1-methylpiperidin-4-yl)acetic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: 93.9% purity, Retention Time = 2.45 min. MS: m/z = 457.3 [M + H]+. 1H NMR (300 MHz, Chloroform-d, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.8 Hz, 1H), 7.97 (d , J = 8.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.10-5.70 (m, 1H), 5.51 (d, J = 7, 2Hz, 1H), 4.35-4.10 (m, 3H), 2.98-2.85 (m, 2H), 2.85-2.62 (m, 4H), 2.28- 1.63 (m, 8H), 1.42-1.06 (m, 4H), 0.95 (d, J = 6.6 Hz, 3H).

[00342] Compound 235 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-difluorocyclobutane-1-carboxamide): deacid 3, 3-difluorocyclobutane-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: 93.9% purity, Retention Time = 4.03 min. EM: m/z = 386.0 [M + H]+. 1H NMR (300 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.81 (d, J = 1.7 Hz, 1H), 7.99 (d , J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.63 (d, J = 6.9 Hz, 1H), 4.30-4.22 (m, 3H), 2.96-2.63 (m, 7H), 2.17-1.99 (m, 2H), 1.21 (td, J = 11.3, 11.3 Hz, 1H), 0.97 (d, J = 6.5 Hz, 3H).

[00343] Compound 236 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-methylpyrrolidine-3-carboxamide): 3,3 acid - difluorocyclobutane-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: 97.5% purity, Retention Time = 2.06 min. MS: m/z = 379.1 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 7.99 (d , J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 7.3 Hz, 1H), 4.33 (dd, J = 12.5, 4.6Hz, 2H), 4.23-4.08 (m, 1H), 2.93-2.86 (m, 3H), 2.83-2.69 (m, 2H), 2.65-2.52 (m, 1H), 2.46-2.40 (m, 4H), 2.28-2.19 (m, 1H), 2.12 (apparent d, J = 12.3 Hz, 1H), 2.08-1.93 (m, 2H), 1,351.10 (m, 1H), 0.98 (d, J = 6.6 Hz, 3H).

[00344] Compound 265 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-hydroxypropanamide): of 2-hydroxypropanoic acid and 8-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.3% purity, Retention Time = 1.16 min. MS: m/z = 340.2 [M + H]+. 1H NMR (300 MHz,CD3OD, ppm) δ 8.95-8.81 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8 .4Hz, 1H), 4.27-4.22 (m, 2H), 4.12-4.07 (m, 2H), 2.86 (dd, J = 12.0, 10.4 Hz, 1H), 2.74-2.60 (m, 1H), 2.07-2.03 (m, 2H), 1.36-1.30 (m, 4H), 0.99 (d , J = 6.4 Hz, 3H).

[00345] Compound 266: (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-3-yl) hydrochloride acetamide): from 2-(1-methylpiperidin-3-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.3% purity, Retention Time = 1.19 min. EM: m/z = 407.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.01-8.89 (m, 2 H), 8.15 (d, J = 8.2 Hz, 1H), 7.57 (dd, J = 7 .8, 2.9 Hz, 1H), 4.29-4.08 (m, 3H), 3.45 (d, J = 12.2 Hz, 2H), 3.07-2.79 (m , 6H), 2.72 (t, J = 11.3 Hz, 1H), 2.31-2.03 (m, 5H), 2.04-1.65 (m, 3H), 1.37- 1.14 (m, 2H), 1.00 (d, J = 6.4Hz, 3H).

[00346] Compound 269 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpyrrolidin-3-yl)acetamide): of 2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.1% purity, Retention Time = 2.41 min. MS: m/z = 393.2 [M + H]+. 1H NMR (300 MHz, Chloroform-d, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.79 (t, J = 1.5 Hz, 1H), 7.96 (d , J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 7.1 Hz, 1H), 4.36-4.08 (m, 3H), 2.84-2.64 (m, 3H), 2.64-2.24 (m, 9H), 2.19- 1.88 (m, 3H), 1.58-1 .52 (m, 1H), 1.25-0.90 (m, 4H). Example 11: Synthesis of compound 16 (8-((3S,5R)-3-methyl-5-(methylamino)piperidin hydrochloride -1-yl)quinoxaline-5-carbonitrile) Method S

[00347] tert-Butyl (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl(methyl)carbamate: A solution of tert-butyl N-[(3R,5S )-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate (152 mg, 0.41 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (18 mg , 0.74 mmol, 1.78 equiv) at room temperature. The mixture was stirred for 10 minutes at room temperature, and then added with iodomethane (70 mg, 0.49 mmol). The reaction mixture was stirred for one hour at room temperature. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield tert-butyl N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-N-methylcarbamate as a yellow solid (180 mg, raw).

[00348] 8-((3S,5R)-3-methyl-5-(methylamino)piperidin-1-yl)quinoxaline-5-carbonitrile hydrochloride: 8-((3S,5R)-3-methyl- hydrochloride 5-(methylamino)piperidin-1-yl)quinoxaline-5-carbonitrile was prepared from tert-butyl(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl(methyl) carbamate and iodomethane using Method Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep Column, 5 µm, 19 mm x 150 mm; Mobile phase, acetonitrile in water (with 0.02% v/v HCl), 30% to 40% gradient in 10 min; Detector, UV 254 nm. 8-[(3S,5R)-3-methyl-5-(methylamino)piperidin-1-yl]quinoxaline-5-carbonitrile hydrochloride was obtained as yellow solid (36 mg, 26% for two steps).Compound 16: HPLC: 90.3% purity, Retention Time = 1.97 min. MS: m/z = 282.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 2.0 Hz, 1H), 8.88 (d, J = 1.6 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.63-4.53 (m, 1H), 4.14-4.04 (m, 1H) , 3.02-2.90 (m, 1H), 2.70-2.55 (m, 2H), 2.50 (s, 3H), 2.26-2.14 (m, 1H), 2.10-1.90 (m, 1H), 1.10-0.96 (m, 4H).

[00349] The following compound was synthesized in an analogous manner:

[00350] Compound 17 ((3R,5S)-N,5-dimethyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine): tert-butyl (3R,5S )-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-ylcarbamate and iodomethane. HPLC: 92.8% purity, Retention Time = 0.71 min. EM: m/z = 258.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.08 (d, J = 5.6 Hz, 1H), 5.05-4.95 (m, 1H), 4.54-4.35 (m, 1H) , 2.99-2.63 (m, 3H), 2.52 (s, 3H), 2.27-2.14 (m, 1H), 2.06 -1.88 (m, 1H), 1 .14-1.00 (m, 4H).Example 12: Synthesis of compound 18 ((3R,5S)-N-(2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazine -8-yl)piperidin-3-amine)

[00351] (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine: (3R,5S)- N-(2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine was prepared from (3R,5S)-5-methyl-1- ( pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 1-bromo-2-methoxyethane using Method N. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep , 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 3% to 80% gradient in 8 min; Detector, UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine as yellow oil (60 mg, 31%) .

[00352] Compound 18: HPLC: 96.8% purity, Retention Time = 1.88 min. MS: m/z = 302.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.08 (d, J = 5.7 Hz, 1H), 4.61 (br s, 2 H), 4.46 (d, J = 12.6 Hz, 1H ), 3.60-3.52 (m, 2H), 3.39 (s, 3H), 3.02-2.90 (m, 3H), 2.80-2.68 (m, 2H ), 2.25-2.15 (m, 1H), 2.05-1.95 (s, 1H), 1.18-1.02 (m, 3H).

[00353] The following compounds were synthesized in an analogous manner:

[00354] Compound 19 (8-((3R,5S)-3-(2-methoxyethylamino)-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile): 8-((3R,5S)-3- amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 1-bromo-2-methoxyethane. HPLC: 97.8% purity, Retention Time = 1.22 min. MS: m/z = 326.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (s, 1H), 8.85 (s, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.18 (d , J = 8.5 Hz, 1H), 4,594.47 (m, 1H), 4.14-4.03 (m, 1H), 3.55-3.45 (m, 2H), 3.34 (s, 3H), 3,062.78 (m, 3H), 2.66-2.51 (m, 2H), 2.20-1.85 (m, 2H), 1.10-0.91 (m, 4H).

[00355] Compound 38 (8-((3R,5S)-3-(cyanomethylamino)-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile): 8-((3R,5S)-3-amino- 5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-chloroacetonitrile. HPLC: 90.7% purity, Retention Time = 1.24 min. MS: m/z = 307.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8,938.86 (m, 2 H), 8.05 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4,654.52 (m, 1H), 4.05 (dd, J = 13.3, 3.4 Hz, 1H), 3.72 (s, 2H), 3.25-3.10 ( m, 1H), 2.66-2.50 (m, 2H), 2.20-1.90 (m, 2H), 1.11-0.93 (m, 4H).

[00356] Compound 39 (2-((3R,5S)-5-methyl-1-(pyrido [2,3-b]pyrazin-8-yl)piperidin-3-ylamino)acetonitrile hydrochloride): from (3R ,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-chloroacetonitrile. HPLC: 87.2% purity, Retention Time = 0.97 min. MS: m/z = 283.0 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 9.12-9.02 (m, 2 H), 8.55 (d, J = 6.6 Hz, 1H), 7.40 (d, J = 6 .9 Hz, 1H), 5.92-5.72 (m, 1H), 4.60-4.30 (m, 2H), 3.95-3.60 (m, 2H), 3, 20-3.10 (m, 1H), 2.48-2.38 (m, 1H), 2.16-2.06 (m, 1H), 1.65-1.52 (m, 1H), 1.16-0.96 (m, 4H).

[00357] Compound 121 (2-[[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]amino]acetamide): from ( 3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-chloroacetamide. HPLC: 99.1% purity, Retention Time = 0.75 min. EM: m/z = 301.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.93 (d, J = 1.8 Hz, 1H), 8.83 (t, J = 1.7 Hz, 1H), 8.64 (dd, J = 5.8, 1.5 Hz, 1H), 7.09-7.02 (m, 1H), 5.03-4.90 (m, 1H), 4.41 (dd, J = 12.8 , 4.2 Hz, 1H), 3.49-3.34 (m, 2H), 3.00-2.86 (m, 1H), 2.80-2.64 (m, 2H), 2.26-2.13 (m, 1H), 2.03-1.90 (m, 1H), 1.19-1.01 (m, 4H).

[00358] Compound 122 (2-[ [ (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]amino]acetamide): 8-((3R,5S) -3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-chloroacetamide. HPLC: 99.5% purity, Retention Time = 1.03 min. MS: m/z = 325.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2H), 8.06 (d, J = 8.4 Hz, 1H), 7.29-7.15 (m , 1H), 4.62-4.48 (m, 1H), 4.12-4.02 (m, 1H), 3.46-3.31 (m, 2H), 2.99 (tt, J = 11.0, 4.0 Hz, 1H), 2.72-2.56 (m, 2H), 2.22-1.88 (m, 2H), 0.96 (m, 4H) .

[00359] Compound 126 (1-methyl-3-[ [ (3R,5S)-5-methyl-1-[pyrido[2,3- b]pyrazin-8-yl]piperidin-3-yl]amino]pyrrolidin -2-one): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-bromo-1-methylpyrrolidin-2- one. HPLC: 99.0% purity, Retention Time = 1.13 min. MS: m/z = 341.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 8.63 (d, J = 5.6 Hz, 1H), 7.07 (t, J = 5.4 Hz, 1H), 5.08-4.88 (m, 1H), 4.48-4.38 (m, 1H) , 3,763.62 (m, 1H), 3.48-3.35 (m, 2H), 3.21-3.04 (m, 1H), 2.87 (s, 3H), 2,802.65 ( m, 2 H), 2.56-2.39 (m, 1H), 2.28-2.12 (m, 1H), 2.02-1.76 (m, 2 H), 1.18- 0.99 (m, 4H).

[00360] Compound 176 (cis-8-[3-cyclopropyl-5-[(2-methoxyethyl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile): of 3,3-dimethylbutanoic acid and cis-8- (3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity, Retention Time = 1.42 min. MS: m/z = 352.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.8 Hz, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 4.61-4.45 (m, 1H), 4.30-4.24 (m, 1H) , 3.61-3.45 (m, 2H), 3.37 (s, 3H), 3.05-2.75 (m, 4H), 2.74-2.68 (m, 1H), 2.37-2.25 (m, 1H), 1.31-1.03 (m, 2H), 0.71-0.41 (m, 3H), 0.300.12 (m, 2H). Example 13: Synthesis of compound 24 ((R)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide)

[00361] (R)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide: (R)-2-amino- N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide was prepared from 8-((3R,5S)-3-amino-5-methylpiperidin- 1-yl)quinoxaline-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)propanoic acid using Method J and Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 one, 19mm x 250mm; MeOH in water (with 10 mmol/L NH4HCO3), 30% to 80% gradient in 10 min; Detector, UV 254 nm. (2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]propanamide was obtained as yellow solid (25 mg, 26% for two steps).

[00362] Compound 24: HPLC: 94.4% purity, Retention Time = 1.39 min. EM: m/z = 339.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.91 (d,J= 1.8 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.44- 4.26 (m, 2H), 4.20-4.03 (m, 1H ), 3.50-3.38 (m, 1H), 2.87-2.62 (m, 2H), 2.20-1.99 (m, 2H), 1,351.17 (m, 4H ), 1.04 (d, J = 6.4 Hz, 3H).

[00363] The following compounds were synthesized in an analogous manner:

[00364] Compound 25 ((S)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide): de 8- ( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-(tert-butoxycarbonylamino)propanoic acid. HPLC: 91.3% purity, Retention Time = 1.40 min. MS: m/z = 339.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.97 (d, J = 1.8 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.44-4.26 (m, 2H), 4.20-4.02 (m, 1H ), 3.52-3.38 (m, 1H), 2.89-2.64 (m, 2H), 2.20-2.01 (m, 3H), 1.37-1.22 ( m, 4H), 1.05 (d, J = 6.4 Hz, 3H).

[00365] Compound 26 ((R)-2-amino-N-((3R,5S)-5-methyl-1-(pyrido [2,3-b]pyrazin-8-yl)piperidin-3-yl) propanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(tert-butoxycarbonylamino)propanoic acid . HPLC: 94.9% purity, Retention Time = 0.55 min. MS: m/z = 315.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.99 (s, 1H), 8.83 (s, 1H), 8.71 (d, J = 4.8 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.15 (d, J = 5.5 Hz, 1H), 4.55 (d, J = 13.4 Hz, 1H), 4.39 (m , J = 13.4 Hz, 1H), 3.92-3.76 (m, 1H), 3.45-3.35 (m, 1H), 2.90-2.60 (m, 2H) , 2.03-1.75 (m, 4H), 1.33-1.08 (m, 4H), 0.92 (d, J = 6.5 Hz, 3H).

[00366] Compound 27 ((S)-2-amino-N-((3R,5S)-5-methyl-1-(pyrido [2,3-b]pyrazin-8-yl)piperidin-3-yl) propanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-(tert-butoxycarbonylamino)propanoic acid. HPLC: 94.0% purity, Retention Time = 0.93 min. EM: m/z = 315.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.7 Hz, 1H), 7.12 (d, J = 5.6 Hz, 1H), 4.72-4.58 (m, 2H), 4.073.93 m, 1H), 3.46 -3.34 (m, 1H), 2.90-2.65 (m, 2H), 2.15-1.92 (m, 2H), 1.36-1.15 (m, 4H) , 0.99 (d,J = 6.5 Hz, 3H).

[00367] Compound 28 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(methylamino) acetamide hydrochloride): 8-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(tert-butoxycarbonyl(methyl)amino)acetic acid. HPLC: 98.3% purity, Retention Time = 1.21 min. EM: m/z = 339.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.84 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.40 (d, J = 12.2 Hz, 1H), 4.28-4.06 (m , 2H), 3.75 (s, 2H), 2.82-2.57 (m, 5H), 2.16-1.97 (m, 2H), 1,251.13 (m, 1H) , 0.99 (d, J = 6.5 Hz, 3H).

[00368] Compound 29 (N-((3R,5S)-5-methyl-1-(pyrido[2,3-b] pyrazin-8-yl)piperidin-3-yl)-2-(methylamino)acetamide) : from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-(tert-butoxycarbonyl(methyl)amino)acetic acid. HPLC: 99.6% purity, Retention Time = 0.83 min. EM: m/z = 315.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.00 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.72 (d , J = 5.4 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 5.5 Hz, 1H), 4.58-4.38 (m, 2H), 4.00-3.85 (m, 1H), 3.40-3.30 (m, 2H), 2.88-2.68 (m, 2H), 2, 38 (s, 3H), 2.01-1.79 (m, 2H), 1.30-1.16 (m, 1H), 0.93 (d, J = 6.4 Hz, 3H).

[00369] Compound 30 (1-amino-N-((3R,5S)-5-methyl-1-(pyrido [2,3-b]pyrazin-8-yl)piperidin-3-yl) cyclopropanecarboxamide hydrochloride) : From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 1-(tert-butoxycarbonylamino) cyclopropanecarboxylic acid. HPLC: 99.8% purity, Retention Time = 0.84 min. EM: m/z = 327.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.44 (d, J = 7.4 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 4.15-4.00 (m, 1H), 3.36-3.13 (m, 2H ), 3,132.99 (m, 1H), 2.13 - 1.86 (m, 2H), 1.67-1.27 (m, 6H), 1.06 (d, J = 6.4 Hz , 3H).

[00370] Compound 31 (1-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl) cyclopropanecarboxamide hydrochloride): 8-((3R ,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid. HPLC: 97.5% purity, Retention Time = 1.22 min. MS: m/z = 351.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.35-4.08 (m, 3H), 2.85-2.60 (m, 2H ), 2,081.93 (m, 2H), 1.59-1.15 (m, 5H), 0.98 (d, J = 6.3 Hz, 3H).

[00371] Compound 34 (2-amino-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)acetamide): from (3R,5S)-5-methyl-1-(pyrido [2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-(tert-butoxycarbonylamino) acetic acid. HPLC: 99.6% purity, Retention Time = 0.83 min. MS: m/z = 300.9 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.98 (s, 1H), 8.81 (s, 1H), 8.69 (d, J = 5.3 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 5.4 Hz, 1H), 4.55-4.46 (m, 1H), 4.46-4.37 ( m, 1H), 3.94-3.82 (m, 1H), 3.07 (s, 2H), 2.86-2.76 (m, 1H), 2.74-2.64 (m , 1H), 2.30-2.78 (m, 4H), 1.29-1.15 (m, 1H), 0.91 (d, J = 6.4 Hz, 3H).

[00372] Compound 35 (2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)acetamide hydrochloride): 8-((3R ,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(tert-butoxycarbonylamino)acetic acid. HPLC: 96.6% purity, Retention Time = 1.19 min. MS: m/z = 325.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.45-4.33 (m, 1H), 4.27-4.07 (m, 2H ), 3.66 (s, 2 H), 2.85-2.60 (m, 2 H), 2.18-1.95 (m, 2 H), 1.27-1.13 (m, 1H), 0.99 (d, J = 6.4 Hz, 3H).

[00373] Compound 102 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(ethyl(methyl)amino)propanoic acid. HPLC: 99.7% purity, Retention Time = 1.54 min. MS: m/z = 367.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8 .5Hz, 1H), 4.46-4.37 (m, 1H), 4.35-4.26 (m, 1H), 4.24-4.12 (m, 1H), 3.08 ( d, J = 5.9 Hz, 1H), 2.81 (t, J = 11.3 Hz, 1H), 2.70 (t, J = 11.3 Hz, 1H), 2.17-1, 85 (m, 3H), 1.33-1.21 (m, 1H), 1.06-0.93 (m, 9H).

[00374] Compound 103 ((2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide): of (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-(ethyl(methyl)amino)propanoic acid. HPLC: 97.8% purity, Retention Time = 2.07 min. MS: m/z = 367.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94-8.90 (m, 2 H), 8.11 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8 .4 Hz, 1H), 4.46-4.37 (m, 1H), 4.36-4.27 (m, 1H), 4.17 (dd, J = 11.2, 7.1 Hz, 1H), 3.07 (d, J = 6.0 Hz, 1H), 2.81 (t, J = 11.4 Hz, 1H), 2.69 (t, J = 11.8 Hz, 1H) , 2.17-2.00 (m, 2H), 1.99-1.89 (m, 1H), 1.32-1.18 (m, 1H), 1.07-0.95 (m , 9H).

[00375] Compound 104 ((2R)-2-amino-3-methyl-N-[(3R,5S)-5-methyl- 1-[pyrido[2,3-b]pyrazin-8-yl]piperidin- 3-yl]butanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(tert) acid -butoxycarbonylamino)-3-methylbutanoic acid. HPLC: 94.0% purity, Retention Time = 0.90 min. MS: m/z = 343.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (s, 1H), 8.75 (s, 1H), 8.62 (d, J = 5.6 Hz, 1H), 7.09 (d , J = 5.6 Hz, 1H), 4.99-4.59 (m, 2H), 4.26-3.92 (m, 1H), 3.07-2.95 (d, J = 11.5Hz, 1H), 2.85-2.62 (m, 2H), 2.12-1.82 (m, 3H), 1.45-1.20 (m, 1H), 1, 13-0.85 (m, 9H).

[00376] Compound 105 ((2S)-2-amino-3-methyl-N-[(3R,5S)-5-methyl- 1-[pyrido[2,3-b]pyrazin-8-yl]piperidin- 3-yl]butanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (S)-2-(tert) acid -butoxycarbonylamino)-3-methylbutanoic acid. HPLC: 97.6% purity, Retention Time = 1.65 min. MS: m/z = 343.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (s, 1H), 8.82 (s, 1H), 8.68 (d, J = 5.6 Hz, 1H), 7.17 (d , J = 5.7Hz, 1H), 4.87 (s, 2H), 4.18-4.02 (m, 1H), 3.08 (d, J = 6.0Hz, 1H), 2 .95-2.84 (m, 1H), 2.79 (t, J = 12.1 Hz, 1H), 2.17-1.85 (m, 3H), 1.30 (d, J = 12 .0Hz, 1H), 1.07-0.9 (m, 9H).

[00377] Compound 106 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-hydroxypropanamide): of 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid. HPLC:92.4% purity, Retention Time = 0.93 min. MS: m/z = 355.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89-9.11 (m, 2 H), 8.10 (d, J = 12 Hz, 1H), 7.29 (d, J = 12 Hz, 1H), 4.39-4.01 (m, 3H), 3.63-3.73 (m, 2H), 3.41-3.2 (m, 1H), 2.84-2.55 (m, 2H), 2.18-1.95 (m, 2H), 1.35-1.20 (m, 1H), 1.02 (d, J = 8Hz, 3H).

[00378] Compound 107 ((2R)-2-amino-3-hydroxy-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin- 3-yl]propanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and (R)-2-(tert) acid -butoxycarbonylamino)-3-hydroxypropanoic acid. HPLC: 95.0% purity, Retention Time = 0.96 min. MS: m/z = 331.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (s, 1H), 8.80 (s, 1H), 8.65 (d, J = 8.0 Hz, 1H), 7.15 (d , J = 8.0 Hz, 1H), 4.75-4.59 (m, 2H), 4.15-4.01 (m, 1H), 3.72-3.62 (m, 2H ), 3.40-3.32 (m, 1H), 2.91-2.80 (m, 1H), 2.79-2.69 (m, 1H), 2.11 (d, J = 16 .0 Hz, 1H), 2.05-1.85 (m, 1H), 1.35-1.23 (m, 1H), 1.01 (d,J= 8.0 Hz, 3H).

[00379] Compound 116 ((2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-(pyridin-3 -yl)propanamide): from 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and acid (S)-2-(tert-butoxycarbonylamino)-3- ( pyridin-3-yl)propanoic acid. HPLC: 98.2% purity, Retention Time = 6.08 min. MS: m/z = 416.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.82 (m, 2 H), 8.38 (dt, J = 3.0, 1.5 Hz, 2 H), 8.06 ( d, J = 8.4 Hz, 1H), 7.70 (dd, J = 7.8, 1.9 Hz, 1H), 7.35 (dd, J = 7.8, 4.9 Hz, 1H ), 7.20 (d, J = 8.4 Hz, 1H), 4.33-4.15 (m, 2H), 4.07-3.92 (m, 1H), 3.51 (t , J = 6.9 Hz, 1H), 2.93 (d, J = 6.9 Hz, 2 H), 2.70-2.49 (m, 2 H), 1.97 (br s, 1H ), 1.82-1.77 (m, 1H), 1.06-0.87 (m, 4H).

[00380] Compound 117 ((2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-phenylacetamide): of 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid. HPLC: 99.9% purity, Retention Time = 1.66 min. EM: m/z = 401.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 1.7 Hz, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.25-8 .09 (m, 2H), 7.45-7.17 (m, 6H), 4.40-4.20 (m, 3H), 3.91-3.80 (m, 1H), 2. 88-2.56 (m, 2H), 1.96-1.82 (m, 2H), 1.28-1.04 (m, 1H), 0.90 (d, J = 6.3 Hz, 3H).

[00381] Compound 118 ((2S)-2-amino-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl] -3-(pyridin-3-yl)propanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and acid (S )-2-(tert-butoxycarbonylamino)-3-(pyridin-3-yl)propanoic acid. HPLC:98.4% purity, Retention Time = 1.79 min. EM: m/z = 392.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.63 (d, J = 5.7 Hz, 1H), 8.40-8.38 (m, 2H), 7,727.68 (m, 1H), 7.36 (dd, J = 7.9, 4.9 Hz, 1H ), 7.09 (d, J = 5.7 Hz, 1H), 4.63-4.54 (m, 2H), 3.99-3.89 (m, 1H), 3.54-3 .49 (m, 1H), 2.93 (d, J = 6.9 Hz, 2 H), 2.80-2.58 (m, 2 H), 2.00-1.74 (m, 2 H), 1.12-0.85 (m, 4H).

[00382] Compound 119 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-phenylacetamide): of 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid. HPLC: 97.3% purity, Retention Time = 1.87 min. MS: m/z = 401.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.02 (d, J = 1.8 Hz, 1H), 8.92 (d, J = 1.8 Hz, 1H), 8.25-8.12 (dd, J = 24.8, 8.0 Hz, 2H), 7.43-7.19 (m, 6H), 4.38-4.15 (m, 3H), 3.96-3, 84 (m, 1H), 2.82-2.68 (m, 2H), 1.99-1.80 (m, 2H), 1.27-1.23 (m, 1H), 0, 92 (d, J = 6.5 Hz, 3H).

[00383] Compound 128 (3-amino-N-[(3R,5S)-5-methyl-1-[pyrido[2,3- b]pyrazin-8-yl]piperidin-3-yl]oxetane-3- carboxamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-((tert-butoxycarbonyl)amino)oxetano- acid 3-carboxylic. HPLC: 97.4% purity, Retention Time = 0.79 min. MS: m/z = 343.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.7 Hz, 1H), 8.79 (d, J = 1.9 Hz, 1H), 8.63 (d, J = 5.7 Hz, 1H), 7.13 (d, J = 5.7 Hz, 1H), 4.73-4.55 (m, 2H), 4.20-3.50 (m, 3H ), 3.00-2.68 (m, 2H), 2.20-1.85 (m, 3H), 1.70-1.58 (m, 1H), 1.40-1.10 ( m, 1H), 1.00 (d, J = 6.8 Hz, 3H).

[00384] Compound 129 (3-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]oxetane-3-carboxamide): 3- (tert-butoxycarbonylamino)oxetane-3-carboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity, Retention Time = 1.05 min. MS: m/z = 367.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.97-8.86 (m, 2 H), 8.10 (dt, J = 8.6, 2.3 Hz, 1H), 7.29 (d , J = 8.4 Hz, 1H), 4.39-4.09 (m, 4H), 3,993.74 (m, 2H), 2.96-2.80 (m, 1H), 2.79 -2.63 (m, 1H), 2.18-1.85 (m, 3H), 1.38-1.23 (m, 1H), 1.04 (dd, J = 6.6, 2, 0Hz, 3H).

[00385] Compound 268 (2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-cyclopropylacetamide): 2-( tert-butoxycarbonylamino)-2-cyclopropylacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 47.7 + 47.3% purity, Retention Time = 2.04 + 2.17 min. MS: m/z = 365.2 [M + H]+. 1H NMR (300 MHz, Chloroform-d, ppm) δ 8.93 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.8 Hz, 1H), 7.99 (dd , J = 8.4, 2.8 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 4.39-4.11 (m, 3H), 3.07-2, 65 (m, 3H), 2.20-1.90 (m, 4H), 1.23 (d, J = 14.2 Hz, 2 H), 1.15-1.01 (m, 1H), 0.96 (d, J = 6.6 Hz, 3H), 0.72-0.50 (m, 3H), 0.37 (s, 1H).

[00386] Compound 277 (4-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): acid 4 -(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 93.8% purity, Retention Time = 2.08 min. EM: m/z = 381.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94-8.83 (m, 2H), 8.07 (dd, J = 8.3, 1.0 Hz, 1H), 7.26 (d , J = 8.4 Hz, 1H), 4.42-4.24 (m, 2 H), 4.13 (tt, J = 10.2, 4.2 Hz, 1H), 2.80-2 .60 (m, 4H), 2.23 (s, 2H), 2.13-1.97 (m, 2H), 1.27 - 1.12 (m, 1H), 1.10-0 .92 (m, 10H).Example 14: Synthesis of compound 42 ((R)-3-amino-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin- 8-yl)piperidin-3-yl)pyrrolidin-2-one)

[00387] (R)-2-(Benzyloxycarbonylamino)-4-(methylthio)butanoic acid: at room temperature, (2R)-2-amino-4-(methylsulfanyl)butanoic acid (4.90 g, 32.84 mmols ) and sodium carbonate (16.91 g, 159.54 mmols) were dissolved in water (100 mL), to which was added a solution of benzyl chloroformate (5.59 g, 32.74 mmols) in dioxane (50 mL) drop by drop over a period of 10 minutes. The resulting solution was then stirred for 5 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (300 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified on a C18 reverse phase column eluting with acetonitrile in water (0% to 50% gradient in 30 min) to yield (2R)-2-[[(benzyloxy) acid carbonyl]amino]-4-(methylsulfanyl)butanoic acid as yellow oil (3.48 g, 36%).

[00388] (3-(Benzyloxycarbonylamino)-3-carboxypropyl)dimethylsulfonium: at room temperature, (2R)-2-[[(benzyloxy)carbonyl] amino]-4-(methylsulfanyl)butanoic acid (3.31 g , 11.67 mmol) was added to CH3I (15 mL, 0.48 mol) slowly. The resulting solution was stirred for 15 hours at room temperature. When the reaction was done, the reaction mixture was concentrated under reduced pressure to yield [(3R)-3-[[(benzyloxy)carbonyl]amino]-3-carboxypropyl]dimethylsulfanium as brown oil (3.50 g, crude) . The raw material was used in the next step directly without further purification.

[00389] ((R)-3-(benzyloxycarbonylamino)-4-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-ylamino) -4-oxobutyl)dimethylsulfonium: ((R)-3-(benzyloxycarbonylamino)-4-((3R,5S)-5-methyl-1-(pyrido[3,2- b]pyrazin-8-yl) piperidin-3-ylamino)-4-oxobutyl) dimethylsulfonium was prepared from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl) piperidin-3-amine and (3 -(benzyloxycarbonylamino)-3-carboxypropyl) dimethylsulfonium using Method J to produce N-[(1R)-3-(dimethylsulfaniomyl)-1- [[(3R,5S)-5-methyl-1-[pyrido[2,3 -b]pyrazin-8-yl]piperidin-3-yl]carbamoyl] propyl] carbamate as brown solid (3.10 g, raw). The raw material was used in the next step directly without further purification.

[00390] Benzyl (R)-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-yl)-2-oxopyrrolidin-3 -ylcarbamate: benzyl (R)-1-((3R,5S)- 5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-yl)-2-oxopyrrolidin-3 -ylcarbamate was prepared from ((R)-3-(benzyloxycarbonylamino)-4- ((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3- ylamino)-4-oxobutyl)dimethylsulfonium using Method N. The crude product was purified on a C18 reverse phase column eluting with acetonitrile in water (0% to 80% gradient in 45 min) to yield benzyl N-[(3R) -1- [(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-oxopyrrolidin-3-yl]carbamate as yellow solid (270 mg, 5% for 3 steps).

[00391] (R)-3-amino-1-((3R,5S)-5-methyl-1-(pyrido[3,2-b]pyrazin-8-yl)piperidin-3-yl)pyrrolidin-2 -one: To a solution of benzyl N-[(3R)-1-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl ]-2-oxopyrrolidin-3-yl]carbamate (125 mg, 0.27 mmol) in acetic acid (2 mL) was added a solution of HBr in AcOH (40%, 7 mol/L, 3 mL, 21 mmol) drop by drop at room temperature. The resulting solution was stirred for two hours at room temperature. When the reaction was done, the reaction mixture was concentrated under vacuum. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 80% gradient in 10 min; Detector, UV 254 nm. (3R)-3-amino-1-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]pyrrolidin-2-one was obtained as brown solid (30 mg, 32%).

[00392] Compound 42: HPLC: 96.0% purity, Retention Time = 1.84 min. EM: m/z = 327.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.98 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.70 (d , J = 5.3 Hz, 1H), 7.11 (d, J = 5.4 Hz, 1H), 4.44 (dd, J = 12.8, 3.9 Hz, 1H), 4.28 -4.17 (m, 1H), 4.05-3.95 (m, 1H), 3.39-3.10 (m, 4H), 2.75-2.63 (m, 1H), 2 .28-1.70 (m, 5H), 1.63-1.38 (m, 2H), 0.92 (d, J = 6.5 Hz, 3H). Example 15: Synthesis of compound 43 ((2S,6R)-2,6-dimethyl-4- (pyrido[2,3-b]pyrazin-8-yl)morpholine)

[00393] (2S,6R)-2,6-dimethyl-4-(pyrido[2,3-b]pyrazin-8-yl): (2S,6R)-2,6-dimethyl-4-(pyrido[ 2,3-b]pyrazin-8-yl)morpholine was prepared from 8-chloropyrido[2,3-b]pyrazine and (2R,6S)-2,6-dimethylmorpholine using Method H. The crude product was purified by HPLC preparative under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 25% to 75% gradient in 10 min; Detector, UV 254 nm. (2R,6S)-2,6-dimethyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as yellow solid (30 mg, 21%).

[00394] Compound 43: HPLC: 99.0% purity, Retention Time = 0.93 min. MS: m/z = 245.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.91 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.02 (d, J = 5.6 Hz, 1H), 4.52-4.41 (m, 2 H), 3,973.83 (m, 2 H), 2 .84-2.68 (m, 2H), 1.22 (d, J = 6.3 Hz, 6H).Example 16: Synthesis of compound 44 (8-((2R,6S)-2.6- dimethylmorpholino) quinoxaline-5-carbonitrile)

[00395] 8-((2R,6S)-2,6-dimethylmorpholino)quinoxaline-5-carbonitrile: 8-((2R,6S)-2,6-dimethylmorpholino)quinoxaline-5-carbonitrile was prepared from 8-bromoquinoxaline -5-carbonitrile and (2R,6S)-2,6-dimethylmorpholine using Method M. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 80% gradient in 10 min; Detector, UV 254 nm. 8-[(2R,6S)-2,6-dimethylmorpholin-4-yl]quinoxaline-5-carbonitrile was obtained as yellow solid (30 mg, 39%).

[00396] Compound 44: HPLC: 98.0% purity, Retention Time = 1.30 min. EM: m/z = 269.2 [M + H]+. 1H NMR (400 MHz, DMSO, ppm) δ 9.04 (d, J = 1.8 Hz, 1H), 8.95 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 4.19-4.10 (m, 2 H), 3,913.79 (m, 2 H), 2 .75-2.61 (m, 2H), 1.14 (d, J = 6.2 Hz, 6H).

[00397] The following compound was synthesized in an analogous manner:

[00398] Compound 45 ((2S,6R)-2,6-dimethyl-4-(quinolin-4-yl)morpholine): of 4-chloroquinoline and (2R,6S)-2,6-dimethylmorpholine. HPLC: 99.9% purity, Retention Time = 1.33 min. MS: m/z = 243.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.60 (d, J = 5.2 Hz, 1H), 8.06 (dd, J = 8.6, 1.5 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.73-7.63 (m, 1H), 7.57-7.47 (m, 1H), 6.97 (dd, J = 5.3 , 1.8 Hz, 1H), 4.06-3.94 (m, 2 H), 3.47 (d, J = 11.7 Hz, 2 H), 2.64-2.50 (m, 2 H), 1.21 (dd, J = 6.3, 1.1 Hz, 6H). Example 17: Synthesis of compound 46 ((2S,6R)-4-(1,2-dimethyl-1H-pyrrole [2,3-b]pyridin-4-yl)-2,6-dimethylmorpholine)

[00399] (2S,6R)-4-(1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylmorpholine: (2S,6R)-4- (1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2,6-dimethylmorpholine was prepared from 4-chloro-1,2-dimethyl-1H-pyrrolo[2,3- b]pyridine and (2R,6S)-2,6-dimethylmorpholine using Method R. Column, 5 µm, 19 mm x 250 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 25% to 70% gradient in 10 min; Detector, UV 254 nm. (2R,6S)-4-[1,2-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-2,6-dimethylmorpholine was obtained as white solid (32 mg, 12%).

[00400] Compound 46: HPLC: 95.0% purity, Retention Time = 1.88 min. MS: m/z = 260.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 7.88 (d, J = 5.7 Hz, 1H), 6.44 (d, J = 5.7 Hz, 1H), 6.22 (s, 1H ), 3.92-3.74 (m, 4H), 3.67 (s, 3H), 2.63-2.48 (m, 2H), 2.40 (s, 3H), 1.21 (d, J = 6.2 Hz, 6H). Example 18: Synthesis of compound 47 ((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(pyrido[2,3-b]pyrazin-8-yl) morpholine)

[00401] (R)-1-amino-3-(benzyloxy)propan-2-ol: at room temperature, to a solution of (2R)-2-[(benzyloxy)methyl]oxirane (5.22 g, 31 .82 mmols) in ethanol (25 mL) was added a solution of NH3 in MeOH (25 mL, 7 M, 175 mmols) and NH3.H2O (28%, 14.8 mol/L, 53 mL, 0.78 mol ) in sequence. The resulting solution was stirred for 16 hours at room temperature. When the reaction was done, the reaction mixture was concentrated under reduced pressure to yield (2R)-1-amino-3-(benzyloxy)propan-2-ol as colorless oil (6.2 g, crude).

[00402] (R)-1-amino-3-(benzyloxy)propan-2-ol: To a solution of (2R)-1-amino-3-(benzyloxy)propan-2-ol (6.20 g, raw) in ethanol (50 mL) was added methyl (2S)-2-chloropropanoate (3.33 g, 54.42 mmols) at room temperature. The resulting solution was stirred for 20 hours at 70°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to yield (2S)-N-[(2R )-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide as light yellow oil (5.65 g, 65% for two steps).

[00403] (2R,6R)-6-(benzyloxymethyl)-2-methylmorpholin-3-one: A solution of (2S)-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2 -chloropropanamide (4.12 g, 15.18 mmols) in tetrahydrofuran (30 mL) was added sodium hydride (1.02 g, 42.50 mmols) in portions at room temperature. The resulting mixture was stirred for two hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (30 mL) slowly. The mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 100% gradient) to yield (2R,6R)-6-[(benzyloxy)methyl]-2- methylmorpholin-3-one as light yellow oil (2.68 g, 75%).

[00404] (2R,6R)-2-(benzyloxymethyl)-6-methylmorpholine: To a solution of (2R,6R)-6-[(benzyloxy)methyl]-2-methylmorpholin-3-one (5.40 g , 22.93 mmols) in tetrahydrofuran (50 mL) LiAlH4 (2.00 g, 52.56 mmols) was added in portions at room temperature. The resulting mixture was stirred for two hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (40 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield (2R,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine as light yellow oil (5.40 g, crude).

[00405] ((2R,6R)-6-methylmorpholin-2-yl)methanol: At -78°C, to a solution of (2R,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine (1 .00 g, raw) in dichloromethane (20 mL) a solution of BBr3 in dichloromethane (5 mL, 3 M, 15.00 mmols) was added dropwise over a period of 10 minutes. The resulting solution was then stirred for 3 hours at -78°C. When the reaction was done, it was stopped abruptly by adding NaOH solution (1 M, 15 mL) slowly. The resulting mixture was extracted with dichloromethane (60 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield [(2R,6R)-6-methylmorpholin-2-yl]methanol as a white solid (500 mg, crude).

[00406] ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl) methanol: ((2R,6R)-6-methyl- 4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanol was prepared from ((2R,6R)-6-methylmorpholin-2-yl)methanol and 8-chloropyrido[2, 3- b]pyrazine using Method M. The crude product was purified by flash chromatography eluting with EtOAc in petroleum ether (0% to 50% gradient) to yield [(2R,6R)-6-methyl-4-[pyrido [2,3-b]pyrazin-8-yl]morpholin-2-yl]methanol as yellow oil (2.00 g, 28% for 3 steps).Method T

[00407] ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate: At 5°C, to a solution of [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methanol (638 mg, 2.45 mmols) in N,N- Dimethylformamide (30 mL) was added to sodium hydride (203 mg, 8.45 mmols) in portions. The resulting mixture was stirred for 10 min at 5°C, and then added by a solution of 4-methylbenzene-1-sulfonyl chloride (926 mg, 4.86 mmol) in dichloromethane (3 mL) dropwise over a period of period of 5 minutes. The reaction mixture was then stirred for 8 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (50 mL). The mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methyl 4-methylbenzene-1- sulfonate as yellow solid (600 mg, raw).Method U

[00408] (2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(pyrido [2,3-b]pyrazin-8-yl)morpholine: A solution of [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methyl 4-methylbenzene-1-sulfonate (60 mg, raw) in N,N-dimethylformamide (5 mL) was added to 1-methylpiperazine (21 mg, 0.21 mmol) and TEA (42 mg, 0.41 mmol) at room temperature. The resulting solution was stirred for 10 hours at 130°C. After cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with DCM (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column, SunFire Prep C18 OBD, 19 x 150 mm 5 µm 10 nm; Mobile phase, MeOH in water (with 10 mmols/L NH4HCO3), 25% to 75% gradient in 10 min; Detector, UV 254 nm. (2R,6S)-2-methyl-6-[(4-methylpiperazin-1-yl)methyl]-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as a yellow solid (30 mg, 36% for two steps).

[00409] Compound 47: HPLC: 94.7% purity, Retention Time = 1.41 min. MS: m/z = 343.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.65-4.53 (m, 1H), 4.47-4.37 (m, 1H) , 4.10-3.85 (m, 2H), 2.85-2.39 (m, 11H), 2.35-2.25 (m, 4H), 1.23 (d, J = 6 .2 Hz, 3H).Example 19: Synthesis of compound 48 ((2R,6S)-2-methyl-6-(piperazin - 1-ylmethyl)-4-(pyrido[2,3-b]pyrazin-8- il)morpholine)

[00410] (2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-(pyrido[2,3-b] pyrazin-8-yl)morpholine: (2R,6S)-2- Methyl-6-(piperazin-1-ylmethyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine was prepared from ((2R,6R)-6-methyl-4-(pyrido[2 ,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and tert-butyl piperazine-1-carboxylate using Method U and Q. The crude product was purified by preparative HPLC under the following conditions: Column , XBridge C18 OBD Prep, 5um, 19mm x 150mm; Mobile phase, MeOH in water (with 0.02% v/v HCl), 3% to 8% gradient in 10 min;Detector, UV 254 nm. (2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as light brown solid (15 mg, 22% for two steps).

[00411] Compound 48: HPLC: 99.5% purity, Retention Time = 0.92 min. MS: m/z = 329.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.64-4.52 (m, 1H), 4.47-4.37 (m, 1H) , 4.12-3.83 (m, 2H), 2.95-2.40 (m, 12H), 1.23 (d, J = 6.2 Hz, 3H).Example 20: Synthesis of compound 49 ((2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-(quinolin-5-yl)morpholine)

[00412] (2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-(quinolin-5-yl)(2R,6S)-2-methyl-6-(piperazin-1-ylmethyl )-4-(quinolin-5-yl)morpholine was prepared from ((2R,6R)-6-methylmorpholin-2-yl)methanol, 5-chloroquinoline, 4-methylbenzene-1-sulfonyl chloride, and tert-butyl piperazine-1-carboxylate using Method M, T, U, and Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 80% gradient in 10 min; Detector, UV 254 nm. 4-[(2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)morpholin-4-yl]quinoline was obtained as an off-white solid (35 mg, 15% for 4 steps).

[00413] Compound 49: HPLC: 95.1% purity, Retention Time = 0.53 min. MS: m/z = 327.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.61 (d, J = 5.1 Hz, 1H), 8.13-8.03 (m, 1H), 7.98-7.88 (m, 1H), 7.74-7.64 (m, 1H), 7.58-7.48 (m, 1H), 6.99 (d, J = 5.2 Hz, 1H), 4.20-3 .94 (m, 2H), 3.72-3.32 (m, 2H), 2.92-2.82 (m, 4H), 2.75-2.38 (m, 8H), 1 .22 (d, J = 6.2 Hz, 3H). Example 21: Synthesis of compound 50 (8-((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl) morpholino)quinoxaline-5-carbonitrile)

[00414] 8-((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile hydrochloride: 8-((2R,6S) hydrochloride -2-methyl-6-((4-methylpiperazin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile was prepared from ((2R,6R)-6-methylmorpholin-2-yl)methanol, 8-bromoquinoxaline- 5-carbonitrile, 4-methylbenzene-1-sulfonyl chloride, and 1-methylpiperazine using Method M, T, and U. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 0.02% v/v HCl), 15% to 40% gradient in 10 min; Detector, UV 254 nm. 8-((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile hydrochloride was obtained as black solid (50 mg, 20% for 3 steps ).

[00415] Compound 50: HPLC: 98.5% purity, Retention Time = 1.48 min. MS: m/z = 367.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 4.57-4.39 (m, 1H), 4.30-4.20 (m, 1H) , 4.18-3.40 (m, 12H), 3.02 (s, 3H), 2.90-2.74 (m, 2H), 1.30 (d, J = 6.1 Hz , 3H).Example 22: Synthesis of compound 51 ((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(quinolin-5-yl)morpholine)

[00416] (2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4- (quinolin-5-yl)morpholine: (2R,6S)-2-methyl-6 -((4-methylpiperazin-1-yl)methyl)-4-(quinolin-5-yl)morpholine was prepared from ((2R,6R)-6-methyl-4-(quinolin-5-yl)morpholin-2 -yl)methyl 4-methylbenzenesulfonate and 1-methylpiperazine using Method U. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 20% to 40% gradient in 8 min; Detector, UV 254 nm. 4-[(2R,6S)-2-methyl-6-[(4-methylpiperazin-1-yl)methyl]morpholin-4-yl]quinoline was obtained as light brown solid (45 mg, 55%).

[00417] Compound 51: HPLC: 99.9% purity, Retention Time = 1.10 min. MS: m/z = 341.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.61 (d, J = 5.1 Hz, 1H), 8.13-8.03 (m, 1H), 8.01-7.88 (m, 1H), 7.77-7.61 (m, 1H), 7.59-7.47 (m, 1H), 6.99 (d, J = 5.1 Hz, 1H), 4.19-3 .94 (m, 2H), 3.62-3.42 (m, 2H), 2.84 (s, 2H), 2.70-2.36 (m, 10H), 2.26 ( s, 3H), 1.22 (d, J = 6.2 Hz, 3H).

[00418] The following compounds were synthesized in an analogous manner:

[00419] Compound 52 ((2R,6S)-2-methyl-6-((4-propylpiperazin-1-yl)methyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) : of ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 1-propylpiperazine. HPLC: 96.3% purity, Retention Time = 0.99 min. MS: m/z = 371.30 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.64-4.52 (m, 1H), 4.47-4.35 (m, 1H) , 4,113.83 (m, 2H), 2.88 -2.25 (m, 14H), 1.62-1.43 (m, 2H), 1.23 (d, J = 6.2 Hz , 3H), 0.90 (t, J = 7.4 Hz, 3H).

[00420] Compound 53 ((2S,6R)-2-(((S)-3,4-dimethylpiperazin-1-yl)methyl)-6-methyl-4-(pyrido[2,3-b]pyrazin- 8-yl)morpholine): ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and hydrochloride ( S)-1,2-dimethylpiperazine. HPLC: 97.8% purity, Retention Time = 0.86 min. MS: m/z = 357.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.68-4.52 (m, 1H), 4.49-4.37 (m, 1H) , 4.11-3.85 (m, 2H), 2.98 (d, J = 15.9 Hz, 1H), 2.89-2.70 (m, 4H), 2.59 - 2, 20 (m, 8H), 2.06-1.92 (m, 1H), 1.23 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H ).

[00421] Compound 54 ((2R,6S)-2-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)-6-((3,3,4-trimethylpiperazin-1-yl) methyl)morpholine): from ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 1,2,2 -trimethylpiperazine. HPLC: 98.2% purity, Retention Time = 1.63 min. MS: m/z = 371.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.77 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.02 (d, J = 5.6 Hz, 1H), 4.81-4.67 (m, 1H), 4.41-4.29 (m, 1H) , 4.05-3.82 (m, 2H), 2.89-2.15(m, 13H), 1.22 (d, J = 6.3 Hz, 3H), 1.08 (s, 6H).

[00422] Compound 55 (N,N-dimethyl-1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl )piperidin-4-amine): from ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and N, N-dimethylpiperidin-4-amine. HPLC: 93.3% purity, Retention Time = 0.83 min. MS: m/z = 371.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.644.52 (m, 1H), 4.48-4.36 (m, 1H), 4.09 -3.83 (m, 2H), 3.24-3.08 (m, 1H), 3.02 (d, J = 11.2 Hz, 1H), 2.85-2.73 (m, 2H), 2.60-2.39 (m, 2H), 2,351.99 (m, 9H), 1.92-1.78 (m, 2H), 1.63-1.49 (m , 2H), 1.23 (d, J = 6.2 Hz, 3H).

[00423] Compound 56 ((2R,6S)-2-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)-6-((4-(pyrrolidin-1-yl)piperidin-1 -yl)methyl)morpholine): from ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 4- (pyrrolidin-1-yl)piperidine. HPLC: 98.8% purity, Retention Time = 0.90 min. EM: m/z = 397.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.66-4.54 (m, 1H), 4.47-4.35 (m, 1H) , 4.09-3.83 (m, 2H), 3.19-3.06 (m, 1H), 3.042.91 (m, 1H), 2.87-2.71 (m, 2H) , 2.70-2.39 (m, 6H), 2.22-1.86 (m, 5H), 1.88-1.72 (m, 4H), 1.68-1.47 (m, 2H), 1.23 (d, J = 6.2 Hz, 3H).

[00424] Compound 57 (8-((2R,6S)-2-methyl-6-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile): A from ((2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate and 4-(pyrrolidin-1-yl)piperidine. HPLC: 97.4% purity, Retention Time = 2.24 min. MS: m/z = 421.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.98 (d, J = 1.8 Hz, 1H), 8.84 (s, 1H), 8.03 (d, J = 8.3 Hz, 1H ), 7.06 (d, J = 8.3 Hz, 1H), 4.24 (d, J = 12.2 Hz, 1H), 4.13-3.97 (m, 3H), 3.08 (s, 1H), 2.91 (s, 1H), 2.80-2.40 (m, 6H), 2.20-1.40 (m, 13H), 1.27 (d, J = 6 .2Hz, 3H).

[00425] Compound 58 ((2S,6R)-2-(1,4'-bipiperidin-1'-ylmethyl)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine ): From ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 1,4'-bipiperidine . HPLC: 94.8% purity, Retention Time = 1.11 min. EM: m/z = 411.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.5 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.64-4.50 (m, 1H), 4.49-4.35 (m, 1H) , 4.09-3.85 (m, 2 H), 3.25-2.97 (m, 2 H), 2.86-2.72 (m, 2 H), 2.65-2.29 (m, 6H), 2.15-1.80 (m, 4H), 1.69-1.41 (m, 9H), 1.23 (d, J = 6.2 Hz, 3H).

[00426] Compound 59 (8-((2S,6R)-2-(1,4'-bipiperidin-1'-ylmethyl)-6-methylmorpholino)quinoxaline-5-carbonitrile): de ((2R,6R)- 4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate and 1,4'-bipiperidine. HPLC: 98.8% purity, Retention Time = 0.72 min. MS: m/z = 435.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.85 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 4.28-3.90 (m, 4H), 3.25-3.15 (m, 1H) , 3.10-3.00 (m, 1H), 2.80-2.35 (m, 9H), 2.20-1.80 (m, 4H), 1.70-1.40 (m, 8H), 1.22 (d, J = 6.2 Hz, 3H).

[00427] Compound 60 ((2R,6S)-2-methyl-6-((4-morpholinopiperidin-1-yl)methyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine) : of ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and 4-(piperidin-4-yl) morpholine. HPLC: 96.3% purity, Retention Time = 1.85 min. EM: m/z = 413.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.03 (d, J = 5.6 Hz, 1H), 4.65-4.43 (m, 1H), 4.47-4.35 (m, 1H) , 4.10-3.83 (m, 2H), 3.72-3.63 (m, 4H), 3.24-3.10 (m, 1H), 3.09-2.98 (m , 1H), 2.88-2.70 (m, 2H), 2.61-2.41 (m, 6H), 2.27-2.01 (m, 3H), 1.96-1, 82 (m, 2H), 1.62-1.44 (m, 2H), 1.23 (d, J = 6.2Hz, 3H).

[00428] Compound 467 (8-[(2R,6S)-2-methyl-6-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}morpholin-4-yl]quinoxaline-5- carbonitrile: From [(2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholin-2-yl]methyl 4-methylbenzene-1-sulfonate and 4-(piperidin-4-yl) morpholine. HPLC: 99.8% purity, Retention Time = 1.46 min. MS: m/z = 437.3 [M + H]+ (400 MHz, CD3OD, ppm) δ 8.97. (d, J = 1.8 Hz, 1H), 8.90 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.23 (d , J = 8.4 Hz, 1H), 4.28 (dt, J = 12.2, 2.3 Hz, 1H), 4.19-4.08 (m, 2H), 4.01 (ddd , J = 10.3, 6.4, 2.5 Hz, 1H), 3.76-3.69 (m, 4H), 3.22 (d, J = 12.0 Hz, 1H), 3, 07 (d, J = 11.6 Hz, 1H), 2.75 (ddd, J = 12.5, 10.3, 2.7 Hz, 2 H), 2.64-2.45 (m, 6H ), 2,282.07 (m, 3H), 1.93 (d, J = 9.9 Hz, 2 H), 1.66-1.54 (m, 2 H), 1.27 (d, J = 6.2 Hz, 3H).Example 23: Synthesis of compound 61 (N-(1-(((2S,6R)-6-methyl-4- (pyrido[2,3-b]pyrazin-8-yl) morpholin-2-yl)methyl)piperidin-4-yl)isobutyramide)

[00429] N-(1 -(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl) morpholin-2-yl)methyl)piperidin-4-yl )isobutyramide: N-(1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidin-4-yl )isobutyramide was prepared from tert-butyl 4-aminopiperidine-1-carboxylate, isobutyric acid, and ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin- 2-yl)methyl trifluoromethanesulfonate using Method J, Q, and U. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 80% gradient in 8 min; Detector, UV 254 nm. (2R,6S)-2-methyl-6-[[4-(morpholin-4-yl)piperidin-1-yl]methyl]-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as a yellow solid (15 mg, 1.4%).

[00430] Compound 61: HPLC: 96.6% purity, Retention Time = 1.21 min. EM: m/z = 413.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.8 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.66-4.54 (m, 1H), 4.47-4.35 (m, 1H) , 4.10-3.85 (m, 2H), 3.71-3.54 (m, 1H), 3.08 (d, J = 12.0 Hz, 1H), 2.96 (d, J = 11.9 Hz, 1H), 2.87-2.61 (m, 2H), 2.64-2.12 (m, 5H), 1.83 (d, J = 12.4 Hz, 2 H), 1.65-1.45 (m, 2 H), 1.24 (d,J= 6.2 Hz, 3H), 1.07 (d, J = 6.9 Hz, 6H). Example 24: Synthesis of compound 62 (N-ethyl-1-(((2S,6R)-6-methyl-4- (pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl )piperidine-4-carboxamide)

[00431] 1-(tert-Butoxycarbonyl)piperidine-4-carboxylic acid: A solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (1.19 g, 4.87 mmols) in methanol ( 24 mL) and tetrahydrofuran (24 mL) a solution of LiOH (599 mg, 24.99 mmols) in water (8 mL) at room temperature was added. The resulting mixture was stirred for 15 hours at room temperature. When the reaction was done, the pH value of the reaction mixture was adjusted to 2 with hydrogen chloride solution (1 M). The resulting mixture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid as a white solid (1.10 g, 84%). MS: m/z = 128.0 [M-H]+.

[00432] N-ethyl-1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl) morpholin-2-yl) methyl)piperidine-4- carboxamide: N-ethyl-1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidine-4-carboxa -mide was prepared from 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, ethanamine and ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin -2-yl)methyl trifluoromethanesulfonate using Method J, Q, and U. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 80% gradient in 10 min; Detector, UV 254 nm. N-ethyl-1-[[(2S,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methyl]piperidine-4-carboxamide was obtained as yellow solid (20 mg, 10%).

[00433] Compound 62: HPLC: 90.4% purity, Retention Time = 1.11 min. MS: m/z = 399.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1H), 8.78 (d, J = 1.7 Hz, 1H), 8.67 (d, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H), 4.66-4.54 (m, 1H), 4.47-4.35 (m, 1H) , 4.08-3.83 (m, 2H), 3.23-3.09 (m, 3H), 3.05-2.93 (m, 1H), 2,862.72 (m, 2H) , 2.60-2.40 (m, 2H), 2.23-2.01 (m, 3H), 1.87-1.68 (m, 4H), 1.23 (d, J = 6 .2 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H). Example 25: Synthesis of compound 63 ((3-aminoazetidin-1-yl) ((2R, 6R)-6-methyl -4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanone)

[00434] (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl) morpholine-2-carboxylic acid: At 10°C, in a solution of [(2R, 6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methanol (90 mg, 0.35 mmol) in dichloromethane (15 mL) was added (acetyloxy)(phenyl)-lambda3-iodanyl (234 mg, 0.73 mmol) and TEMPO (11 mg, 0.07 mmol). The resulting solution was stirred for 30 min at 10°C, and then warmed to room temperature and stirred for a further 17 hours at room temperature. When the reaction was done, it was stopped abruptly by sat. Na2S2O4 solution. (2.5 mL). The pH value of the mixture was adjusted to 9 with sodium hydroxide solution (1 M). The resulting mixture was washed with water (5 mL x 3) and the combined aqueous phases were diluted by BuOH (10 mL). The pH of the aqueous solution was adjusted to 5 by H2SO4 (5 M) and the resulting solution was extracted with BuOH (10 mL x 3). The organic phases were combined and concentrated under reduced pressure to yield (2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine-2-carboxylic acid which was obtained as a solid yellow (76 mg, raw). MS: m/z = 275.0 [M-H]+. The raw product was used in the next step without further purification.

[00435] (3-aminoazetidin-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b] pyrazin-8-yl)morpholin-2-yl)methanone: (3 -aminoazetidin-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanone was prepared from acid (2R,6R )-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxylic acid and tert-butyl azetidin-3-ylcarbamate hydrochloride using Method J and Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; Mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 70% gradient in 10 min; Detector, UV 254 nm. 1-[[(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]carbonyl]azetidin-3-amine was obtained as light yellow solid (15 mg, 6%).

[00436] Compound 63: HPLC: 98.5% purity, Retention Time = 0.86 min. EM: m/z = 329.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.98 (d, J = 1.7 Hz, 1H), 8.86 (dd, J = 3.3, 1.8 Hz, 1H), 8.74 (d, J = 5.5 Hz, 1H), 7.11 (d, J = 5.6 Hz, 1H), 4.88-4.78 (m, 1H), 4.76-4.64 ( m, 1H), 4.59-4.07 (m, 4H), 4.06-3.62 (m, 3H), 3.17-3.05 (m, 1H), 2.97-2, 81 (m, 1H), 1.32 (d, J = 6.0 Hz, 3H).

[00437] The following compounds were synthesized in an analogous manner:

[00438] Compound 64 ((2R,6R)-6-methyl-N-((R)-piperidin-3-yl)-4- (pyrido[2,3-b]pyrazin-8-yl)morpholine-2 -carboxamide): from (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxylic acid and (R)-tert-butyl 3-aminopiperidine- 1-carboxylate. HPLC: 93.0% purity, Retention Time = 0.96 minutes. MS: m/z = 357.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.71 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.5 Hz, 1H), 4.91-4.83 (m, 1H), 4.49-4.29 (m, 2H ), 4.07-3.95 (m, 2H), 3.11 (d, J = 11.5 Hz, 1H), 3.062.79 (m, 3H), 2.70-2.52 (m , 2 H), 1.9-1.72 (m, 2 H), 1.65-1.53 (m, 2 H), 1.33 (d, J = 6.2 Hz, 3H).

[00439] Compound 65 ((2R,6R)-6-methyl-N-(1-methylpiperidin-4-yl)-4- (pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxamide ): of (2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxylic acid and 1-methylpiperidin-4-amine. HPLC: 95.8% purity, Retention Time = 1.00 min. MS: m/z = 371.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.7 Hz, 1H), 8.82 (d, J = 1.7 Hz, 1H), 8.71 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 4.49-4.27 (m, 2H), 4.06-3.94 (m, 1H ), 3,873.68 (m, 2H), 3.05-2.83 (m, 4H), 2.32-2.10 (m, 5H), 1.91-1.77 (m, 2H ), 1.72-1.56 (s, 2H), 1.33 (d, J = 6.2 Hz, 3H).

[00440] Compound 468 ((2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methyl-N-(1-methylpiperidin-4-yl)morpholine-2-carboxamide): From acid (2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholine-2-carboxylic acid and 1-methylpiperidin-4-amine. HPLC: 98.0% purity, Retention Time = 1.19 min. EM: m/z = 395.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.96 (dd, J = 17.8, 1.7 Hz, 2 H), 8.16 (d, J = 8.3 Hz, 1H), 7, 27 (d, J = 8.4 Hz, 1H), 4.96-4.87 (m, 1H), 4.54 (dt, J= 12.4, 2.4 Hz, 1H), 4.42 (dd, J = 10.7, 2.8 Hz, 1H), 4.21-4.04 (m, 2 H), 3.79 (td, J = 11.0, 5.6 Hz, 1H) , 2.98-2.78 (m,4H), 2.32 (s,3H), 2.19 (t, J = 12.0 Hz, 2H), 1.95-1.83 (m, 2 H), 1.74-1.58 (m, 2 H), 1.40-1.25 (m, 3H). Example 26: Synthesis of compound 66 ((3R,5S)-5-methyl-1 -[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine)

[00441] tert-Butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]carbamate: at room temperature, in a solution of 5 -bromo-8-(trifluoromethyl)quinoline (950 mg, 3.44 mmol) in DMF (10 mL) was added tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (718 mg , 3.35 mols), K3PO4 (2.19 g, 10.29 mmols), Pd2(dba)3CHCl3 (356 mg, 0.34 mmol) and DavePhos (270 mg, 0.69 mmol). The resulting mixture was heated to 130°C and stirred for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 14% gradient) to yield tert-butyl N-[(3R,5S)-5-methyl-1-[ 8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate as yellow solid (1.10 g, 77%). EM: m/z = 410.2 [M + H]+.

[00442] (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine: at room temperature, in a solution of tert-butyl N-[(3R ,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate (787 mg, 1.92 mmol) in methanol (10 mL) was added a chloride solution of hydrogen in 1,4-dioxane (5 mL, 4 M). The resulting solution was stirred for one hour at room temperature. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD, 150 mm, 5 µm, 13 nm; mobile phase, acetonitrile in water (with 0.05% NH4OH), 30% to 60% gradient in 10 min; detector, UV 254 nm. (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine was obtained as light yellow solid (500 mg, 83%).

[00443] Compound 66: HPLC: 99.7% purity, Retention Time = 3.18 min. EM: m/z = 310.0 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (dd, J = 4.4, 1.6 Hz, 1H), 8.67-8.57 (m, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.62 (dd, J = 8.6, 4.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 3.59- 3.50 (m, 1H), 3.42-3.33 (m, 1H), 3.27-3.17 (m, 1H), 2.52-2.36 (m, 2H), 2 .21-2.07 (m, 2H), 1.08-0.93 (m, 4H). Example 27: Synthesis of compound 67 ((3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine)

[00444] 3-Methoxybenzene-1,2-diamine: at room temperature, to a solution of 2-methoxy-6-nitroaniline (4.75 g, 28.25 mmols) in methanol (150 mL) Pd/C was added (10%, 500 mg) under nitrogen atmosphere. The reaction flask was aspirated and flooded with hydrogen. The reaction mixture was hydrogenated for two hours at room temperature under an H2 atmosphere using a hydrogen balloon. When the reaction was done, the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to yield 3-methoxybenzene-1,2-diamine as dark red oil (3.66 g, 94%) . MS: m/z = 139.1 [M + H]+.

[00445] 5-Methoxyquinoxaline: at room temperature, a solution of oxaldehyde in H2O (40%, 4 mL) was added to a solution of 3-methoxybenzene-1,2-diamine (3.66 g, 26.53 mmols) in water (100.00 mL). Then, NaHSO3 (7.59 g, 72.94 mmols) was added slowly. The resulting solution was stirred for 15 minutes at room temperature. When the reaction was done, the insoluble solids in the reaction mixture were filtered out. The filtrate was extracted with DCM (300 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 100% gradient) to give 5-methoxyquinoxaline as dark red oil (3.02 g, 71%). EM: m/z = 161.0 [M + H]+.

[00446] 5-Bromo-8-methoxyquinoxaline: To a solution of 5-methoxyquinoxaline (3.02 g, 18.86 mmols) in toluene (100 mL) and acetonitrile (100 mL) was added NBS (5.04 g, 28.29 mmols) at room temperature. The resulting solution was then stirred for 16 hours at 50°C. After cooling to room temperature, the reaction mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 100% gradient) to give 5-bromo-8-methoxyquinoxaline as a yellow solid (4.23 g, 94%) . EM: m/z = 238.8 [M + H]+.

[00447] tert-Butyl N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate: A solution of 5-bromo-8-methoxyquinoxaline (1 .92 g, 8.04 mmols) in DMF (30 mL) tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (1.52 g, 7.09 mmols) was added. K3PO4 (5.13 g, 24.17 mmols), Pd2(dba)3CHCl3 (760 mg, 0.73 mmol) and Davephos (570 mg, 1.45 mmol) at room temperature. The resulting mixture was then stirred for 3 hours at 130°C. After cooling to room temperature, the reaction mixture was diluted with water (100 mL). The resulting mixture was extracted with DCM (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 100% gradient) to yield tert-butyl N-[(3R,5S)-1-(8-methoxyquinoxalin- 5-yl)-5-methylpiperidin-3-yl]carbamate as dark red oil (1.11 g, 37%). MS: m/z = 373.1 [M + H]+.

[00448] (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine: A solution of tert-butyl N-[(3R,5S)-1-(8- methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate (429 mg, 1.15 mmol) in dioxane (10 mL) was added to a solution of hydrogen chloride in dioxane (4 M, 30 mL) at temperature environment. The resulting solution was then stirred for one hour at room temperature. When the reaction was done, it was stopped abruptly by the addition of H2O (50 mL). Then, the pH value of the resulting mixture was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with DCM (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine as dark red oil (180 mg, 57%). MS: m/z = 273.1 [M + H]+, 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.92 (s, 1H), 8.86 (s, 1H), 7.20 - 7.13 (m, 2H), 3.94 (s, 3H), 3.67 (d, J = 10.0 Hz, 1H), 3.59 (dd, J = 11.4, 3, 1 Hz, 1H), 2.96 (td, J = 10.1, 9.0, 5.2 Hz, 1H), 2.20 (dt, J = 15.5, 10.8 Hz, 2H) , 1.95 (d, J = 12.2 Hz, 2 H), 0.91 (d, J = 6.3 Hz, 3H), 0.79 (q, J = 12.0 Hz, 1H).

[00449] (3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine: A solution of (3R,5S)-1-( 8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine (90 mg, 0.33 mmol) in acetonitrile (5 mL) was added 1-bromo-2-methoxyethane (45 mg, 0.34 mmol) and potassium carbonate (238 mg, 1.72 mmol) at room temperature. The resulting solution was heated to 100°C and stirred for 16 hours. After cooling to room temperature, the reaction mixture was stopped abruptly by adding water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD, 150 mm, 5 µm, 13 nm; mobile phase, acetonitrile in water (with 0.05% NH4OH), 35% to 65% gradient in 10 min; detector, UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine was obtained as yellow syrup (38 mg, 32%).

[00450] Compound 67: HPLC: 92.7% purity, Retention Time = 0.99 min. MS: m/z = 331.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1H), 8.81 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 4.04 (s, 3H), 3.92-3.84 (m, 1H), 3.60 -3.48 (m, 3H), 3.36 (s, 3H), 3.11 (dd, J = 13.9, 8.0 Hz, 1H), 2.97-2.81 (m, 2 H), 2.41-2.29 (m, 2H), 2.20-2.04 (m, 2H), 1.04-0.87 (m, 4H).

[00451] The following compounds were synthesized in an analogous manner:

[00452] Compound 201 ((2R)-2-hydroxy-N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide): of (S)-2-hydroxy-3-methylbutanoic acid and (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: 97.9% purity, Retention Time = 1.12 min. EM: m/z = 373.3 [M + H]+. 1H NMR (400 MHz,DMSO-d6, ppm) δ 8.99-8.85 (m, 2 H), 7.61 (d, J = 8.3 Hz, 1H), 7,227.12 (m, 2 H), 5.29 (d, J = 5.8 Hz, 1H), 4.04 (s, 1H), 3.93 (s, 3H), 3,693.55 (m, 3H), 2.62- 2.50 (m, 1H), 2.27 (t, J = 11.0 Hz, 1H), 2.03-1.85 (m, 3H), 1.23-1.12 (m, 1H) , 0.91 and 0.89 (d, J = 8.2 Hz, 6H), 0.76 (d, J = 6.7 Hz, 3H).

[00453] Compound 202 (N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): 3,3-dimethylbutanoic acid and (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: 98.8% purity, Retention Time = 1.33 min. MS: m/z = 371.3 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8,988.82 (m, 2 H), 7.70 (d, J = 7.8 Hz, 1H), 7.22-7.12 (m, 2 H), 4.08-3.90 (m, 4H), 3.70-3.61 (m, 2H), 2.48-2.32 (m, 1H), 2.30-2.28 (m, 1H), 2.02-1.86 (m, 4H), 1.05-0.85 (m, 13H).

[00454] Compound 203 (2-(dimethylamino)-N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide): 2-(dimethylamino) acid )acetic and (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: 98.3% purity, Retention Time = 1.92 min. MS: m/z = 371.3 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.84 (d, J = 1.8 Hz, 1H), 8.71 (d, J = 1.8 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 4.24-4.12 (m, 1H), 3.94 (s, 3H), 3.66 (dd, J = 10.9, 4.3 Hz, 1H), 3.56-3.48 (m, 1H), 2.89 (s, 2H), 2.45 (t, J = 10, 6 Hz, 1H), 2.33-2.15 (m, 7H), 2.09-1.91 (m, 2H), 1.04 (td, J = 11.9, 11.9 Hz, 1H), 0.90 (d, J = 6.5 Hz, 3H). Example 28: Synthesis of compound 68 ((3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine)

[00455] tert-Butyl (3R,5S)-5-methyl-1-(quinolin-5-yl)piperidin-3-ylcarbamate: A solution of tert-butyl N-[(3R,5S)-5-methylpiperidin -3- yl]carbamate (4.75 g, 22.16 mmols) in DMF (50 mL) were added 5-bromoquinoline (5.07 g, 24.38 mmols), K3PO4 (14.16 g, 66.73 mmols), Davephos (1.75 g, 4.44 mmols) and Pd2(dba)3.CHCl3 (2.30 g, 2.22 mmols) at room temperature. The resulting mixture was then stirred for 3 hours at 130°C. After cooling to room temperature, the reaction mixture was diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 20% gradient) to yield tert-butyl N-[(3R,5S)-5-methyl-1-( quinolin-5-yl)piperidin-3-yl]carbamate as yellow solid (4.00 g, 53%). MS: m/z = 342.1 [M + H]+.

[00456] tert-Butyl N-[(3R,5S)-1-(8-iodoquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate: A solution of tert-butyl N-[(3R, 5S)-5-methyl-1-(quinolin-5-yl)piperidin-3-yl]carbamate (3.80 g, 11.13 mmol) in DMF (50 mL) was added NIS (2.76 g, 12 .25 mmols) at room temperature. The resulting solution was then stirred for 16 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (30 mL). The resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 35% gradient) to yield tert-butyl N-[(3R,5S)-1-(8-iodoquinolin- 5-yl)-5-methylpiperidin-3-yl]carbamate as yellow solid (4.30 g, 83%). MS: m/z = 468.1 [M + H]+.

[00457] tert-Butyl N-[(3R,5S)-1-(8-ethenylquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate: A solution of tert-butyl N-[(3R, 5S)-1-(8-iodoquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate (4.09 g, 8.74 mmol) in toluene (50 mL) Pd(PPh3)4 (1 .01 g, 0.87 mmol) and tributyl(ethenyl)stannan (4.16 g, 13.12 mmol) at room temperature. The reaction mixture was then stirred for 3 hours at 120°C. After cooling to room temperature, the reaction mixture was diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 17% gradient) to yield tert-butyl N-[(3R,5S)-1-(8-ethenylquinolin- 5-yl)-5-methylpiperidin-3-yl]carbamate as yellow solid (2.20 g, 68%). EM: m/z = 368.2 [M + H]+.

[00458] tert-Butyl N-[(3R,5S)-1-(8-formylquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate: A solution of tert-butyl N-[(3R, 5S)-1-(8-ethenylquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate (2.09 g, 5.69 mmol) in THF (73 mL) was added OsO4 (145 mg, 0. 57 mmol), NaIO4 (4.86 g, 22.74 mmols), and water (14 mL) at room temperature. The reaction mixture was stirred for 14 hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of sat. Na2S2O3 solution. (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to give tert-butyl N-[(3R,5S)-1-(8-formylquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate as a yellow solid (800 mg, 38 %). MS: m/z = 370.1 [M + H]+.

[00459] tert-Butyl N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]carbamate: A solution of tert-butyl N-[ (3R,5S)-1-(8-formylquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate (760 mg, 2.06 mmol) in DCM (10 mL) was added BAST (1.37 g , 6.18 mmols) at room temperature. The resulting solution was stirred for 3 hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of saturated sodium bicarbonate solution (30 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 17% gradient) to yield tert-butyl N-[(3R,5S)-1-[8-(difluoromethyl )quinolin-5-yl]-5-methylpiperidin-3-yl]carbamate as yellow solid (400 mg, 50%). EM: m/z = 392.2 [M + H]+.

[00460] (3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine: A solution of tert-butyl N-[(3R,5S)-1- [8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]carbamate (45 mg, 0.12 mmol) in methanol (5 mL) was added concentrated HCl solution (12 M, 0.2 mL) at room temperature. The resulting solution was stirred for two hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with DCM (20 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD, 150 mm, 5 µm, 13 nm; mobile phase, acetonitrile in water (with 0.05% NH4OH), 45% to 75% gradient in 10 min; detector, UV 254 nm. (3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine was obtained as yellow oil (20 mg, 57%).

[00461] Compound 68: HPLC: 97.3% purity, Retention Time = 1.34 min. EM: m/z = 292.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.86 (dd, J = 4.2, 1.8 Hz, 1H), 8.52 (dd, J = 8.6, 1.8 Hz, 1H) , 7.96-7.87 (m, 1H), 7.86-7.44 (m, 2H), 7.23 (d, J = 7.9 Hz, 1H), 3.523.42 (m, 1H), 3.34-3.11 (m, 2H), 2.49-2.29 (m, 2H), 2.19-1.97 (m, 2H), 1.07-0 .86 (m, 4H).Example 29: Synthesis of compound 69 and compound 70 (8-(3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile):

[00462] 5-Cyclopropylpyridin-3-amine: To a solution of 5-bromopyridin-3-amine (4.75 g, 27.45 mmols) in dioxane (45 mL) was added cyclopropylboronic acid (4.75 g, 55 .30 mmols), Cs2CO3 (28 g, 85.67 mmols), tetracys(triphenylphosphane)palladium (1.66 g, 1.44 mmol) and water (5 mL) at room temperature. The resulting mixture was then stirred for 15 hours at 100°C. After cooling to room temperature, the reaction mixture was diluted with water (200 mL). The resulting mixture was extracted with ethyl acetate (500 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 100% gradient) to give 5-cyclopropylpyridin-3-amine as light brown oil (2.08 g, 56% ). EM: m/z = 135.0 [M + H]+.

[00463] tert-Butyl N-(5-cyclopropylpyridin-3-yl)carbamate: At 0°C, to a solution of 5-cyclopropylpyridin-3-amine (2.08 g, 15.49 mmols) in tetrahydrofuran (30 mL) a solution of NaHMDS (6.84 g, 37.30 mmols) in tetrahydrofuran (20 mL) was added dropwise over a period of 10 minutes. The resulting solution was stirred for one hour at 0°C, and then added with a solution of di-tert-butyl dicarbonate (4.85 g, 22.20 mmol) in tetrahydrofuran (25 mL) dropwise. . The resulting mixture was stirred for a further two hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of saturated NH4Cl solution (100 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in EtOAc (0% to 80% gradient) to give tert-butyl N-(5-cyclopropylpyridin-3-yl)carbamate as a white solid ( 2.52 g, 69%). MS: m/z = 235.0 [M + H]+.

[00464] tert-Butyl 5-cyclopropylpiperidin-3-ylcarbamate: In a sealed tube, tert-butyl N-(5-cyclopropylpyridin-3-yl)carbamate (2.52 g, 10.74 mmols), PtO2 (520 mg, 2.29 mmols), Rh/C (520 mg, 5%) and acetic acid (220 mL) at room temperature under a nitrogen atmosphere. The reaction tube was aspirated and flooded with hydrogen. Then, the reaction was hydrogenated for 24 hours at 70°C under 15 atm of hydrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was diluted with H2O (50 mL) and the pH value of the mixture was adjusted to 9 by NaOH solution (0.5 mol/L). The resulting mixture was extracted with DCM (150 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield tert-butyl N-(5-cyclopropylpiperidin-3-yl)carbamate as a white solid (2.47 g, 57%). EM: m/z = 241.1 [M + H]+.

[00465] tert-Butyl N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]carbamate: A solution of 8-bromoquinoxaline-5-carbonitrile (2.47 g, 10. 55 mmols) in N,N-dimethylformamide (25 ml) tert-butyl N-(5-cyclopropylpiperidin-3-yl)carbamate (2.10 g, 8.74 mmols) and DIEA (3.14 g, 24 mmol) were added. .26 mmols) at room temperature. The resulting solution was then stirred for 15 hours at 130°C. After cooling to room temperature, the reaction mixture was stopped abruptly by adding water (80 mL). The resulting mixture was extracted with DCM (150 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0% to 20% gradient) to yield tert-butyl N-[1-(8-cyanoquinoxalin-5-yl)-5 - cyclopropylpiperidin-3-yl]carbamate as yellow solid (2.80 g, 67%). EM: m/z = 394.2 [M + H]+.

[00466] 8-(3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile: A solution of tert-butyl N-[1-(8-cyanoquinoxalin-5-yl)-5- cyclopropylpiperidin-3-yl]carbamate (850 mg, 2.16 mmols) in methanol (15 mL) was added to a solution of hydrogen chloride in dioxane (4 M, 4 mL). The resulting solution was stirred for one hour at 40°C. When the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was first purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD, 150 mm, 5 µm, 13 nm; mobile phase, acetonitrile in water (with 0.05% NH4OH), 30% to 60% gradient in 10 min; detector, UV 254 nm. Then, the two enantiomers were obtained by separation on chiral preparative HPLC under the following conditions: column, CHIRALPAK AD-3, 0.46 x 10 cm, 5 µm; mobile phase, hexane (0.1% DEA) in EtOH, 60% isocratic in 15 min; detector, UV 254 nm. 8-[(3S,5S)-3-amino-5-cyclopropylpiperidin-1-yl]quinoxaline-5-carbonitrile was obtained as yellow solid (78 mg, 12%).Isomer 1: HPLC: 99.3% purity , Retention Time = 1.44 min. EM: m/z = 294.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.87 (dd, J = 15.6, 1.8 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 1H), 7, 18 (d, J = 8.4 Hz, 1H), 4.39-4.17 (m, 2H), 3.09-2.97 (m, 1H), 2.81-2.60 (m , 2 H), 2.23 (d, J = 11.1 Hz, 1H), 1.28-1.06 (m, 2 H), 0.65-0.38 (m, 3H), 0, 23-0.11 (m, 2H). Isomer 2: HPLC: 99% purity, MS: m/z = 294.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.87 (dd, J = 15.6, 1.8 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 1H), 7, 18 (d, J = 8.4 Hz, 1H), 4.39-4.17 (m, 2H), 3.09-2.97 (m, 1H), 2.81-2.60 (m , 2 H), 2.23 (d, J = 11.1 Hz, 1H), 1.28-1.06 (m, 2 H), 0.65-0.38 (m, 3H), 0, 23-0.11 (m, 2 H).Example 30: Synthesis of compound 71 (cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile)

[00467] cis-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-carbamic acid tert-Butyl ester: a mixture of 5-bromo-quinoline-8- carbonitrile (500 mg; 2.15 mmols), cis-3-(boc-amino)-5-(trifluoromethyl)piperidine (691 mg; 2.57 mmols), chloro(2-dicyclohexylphosphine-2',6'- di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butyl ether adduct (88 mg; 0.11 mmol), 2-dicyclohexylphosphino- 2',6'-di-i-propoxy-1,1'-biphenyl (50 mg; 0.11 mmol) and cesium carbonate (1.4 g; 4.3 mmols) in anhydrous tert-butanol (15 mL ) was treated with microwaves at 85°C for 8 hours. The reaction mixture was concentrated under reduced pressure and purified by chromatography, eluting with hexanes and ethyl acetate to provide acid tert-butyl ester [1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin- 3-yl]-carbamic acid (731 mg; 80%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.09 (dd, J = 4.2, 1.7 Hz, 1H), 8.44 (dd, J = 8.6, 1.7 Hz, 1H), 8 .04 (d, J = 7.9 Hz, 1H), 7.57 (ddd, J = 8.3, 6.2, 4.2 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.50 (s, 1H), 4.06 (s, 1H), 3.75 (dd, J = 11.8, 4.6 Hz, 1H), 3.65 - 3.55 (m, 1H), 2.89 (t, J = 11.3 Hz, 1H), 2.79 (dtq, J = 15.3, 7.5, 3.8 Hz, 1H), 2.56 - 2.39 (m, 2H), 1.54 - 1.33 (m, 10H); MS: m/z = 421 [M + H]+. (Note: In Method V, the palladium complex can also be third-generation RuPhos Paladacycle (Methanesulfonate(2-dicyclohexylphosphino-2',6'-di- i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl) palladium(II)) instead of RuPhos first generation Paladacycle (chloro(2-dicyclohexylphosphino- 2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)] palladium(II)), the solvent can also be THF or dioxane instead of tert-butanol, the base may also be sodium tert-butoxide instead of cesium carbonate and the reaction temperature may vary from 85°C to 100°C)

[00468] Cys-5-(3-Amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile: A solution of tert-butyl acid ester [1-(8-cyano-quinolin-5 -yl)-5-trifluoromethyl-piperidin-3-yl]-carbamic acid (720 mg; 1.71 mmol) in anhydrous methanol (17 mL) was added a solution of hydrochloric acid (12.8 mL; 51.4 mmols) at 4 M in dioxane and the orange solution was stirred at room temperature overnight. Ether (40 mL) was added to the reaction mixture and the orange solution was stirred at room temperature for 20 minutes. The orange suspension was filtered, the yellow solid was washed with ether and dried under vacuum to provide 5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride (571 mg; 94% ) as a yellow solid.

[00469] Compound 71: 1H NMR (400 MHz, D2O) δ 8.94 (dd, J = 4.6, 1.7 Hz, 1H), 8.66 (dd, J = 8.6, 1.8 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.77 (dd, J = 8.8, 4.5 Hz, 1H), 7.34 (d, J = 8 .2 Hz, 1H), 4.02 - 3.87 (m, 1H), 3.82 (dd, J = 11.5, 3.6 Hz, 1H), 3.71 (d, J = 11, 8 Hz, 1H), 3.17 (td, J = 8.0, 3.9 Hz, 1H), 3.05 (td, J = 11.4, 8.8 Hz, 2H), 2.64 (d, J = 12.3 Hz, 1H), 1.81 (q, J = 12.2 Hz, 1H); EM: m/z = 321 [M + H]+.

[00470] The following compounds were synthesized in an analogous manner:

[00471] Compound 423 (5-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride): From 5-bromo-quinoline-8-carbonitrile and tert- (5,5-difluoro-piperidin-3-yl)-carbamic acid butyl ester. HPLC: > 99% purity, Retention Time = 1.88 min. EM: m/z = 289 [M + H]+. 1H NMR (400 MHz, Deuterium oxide, ppm) δ 8.96 (dd, J = 4.6, 1.6 Hz, 1H), 8.89 (dd, J = 8.7, 1.6 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 8.7, 4.6 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 4.17 (s, 1H), 3.81 - 3.68 (m, 2H), 3.64 - 3.40 (m, 2H), 2.74 (tdd, J = 19.9, 7.8, 5.4 Hz, 1H), 2.67 - 2.48 (m, 1H).

[00472] Compound 510 (5,5-Difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine): From 5-bromo-8-trifluoromethyl-quinoline and tert-butyl ester of (5,5-difluoro-piperidin-3-yl)-carbamic acid. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1H), 8.58 (dd, J = 8.6, 1.8 Hz, 1H) , 8.10 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.6, 4.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 3.53 (t, J = 9.8 Hz, 1H), 3.47 - 3.36 (m, 1H), 3.30 - 3.17 (m, 2H), 2.78 - 2.64 (m, 1H), 2.43 (d, J = 11.3 Hz, 1H), 1.95 - 1.65 (m, 3H). EM: m/z = 332 [M + H]+.

[00473] Compound 524 (8-(3-amino-4-fluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride): From 8-bromo-quinoxaline-5-carbonitrile and tert-butyl ester of 4-fluoro-piperidin-3-yl)-carbamic acid. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.8 Hz, 1H), 9.02 (d, J = 1.8 Hz, 1H), 8.60 (s, 3H ), 8.29 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 5.03 (td, J = 9.0, 4.8 Hz , 1H), 4.90 (td, J = 8.9, 4.8 Hz, 1H), 4.39 (d, J = 12.8 Hz, 1H), 4.10 (d, J = 13, 2 Hz, 1H), 3.58 (d, J = 8.1 Hz, 1H), 3.54 - 3.37 (m, 1H), 2.32 (ddt, J = 13.0, 8.6 , 3.7 Hz, 1H), 2.06 - 1.81 (m, 1H). MS: m/z = 272 [M + H]+.

[00474] Compound 553 ((3R,5S)-5-methyl-1-(8-methyl-1,7-naphthyridin-5-yl)piperidin-3-amine): From 5-bromo-8-methyl -[1,7]naphthyridine and tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate. MS: m/z = 257 [M + H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.27 (dd, J = 4.1, 1.5 Hz, 1H), 8.64 (dd, J = 8.7, 1.7 Hz, 1H) , 8.17 (s, 1H), 8.06 (dd, J = 8.6, 4.2 Hz, 1H), 3.67 (d, J = 11.3 Hz, 1H), 3.61 - 3.56 (m, 1H), 3.34 (d, J = 12.0 Hz, 1H), 3.08 (s, 3H), 2.79 (t, J = 11.0 Hz, 1H), 2.58 (d, J = 11.4 Hz, 1H), 2.19 (d, J = 12.5 Hz, 1H), 2.13 - 1.98 (m, 1H), 1.22 (q , J = 12.0 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H). Example 31: Separation of compound72 and compound 73 (5-((3S,5R)- 3-Amino- 5-Trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile and 5-((3R,5S)-3-Amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile):

[00475] The title compounds were isolated using chiral SFC chromatography of compound 71. (Column: 2.1 x 25.0 cm Chiralpak AD-H from Chiral Technologies (West Chester, PA); CO2 Co-Solvent (Solvent B): Methanol with 0.2% ammonium hydroxide; Isocratic Method: 20% Co-Solvent at 80 g/min; (400 MHz, Acetone-d6) δ 8.60 (dd, J = 4.2, 1.7 Hz, 1H), 8.06 (dd, J = 8.6, 1.7 Hz, 1H), 7 .78 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 8.6, 4.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H) , 3.07 (dt, J = 12.0, 2.3 Hz, 1H), 3.05 - 2.96 (m, 1H), 2.66 (tt, J = 11.2, 4.3 Hz , 1H), 2.57 (ddd, J = 15.5, 7.4, 3.4 Hz, 1H), 2.40 (t, J = 11.4 Hz, 1H), 2.04 - 1, 97 (m, 1H), 1.78 - 1.67 (m, 1H), 1.29 (s, 2H), 0.80 (q, J = 12.1 Hz, 1H). MS: m/z = 321 [M + H]+.Isomer 2: 1H NMR (400 MHz, Acetone-d6) δ 8.63 (dd, J = 4.2, 1.7 Hz, 1H), 8, 12 (dd, J = 8.6, 1.7 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.6, 4.2 Hz , 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.09 (dt, J = 12.0, 2.3 Hz, 1H), 3.11 - 2.99 (m, 1H), 2.66 (tt, J = 11.2, 4.3 Hz, 1H), 2.58 (ddd, J = 15.5, 7.4, 3.4 Hz, 1H), 2.47 (t, J = 11.4 Hz, 1H), 2.07 - 1.79 (m, 1H), 1.75 - 1.67 (m, 1H), 1.23 (s, 2H), 0 .84 (q, J = 12.1 Hz, 1H). MS: m/z = 321 [M + H]+.Example 32: Synthesis of compound 74 (5-((3R,5S)-3-Amino-5-methyl-piperidin-1-yl)-quinazoline-8- carbonitrile)

[00476] [(3R,5S)-1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-Butyl ester: a solution of 5-bromo- quinazoline-8-carbonitrile (200 mg; 0.855 mmol), tert-butyl-N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (220 mg; 1.03 mmol) and DIPEA (450 μl; 2.6 mmols) in anhydrous ethanol (3 mL) was microwaved at 100°C for 4 h. The brown solution was concentrated under reduced pressure and purified by chromatography, eluting with hexanes and ethyl acetate to give acid tert-butyl ester [1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3 -yl]-carbamic acid (270 mg; 86%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.58 (s, 1H), 9.41 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 4.46 (s, 1H), 3.93 (d, J = 11.0 Hz, 2 H), 3.58 (d, J = 12.3 Hz, 1H) , 2.73 - 2.56 (m, 2H), 2.28 - 2.16 (m, 1H), 2.17 - 2.04 (m, 1H), 1.46 (s, 9H), 1.05 (t, J = 11.9 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H); EM: m/z = 368 [M + H]+.

[00477] 5-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-quinazoline-8-carbonitrile hydrochloride: A solution of tert-butyl acid ester [(3R,5S )-1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid (220 mg; 0.612 mmol) in anhydrous methanol (6 mL) was added a solution of hydrochloric acid ( 4.6 mL; 18.4 mmols) at 4 M in dioxane and the orange solution was stirred at room temperature overnight. Methanol (5 mL) was added to the cloudy solution and ether (20 mL) was added. The orange solution was stirred at room temperature for 30 minutes and the orange suspension was filtered, the light orange solid was washed with ether and dried under vacuum to provide 5-(3-amino-5-methyl-1-piperidyl)quinazoline hydrochloride -8-carbonitrile (204 mg; 99%) as an orange solid.

[00478] Compound 74: 1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.41 (s, 1H), 8.43 (d, J = 8.3 Hz, 1H) , 8.32 (s, 3H), 7.29 (d, J = 8.3 Hz, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.58 (d, J = 11.7 Hz, 2 H), 2.94 (t, J = 11.5 Hz, 1H), 2.65 (t, J = 11.8 Hz, 1H), 2.19 (d, J = 12 .1 Hz, 1H), 2.14 - 1.97 (m, 1H), 1.25 (q, J = 12.0 Hz, 1H), 0.97 (d, J = 6.6 Hz, 3H ); EM: m/z = 268 [M + H]+.

[00479] The following compounds were synthesized in an analogous manner:

[00480] Compound 457 (5-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-quinazoline-8-carbonitrile hydrochloride): From 5-bromo-quinazoline-8- carbonitrile and tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate. HPLC: > 99% purity, Retention Time = 4.02 min. MS: m/z = 368 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.58 (s, 1H), 9.41 (s, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 4.46 (s, 1H), 3.93 (d, J = 11.0 Hz, 2 H), 3.58 (d, J = 12.3 Hz, 1H), 2.73 -2.56 (m, 2H), 2.28 - 2.16 (m, 1H), 2.17 - 2.04 (m, 1H), 1.46 (s , 9H), 1.05 (t, J = 11.9 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H).

[00481] Compound 459 ((3R,5S)-1-(8-fluoro-pyrido [3,4-b] pyrazin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride): From 5-chloro-8-fluoropyrido[3,4-b]pyrazine and tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate. HPLC: > 99% purity, Retention Time = 3.62 min. MS: m/z = 362 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.8 Hz, 1H), 8.82 (d, J = 1.8 Hz, 1H), 8.22 (d , J = 1.3 Hz, 1H), 4.92 (d, J = 12.2 Hz, 1H), 4.64 (ddt, J = 12.7, 3.8, 1.8 Hz, 1H) , 4.45 (s, 1H), 3.82 (s, 1H), 2.72 (d, J = 11.6 Hz, 1H), 2.58 (dd, J = 12.7, 11.1 Hz, 1H), 2.18 (d, J = 12.5 Hz, 1H), 2.09 - 1.95 (m, 1H), 1.45 (s, 9H), 1.04 (t, J = 11.9 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H). Example 33: Synthesis of compound 75 and compound 76 (8-((S)-5-amino-3,3 -difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile and 8- ((R)-5-Amino-3,3-difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile)

[00482] [1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-carbamic acid tert-Butyl ester: The title compound was prepared from 8-bromo-quinoxaline -5-carbonitrile and (5,5-difluoro-piperidin-3-yl)-carbamic acid tert-butyl ester to give [1-(8-cyano-quinoxalin-5-yl)-5 tert-butyl ester ,5-difluoro-piperidin-3-yl]-carbamic acid (245 mg, 45%) as a yellow solid. EM: m/z = 390 [M + H]+.

[00483] 8-(5-Amino-3,3-difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile: A solution of tert-butyl acid ester [1-(8-cyano-quinoxalin-5 -yl)-5,5-difluoro-piperidin-3-yl]-carbamic acid (245 mg; 0.63 mmol) in ethanol (3 mL) was added a solution of hydrogen chloride (4.0 M in dioxane) ( 3.1 mL; 12.58 mmols) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting solid was washed with acetonitrile to provide a racemic mixture of 8-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride. (200 mg, 97%) as a yellow solid. The two enantiomers were separated by chiral SFC (ASH column, methanol, carbon dioxide, 20 minutes run) to give the desired pure chiral compounds.Isomer 1: MS: m/z = 290 [M + H]+, 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.8 Hz, 1H), 8.98 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 8 .4 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 4.71 (s, 1H), 4.15 - 4.06 (m, 1H), 3.60 (ddd , J = 29.7, 13.6, 2.1 Hz, 1H), 3.23 (s, 1H), 2.94 (dd, J = 12.7, 10.2 Hz, 1H), 2, 38 (s, 1H), 1.94 - 1.73 (m, 1H), 1.81 (s, 2 H).Isomer 2: MS: m/z = 290 [M + H]+, 1H NMR ( 400 MHz, DMSO-d6) δ 9.07 (d, J = 1.8 Hz, 1H), 8.98 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 8, 4 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 4.71 (s, 1H), 4.15 - 4.06 (m, 1H), 3.60 (ddd, J = 29.7, 13.6, 2.1 Hz, 1H), 3.23 (s, 1H), 2.94 (dd, J = 12.7, 10.2 Hz, 1H), 2.38 (s, 1H), 1.94 - 1.73 (m, 1H), 1.81 (s, 2H).Example 34: Synthesis of compound 77 ((3R,5S)-5-methyl-1-[ 8- (trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine) Method 1

[00484] N-(2-bromo-5-(trifluoromethyl)phenyl)acetamide: At 0°C, triethylamine (798 mg, 7.89 mmols) was added to a solution of 2-bromo-5-(trifluoromethyl)aniline (950 mg, 3.96 mmols) in DCM (30 mL), to which acetyl chloride (18 mg, 7.87 mmols) was added dropwise. The resulting solution was stirred for 16 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (100 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield N-[2-bromo-5-(trifluoromethyl)phenyl]acetamide as light yellow solid (1.08 g, 98%). EM: m/z = 281.9 [M + H]+.Method 2

[00485] N-(6-bromo-2-nitro-3-(trifluoromethyl)phenyl)acetamide: At 0°C, to a solution of HNO3 (7.5 mL, 68%) in sulfuric acid (12.5 mL , 98%) N-[2-bromo-5-(trifluoromethyl)phenyl]acetamide (1.08 g, 3.84 mmols) was added in portions over a period of 20 minutes. The resulting solution was stirred for two hours at 0°C. When the reaction was done, it was stopped abruptly by adding water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by reversed-phase flash chromatography eluting with acetonitrile in water (with 0.02% HCl), 0% to 80% gradient in 45 min, to yield N-[6 -bromo-2-nitro-3-(trifluoromethyl)phenyl]acetamide as yellow solid (445 mg, 32%). MS: m/z = 326.9 [M + H]+. Method 3

[00486] 6-Bromo-2-nitro-3-(trifluoromethyl)benzenamine: A solution of N-[6-bromo-2-nitro-3-(trifluoromethyl)phenyl]acetamide (240 mg, 0.73 mmol) in methanol (16 mL) hydrogen chloride solution (6 M in water, 4 mL, 24 mmols) was added at room temperature. The resulting solution was heated to reflux and stirred for 16 hours. When the reaction was done, the pH value of the reaction mixture was adjusted to 8 with saturated sodium bicarbonate solution. The resulting mixture was extracted with EtOAc (50 mL x 3) and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 6-bromo-2-nitro-3-(trifluoromethyl)aniline as brown oil (165 mg, 79%). 1H NMR (400 MHz, CD3OD, ppm) δ 7.81 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H).Method 4

[00487] 3-Bromo-6-(trifluoromethyl)benzene-1,2-diamine: A solution of 6-bromo-2-nitro-3-(trifluoromethyl)aniline (189 mg, 0.66 mmol) in AcOH ( 10 mL) Fe powder (252 mg, 4.51 mmols) was added at room temperature. The resulting mixture was then stirred for 3 hours at 50°C. After the reaction was done, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The pH value of the residue was adjusted to 8 with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 3-bromo-6-(trifluoromethyl)benzene-1,2-diamine as brown solid (143 mg, 84%). EM: m/z = 326.9 [M + H]+.Method 5

[00488] 5-Bromo-8-(trifluoromethyl)quinoxaline: A solution of 3-bromo-6-(trifluoromethyl)benzene-1,2-diamine (143 mg, 0.56 mmol) in ethanol (5 mL) was oxaldehyde (409 mg, 8.18 mmols) was added at room temperature. The resulting solution was heated to reflux and stirred for one hour. After the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (1% isotropic) to give 5-bromo-8-(trifluoromethyl)quinoxaline as a yellow solid (150 mg, 95%). EM: m/z = 278.9 [M + H]+.

[00489] (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine: A solution of 5-bromo-8-(trifluoromethyl)quinoxaline (157 mg , 0.57 mmol) in DMF (5 mL) were added tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (118 mg, 0.55 mmol), Pd2(dba)3CHCl3 (57 mg, 0.06 mmol), K3PO4 (351 mg, 1.65 mmol), Davephos (43 mg, 0.11 mmol) at room temperature. The resulting mixture was stirred for 3 hours at 130°C. After cooling to room temperature, the reaction mixture was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 16% gradient) to yield tert-butyl N-[(3R,5S)-5-methyl-1-[ 8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]carbamate as yellow solid (107 mg, 46%). EM: m/z = 411.2 [M + H]+.Method 6

[00490] (3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine: A solution of tert-butyl N-[(3R,5S)- 5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]carbamate (107 mg, 0.26 mmol) in methanol (5 mL) was added to a solution of HCl in dioxane (5 M, 3.1 mL, 15.63 mmols) at room temperature. The resulting solution was stirred for one hour at room temperature. When the reaction was done, the pH value of the reaction mixture was adjusted to 7 with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 150 mm, 5 µm, 13 nm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 48% to 68% gradient in 8 min; detector, UV 254 nm. (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine was obtained as yellow solid (30 mg, 37%).

[00491] Compound 77: HPLC: 99.2% purity, Retention Time = 0.88 min. MS: m/z = 311.0 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ9.01-8.87 (m, 2 H), 8.05 (d, J = 8.3 Hz, 1H), 7.26 (d,J= 8, 3Hz, 1H), 4.22 (m, 1H), 4.09-3.93 (m, 1H), 3.21 (m, 1H), 2.60-2.44 (m,2H) , 2.26-2.01 (m, 2H), 1.10-0.84 (m, 4H).Example 35: Synthesis of compound 78 ((3R,5S)-1-(8-chloroquinolin-5 -yl)-5-methylpiperidin-3-amine)

[00492] 2-Bromo-5-chlorobenzenamine: To a solution of 4-bromo-1-chloro-2-nitrobenzene (2.94 g, 12.43 mmols) in AcOH (50 mL) was added Fe powder (5 .67 g, 100.52 mmols) at room temperature. The resulting mixture was stirred for one hour at 80°C. When the reaction was done, the solids in the reaction mixture were filtered and the filtrate was concentrated under reduced pressure. The pH value of the residue was adjusted to 7-8 with sodium hydroxide solution (2N). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 5-bromo-2-chloroaniline as a yellow solid (2.06 g, 80%). EM: m/z = 207.9 [M + H]+.Method 7

[00493] 5-Bromo-8-chloroquinoline: A solution of 5-bromo-2-chloroaniline (2.06 g, 9.88 mmols) in propane-1,2,3-triol (4.23 g, 45 .90 mmols) FeSO4.7H2O (520 mg, 1.87 mmol) and sulfuric acid (3 g, 29.67 mmols) were added at room temperature. The resulting mixture was stirred for 4 hours at 120°C. After cooling to room temperature, the reaction mixture was adjusted to pH 13 using sodium hydroxide solution (2 M). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 94% gradient) to give 5-bromo-8-chloroquinoline as a yellow solid (760 mg, 32%). MS: m/z = 243.8 [M + H]+.

[00494] (3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine: (3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin -3-amine was prepared from 5-bromo-8-chloroquinoline and tert-butyl(3R,5S)-5-methylpiperidin-3-ylcarbamate using Method R and 6. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5um, 19mm x 150mm; mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 20% to 50% gradient in 10 min; detector, UV 254 nm. (3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine was obtained as light yellow solid (25 mg, 35%).

[00495] Compound 78: HPLC: 99.6% purity, Retention Time = 0.76 min. EM: m/z = 276.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.93 (dd, J = 4.3, 1.6 Hz, 1H), 8.66 (dd, J = 8.5, 1.7 Hz, 1H) , 7.83 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.5, 4.2 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 3.52-3.36 (m, 1H), 3.36-3.19 (m, 2H), 2.48 (t, J = 10.7 Hz, 1H), 2.38 ( t, J = 11.1 Hz, 1H), 2.20-2.08 (m, 2H), 1.06-1.00 (m, 4H).Example 36: Synthesis of compound 79 (N-[ (3R,5S)-1-[8-quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxypropanamide)

[00496] tert-butyl N-[(3R,5S)-1-(8-formylquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate: tert-butyl (3R,5S)-1-(8 -formylquinoxalin-5-yl)-5-methylpiperidin-3-ylcarbamate was prepared from 8-bromoquinoxaline-5-carbaldehyde and tert-butyl(3R,5S)-5-methylpiperidin-3-ylcarbamate using Method R. The crude product was purified by flash chromatography eluting with EtOAc in hexane (0% to 20% gradient) to yield tert-butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl] piperidin-3-yl]carbamate as yellow solid (467 mg, 39%). EM: m/z = 371.1 [M + H]+.Method 8

[00497] tert-butyl (3R,5S)-1-(8-(difluoromethyl)quinoxalin-5-yl)-5-methylpiperidin-3-ylcarbamate: A solution of tert-butyl N-[(3R,5S) - 1-(8-formylquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate (140 mg, 0.38 mmol) in dichloromethane (5 mL) was added DAST (1.24 g, 7.66 mmol ) at room temperature. The resulting solution was stirred for 16 hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of sodium bicarbonate solution (10%, 30 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 15% gradient) to yield tert-butyl N-[(3R,5S)-1-[8-(difluoromethyl )quinoxalin-5-yl]-5-methylpiperidin-3-yl]carbamate as light brown solid (49 mg, 33%). MS: m/z = 393.2 [M + H]+.

[00498] N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxypropanamide: N-[(3R,5S)-1 -[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxypropanamide was prepared from 2-hydroxypropanoic acid and tert-butyl(3R,5S)-1-(8-(difluoromethyl )quinoxalin-5-yl)-5-methylpiperidin-3-ylcarbamate using Method 6 and J. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 60% gradient in 10 min; detector, UV 254 nm. N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxypropanamide was obtained as yellow solid (21 mg, 18%).

[00499] Compound 79: HPLC: 95.6% purity, Retention Time = 1.58 min. MS: m/z = 365.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.88-8.80 (m, 2H), 7.94 (d, J = 8.2 Hz, 1H), 7.80-7.40 (m , 1H), 7.31 (d, J = 8.2 Hz, 1H), 4.26-3.89 (m, 4H), 2.73 (t, J = 10.8 Hz, 1H), 2 .52 (t, J = 11.1 Hz, 1H), 2.15-1.95 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H), 1.27-1 .16 (m, 1H), 0.99 (d, J = 6.4 Hz, 3H). Example 37: Synthesis of compound 80 ((R)-5,5-dimethyl-1-(pyrido[2,3 - b]pyrazin-8-yl)piperidin-3-amine) Method 9

[00500] (R)-tert-butyl 5,5-dimethyl-1-(pyrido[2,3-b]pyrazin-8-yl) piperidin-3-ylcarbamate: A solution of tert-butyl N-[( 3R)-5,5-dimethylpiperidin-3-yl]carbamate (27 mg, 0.12 mmol) in DMF (2 mL) was added 8-chloropyrido[2,3-b]pyrazine (22 mg, 0.13 mmol ) and DIEA (24 mg, 0.19 mmol) at room temperature. The resulting solution was stirred for 12 hours at 130°C. After cooling to room temperature, the reaction mixture was stopped abruptly by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 50% gradient) to yield tert-butyl N-[(3R)-1-(8-cyanoquinoxalin-5- yl)-5,5-dimethylpiperidin-3-yl] carbamate as yellow solid (40 mg, 98%). MS: m/z = 358.2 [M + H]+.

[00501] (3R)-5,5-dimethyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine: A a solution of tert-butyl N-[(3R)- 5,5-dimethyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]carbamate (39 mg, 0.11 mmol) in methanol (5 mL) was added to a solution of HCl in dioxane (4 M, 5 mL, 20 mmols) at room temperature. The resulting solution was stirred for 12 hours at room temperature. After the reaction was carried out, the resulting mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD, 150 mm, 5 µm, 13 nm; mobile phase, acetonitrile in water (with 0.05% NH4OH), 30% to 80% gradient in 10 min; detector, UV 254 nm. (3R)-5,5-dimethyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine was obtained as yellow oil (12 mg, 44%).

[00502] Compound 80: HPLC: 99.2% purity, Retention Time = 0.77 min. MS: m/z = 258.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.7 Hz, 1H), 8.66 (d, J = 5.6 Hz, 1H), 7.10 (d, J = 5.7 Hz, 1H), 4.72 (dd, J = 12.3, 4.1 Hz, 1H), 4.34 (d , J = 12.7 Hz, 1H), 3.49-3.36 (m, 1H), 2.93 (d, J = 12.6 Hz, 1H), 2.78 (t, J = 11, 4 Hz, 1H), 1.90 (dd, J = 12.7, 3.9 z, 1H), 1.40-1.27 (m, 1H), 1.08 and 1.06 (s, 6H ).Example 38: Synthesis of compound 81 (8-[(3R,5S)-3-hydroxy-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile)

[00503] 8-[(3R,5S)-3-hydroxy-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile: At 0°C, to a solution of 8-[(3R,5S)-3- amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile (178 mg, 0.67 mmol) in AcOH (5 mL) was added a solution of NaNO2 (229 mg, 3.33 mmol) in water (1 mL ) dropwise. The resulting solution was stirred for 10 hours at room temperature. After the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD, 19 x 150 mm, 5 µm, 13 nm; mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 80% gradient in 10 min; detector, UV 254 nm. 8-[(3R,5S)-3-hydroxy-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile was obtained as yellow solid (30 mg, 17%).

[00504] Compound 81: HPLC: 99.9% purity, Retention Time = 1.13 min. MS: m/z = 269.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.88 (m, 2 H), 8.11 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8 .4 Hz, 1H), 4.42 (dd, J = 11.5, 4.2 Hz, 1H), 4.14-3.92 (m, 2H), 2.73 (dd, J = 11 .5, 10.3 Hz, 1H), 2.62 (t, J = 11.7 Hz, 1H), 2.30-2.12 (m, 1H), 2.11-1.99 (m, 1H), 1.24-1.10 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H).

[00505] Example 39: Synthesis of compound 82 and compound 83 (8-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5-carbonitrile and 8-[(3S, 5R)-3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5-carbonitrile)

[00506] Cys-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl] quinoxaline-5-carbonitrile: cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl] quinoxaline -5-carbonitrile was prepared from 8-bromoquinoxaline-5-carbonitrile and tert-butyl cis-5-(trifluoromethyl)piperidin-3-ylcarbamate using Method 9 and 6. Cis-8-[3-amino-5-(trifluoromethyl) piperidin-1-yl]quinoxaline-5-carbonitrile was obtained by purification on preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 20% to 50% gradient in 10 min; detector, UV 254 nm. HPLC: 99.0% purity, Retention Time = 1.21 min. EM: m/z = 322.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.15 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8 .3 Hz, 1H), 4.54 (d,J = 10.5 Hz, 1H), 4.28-4.19 (m, 1H), 3.24-3.12 (m, 1H), 3 .03-2.84 (m, 2H), 2.75 (t, J = 11.2 Hz, 1H), 2.36 (d, J = 12.3 Hz, 1H), 1.52-1 .38 (m, 1H).

[00507] 8-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl] quinoxaline-5-carbonitrile and 8-[(3S,5R)-3-amino-5-(trifluoromethyl ) piperidin-1-yl]quinoxaline-5-carbonitrile: The two enantiomers of cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5-carbonitrile were obtained by separation on chiral preparative HPLC under the following conditions: column, Repaired ADH, 0.46 x 15 cm, 5 µm; mobile phase, EtOH in hexane (0.1% DEA), 30% isocratic in 20 min; detector, UV 254 nm. Two products were separated and obtained. Isomer 1: (60 mg, 13%, yellow solid) HPLC: 99.3% purity, Retention Time = 1.21 min. EM: m/z = 322.0 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.15 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8 .3 Hz, 1H), 4.54 (d,J = 10.5 Hz, 1H), 4.28-4.19 (m, 1H), 3.243.12 (m, 1H), 3.03-2 .84 (m, 2H), 2.75 (t, J = 11.2 Hz, 1H), 2.36 (d, J = 12.3 Hz, 1H), 1.52-1.38 (m , 1H).Isomer 2: (56 mg, 12%, yellow solid) HPLC: 99.2% purity, Retention Time = 1.21 min. MS: m/z = 322.0 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.15 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8 .3 Hz, 1H), 4.54 (d,J = 10.5 Hz, 1H), 4.28-4.19 (m, 1H), 3.243.12 (m, 1H), 3.03-2 .84 (m, 2H), 2.75 (t, J = 11.2 Hz, 1H), 2.36 (d, J = 12.3 Hz, 1H), 1.52-1.38 (m , 1H).

[00508] The following compounds were synthesized in an analogous manner:

[00509] Compound 84 (cis-8-(3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile): of 8-chloropyrido[2,3-b]pyrazine and tert-butyl cis -5-(trifluoromethyl)piperidin-3-ylcarbamate. HPLC: 99.1% purity, Retention Time = 0.88 min. EM: m/z = 298.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.96 (d, J = 1.7 Hz, 1H), 8.83 (d, J = 1.7Hz, 1H), 8.71 (d, J = 5.6 Hz, 1H), 7.12 (d, J = 5.5 Hz, 1H), 4.91-4.98 (m, 1H), 4.46-4.55 (m, 1H), 3.21-3.00 (m, 2H), 2.94-2.74 (m, 2H), 2.39-2.29 (m, 1H), 1.59-1.41 (m , 1H).Example 40: Synthesis of compound 85 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-3,3-dimethylbutanamide)

[00510] Cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-3,3-dimethylbutanamide: cis-N-[1-(8- cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-3,3-dimethylbutanamide was prepared from cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5 -carbonitrile and 3,3-dimethylbutanoic acid using Method J. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; mobile phase, MeOH in water (with 10 mmol/L NH4HCO3), 30% to 80% gradient in 10 min; detector, UV 254 nm. Cys-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-3,3-dimethylbutanamide was obtained as yellow solid (50 mg, 45%).

[00511] Compound 85: HPLC: 99.3% purity, Retention Time = 2.12 min. EM: m/z = 420.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.10 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8 .4 Hz, 1H), 4.62 (d, J = 11.5 Hz, 1H), 4.27-4.12 (m, 2H), 3.08-2.73 (m, 3H), 2.28 (d, J = 12.5 Hz, 1H), 2.07 (s, 2 H), 1.59 (d, J = 12.2 Hz, 1H), 1.01 (s, 9H) .

[00512] The following compounds were synthesized in an analogous manner:

[00513] Compound 86 (cis-3,3-dimethyl-N-[1-[pyrido[2,3-b]pyrazin-8-yl]-5-(trifluoromethyl)piperidin-3-yl]butanamide): A from cis-1-(pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)piperidin-3-amine and 3,3-dimethylbutanoic acid. HPLC: 99.4% purity, Retention Time = 1.33 min. EM: m/z = 396.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99 (d, J = 1.7 Hz, 1H), 8.87 (d, J = 1.7 Hz, 1H), 8.76 (d, J = 5.5 Hz, 1H), 7.24 (d, J = 5.6 Hz, 1H), 5.18-5.10 (m, 1H), 4.60-4.51 (m, 1H) , 4.22-4.12 (m, 1H), 3.24-3.13 (m, 1H), 2.99-2.87 (m, 2H), 2.32 (d, J = 12 .5Hz, 1H), 2.13 (s, 2H), 1.78-1.62 (m, 1H), 1.07 (s, 9H).

[00514] Compound 222 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-2-(dimethylamino)acetamide): 2-(dimethylamino) acid acetic acid and 8-(cis-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.1% purity, Retention Time = 2.57 min. EM: m/z = 407.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.10 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8 .3Hz, 1H), 4.58 (d, J = 11.3Hz, 1H), 4.29-4.12 (m, 2H), 3.10-2.83 (m, 5H), 2.32-2.27 (m, 7H), 1.70 (td, J = 12.1, 12.1 Hz, 1H).

[00515] Compound 223 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-2-hydroxyacetamide): of 2-hydroxyacetic acid and cis-8- (3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.3% purity, Retention Time = 1.16 min. MS: m/z = 380.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.14 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8 .3Hz, 1H), 4.65-4.54 (m, 1H), 4.36-4.14 (m, 2H), 4.02 (s, 2H), 3.152.88 (m, 3H), 2.32 (d, J = 12.9 Hz, 1H), 1.78 (td, J = 12.1, 12.1 Hz, 1H).

[00516] Compound 228 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-2-(morpholin-4-yl)acetamide): acid 2 - (morpholin-4-yl)acetic acid and 8-(cis-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 90.3% purity, Retention Time = 1.73 min. MS: m/z = 449.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.09 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 8 .3Hz, 1H), 4.64-4.53 (m, 1H), 4.31-4.12 (m, 2H), 3.75-3.65 (m, 4H), 3.12 -2.84 (m, 5H), 2.56-2.46 (m, 4H), 2.35-2.21 (m, 1H), 1.71 (td, J = 12.1, 12, 1Hz, 1H).

[00517] Compound 229 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide): from 2-(4-methylpiperazin-1-yl)acetic acid and cis-8-(3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.4% purity, Retention Time = 1.26 min. EM: m/z = 462.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.13 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8 .4 Hz, 1 H), 4.62 (apparent d, J = 11.7 Hz, 1 H), 4.34-4.16 (m, 2 H), 3.17-2.87 (m, 5 H), 2.75-2.45 (m, 8 H), 2.39-2.27 (m, 4 H), 1.73 (td, J = 12.1, 12.1 Hz, 1 H).

[00518] Compound 424 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-morpholin-4-yl-acetamide): From cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and 2-morpholinoacetic acid hydrochloride. HPLC: > 99% purity, Retention Time = 2.66 min. EM: m/z = 448 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J = 4.2, 1.7 Hz, 1 H), 8.47 (dd, J = 8.6, 1.7 Hz , 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.59 (dd, J = 8.6, 4.2 Hz, 1 H), 7.13 (dd, J = 8.1, 4.0 Hz, 2 H), 4.41 (dtt, J = 12.2, 8.4, 4.3 Hz, 1 H), 3.84 - 3.71 (m, 1 H), 3.71 (t, J = 4.6 Hz, 4 H), 3.63 (ddd, J = 11.4, 3.8, 1.9 Hz, 1 H), 3.09 - 2 .95 (m, 2 H), 2.94 (t, J = 11.2 Hz, 1 H), 2.84 (dtq, J = 15.5, 7.6, 4.1 Hz, 1 H) , 2.64 - 2.45 (m, 5 H), 2.48 - 2.35 (m, 1 H), 1.54 (q, J = 12.2 Hz, 1 H).

[00519] Compound 426 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-dimethylamino-acetamide): From cis-hydrochloride 5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile and N,N-dimethylglycine. HPLC: 98.8% purity, Retention Time = 2.61 min. MS: m/z = 406 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J = 4.2, 1.7 Hz, 1 H), 8.48 (dd, J = 8.6, 1.7 Hz , 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.59 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (s, 1 H), 7.12 (d, J = 7.9 Hz, 1 H), 4.41 (dtd, J = 15.5, 8.4, 4.2 Hz, 1 H), 3.81 - 3 .73 (m, 1 H), 3.63 (d, J = 11.1 Hz, 1 H), 2.97 - 2.90 (m, 2 H), 2.83 (ddp, J = 11, 4, 7.6, 3.7 Hz, 1 H), 2.54 (t, J = 11.1 Hz, 1 H), 2.44 (d, J = 12.2 Hz, 1 H), 2 .28 (s, 6 H), 1.55 (q, J = 12.3 Hz, 1 H), 1.28 - 1.24 (m, 1 H).

[00520] Compound 428 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3,3,3-trifluoro-propionamide): From cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and 3,3,3-trifluoropropionic acid. HPLC: > 99% purity, Retention Time = 4.03 min. MS: m/z = 431 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1 H), 8.45 (dd, J = 8.6, 1.7 Hz , 1 H), 8.02 (d, J = 7.9 Hz, 1 H), 7.59 (dd, J = 8.6, 4.2 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 5.93 (d, J = 7.6 Hz, 1 H), 4.42 (dtd, J = 15.0, 8.6, 8.1, 4.1 Hz, 1 H), 3.79 (ddt, J = 11.6, 4.1, 1.7 Hz, 1 H), 3.62 (ddt, J = 11.3, 3.7, 1.5 Hz, 1 H), 3.11 (q, J = 10.5 Hz, 2 H), 2.93 (t, J = 11.2 Hz, 1 H), 2.83 (dtq, J = 15, 4, 7.6, 3.9 Hz, 1 H), 2.56 (dd, J = 11.6, 10.7 Hz, 1 H), 2.47 (dt, J = 12.6, 4, 0 Hz, 1 H), 1.55 (q, J = 12.2 Hz, 1 H).

[00521] Compound 431 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3,3-dimethyl-butyramide): cis-5 hydrochloride -(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile and 3,3-dimethylbutyric acid. HPLC: > 99% purity, Retention Time = 4.37 min. EM: m/z = 419 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.08 (dd, J = 4.2, 1.7 Hz, 1 H), 8.48 (dd, J = 8.6, 1.7 Hz , 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 1 H), 5.28 (d, J = 7.8 Hz, 1 H), 4.41 (dddd, J = 16.2, 12.4, 8.2, 4.3 Hz, 1 H), 3.79 (dq, J = 10.0, 2.2 Hz, 1 H), 3.66 - 3.57 (m, 1 H), 2.92 (t, J = 11 .3 Hz, 1 H), 2.82 (ddq, J = 15.5, 7.9, 3.8 Hz, 1 H), 2.53 - 2.36 (m, 2 H), 2.05 (d, J = 1.7 Hz, 2 H), 1.48 (q, J = 12.2 Hz, 1 H), 1.03 (s, 9H).

[00522] Compound 511 (N-[5,5-Difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-2-(4-methyl-piperazin-1-yl)- acetamide): From (4-methyl-piperazin-1-yl)-acetic acid and 5,5-difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 4.0 Hz, 1 H), 8.61 (d, J = 8.7 Hz, 1 H), 8.13 (d , J = 8.2 Hz, 1 H), 8.05 - 7.92 (m, 1 H), 7.74 (dd, J = 8.3, 3.8 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 4.41 (s, 2 H), 3.47 (dt, J = 33.3, 11.5 Hz, 4 H), 3.11 (s , 1 H), 2.95 (t, J = 3.6 Hz, 2 H), 2.43 (s, 4 H), 2.29 (s, 4 H), 2.12 (d, J = 2.8Hz, 3H). MS: m/z = 472 [M + H]+.

[00523] Compound 512 (N-[5,5-Difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-2-morpholin-4-yl-acetamide): From morpholin-4-yl-acetic acid and 5,5-difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 3.8 Hz, 1 H), 8.59 (d, J = 8.6 Hz, 1 H), 8.12 (d , J = 7.8 Hz, 1 H), 8.02 (d, J = 8.3 Hz, 1 H), 7.75 (dd, J = 8.5, 3.9 Hz, 1 H), 7.37 (d, J = 8.1 Hz, 1 H), 4.39 (s, 1 H), 3.57 (d, J = 5.5 Hz, 4 H), 3.43 (d, J = 13.6 Hz, 3 H), 3.08 (d, J = 9.7 Hz, 2 H), 2.97 (s, 2 H), 2.47 - 2.37 (m, 4 H ), 2.28 (d, J = 15.5 Hz, 1 H). MS: m/z = 459 [M + H]+.

[00524] Compound 513 (2-Cyclopropyl-N-[5,5-difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-2-hydroxy-acetamide): From cyclopropylhydroxyl-acetic acid and 5,5-difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (dd, J = 4.2, 1.6 Hz, 1 H), 8.57 (ddd, J = 8.6, 4.7, 1, 8 Hz, 1 H), 8.12 (dd, J = 8.1, 2.0 Hz, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.73 (ddd , J = 8.7, 4.2, 3.1 Hz, 1 H), 7.35 (dd, J = 8.0, 4.6 Hz, 1 H), 5.56 (d, J = 4 .4 Hz, 1 H), 4.35 (dd, J = 8.8, 4.4 Hz, 1 H), 3.65 - 3.49 (m, 2 H), 3.49 - 3.36 (m, 2 H), 3.01 (q, J = 9.8, 8.9 Hz, 1 H), 2.48 - 2.16 (m, 2 H), 1.12 - 1.00 ( m, 1 H), 1.00 - 0.85 (m, 1 H), 0.54 - 0.19 (m, 4 H). MS: m/z = 430 [M + H]+.

[00525] Compound 576 (N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-piperidin-1-yl-isobutyramide) : From 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and 2-methyl-2-piperidin-1-yl-propionic acid . HPLC: > 99% purity, Retention Time = 2.92 min. MS: m/z = 474.6 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz , 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 7.75 - 7.68 (m, 2 H), 7.33 (d, J = 8.1 Hz, 1 H), 4.23 - 4.11 (m, 1 H), 3.59 - 3.43 (m, 2 H), 3.20 (s, 1 H), 2.94 (t, J = 11 .5 Hz, 1 H), 2.75 (t, J = 11.1 Hz, 1 H), 2.33 (t, J = 5.4 Hz, 4 H), 2.14 - 2.06 ( m, 1 H), 1.76 (q, J = 12.2 Hz, 1 H), 1.55 (q, J = 5.0 Hz, 4 H), 1.40 (d, J = 6, 9 Hz, 2 H), 1.06 (d, J = 13.1 Hz, 6 H).

[00526] Compound 577 (N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(3,3-dimethyl-pyrrolidin -1-yl)-acetamide): From 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and acid (3,3- dimethyl-pyrrolidin-1-yl)-acetic acid. HPLC: > 99% purity, Retention Time = 2.98 min. EM: m/z = 460.5 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz , 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.72 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 3.62 - 3.47 (m, 2 H), 3.21 (s, 1 H) , 2.93 (t, J = 11.5 Hz, 1 H), 2.75 (t, J = 11.1 Hz, 1 H), 2.66 - 2.58 (m, 2 H), 2 .37 - 2.28 (m, 2 H), 2.15 (d, J = 12.3 Hz, 1 H), 1.71 (q, J = 12.3 Hz, 1 H), 1.53 (t, J = 7.0 Hz, 2 H), 1.05 (d, J = 1.0 Hz, 6 H).

[00527] Compound 578 ([(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-1-cyclopropyl-piperidine-4-carboxylic acid amide ): From 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and 1-cyclopropyl-piperidine-4-carboxylic acid. HPLC: > 99% purity, Retention Time = 2.77 min. MS: m/z = 472.30 [M + H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.91 (d, J = 7.3 Hz, 1 H), 7.72 (dd, J = 8.6, 4 .2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 3.62 - 3.50 (m, 2 H), 3.19 (d, J = 11.4 Hz, 1 H), 2.93 (td, J = 9.6, 7.8, 4.0 Hz, 3 H), 2.60 (t, J =11.2 Hz, 1 H), 2, 23 - 2.01 (m, 4 H), 1.71 - 1.37 (m, 6 H), 0.38 (dt, J = 6.5, 3.2 Hz, 2 H), 0.30 - 0.20 (m, 2 H).

[00528] Compound 579 (N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-N',N'-diethyl-succinamide) : From 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and N,N-diethyl-succinamic acid. HPLC: > 99% purity, Retention Time = 3.82 min. MS: m/z = 476.5 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz , 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 7.4 Hz, 1 H), 7.71 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 4.13 (s, 1 H), 3.61 - 3.51 (m, 2 H) , 3.30 (d, J = 7.0 Hz, 2 H), 3.27 - 3.16 (m, 3 H), 2.95 (t, J = 11.6 Hz, 1 H), 2 .60 (t, J = 11.2 Hz, 1 H), 2.42 - 2.27 (m, 3 H), 2.18 (d, J = 12.2 Hz, 1 H), 1.51 (q, J = 12.3 Hz, 1 H), 1.11 (t, J = 7.1 Hz, 3 H), 0.96 (t, J = 7.1 Hz, 3 H).

[00529] Compound 584 (N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(4,4-difluoro-cyclo -hexyl)-acetamide): From 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (4,4-difluoro- cyclohexyl)-acetic. HPLC: > 99% purity, Retention Time = 4.39 min. MS: m/z = 481.5 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.07 (dd, J = 4.2, 1.6 Hz, 1 H), 8.59 (dd, J = 8.6, 1.7 Hz , 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 7.2 Hz, 1 H), 7.72 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 4.15 (s, 1 H), 3.62 - 3.52 (m, 2 H) , 3.21 (d, J = 11.6 Hz, 1 H), 2.95 (t, J = 11.6 Hz, 1 H), 2.61 (t, J = 11.2 Hz, 1 H ), 2.19 (d, J = 12.4 Hz, 1 H), 2.07 - 2.02 (m, 2 H), 1.96 (s, 2 H), 1.82 (s, 2 H), 1.71 (t, J = 11.1 Hz, 3 H), 1.51 (q, J = 12.3 Hz, 1 H), 1.19 (dq, J = 11.9, 6 ,1Hz, 2H).

[00530] Compound 585 (N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(1-isopropyl-piperidin-4 -yl)-acetamide): From 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile and acid (1-isopropyl-piperidin-4- il)-acetic. HPLC: > 99% purity, Retention Time = 2.85 min. MS: m/z = 488.5 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz , 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.99 (d, J = 7.3 Hz, 1 H), 7.72 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 4.14 (s, 1 H), 3.57 (d, J = 8.9 Hz, 2 H), 3.19 (s, 1 H), 2.94 (t, J = 11.6 Hz, 1 H), 2.69 (s, 2 H), 2.66 - 2.56 (m , 2 H), 2.17 (d, J = 12.1 Hz, 1 H), 2.08 - 1.97 (m, 4 H), 1.65 - 1.45 (m, 4 H), 1.10 (d, J = 12.6 Hz, 2H), 0.93 (d, J = 6.6 Hz, 6 H).Example 41: Synthesis of compound 87 and compound88 ((S)-N-( (3R,5S)- 1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl)-2-hydroxy-3-methylbutanamide and (S)-N-((3S,5R) -1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl)-2-hydroxy-3-methylbutanamide)

[00531] (S)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl) piperidin-3-yl)-2-hydroxy-3-methylbutanamide and (S )-N- ((3S,5R)-1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl)-2-hydroxy-3-methylbutanamide: (S)-N-( (3R,5S)-1-(8-cyanoquinoxalin-5-yl)- 5-(trifluoromethyl)piperidin-3-yl)-2-hydroxy-3-methylbutanamide and (S)-N- ((3S,5R) -1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl)-2-hydroxy-3-methylbutanamide were prepared from cis-8-(3-amino-5-(trifluoromethyl)piperidin -1-yl)quinoxaline-5-carbonitrile and (S)-2-hydroxy-3-methylbutanoic acid using Method J. The product was first purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 19 x 250 mm 10 um; mobile phase, acetonitrile in water (0.05% NH3H2O), 30% to 40% gradient in 15 min; detector, UV 254 nm. Then, the two diastereomeric isomers of (S)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl)-2-hydroxy-3 -methylbutanamide were obtained by chiral preparative HPLC separation under the following conditions: column, CHIRALPAK AD-3, 0.46 x 5 cm, 3 µm; mobile phase, EtOH (0.1% DEA) in hexane, 40% isocratic in 20 min; detector, UV 254 nm. Two diastereomeric products were separated and obtained.

[00532] Isomer 1: (54 mg, 18%, yellow solid) HPLC: 98.5% purity, Retention Time = 2.58 min. EM: m/z = 294.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.93 (d,J = 1.8 Hz, 1 H), 8.89 (d, J = 1.8 Hz, 1 H), 8.11 (d , J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.30- 4.09 (m, 2 H), 3.83 (d, J = 3.7 Hz, 1 H), 3.11-2.82 (m, 3 H), 2.29-2.25 (m , 1 H), 2.09-2.03 (m, 1 H), 1.81-1.69 (m, 1 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.85 (d,J = 6.8 Hz, 3 H).

[00533] Isomer 2: (19 mg, 6%, yellow solid) HPLC: 95.7% purity, Retention Time = 3.03 min. EM: m/z = 422.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.93 (d,J = 1.8 Hz, 1 H), 8.89 (d, J = 1.8 Hz, 1 H), 8.11 (d , J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.30- 4.09 (m, 2 H), 3.83 (d, J = 3.7 Hz, 1 H), 3.11-2.82 (m, 3 H), 2.29-2.25 (m , 1 H), 2.09-2.03 (m, 1 H), 1.81-1.69 (m, 1 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.85 (d,J = 6.8 Hz, 3 H).

[00534] The following compounds were synthesized in an analogous manner:

[00535] Compound 89 and compound 90 ((2S)-2-hydroxy-3-methyl-N-[(3R,5S)-1-[pyrido[2,3-b]pyrazin-8-yl]- hydrochloride 5-(trifluoromethyl)piperidin-3-yl]butanamide and (2S)-2-hydroxy-3-methyl-N-[(3S,5R)-1-[pyrido[2,3-b] hydrochloride pyrazin-8-yl]-5-(trifluoromethyl)piperidin-3-yl]butanamide): cis-1-(pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)piperidin -3-amine and (S)-2-hydroxy-3-methylbutanoic acid. Isomer 1: HPLC: 99.6% purity, Retention Time = 1.42 min. MS: m/z = 398.1 [M. + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.10-8.95 (m, 2 H), 8.63 (d, J = 1.5 Hz, 1 H), 7.41 -7.32 (d, J = 5.6 Hz, 1 H), 6.12-5.31 (m, 1 H), 5.21-4.82 (s, 1 H), 4.29- 4.19 (m, 1 H), 3.75 (d, J = 10.5 Hz, 1 H), 3.61-3.52 (m, 1 H), 3.41-3.27 (m , 1 H), 3.06-2.99 (m, 1 H), 2.38-2.20 (m, 1 H), 2.15-1.88 (m, 2 H), 1.16 -1.01 (m, 3 H), 0.82-0.93 (m, 3 H). Isomer 2: HPLC: 95.8% purity, Retention Time = 0.89 min. z = 398.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9108.95 (m, 2 H), 8.63 (d, J = 1.5 Hz, 1 H), 7.41-7.32 (d, J = 5.6 Hz, 1 H), 6.12-5.31 (m, 1 H), 5.21-4.82 (s, 1 H), 4 .29-4.19 (m, 1 H), 3.75 (d, J = 10.5 Hz, 1 H), 3.61-3.52 (m, 1 H), 3.41-3, 27 (m, 1 H), 3.06-2.99 (m, 1 H), 2.38-2.20 (m, 1 H), 2.15-1.88 (m, 2 H), 1.16-1.01 (m, 3 H), 0.82-0.93 (m, 3 H).

[00536] Compound 146 and compound 147 ((R)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3-hydroxy-4,4 -dimethylpentanamide and (S)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3-hydroxy-4,4-dimethylpentanamide): From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 3-hydroxy-4,4-dimethylpentanoic acid. Isomer 1: HPLC: 98.0% purity, Retention Time = 1.39 min. EM: m/z = 396.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.82 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 4.35 (dd, J = 28.2, 11.8 Hz, 2 H), 4.22-4.08 (m, 1 H), 3.69 (dd, J = 10.2, 2.6 Hz, 1 H), 2.80-2.60 (m, 2 H), 2.40 (dd, J = 14.2, 2.6 Hz, 1 H), 2.28-2.06 (m, 3 H), 1.23 (td, J = 12.0, 12.0 Hz, 1 H), 1.00 (d, J = 6.5 Hz, 3 H ), 0.92 (s, 9H). Isomer 2: HPLC: 99.3% purity, Retention Time = 1.41 min. EM: m/z = 396.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ8.95-8.82 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8 .4 Hz, 1 H), 4.34 (t, J = 11.4 Hz, 2 H), 4.13 (d, J = 12.1 Hz, 1 H), 3.68 (dd, J = 10.3, 2.6 Hz, 1 H), 2.83-2.63 (m, 2 H), 2.40 (dd, J = 14.1, 2.6 Hz, 1 H), 2, 29-2.04 (m, 3 H), 1.22 (td, J = 12.0, 12.0 Hz, 1 H), 1.01 (d, J = 6.4 Hz, 3 H), 0.92 (s, 9H).

[00537] Compound 148 and compound 149 ((R)-3-hydroxy-4,4-dimethyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8 -yl)piperidin-3-yl)pentanamide and (S)-3-hydroxy-4,4-dimethyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3- b ]pyrazin-8-yl)piperidin-3-yl)pentanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-hydroxy-4,4-dimethylpentanoic acid. Isomer 1: HPLC: 99.0% purity, Retention Time = 1.09 min. EM: m/z = 372.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1 H), 8.78 (d, J = 1.8 Hz, 1 H), 8.62 (d , J = 5.7 Hz, 1 H), 7.13 (d, J = 5.7 Hz, 1 H), 4.67 (t, J = 11.0 Hz, 2 H), 4.10- 3.98 (m, 1 H), 3.66 (dd, J = 10.2, 2.6 Hz, 1 H), 2.88-2.65 (m, 2 H), 2.38 (dd , J = 14.2, 2.7 Hz, 1 H), 2.26-2.07 (m, 2 H), 1.99-1.89 (m, 1 H), 1.23 (td, J = 12.1, 12.1 Hz, 1 H), 0.98 (d, J = 6.6 Hz, 3 H), 0.89 (s, 9H). Isomer 2: HPLC: 99.3% purity, Retention Time = 1.12 min. EM: m/z = 372.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1 H), 8.78 (d, J = 1.8 Hz, 1 H), 8.62 (d , J = 5.7 Hz, 1 H), 7.13 (d, J = 5.7 Hz, 1 H), 4.67 (t, J = 11.0 Hz, 2 H), 4.10- 3.98 (m, 1 H), 3.66 (dd, J = 10.2, 2.6 Hz, 1 H), 2.88-2.65 (m, 2 H), 2.38 (dd , J = 14.2, 2.7 Hz, 1 H), 2.26-2.07 (m, 2 H), 1.99-1.89 (m, 1 H), 1.23 (td, J = 12.1, 12.1 Hz, 1 H), 0.98 (d, J = 6.6 Hz, 3 H), 0.89 (s, 9H).

[00538] Compound 150 and compound 151 ((S)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3-methylpentanamide and (R) -N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3-methylpentanamide): From 8-((3R,5S)-3- amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 3-methylpentanoic acid. Isomer 1: HPLC: 92.2% purity, Retention Time = 2.86 min. MS: m/z = 366.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.11 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 4.40 (d, J = 11.9 Hz, 1 H), 4.32 (d, J = 12.5 Hz, 1 H), 4.22-4.10 (m, 1 H), 2.83-2.63 (m, 2 H), 2.23 (dd, J = 13.4, 6.1 Hz, 1 H), 2.15-1.95 ( m, 3 H), 1.94-1.84 (m, 1 H), 1.47-1.36 (m, 1 H), 1.34-1.16 (m, 2 H), 1, 02 (d, J = 6.4 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 6 H). Isomer 2: HPLC: 90.4% purity, Retention Time = 1.54 min. MS: m/z = 366.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.11 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 4.40 (d, J = 11.9 Hz, 1 H), 4.32 (d, J = 12.5 Hz, 1 H),4.22-4.10 (m, 1 H), 2.83-2.63 (m, 2 H), 2.23 (dd, J = 13.4, 6.1 Hz, 1 H),2.15-1.95 ( m, 3 H), 1.94-1.84 (m, 1 H), 1.47-1.36 (m, 1 H), 1.34-1.16 (m, 2 H), 1, 02 (d, J = 6.4 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 6 H).

[00539] Compound 152 and compound 153 ((S)-3-methyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3 -yl)pentanamide and (R)-3-methyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)pentanamide ): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-methylpentanoic acid. Isomer 1: HPLC: 97.4% purity, Retention Time = 1.23 min. MS: m/z = 342.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.8 Hz, 1 H), 8.83 (d, J = 1.8 Hz, 1 H), 8.68 (d , J = 5.6 Hz, 1 H), 7.17 (dd, J = 5.8, 1.6 Hz, 1 H), 4.77-4.65 (m, 2 H), 4.16 -4.02 (m, 1 H), 2.91-2.72 (m, 2 H), 2.25 (dd, J = 13.4, 6.1 Hz, 1 H), 2.16- 1.94 (m, 3H), 1.98-1.82 (m, 1H), 1.50-1.19 (m, 3H), 1.11-0.91 (m, 9H) . Isomer 2: HPLC: 96.6% purity, Retention Time = 1.23 min. MS: m/z = 342.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (d, J = 1.8 Hz, 1 H), 8.83 (d, J = 1.8 Hz, 1 H), 8.68 (d , J = 5.6 Hz, 1 H), 7.17 (dd, J = 5.8, 1.6 Hz, 1 H), 4.77-4.65 (m, 2 H), 4.16 -4.02 (m, 1 H), 2.91-2.72 (m, 2 H), 2.25 (dd, J = 13.4, 6.1 Hz, 1 H), 2.16- 1.94 (m, 3H), 1.98-1.82 (m, 1H), 1.50-1.19 (m, 3H), 1.11-0.91 (m, 9H) .

[00540] Compound 154 and compound 155 ((R)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-methylbutanamide and (S) - N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-methyl-butanamide): From 8-((3R,5S)- 3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-methylbutanoic acid. Isomer 1: HPLC: 92.2% purity, Retention Time = 2.41 min. MS: m/z = 352.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.82 (m, 2 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4.40-4.24 (m, 2 H), 4.20-4.04 (m, 1 H), 2.80-2.60 (m, 2 H) , 2.29 - 2.16 (m, 1 H), 2.13-1.96 (m, 3 H), 1.68-1.32 (m, 2 H), 1.35-1.07 (m, 5 H), 1.03-0.86 (m, 6 H). Isomer 2: HPLC: 95.1% purity, Retention Time = 1.42 min. MS: m/z = 342.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.90 (dd, J = 13.6, 1.8 Hz, 2 H), 8.08 (d, J = 8.4 Hz, 1 H), 7 .28 (d, J = 8.4 Hz, 1 H), 4.404.24 (m, 2 H), 4.20-4.04 (m, 1 H), 2.80-2.60 (m, 2 H), 2.29 - 2.16 (m, 1 H), 2.13-1.96 (m, 3 H), 1.68-1.32 (m, 2 H), 1.35- 1.07 (m, 5 H), 1.03-0.86 (m, 6 H).

[00541] Compound 156 and compound 157 ((R)-2-methyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3 -yl)butanamide and (S)-2-methyl-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)butanamide ): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-methylbutanoic acid. Isomer 1: HPLC: 96.0% purity, Retention Time = 1.11 min. EM: m/z = 328.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1 H), 8.85 (d, J = 1.8 Hz, 1 H), 8.62 (d , J = 6.0 Hz, 1 H), 7.21 (d, J = 6.0 Hz, 1 H), 4.704.50 (m, 2 H), 4.13-3.99 (m, 1 H), 2.97-2.77 (m, 2 H), 2.32-2.15 (m, 1 H), 2.14-1.91 (m, 2 H), 1.70-1 .54 (m, 1 H), 1.51-1.36 (m, 1 H), 1.37-1.23 (m, 3 H), 1.19-1.00 (m, 6 H) , 0.92 (t, J = 7.4 Hz, 3 H). Isomer 2: HPLC: 91.8% purity, Retention Time = 1.11 min. EM: m/z = 328.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1 H), 8.85 (d, J = 1.8 Hz, 1 H), 8.62 (d , J = 6.0 Hz, 1 H), 7.21 (d, J = 6.0 Hz, 1 H), 4.70-4.50 (m, 2 H), 4.13-3.99 (m, 1 H), 2.97-2.77 (m, 2 H), 2.32-2.15 (m, 1 H), 2.14-1.91 (m, 2 H), 1 .70-1.54 (m, 1 H), 1.51-1.36 (m, 1 H), 1.371.23 (m, 3 H), 1.19-1.00 (m, 6 H) , 0.92 (t, J = 7.4 Hz, 3 H).

[00542] Compound 158 and compound 159 ((S)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-methoxypropanamide and (R) -N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-methoxypropanamide): From 8-((3R,5S)-3- amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-methoxypropanoic acid. Isomer 1: HPLC: 99.6% purity, Retention Time = 1.27 min. MS: m/z = 354.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.98-8.84 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4.32-4.10 (m, 3 H), 3.75 (q, J = 6.7 Hz, 1 H), 3.37 (s, 3 H), 2.89 (dd, J = 12.0, 10.4 Hz, 1 H), 2.70 (dd, J = 12.6, 10.6 Hz, 1 H), 2.15-1.99 ( m, 2 H), 1.41-1.27 (m, 4 H), 1.02 (d, J = 6.4 Hz, 3 H). Isomer 2: HPLC: 96.0% purity, Retention Time = 2.60 min. MS: m/z = 354.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.96-8.82 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4.32-4.10 (m, 3 H), 3.75 (q, J = 6.7 Hz, 1 H), 3.37 (s, 3 H), 2.89 (dd, J = 12.0, 10.4 Hz, 1 H), 2.70 (dd, J = 12.6, 10.6 Hz, 1 H), 2.15-1.99 ( m, 2 H), 1.41-1.27 (m, 4 H), 1.02 (d, J = 6.4 Hz, 3 H).

[00543] Compound 160 and compound 161 ((S)-2-methoxy-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3 -yl)propanamide and (R)- 2-methoxy-N-((3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-yl)propanamide ): From (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 2-methoxypropanoic acid. Isomer 1: HPLC: 99.6% purity, Retention Time = 1.27 min. EM: m/z = 354.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1 H), 8.81 (d, J = 1.8 Hz, 1 H), 8.65 (d , J = 5.6 Hz, 1 H), 7.14 (d, J = 5.6 Hz, 1 H), 4.70-4.54 (m, 2 H), 4.10 (tt, J = 11.1, 4.2 Hz, 1 H), 3.75 (q, J = 6.7 Hz, 1 H), 3.37 (s, 3 H), 2.96 (dd, J = 12 .4, 10.8 Hz, 1 H), 2.77 (dd, J = 12.9, 11.1 Hz, 1 H), 2.13-1.92 (m, 2 H), 1.43 -1.26 (m, 4 H), 1.02 (d, J = 6.5 Hz, 3 H). Isomer 2: HPLC: 96.0% purity, Retention Time = 2.60 min. MS: m/z = 354.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1 H), 8.81 (d, J = 1.8 Hz, 1 H), 8.65 (d , J = 5.6 Hz, 1 H), 7.14 (d, J = 5.6 Hz, 1 H), 4.70-4.54 (m, 2 H), 4.10 (tt, J = 11.1, 4.2 Hz, 1 H), 3.75 (q, J = 6.7 Hz, 1 H), 3.37 (s, 3 H), 2.96 (dd, J = 12 .4, 10.8 Hz, 1 H), 2.77 (dd, J = 12.9, 11.1 Hz, 1 H), 2.13-1.92 (m, 2 H), 1.43 -1.26 (m, 4 H), 1.02 (d, J = 6.5 Hz, 3 H).

[00544] Compound 173 and compound 174 ((S)-N-((3R,5R)-1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl)-2-hydroxy-3-methylbutanamide and (S)-N-((3S,5S)-1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl)-2-hydroxy-3-methylbutanamide): from cis-8-( 3-amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-hydroxy-3-methylbutanoic acid. Isomer 1: HPLC: 94.0% purity, Retention Time = 2.52 min. MS: m/z = 394.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1 H), 8.85 (d, J = 1.8 Hz, 1 H), 8.05 (d , J = 8.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.34-4.00 (m, 3 H), 3.82 (d, J = 3.7 Hz, 1 H), 3.03-2.85 (m, 2 H), 2.20-1.97 (m, 2 H), 1.54 (q, J = 11.6 Hz , 1 H), 1.22-1.04 (m, 1 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3 H), 0.72-0.56 (m, 1 H), 0.52-0.38 (m, 2 H), 0.18 (dd, J = 4.8, 2.9 Hz, 2 H ). Isomer 2: HPLC: 93.8% purity, Retention Time = 2.57 min. EM: m/z = 394.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ8.89 (d, J = 1.8 Hz, 1 H), 8.85 (d, J = 1.8 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.34-4.00 (m, 3 H), 3.82 (d, J = 3.7 Hz, 1 H), 3.03-2.85 (m, 2 H), 2.20-1.97 (m, 2 H), 1.54 (q, J = 11.6 Hz, 1 H), 1.22-1.04 (m, 1 H), 0.99 (d, J = 6.9 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3 H ), 0.72-0.56 (m, 1 H), 0.52-0.38 (m, 2 H), 0.18 (dd, J = 4.8, 2.9 Hz, 2 H) .

[00545] Compound 429 and compound 430 ((S)-N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-hydroxy -3-methyl-butyramide and (S)-N-[(3S,5R)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-hydroxy-3 -methyl-butyramide): From cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (2S)-2-hydroxy-3-methylbutanoic acid. Isomer 1: HPLC: 98.8% purity, Retention Time = 3.80 min. EM: m/z = 341 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.08 (dd, J = 4.2, 1.7 Hz, 1 H), 8.48 (dd, J = 8.6, 1.7 Hz , 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.59 (dd, J = 8.6, 4.2 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 6.59 (d, J = 8.1 Hz, 1 H), 4.41 (dtd, J = 16.1, 8.2, 4.2 Hz, 1 H ), 4.02 (d, J = 3.1 Hz, 1 H), 3.82 - 3.73 (m, 1 H), 3.68 - 3.59 (m, 1 H), 2.94 (t, J = 11.3 Hz, 1 H), 2.83 (dtd, J = 12.0, 8.0, 4.1 Hz, 1 H), 2.54 (t, J = 11.2 Hz, 1 H), 2.44 (d, J = 12.6 Hz, 1 H), 2.24 (pd, J = 6.9, 3.0 Hz, 1 H), 1.54 (q, J = 12.3 Hz, 1 H), 1.04 (d, J = 7.0 Hz, 3 H), 0.88 (d, J = 6.9 Hz, 3 H). Isomer 2: HPLC: > 99% purity, Retention Time = 3.70 min. EM: m/z = 341 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J = 4.2, 1.7 Hz, 1 H), 8.48 (dd, J = 8.6, 1.7 Hz , 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.13 (d, J = 8.0 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 4.40 (dtt, J = 16.3, 8.3, 4.2 Hz, 1 H ), 4.03 (d, J = 3.0 Hz, 1 H), 3.81 - 3.72 (m, 1 H), 3.68 - 3.60 (m, 1 H), 2.93 (t, J = 11.2 Hz, 1 H), 2.82 (ddt, J = 15.0, 7.5, 3.9 Hz, 1 H), 2.54 (t, J = 11.1 Hz, 1 H), 2.45 (d, J = 12.5 Hz, 1 H), 2.19 (pd, J = 6.9, 3.0 Hz, 1 H), 1.56 (q, J = 12.2 Hz, 1 H), 1.02 (d, J = 7.0 Hz, 3 H), 0.80 (d, J = 6.9 Hz, 3 H).

[00546] Compound 437 and compound 438 [(3S,5R)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-acid amide ((S)-1- ethyl-pyrrolidine-2-carboxylic acid and [(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-amide) (S)-1- ethyl-pyrrolidine-2-carboxylic: From cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and 1-ethyl-1-proline. Isomer 1: HPLC: > 99% purity, Retention Time = 2.77 min. MS: m/z = 446 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J = 4.2, 1.7 Hz, 1 H), 8.49 (dd, J = 8.5, 1.7 Hz , 1 H), 8.04 (d, J = 7.9 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.54 (d, J = 8.2 Hz, 1 H), 7.13 (d, J = 7.9 Hz, 1 H), 4.34 (dddd, J = 16.3, 12.6, 8.4, 4.3 Hz, 1 H), 3.77 - 3.69 (m, 1 H), 3.67 - 3.57 (m, 1 H), 3.14 (dd, J = 8.7, 6.8 Hz , 1 H), 3.05 (dd, J = 10.5, 4.3 Hz, 1 H), 2.93 (t, J = 11.2 Hz, 1 H), 2.83 (ddp, J = 11.6, 7.8, 3.8 Hz, 1 H), 2.71 - 2.46 (m, 3 H), 2.41 (d, J = 12.4 Hz, 1 H), 2 .33 (ddd, J = 10.6, 9.2, 6.0 Hz, 1 H), 2.14 (dtd, J = 13.0, 9.8, 7.5 Hz, 1 H), 1 .84 - 1.69 (m, 2 H), 1.68 - 1.57 (m, 1 H), 1.54 - 1.46 (m, 1 H), 1.10 (t, J = 7 .2Hz, 3H). Isomer 2: HPLC: > 99% purity, Retention Time = 2.79 min. MS: m/z = 446 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J = 4.2, 1.7 Hz, 1 H), 8.50 (dd, J = 8.6, 1.7 Hz , 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 4.42 - 4.29 (m, 1 H), 3.82 - 3.73 (m , 1 H), 3.66 - 3.58 (m, 1 H), 3.17 (t, J = 7.6 Hz, 1 H), 3.03 (dd, J = 10.3, 4, 4 Hz, 1 H), 2.95 (t, J = 11.3 Hz, 1 H), 2.82 (ddt, J = 15.5, 7.9, 3.8 Hz, 1 H), 2 .60 - 2.38 (m, 4 H), 2.38 - 2.29 (m, 1 H), 2.18 (dtd, J = 13.0, 10.3, 7.8 Hz, 1 H ), 1.88 (ddd, J = 12.6, 8.2, 4.0 Hz, 1 H), 1.84 - 1.76 (m, 1 H), 1.71 (dd, J = 12 .7, 5.9 Hz, 1 H), 1.54 - 1.47 (m, 1 H), 1.01 (t, J = 7.2 Hz, 3 H).Example 42: Synthesis of compound 91 and compound 92 (cis,cis-8-(3-((4-hydroxycyclohexyl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile and cis,trans-8-( -3-((4-hydroxycyclohexyl)amino)- 5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile) Method 10

[00547] Cis,cis-8-(3-((4-hydroxycyclohexyl)amino)-5-(trifluoromethyl) piperidin-1-yl)quinoxaline-5-carbonitrile and cis,trans-8-(3-( (4-hydroxycyclohexyl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile): A solution of cis-8-[3-amino-5-(trifluoromethyl)piperidin-1- yl]quinoxaline-5-carbonitrile (220 mg, 0.68 mmol) in methanol (5 mL) were added 4-hydroxycyclohexan-1-one (118 mg, 1.03 mmol), NaBH3CN (124 mg, 1. 97 mmol), acetic acid (0.5 mL) at room temperature. The resulting solution was stirred for 15 hours at room temperature. When the reaction was done, it was stopped abruptly by the addition of sat NH4Cl. (10 mL). The resulting mixture was extracted with EtOAc (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure, and the cis and trans isomers (each as a racemic mixture) were separated by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 19 x 150 mm 10 µm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 45% gradient in 11 min; detector, UV 254 nm.

[00548] Isomer 1: (25 mg, 23%, yellow solid) HPLC: 99.4% purity, Retention Time = 1.25 min. EM: m/z = 420.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.84 (m, 2 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.24 (d, J = 8.3 Hz, 1 H), 4.46-4.28 (m, 2 H), 3.59-3.44 (m, 1 H), 3.24-3.13 (m, 1 H) , 3.01 - 2.93 (m, 1 H), 3.01-2.80 (m, 2 H), 2.70-2.57 (m, 2 H), 2.33 (d, J = 12.5 Hz, 1 H), 2.13 (dd, J = 9.3, 6.1 Hz, 1 H), 2.041.87 (m, 3 H), 1.49-1.08 (m , 5H).

[00549] Isomer 2: (19 mg, 18%, yellow solid) HPLC: 97.6% purity, Retention Time = 1.87 min. EM: m/z = 420.0 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.84 (m, 2 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 4.43-4.33 (m, 2 H), 3.87 (br s, 1 H), 3.24-3.16 (m, 1 H), 3, 08-2.58 (m, 4H), 2.35 (apparent d, J = 12.4 Hz, 1H), 1.89-1.35 (m, 9H).

[00550] The following compounds were synthesized in an analogous manner:

[00551] Compound 93 and Compound 94 (cis,cis-4-((1-(pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)piperidin-3-yl)amino)cyclo- hexanol and trans,cis-4-((1-(pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)piperidin-3-yl)amino)cyclohexanol): from cis-1 -(pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)piperidin-3-amine and 4-hydroxycyclohexanone. Isomer 1: HPLC: 98.3% purity, Retention Time = 0.98 min. EM: m/z = 396.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.7 Hz, 1 H), 8.79 (d, J = 1.7 Hz, 1 H), 8.69 (d , J = 5.5 Hz, 1 H), 7.09 (d, J = 5.6 Hz, 1 H), 4.83-4.63 (m, 2 H), 3.59-3.44 (m, 1 H), 3.23-3.00 (m, 2 H), 2.84 (dd, J = 8.1, 3.9 Hz, 1 H), 2.75-2.65 ( m, 2 H), 2.40-2.28 (m, 1 H), 2.18-2.05 (m, 1 H), 2.03-1.88 (m, 3 H), 1, 50-1.42 (m, 1 H), 1.35-1.15 (m, 4 H). Isomer 2: NMR (300 MHz, CD3OD, ppm) δ 8.93 (d, J = 1.7 Hz, 1 H), 8.79 (d, J = 1.7 Hz, 1 H), 8.69 (d, J = 5.5 Hz, 1 H), 7.09 (d, J = 5.6 Hz, 1 H), 4.78-4.69 (m, 2 H), 3.88 (d , J = 4.6 Hz, 1 H), 3.23-2.99 (m, 2 H), 2.94-2.67 (m, 3 H), 2.36 (dd, J = 12, 2, 4.2 Hz, 1 H), 1.83-1.73 (m, 3 H), 1.71-1.53 (m, 5 H), 1.53-1.37 (m, 1 H).

[00552] Compound 95 (cis-8-[3-(trifluoromethyl)-5-[(3,3,3-trifluoropropyl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile): from cis-8-( 3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile and 3,3,3-trifluoropropanal. HPLC: 98.5% purity, Retention Time = 2.95 min. EM: m/z = 418.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.25 (d,J = 8.4 Hz, 1 H), 4.44-4.34 (m, 2 H), 3.12-2.80 (m, 5 H), 2.73-2.57 (m, 1 H) , 2.40-2.20 (m, 3 H), 1.45-1.33 (m, 1 H).

[00553] Compound 96 (cis-1-[pyrido[2,3-b]pyrazin-8-yl]-5-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)piperidin-3-amine hydrochloride ): From cis-1-(pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)piperidin-3-amine and 3,3,3-trifluoropropanal. HPLC: 95.0% purity, Retention Time = 1.33 min. EM: m/z = 394.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.8 Hz, 1 H), 8.80 (d, J = 1.8 Hz, 1 H), 8.70 (d , J = 5.6 Hz, 1 H), 7.11 (d,J = 5.6 Hz, 1 H), 4.82-4.68 (m, 2 H), 3,122.69 (m, 6 H), 2.49-2.31 (m, 3 H), 1.50-1.38 (m, 1 H).

[00554] Compound 135 and compound 136 (cis-8-((3R,5S)-3-((4-hydroxycyclohexyl)amino)-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and trans-8 -((3R,5S)-3-((4-hydroxycyclohexyl)amino)-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile): From 8-((3R,5S)- 3- amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 4-hydroxycyclohexanone. Isomer 1: (40 mg, 13%, yellow solid) HPLC: 98.9% purity, Retention Time = 1.07 min. MS: m/z = 366.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1 H), 8.84 (d, J = 1.7 Hz, 1 H), 8.07 (d , J = 8.4 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 4.63 (dd, J = 13.4, 3.8 Hz, 1 H), 4.04-3.95 (m, 1 H), 3.54 (tt, J = 10.7, 4.0 Hz, 1 H), 3.24-3.11 (m, 1 H), 2 .74-2.49 (m, 3 H), 2.22-2.08 (m, 2 H), 2.06-1.89 (m, 4 H), 1.41-1.11 (m , 4 H), 1.09-0.95 (m, 4 H). Isomer 2: HPLC: 93.0% purity, Retention Time = 1.12 min. MS: m/z = 366.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.8 Hz, 1 H), 8.84 (d, J = 1.8 Hz, 1 H), 8.08 (d , J = 8.4 Hz, 1 H), 7.20 (d, J = 8.4 Hz, 1 H), 4,694.55 (m, 1 H), 4.06-3.97 (m, 1 H), 3.96-3.86 (m, 1 H), 3.30-3.16 (m, 1 H), 2.84-2.70 (m, 1 H), 2.66-2 .52 (m, 2 H), 2.19-1.94 (m, 2 H), 1.92-1.74 (m, 3 H), 1.73-1.51 (m, 5 H) , 1.12-0.92 (m, 4 H).

[00555] Compound 137 (8-[(3S,5R)-3-methyl-5-[(oxetan-3-yl)amino] piperidin-1-yl]quinoxaline-5-carbonitrile): from oxetan-3-one and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.1% purity, Retention Time = 1.12 min. EM: m/z = 324.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.16 (d, J = 8.4 Hz, 1 H), 4.88-4.76 (m, 2 H), 4.59-4.40 (m, 3 H), 4.26-4.12 (m, 1 H) , 4.07-3.98 (m, 1 H), 3.04-2.90 (m, 1 H), 2,682.48 (m, 2 H), 2.16-1.91 (m, 2 H), 1.14-0.96 (m, 4 H).

[00556] Compound 138 (8-[(3S,5R)-3-methyl-5-[(oxolan-3-yl)amino] piperidin-1-yl]quinoxaline-5-carbonitrile): dihydrofuran-3 (2H)-one and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.6% purity, Retention Time = 1.20 min. EM: m/z = 338.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.83 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 4.68-4.54 (m, 1 H), 4.09-3.72 (m, 4 H), 3.68-3.48 (m, 2 H) , 3.14-2.98 (m, 1 H), 2.65-2.52 (m, 2 H), 2.31-2.11 (m, 2 H), 2.08-1.93 (m, 1 H), 1.89-1.69 (m, 1 H), 1.11-0.95 (m, 4 H).

[00557] Compound 139 ((3R,5S)-5-methyl-N-(oxolan-3-yl)-1-[pyrido [2,3-b]pyrazin-8-yl]piperidin-3-amine): of dihydrofuran-3(2H)-one and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: 97.1% purity, Retention Time = 0.89 min. EM: m/z = 314.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 1.7 Hz, 1 H), 8.80 (t, J = 1.8 Hz, 1 H), 8.63 (d , J = 5.6 Hz, 1 H), 7.05 (d, J = 5.7 Hz, 1 H), 5.09-4.99 (m, 1 H), 4.43-4.28 (m, 1 H), 4.00-3.84 (m, 2 H), 3.87-3.49 (m, 3 H), 3.06-2.94 (m, 1 H), 2 .76-2.61 (m, 2 H), 2.31-2.13 (m, 2 H), 2.031.88 (m, 1 H), 1.88-1.70 (m, 1 H) , 1.16-1.00 (m, 4 H).Example 43: Synthesis of compound 98 ((2R)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5- methylpiperidin-3-yl]-2-[ethyl(methyl)amino]propanamide) Method 11

[00558] (S)-2-((benzyloxycarbonyl)(ethyl)amino)propanoic acid: At 0°C, sodium hydride (324 mg, 13.50 mmols) was added to a solution of (2R)-2- acid [[(benzyloxy)carbonyl]amino]propanoic acid (950 mg, 4.26 mmols) in tetrahydrofuran (50 mL). The mixture was stirred for 10 minutes at 0°C, and then added with iodoethane (5.32 g, 34.11 mmols). The reaction mixture was heated to 60°C and stirred for 20 hours. When the reaction was done, it was stopped abruptly by adding water (50 mL). The resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield (2R)-2-[[(benzyloxy)carbonyl](ethyl)amino]propanoic acid as light yellow oil (900 mg, 32%). MS: m/z = 252.2 [M + H]+. Method 12

[00559] (S)-2-(ethyl(methyl)amino)propanoic acid: Under a nitrogen atmosphere, Pd/C (0.1 g, 10%) was added to a solution of (2R)-2-[ [(benzyloxy)carbonyl](ethyl)amino]propanoic acid (900 mg, 3.58 mmols, 1.00 equiv) and formalin (0.8 mL, 8.74 mmols, 40%) in ethanol (20 mL) and water (20 mL) at room temperature. The reaction vial was aspirated and purged with hydrogen. The reaction mixture was stirred and hydrogenated for 20 hours at room temperature under a hydrogen balloon. When the reaction was done, the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to yield (2R)-2-[ethyl(methyl)amino]propanoic acid as white solid (387 mg, 82%). EM: m/z = 132.2 [M + H]+.

[00560] (R)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(ethyl(methyl)amino)propanamide: (R )-N-((3R,5S)-1-(8-cyanoquino-xalin-5-yl)-5-methylpiperidin-3-yl)-2-(ethyl(methyl)amino)propanamide was prepared from 8-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (S)-2-(ethyl(methyl)amino)propanoic acid using Method J. The crude product was purified by HPLC preparative under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 150 mm; mobile phase, MeOH in water (with 0.05% NH3.H2O), 15% to 45% gradient in 10 min; detector, UV 254 nm. (2R)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-[ethyl(methyl)amino]propanamide was obtained as a yellow solid ( 36 mg, 32%).

[00561] Compound 98: HPLC: 90.0% purity, Retention Time = 1.95 min. EM: m/z = 381.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.7 Hz, 1 H), 8.85 (d, J = 1.8 Hz, 1 H), 8.05 (d , J = 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 4.33-4.22 (m, 2 H), 4.16- 4.05 (m, 1 H), 3.20-3.13 (m, 1 H), 2.82-2.75 (m,1H), 2.70-2.62 (m,1H), 2.55 -2.42 (m, 2 H), 2.2 5 (s, 3 H), 2.08-1.95 (m, 2 H), 1.25-1.16 (m, 4 H), 1.08 (t, J = 7.0 Hz, 3 H), 0.98 (d, J = 6.4 Hz, 3 H).

[00562] The following compounds were synthesized in an analogous manner:

[00563] Compound 99 ((2S)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-[ethyl(methyl)amino]propanamide ): From 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and (R)-2-(ethyl(methyl)amino)propanoic acid. HPLC: 97.5% purity, Retention Time = 2.81 min. MS: m/z = 381.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89 (d, J = 1.8 Hz, 1 H), 8.85 (d, J = 1.8 Hz, 1 H), 8.06 (d , J = 8.4 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 4.34-4.23 (m, 2 H), 4.13-4.05 (m, 1H), 3.18-3.11 (m,1H), 2.83-2.75 (m, 1H), 2.71-2.61 (m, 1H), 2, 54-2.45 (m, 2 H), 2.25 (s, 3 H), 2.10-1.96 (m, 2 H), 1.29-1.15 (m, 4 H), 1.06 (t, J = 7.2 Hz, 3 H), 0.98 (d, J = 6.4 Hz, 3 H).

[00564] Compound 100 ((2R)-2-[ethyl(methyl)amino]-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl] piperidin-3-yl]propanamide): de(3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and acid (S)- 2- (ethyl(methyl)amino)propanoic acid. HPLC: 95.7% purity, Retention Time = 1.11 min. EM: m/z = 357.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d,J = 1.7 Hz, 1 H), 8.77 (d,J = 1.8 Hz, 1 H), 8.63 (d , J = 5.6 Hz, 1 H), 7.12 (d,J = 5.7 Hz, 1 H), 4.63 (d, J = 13.3 Hz, 2 H), 4.12- 3.95 (m, 1 H), 3.18-3.12 (m, 1 H), 2.92-2.84 (m, 1 H), 2.79-2.71 (m, 1 H ), 2.55-2.46 (m, 2 H), 2.26 (s, 3 H), 2.10-1.92 (m, 2 H), 1.34-1.24 (m, 1 H), 1.20 (d, J = 6.9 Hz, 3 H), 1.09-1.04 (m, 3 H), 0.99 (d,J = 6.5 Hz, 3 H ).

[00565] Compound 101 ((2S)-2-[ethyl(methyl)amino]-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl] piperidin-3-yl]propanamide): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and acid (R)- 2- (ethyl(methyl)amino)propanoic acid. HPLC: 95.7% purity, Retention Time = 1.11 min. MS: m/z = 357.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (d,J = 1.7 Hz, 1 H), 8.77 (d,J = 1.8 Hz, 1 H), 8.63 (d , J = 5.6 Hz, 1 H), 7.12 (d,J = 5.7 Hz, 1 H), 4.63 (d, J = 13.3 Hz, 2 H), 4.12- 3.95 (m, 1 H), 3.18-3.12 (m, 1 H), 2.92-2.84 (m, 1 H), 2.79-2.71 (m, 1 H ), 2.55-2.46 (m, 2 H), 2.26 (s, 3 H), 2.10-1.92 (m, 2 H), 1.34-1.24 (m, 1 H), 1.20 (d, J = 6.9 Hz, 3 H), 1.09-1.04 (m, 3 H), 0.99 (d,J = 6.5 Hz, 3 H ). Example 44: Synthesis of compound 112 and compound 113 ((S)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl hydrochloride) -3,3,3-trifluoropropanamide and (R)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3 hydrochloride ,3,3-trifluoropropanamide)

[00566] 2-(Benzyloxycarbonylamino)-3,3,3-trifluoropropanoic acid: At 0°C, to a solution of 2-amino-3,3,3-trifluoropropanoic acid (475 mg, 3.32 mmols) in dioxane (15 mL) and water (15 mL) were added sodium carbonate (1.90 g, 17.93 mmols) and Cbz-Cl (624 mg, 3.65 mmols). The resulting mixture was stirred for 5 hours at room temperature. When the reaction was done, the pH value of the reaction mixture was adjusted to 2-3 with hydrogen chloride solution (4 M). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by reversed-phase flash chromatography eluting with acetonitrile in water (15% to 35% gradient over 30 min) to yield 2-[[(benzyloxy)carbonyl]amino acid]- 3,3,3-trifluoropropanoic as white solid (500 mg, 54%). MS: m/z = 276 [M-H]+.

[00567] Benzyl 3-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-ylamino)-1,1,1-trifluoro-3-oxopropan-2-ylcarbamate: 3-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-ylamino)-1,1,1-trifluoro-3-oxopropan-2-ylcarbamate was prepared from 8- ((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(benzyloxycarbonylamino)-3,3,3-trifluoropropanoic acid using Method J. The crude product was purified by chromatography flash eluting with EtOAc in hexane (0% to 50% gradient) to produce benzyl N-(1-[[(3R,5S)- 1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl ]carbamoyl]-2,2,2-trifluoroethyl)carbamate as yellow solid (220 mg, 50%). EM: m/z = 527 [M-H]+.Method 14

[00568] (S)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3,3,3-trifluoropropanamide hydrochloride and (R)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3,3,3-trifluoropropanamide hydrochloride: A a solution of benzyl N-(1-[[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamoyl]-2,2,2-trifluoroethyl)carbamate ( 110 mg, 0.21 mmol) in acetic acid (5 mL) was added HBr solution (40% in dioxane, 2 mL). The resulting solution was stirred for two hours at room temperature. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, MeOH in water (with 0.02% HCl), 10% to 27% gradient in 10 min; detector, UV 254 nm. Two diastereomeric products were separated and obtained.

[00569] Isomer 1: (30 mg, 20%, brown solid) HPLC: 99.1% purity, Retention Time = 1.01 min. MS: m/z = 393.0 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90-8.82 (m, 2 H), 8.07 (d, J = 8.3 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 4.78-4.71 (m, 1 H), 4.39-4.15 (m, 3 H), 2.85-2.60 (m, 2 H) , 2.21-2.02 (m, 2 H), 1.33-1.21 (m, 1 H), 1.00 (d, J = 6.5 Hz, 3 H).

[00570] Isomer 2: (60 mg, 40%, brown solid) HPLC: 99.1% purity, Retention Time = 1.05 min. MS: m/z = 393.0 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.00-8.80 (m, 2 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 4.76-4.69 (q, J = 7.4 Hz, 1 H), 4.49-4.03 (m, 3 H), 2.86-2, 60 (m, 2 H), 2.20-1.96 (m, 2 H), 1.33-1.15 (m, 1 H), 1,030.95 (m, 3 H).

[00571] The following compounds were synthesized in an analogous manner:

[00572] Compound 114 and compound 115 ((S)-2-amino-3,3,3-trifluoro-N-((3R,5S)-5-methyl-1-(quinoxalin-5-yl)piperidin hydrochloride - 3-yl)propanamide and (R)-2-amino-3,3,3-trifluoro-N-((3R,5S)-5-methyl-1-(quinoxalin-5-yl)piperidin-3 hydrochloride -yl)propanamide): from (3R,5S)-5-methyl-1-(quinoxalin-5-yl)piperidin-3-amine and 2-(benzyloxycarbonylamino)-3,3,3-trifluoropropanoic acid. Isomer 1: HPLC: 93.9% purity, Retention Time = 0.97 min. EM: m/z = 369.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.12 (d, J = 1.8 Hz, 1 H), 8.97 (d, J = 1.9 Hz, 1 H), 8.61 (d , J = 7.3 Hz, 1 H), 7.35 (d, J = 7.5 Hz, 1 H), 5.10-4.90 (m, 3 H), 4.11-3.91 (m, 1 H), 3.37 (t, J = 11.8 Hz, 1 H), 3.16 (t, J = 12.3 Hz, 1 H), 2.12-1.92 (m , 2 H), 1.49-1.45 (m, 1 H), 1.03 (d, J = 6.4 Hz, 3 H).Isomer 2: HPLC: 95.8% purity, Time of Retention = 1.04 min. EM: m/z = 369.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.02 (d, J = 2.2 Hz, 1 H), 8.68-8.58 (m, 1 H), 7.33 (d, J = 7.4 Hz, 1 H), 5.00-4.84 (m, 3 H), 4.10-3.90 (m, 1 H), 3.33 (t, J = 11.9 Hz, 1 H), 3.17 (t, J = 12.4 Hz, 1 H), 2.10-1.89 (m, 2 H), 1.45-1.40 (m, 1 H), 1 .02 (d, J = 6.3 Hz, 3 H). Example 45: Synthesis of compound 123 (8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino ]piperidin-1-yl]quinoxaline-5-carbonitrile) Method 15

[00573] 8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile: To a solution of 8-[( 3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile (50 mg, 0.19 mmol) in acetonitrile (3 mL) was added 3-bromopyrrolidin-2-one (36 mg, 0.22 mmol), 4-dimethylaminopyridine (4 mg, 0.03 mmol) and triethylamine (48 mg, 0.47 mmol) at room temperature. The resulting solution was stirred for 4 days at 100°C. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 10% to 40% gradient in 10 min; detector, UV 254 nm. 8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile was obtained as yellow solid (15 mg, 23%) .

[00574] Compound 123: HPLC: 97.9% purity, Retention Time = 1.90 min. EM: m/z = 351.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.96-8.87 (m, 2 H), 8.08 (dd, J = 9.5, 3.7 Hz, 1 H), 7.23 ( dt, J = 8.2, 4.0 Hz, 1 H), 4.71- 4.52 (m, 1 H), 4.12 (dt, J = 10.7, 5.1 Hz, 1 H ), 3.67 (dd, J = 10.1, 8.0 Hz, 1 H), 3.47-3.12 (m, 3 H), 2.73-2.45 (m, 3 H) , 2.30-2.15 (m, 1 H), 2.11-1.86 (m, 2 H), 1.16- 0.99 (m, 4 H).

[00575] The following compounds were synthesized in an analogous manner:

[00576] Compound 127 (3-[[(3R,5S)-5-methyl-1-[pyrido[2,3-b] pyrazin-8-yl]piperidin-3-yl]amino]pyrrolidin-2-one ): from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine and 3-bromopyrrolidin-2-one. HPLC: 90.8% purity, Retention Time = 1.70 min. EM: m/z = 327.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.96 (d, J = 1.7 Hz, 1 H), 8.83-8.70 (m, 2 H), 6.90 (dd, J = 5.5, 4.0 Hz, 1 H), 4.84-4.65 (m, 1 H), 4.30-4.19 (m, 1 H), 3.62-3.51 (m , 1 H), 3.46-3.28 (m, 2 H), 3.12-2.98 (m, 1 H), 2.74-2.44 (m, 3 H), 2.20 (dd, J = 28.8, 12.5 Hz, 1 H), 2.07-1.91 (m, 2 H), 1.14-0.98 (m, 4 H).Example 46: Synthesis of compound 124 and compound 125 (8-[(3S,5R)- 3-methyl-5-{[(3R)-1-methyl-2-oxopyrrolidin-3-yl]amino}piperidin-1-yl]quinoxaline- 5-carbonitrile and 8-[(3S,5R)-3-methyl-5-{[(3S)-1-methyl-2-oxopyrrolidin-3-yl]amino}piperidin-1-yl]quinoxaline-5-carbonitrile )

[00577] 8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile): 8-[(3S,5R )-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile was prepared from 8-((3R,5S)-3-amino-5-methylpiperidin -1-yl)quinoxaline-5-carbonitrile and 3-bromo-1-methylpyrrolidin-2-one using Method N. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 10% to 40% gradient in 10 min; detector, UV 254 nm. (19 mg, 28%, yellow solid). HPLC: 94.2% purity, Retention Time = 0.63 min. EM: m/z = 365.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.88 (m, 2 H), 8.13 (dd, J = 8.4, 3.1 Hz, 1 H), 7.27 ( dd, J = 8.4, 5.0 Hz, 1 H), 4.75-4.55 (m, 1 H), 4.17-4.04 (m, 1 H), 3.93-3 .84 (m, 1 H), 3.52-3.38 (m, 3 H), 2.91 (s, 3 H), 2.83-2.57 (m, 3 H), 2.36 -2.20 (m, 1 H), 2.13-1.86 (m, 2 H), 1.27-1.04 (m, 4 H). Then, the 2 isomers of 8-[(3S,5R)- 3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile were obtained by separation over Chiral preparative HPLC under the following conditions: column, EnantioPak A1-5, 2.12 x 25 cm, 5 µm; mobile phase, EtOH in hexane, 55% isocratic in 32 min; detector, UV 254/220 nm.Isomer 1: HPLC: 98.8% purity, Retention Time = 1.15 min. EM: m/z = 365.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.88 (m, 2 H), 8.13 (dd, J = 8.4, 3.1 Hz, 1 H), 7.27 ( dd, J = 8.4, 5.0 Hz, 1 H), 4.75-4.55 (m, 1 H), 4.17-4.04 (m, 1 H), 3.93-3 .84 (m, 1 H), 3.52-3.38 (m, 3 H), 2.91 (s, 3 H), 2.83-2.57 (m, 3 H), 2.36 -2.20 (m, 1 H), 2.13-1.86 (m, 2 H), 1.27-1.04 (m, 4 H). Isomer 2: HPLC: 99.3% purity , Retention Time = 1.15 min. EM: m/z = 365.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.88 (m, 2 H), 8.13 (dd, J = 8.4, 3.1 Hz, 1 H), 7.27 ( dd, J = 8.4, 5.0 Hz, 1 H), 4.75-4.55 (m, 1 H), 4.17-4.04 (m, 1 H), 3.93-3 .84 (m, 1 H), 3.52-3.38 (m, 3 H), 2.91 (s, 3 H), 2.83-2.57 (m, 3 H), 2.36 -2.20 (m, 1 H), 2.13-1.86 (m, 2 H), 1.27-1.04 (m, 4 H).Example 47: Synthesis of compound 162 (N-[ (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-(hydroxymethyl)cyclopropane-1-carboxamide)

[00578] 1-(hydroxymethyl)cyclopropanecarboxylic acid: To a solution of ethyl 1-bromocyclobutane-1-carboxylate (475 mg, 2.29 mmols) in water (10 mL) was added KOH (255 mg, 4.55 mmols) at room temperature. The resulting mixture was stirred at 30°C for 15 h. After the reaction was done, the pH value of the reaction mixture was adjusted to 1 with hydrogen chloride solution (2 M). The resulting mixture was concentrated under reduced pressure and diluted with methanol (15 mL). The insoluble solids were filtered off and the filtrate was concentrated under reduced pressure to yield 1-(hydroxymethyl)cyclopropane-1-carboxylic acid as a light yellow solid (189 mg, 71%). MS: m/z = 117.2 [M + H]+.

[00579] N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-(hydroxymethyl)cyclopropane-1-carboxamide: N-[(3R, 5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-(hydroxymethyl)cyclopropane-1-carboxamide was prepared from 1-(hydroxymethyl)cyclopropanecarboxylic acid and 8-((3R ,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 25% to 45% gradient in 10 min; detector, UV 254 nm. N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-(hydroxymethyl)cyclopropane-1-carboxamide was obtained as a yellow solid (28 mg, 27 %).

[00580] Compound 162: HPLC: 94.2% purity, Retention Time = 1.17 min. EM: m/z = 366.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92-8.82 (m, 2 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 4.30 (t, J = 13.8 Hz, 2 H), 4.11 (d, J = 11.5 Hz, 1 H), 3,693.52 (m, 2 H), 2.84-2.64 (m, 2 H), 2.12-1.96 (m, 2 H), 1.24 (q, J = 11.7 Hz, 1 H), 1, 25-1.11 (m, 2 H), 0.98 (d, J = 6.5 Hz, 3 H), 0.78-0.62 (m, 2 H). Example 48: Synthesis of compound 177 and compound 178 ((R)-2-amino-N-((3R,5R)-1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl)-3 ,3,3-trifluoropropanamide and (R)-2-amino-N-((3S,5S)-1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl)-3,3,3 -trifluoropropanamide)

[00581] (R)-2-amino-N-((3R,5R)-1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl)-3,3,3-trifluoropropanamide and ( R)-2-amino- N-((3S,5S)-1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl)-3,3,3-trifluoropropanamide: cis-(2R) -2-amino-N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]-3,3,3-trifluoropropanamide was prepared from cis-8-(3-amino-5- cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-amino-3,3,3-trifluoropropanoic acid using Method J. The two cis diastereoisomers were separated by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 19 x 150mm 10um; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 35% to 65% gradient in 10 min; detector, UV 254 nm.Isomer 1: (14 mg, 12%, yellow solid) HPLC: 95.0% purity, Retention Time = 2.76 minutes. EM: m/z = 419.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.8 Hz, 1 H), 8.86 (d, J = 1.8 Hz, 1 H), 8.07 (d , J = 8.4 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 4.41-4.24 (m, 2 H), 4.20-4.00 (m, 1 H), 3.99-3.85 (m, 1 H), 2.95-2.75 (m, 2 H), 2.29-2.13 (m, 1 H), 1 .52-1.05 (m, 2 H), 0.70-0.37 (m, 3 H), 0.22-0.12 (m, 2 H). Isomer 2: (14 mg, 12% , yellow solid) HPLC: 94.4% purity, Retention Time = 3.14 minutes. EM: m/z = 419.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.90 (d, J = 1.8 Hz, 1 H), 8.86 (d, J = 1.8 Hz, 1 H), 8.07 (d , J = 8.4 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 4.41-4.24 (m, 2H), 4.20-4.00 ( m, 1 H), 3.99-3.85 (m, 1 H), 2.95-2.75 (m, 2 H), 2.29-2.13 (m, 1 H), 1, 52-1.05 (m, 2 H), 0.70-0.37 (m, 3 H), 0.22-0.12 (m, 2 H).Example 49: Synthesis of compound 180 (5- [(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoline-8-carboxamide)

[00582] tert-butyl N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate: tert-butyl N-[(3R,5S)-1 -(8-cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate was prepared from 5-bromoquinoline-8-carbonitrile and tert-butyl(3R,5S)-5-methylpiperidin-3-ylcarbamate using Method 9 The crude product was purified by flash chromatography eluting with DCM in petroleum ether (0% to 100% gradient) to yield tert-butyl N-[(3R,5S)-1-(8-cyanoquinolin-5-yl) - 5-methylpiperidin-3-yl]carbamate as yellow solid (128 mg, 29%). EM: m/z = 367.0 [M + H]+.

[00583] 5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoline-8-carboxamide: A solution of tert-butyl N-[(3R,5S)-1-(8 -cyanoquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate (128 mg, 0.35 mmol) in trifluoroacetic acid (4 mL) was added sulfuric acid (1 mL) at room temperature. The resulting solution was stirred for 16 hours at 40°C. When the reaction was carried out, it was stopped abruptly by the addition of ice water (30 mL) and the pH value of the solution was adjusted to 10 to 12, with ammonia solution. The resulting solution was extracted with DCM (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 20% to 50% gradient in 10 min; detector, UV 254 nm. 5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoline-8-carboxamide was obtained as light yellow solid (79 mg, 80%).

[00584] Compound 180: HPLC: 99.0% purity, Retention Time = 0.96 minutes. EM: m/z = 285.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (dd, J = 4.3, 1.8 Hz, 1 H), 8.65-8.57 (m, 2 H), 7.56 ( dd, J = 8.6, 4.2 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 1 H), 3.60-3.44 (m, 1 H), 3, 39-3.31 (m, 1 H), 3.24-3.12 (m, 1 H), 2.55-2.35 (m, 2 H), 2.19-2.01 (m, 2 H), 1.03-0.89 (m, 4 H).Example 50: Synthesis of compound 181 (5-[(3R,5S)-3-[(2S)-2-hydroxy-3-methylbutanamido] -5-methylpiperidin-1-yl]quinoline-8-carboxamide)

[00585] 5-[(3R,5S)-3-[(2S)-2-hydroxy-3-methylbutanamido]-5-methylpiperidin-1-yl]quinoline-8-carboxamide: 5-[(3R,5S) -3-[(2S)-2-hydroxy-3-methylbutanamido]-5-methylpiperidin-1-yl]quinoline-8-carboxamide was prepared from (S)-2-hydroxy-3-methylbutanoic acid and 5-(( 3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoline-8-carboxamide using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 60% gradient in 10 min; detector, UV 254 nm. 5-[(3R,5S)- 3-[(2S)-2-hydroxy-3-methylbutanamido]-5-methylpiperidin-1-yl]quinoline-8-carboxamide was obtained as yellow solid (35 mg, 52%) .

[00586] Compound 181: HPLC: 97.4% purity, Retention Time = 1.21 min. EM: m/z = 385.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.98-8.92 (m, 1 H), 8.73-8.65 (m, 1 H), 8.61 (d, J = 8.1 Hz, 1 H), 7.59 (dd, J = 8.6, 4.3 Hz, 1 H), 7.30-7.23 (m, 1 H), 4.35-4.21 (m , 1 H), 3.83 (d, J = 3.8 Hz, 1 H), 3.61-3.52 (m, 1 H), 3.38 (d, J = 11.8 Hz, 1 H), 2.64-2.44 (m, 2 H), 2.23-1.98 (m, 3 H), 1.34-1.19 (m, 1 H), 1.08-0 .92 (m, 6 H), .81 (d, J = 6.8 Hz, 3 H).

[00587] The following compounds were synthesized in an analogous manner:

[00588] Compound 182 (5-[(3R,5S)-3-(3,3-dimethylbutanamido)-5-methylpiperidin-1-yl]quinoline-8-carboxamide): From 3,3-dimethylbutanoic acid and 5-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoline-8-carboxamide. HPLC: 99.6% purity, Retention Time = 1.45 min. MS: m/z = 383.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (dd, J = 4.2, 1.8 Hz, 1 H), 8.69 (dd, J = 8.6, 1.8 Hz, 1 H), 8.61 (d, J = 8.2 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.26 (d, J = 8 .2Hz, 1H), 4.29-4.17 (m, 1H), 3.67-3.55 (m, 1H), 3.42-3.32 (m, 1H), 2.55-2.41 (m, 2 H), 2,202.04 (m, 4 H), 1.15 (td, J = 12.0, 12.0 Hz, 1 H), 1.06-0 .93 (m, 12 H).

[00589] Compound 186 (5-[(3R,5S)-3-[2-(dimethylamino) acetamido]-5-methylpiperidin-1-yl]quinoline-8-carboxamide): of 2-(dimethylamino)acetic acid and 5-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoline-8-carboxamide. HPLC: 97.3% purity, Retention Time = 1.18 min. MS: m/z = 370.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (dd, J = 4.3, 1.8 Hz, 1 H), 8.69 (dd, J = 8.6, 1.8 Hz, 1 H), 8.61 (d, J = 8.1 Hz, 1 H), 7.59 (dd, J = 8.6, 4.2 Hz, 1 H), 7.27 (d, J = 8 .2Hz, 1H), 4.33-4.20 (m, 1H), 3.61-3.57 (m, 1H), 3.39-3.36 (m, 1H), 2.99 (s, 2 H), 2.62-2.42 (m, 2 H), 2.29 (s, 6 H), 2.16-2.09 (m, 2 H), 1, 20 (td, J = 12.0, 12.0 Hz, 1 H), 1.03 (d, J = 6.4 Hz, 3 H).Example 51: Synthesis of compound 183 (5-[(3R, 5S)-3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoline-8-carboxamide)

[00590] 5-[(3R,5S)-3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoline-8-carboxamide: 5-[(3R,5S)-3-[( 2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoline-8-carboxamide was prepared from 1-bromo-2-methoxyethane and 5-((3R,5S)-3-amino-5-methylpiperidin-1- il)quinoline-8-carboxamide using Method M. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 35% to 65% gradient in 10 min; detector, UV 254 nm. 5-[(3R,5S)-3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoline-8-carboxamide was obtained as yellow solid (18 mg, 23%).

[00591] Compound 183: HPLC: 98.9% purity, Retention Time = 1.18 min. MS: m/z = 343.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (dd, J = 4.2, 1.8 Hz, 1 H), 8.69 (dd, J = 8.6, 1.8 Hz, 1 H), 8.61 (d, J = 8.2 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.26 (d, J = 8 .2Hz, 1H), 3.69-3.60 (m, 1H), 3.56-3.44 (m, 2H), 3.42-3.30 (m, 4H), 3.18-3.06 (m, 1 H), 2.97-2.80 (m, 2 H), 2.58-2.38 (m, 2 H), 2.28-2.05 ( m, 2 H), 1.06-0.92 (m, 4 H). Example 52: Synthesis of compound 184 and compound 185 (5-((3R,5S) -3-((R)-2-amino -3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl) quinoline-8-carboxamide and 5-((3R,5S)-3-((S)-2-amino-3,3,3- trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide)

[00592] 5-((3R,5S)-3-((R)-2-amino-3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide and 5-(( 3R,5S)-3-((S)-2-amino-3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide: 5-((3R,5S)-3- (2-amino-3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide was prepared from 5-((3R,5S)- 3-amino-5-methylpiperidin-1-yl )quinoline-8-carboxamide and 2-amino-3,3,3-trifluoropropanoic acid using Method J. The two diastereoisomers were separated by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 19 x 150 mm 10 µm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 60% gradient in 10 min; detector, UV 254 nm.Isomer 1: (16 mg, 12%, off-white solid) HPLC: 98.3% purity, Retention Time = 1.18 minutes. EM: m/z = 410.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ8.96 (dd, J = 4.3, 1.8 Hz, 1 H), 8,728.58 (m, 2 H), 7.60 (dd, J = 8 .6, 4.2 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 4.38-4.22 (m, 1 H), 3.91 (q, J = 7.7 Hz, 1 H), 3.65-3.56 (m, 1 H), 3.40 (dd, J = 11.9, 2.9 Hz, 1 H), 2.60-2 .42 (m, 2 H), 2.23-2.10 (m, 2 H), 1.19 (td, J = 12.6, 12.6 Hz, 1 H), 1.04 (d, J = 6.3 Hz, 3 H).Isomer 2: (16 mg, 12%, yellow solid) HPLC: 96.9% purity, Retention Time = 2.35 minutes. EM: m/z = 410.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.96 (dd, J = 4.3, 1.8 Hz, 1 H), 8.72-8.58 (m, 2 H), 7.60 ( dd, J = 8.6, 4.2 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 4.38-4.22 (m, 1 H), 3, 91 (q, J = 7.7 Hz, 1 H), 3.65-3.56 (m, 1 H), 3.40 (dd, J = 11.9, 2.9 Hz, 1 H), 2.60-2.42 (m, 2 H), 2.23-2.10 (m, 2 H), 1.19 (td, J = 12.6, 12.6 Hz, 1 H), 1 .04 (d, J = 6.3 Hz, 3 H). Example 53: Synthesis of compound 187 ((3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine)

[00593] (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine): (3R,5S)-1-(8-methoxyquinolin-5-yl)-5- Methylpiperidin-3-amine was prepared from 5-bromo-8-methoxyquinoline and tert-butyl(3R,5S)-5-methylpiperidin-3-ylcarbamate using Method R and 6. The crude product was purified by preparative HPLC under the following conditions : column, XBridge Prep C18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 20% to 50% gradient in 10 min; detector, UV 254 nm. (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine was obtained as yellow solid (27 mg, 13% for two steps).

[00594] Compound 187: HPLC: 98.8% purity, Retention Time = 1.42 min. EM: m/z = 272.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.83-8.77 (m, 1 H), 8.66-8.59 (m, 1 H), 7.58 (dd, J = 8.5 , 4.3 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.14 (d, J = 8.3 Hz, 1 H), 4.04 (s, 3 H), 3.40-3.30 (m, 1 H), 3.28-3.12 (m, 2 H), 2.45 (t, J = 10.5 Hz, 1 H), 2 .33 (t, J = 11.0 Hz, 1 H), 2.18-2.03 (m, 2 H), 1.05-0.91 (m, 4 H).Example 54: Compound Synthesis 188 ((2S)-2-hydroxy-N-[(3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide)

[00595] (2S)-2-hydroxy-N-[(3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide: (2S)-2 -hydroxy-N-[(3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide was prepared from (S)-2-hydroxy-3- acid methylbutanoic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD , 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 60% gradient in 10 min; detector, UV 254 nm. (2S)-2-hydroxy-N-[(3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide was obtained as yellow solid (15 mg, 25%).

[00596] Compound 188: HPLC: 93.1% purity, Retention Time = 1.24 min. EM: m/z = 372.3 [M + H]+. 1H NMR (400 MHz,DMSO-d6, ppm) δ 8.83 (d, J = 4.1 Hz, 1 H), 8.46 (d, J = 8.6 Hz, 1 H), 7.62 -7.53 (m, 2 H), 7.15-7.05 (m, 2 H), 5.30 (d, J = 5.7 Hz, 1 H), 4.06 (d, J = 10.8 Hz, 1 H), 3.91 (s, 3 H), 3.64 (t, J = 4.8 Hz, 1 H), 3.16 (d, J = 10.0 Hz, 1 H), 3.12-3.03 (m, 1 H), 2.49-2.41 (m, 1 H), 2.27 (t, J = 11.0 Hz, 1 H), 2, 07-1.98 (m, 1 H), 1.97-1.87 (m, 2 H), 1.18 (td, J = 12.7, 12.7 Hz, 1 H), 0.89 (dd, J = 22.8, 6.7 Hz, 6 H), 0.72 (d, J = 6.7 Hz, 3 H).

[00597] The following compounds were synthesized in an analogous manner:

[00598] Compound 189 (N-[(3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): From acid 3,3 - dimethylbutanoic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.1% purity, Retention Time = 1.45 min. MS: m/z = 370.2 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (dd, J = 4.2, 1.7 Hz, 1 H), 8.57 (dd, J = 8.5, 1.7 Hz , 1 H), 7.50 (dd, J = 8.5, 4.2 Hz, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 6.95 (d, J = 8.3 Hz, 1 H), 5.22 (d, J = 8.0 Hz, 1 H), 4.35-4.33 (m, 1 H), 4.07 (s, 3 H) , 3.55-3.46 (m, 1 H), 3.21-3.13 (m, 1 H), 2.42-2.28 (m, 2 H), 2.22-2.07 (m, 2H), 2.04 (d, J = 1.7Hz, 2H), 1.08-0.92 (m, 13H).

[00599] Compound 193 (2-(dimethylamino)-N-[(3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl]acetamide): 2-(dimethylamino) acid )acetic and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.2% purity, Retention Time = 1.74 min. MS: m/z = 357.1 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.80 (dd, J = 4.3, 1.7 Hz, 1 H), 8.67 (dd, J = 8.5, 1.7 Hz, 1 H), 7.59 (dd, J = 8.5, 4.2 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1 H), 7.13 (d, J = 8 .3 Hz, 1 H), 4.28-4.22 (m, 1 H), 4.04 (s, 3 H), 3.39-3.32 (m, 1 H), 3.22- 3.13 (m, 1 H), 2.99 (s, 2 H), 2.51 (t, J = 10.6 Hz, 1 H), 2.39 (t, J = 11.0 Hz, 1 H), 2.30 (s, 6 H), 2.19-2.04 (m, 2 H), 1.15 (td, J = 12.0, 12.0 Hz, 1 H), 1 .03 (d, J = 6.4 Hz, 3 H). Example 55: Synthesis of compound 190 ((3R,5S)-N-(2-methoxyethyl)-1- (8-methoxyquinolin-5-yl)- 5-methylpiperidin-3-amine)

[00600] (3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine: (3R,5S)-N-(2-methoxyethyl) -1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine was prepared from (S)-2-hydroxy-3-methylbutanoic acid and (3R,5S)-1-(8-methoxyquinolin-5 -yl)-5-methylpiperidin-3-amine using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 35% to 65% gradient in 10 min; detector, UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine was obtained as yellow solid (24 mg, 35%).

[00601] Compound 190: HPLC: 99.2% purity, Retention Time = 1.89 min. MS: m/z = 330.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.80 (dd, J = 4.2, 1.7 Hz, 1 H), 8.61 (dd, J = 8.5, 1.7 Hz, 1 H), 7.58 (dd, J = 8.5, 4.2 Hz, 1 H), 7.22 (d, J = 8.3 Hz, 1 H), 7.13 (d, J = 8 .3 Hz, 1 H), 4.04 (s, 3 H), 3.52 (t, J = 5.3 Hz, 2 H), 3.44-3.30 (m, 4 H), 3 .20-2.95 (m, 2 H), 2.94-2.77 (m, 2 H), 2.48-2.28 (m, 2 H), 2.23-2.00 (m , 2 H), 1.04-0.87 (m, 4 H). Example 56: Synthesis of compound 191 and compound 192 (5-((3R,5S)- 3-((R)-2-amino- 3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide and 5-((3R,5S)-3-((S)-2-amino-3,3,3-trifluoropropanamido )-5-methylpiperidin-1-yl)quinoline-8-carboxamide)

[00602] 5-((3R,5S)-3-((R)-2-amino-3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide and 5-(( 3R,5S)-3-((S)-2-amino-3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide: 2-amino-3,3,3-trifluoro -N-((3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl)propanamide was prepared from (3R,5S)-1-(8-methoxyquinolin-5-yl )-5-methylpiperidin-3-amine and 2-amino-3,3,3-trifluoropropanoic acid using Method J. The two diastereoisomers were separated by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 19 x 150 mm 10 um; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 35% to 65% gradient in 10 min; detector, UV 254 nm. Isomer 1: (7 mg, 6%, light yellow solid) HPLC : 97.3% purity, Retention Time = 1.94 min. EM: m/z = 397.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.79 (dd, J = 4.3, 1.7 Hz, 1 H), 8.65 (dd, J = 8.5, 1.7 Hz, 1 H), 7.58 (dd, J = 8.5, 4.2 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.11 (d, J = 8 .3 Hz, 1 H), 4.25-4.20 (m, 1 H), 4.02 (s, 3 H), 3.90 (q, J = 7.7 Hz, 1 H), 3 .17 (d, J = 11.3 Hz, 1 H), 2.50-2.28 (m, 2 H), 2.15-2.07 (m, 2 H), 1.38-1, 24 (m, 1 H), 1.12 (td, J = 12.7, 12.7 Hz, 1 H), 1.01 (d, J = 6.4 Hz, 3 H). Isomer 2: (7 mg, 6%, light yellow solid) HPLC: 95.7% purity, Retention Time = 2.21 min. EM: m/z = 397.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.79 (dd, J = 4.3, 1.7 Hz, 1 H), 8.65 (dd, J = 8.5, 1.7 Hz, 1 H), 7.58 (dd, J = 8.5, 4.2 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.11 (d, J = 8 .3 Hz, 1 H), 4.22 (t, J = 11.3 Hz, 1 H), 4.02 (s, 3 H), 3.90 (q, J = 7.7 Hz, 1 H ), 3.17 (d, J = 11.3 Hz, 1 H), 2.50-2.28 (m, 2 H), 2.15- 2.07 (m, 2 H), 1.38 -1.24 (m, 1 H), 1.12 (td, J = 12.7, 12.7 Hz, 1 H), 1.01 (d, J = 6.4 Hz, 3 H). Example 57: Synthesis of compound 194 ((2S)-2-hydroxy-3-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3 -il] butanamide)

[00603] (2S)-2-hydroxy-3-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl] butanamide: (2S)-2-hydroxy-3-methyl- N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl] piperidin-3-yl]butanamide was prepared of 2-(dimethylamino)acetic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine using Method J. The crude product was purified by preparative HPLC under the following conditions : column, XBridge Prep C18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 40% to 65% gradient in 10 min; detector, UV 254 nm. (2S)-2-hydroxy-3-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]butanamide was obtained as a solid white (19 mg, 16%).

[00604] Compound 194: HPLC: 93.9% purity, Retention Time = 3.58 minutes. EM: m/z = 410.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95 (dd, J = 4.0, 1.7 Hz, 1 H), 8.67 (dd, J = 8.7, 1.7 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.64 (dd, J = 8.6, 4.3 Hz, 1 H), 7.24 (d, J = 8 .0 Hz, 1 H), 4.32-4.27 (m, 1 H), 3.85 (d, J = 3.7 Hz, 1 H), 3.69-3.54 (m, 1 H), 3.44-3.39 (m, 1 H), 2.66-2.46 (m, 2 H), 2.25-2.00 (m, 3 H), 1,361.18 (m , 1H), 1.09-0.81 (m, 9H).

[00605] The following compounds were synthesized in an analogous manner:

[00606] Compound 195 (3,3-dimethyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]butanamide): acid 2-(dimethylamino)acetic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.9% purity, Retention Time = 2.91 min. MS: m/z = 408.3 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.94 (dd, J = 4.3, 1.5 Hz, 1 H), 8.66 (dd, J = 8.6, 1.6 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (d, J = 8 .1 Hz, 1 H), 4.30-4.20 (m, 1 H), 3.61 (dd, J = 11.0, 4.2 Hz, 1 H), 3.40-3.33 (m, 1 H), 2.60-2.40 (m, 2 H), 2.21-2.06 (m, 4 H), 1.16 (td, J = 12.2, 12.2 Hz, 1H), 1.05 (s, 3H), 1.03 (s, 9H).

[00607] Compound 199 (2-(dimethylamino)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide): acid 2-(dimethylamino)acetic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 96.2% purity, Retention Time = 2.68 minutes. MS: m/z = 395.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.98-8.91 (m, 1 H), 8.71-8.63 (m, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.24 (d, J = 8.1 Hz, 1 H), 4.32-4, 26 (m, 1 H), 3.66-3.57 (m, 1 H), 3.40 (d, J = 12.1 Hz, 1 H), 3.00 (s, 2 H), 2.652 .45 (m, 2 H), 2.31 (s, 6 H), 2.25-2.07 (m, 2 H), 1.22 (td, J = 12.0, 12.0 Hz, 1 H), 1.05 (d, J = 6.4 Hz, 3 H).

[00608] Compound 239 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide ): of 2-(morpholin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 99.7% purity, Retention Time = 1.85 min. MS: m/z = 437.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.61 (dd, J = 8.6, 1.8 Hz, 1 H), 7.99 (d, J = 8.1 Hz, 1 H), 7.58 (dd, J = 8.6, 4.2 Hz, 1 H), 7.18 (d, J = 8 .0Hz, 1H), 4.29-4.19 (m, 1H), 3.73-3.63 (m, 4H), 3.62-3.50 (m, 1H), 3.38-3.30 (m, 1 H), 2.99 (s, 2 H), 2.60-2.38 (m, 6 H), 2.17-2.04 (m, 2 H ), 1.19 (td, J = 12.3, 12.3 Hz, 1 H), 1.00 (d, J = 6.4 Hz, 3 H).

[00609] Compound 240 (2-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide): 2- hydroxyacetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 94.5% purity, Retention Time = 3.23 min. EM: m/z = 368.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.3, 1.7 Hz, 1 H), 8.65 (dd, J = 8.6, 1.8 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.61 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (d, J = 8 .0 Hz, 1 H), 4.34-4.26 (m, 1 H), 3.98 (s, 2 H), 3.60-3.56 (m, 1 H), 3.42- 3.33 (m, 1 H), 2.60 (t, J = 11.0 Hz, 1 H), 2.48 (t, J = 11.2 Hz, 1 H), 2.22-2, 07 (m, 2 H), 1.25 (td, J = 11.9, 11.9 Hz, 1 H), 1.03 (d, J = 6.4 Hz, 3 H).

[00610] Compound 241 (1-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]cyclopropane-1-carboxamide): of 2-(morpholin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 95.9% purity, Retention Time = 3.12 min. EM: m/z = 394.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.3, 1.7 Hz, 1 H), 8.64 (dd, J = 8.6, 1.8 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.61 (dd, J = 8.6, 4.2 Hz, 1 H), 7.22 (d, J = 8 .1 Hz, 1 H), 4.33-4.21 (m, 1 H), 3.62-3.53 (m, 1 H), 3.38 (apparent d, J = 11.5 Hz, 1 H), 2.63 (t, J = 10.9 Hz, 1 H), 2.50 (t, J = 11.3 Hz, 1 H), 2.18-2.11 (m, 2 H ), 1.30 (td, J = 11.9, 11.9 Hz, 1 H), 1.25-1.14 (m, 2 H), 1.07-0.98 (m, 3 H) , 0.98-0.90 (m, 2 H).

[00611] Compound 243 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]-2-(4-methylpiperazin-1-yl )acetamide): 2-(4-methylpiperazin-1-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 98.9% purity, Retention Time = 2.66 min. MS: m/z = 450.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.3, 1.7 Hz, 1 H), 8.61 (dd, J = 8.6, 1.8 Hz, 1 H), 7.99 (d, J = 8.1 Hz, 1 H), 7.58 (dd, J = 8.6, 4.2 Hz, 1 H), 7.18 (d, J = 8 .0Hz, 1H), 4.29-4.19 (m, 1H), 3.62-3.51 (m, 1H), 3.383.30 (m, 1H), 3.04- 2.97 (m, 2H), 2.59-2.38 (m, 10H), 2.26 (s, 3H), 2.202.02 (m, 2H), 1.17 (td, J = 12.2, 12.2 Hz, 1 H), 1.00 (d, J = 6.4 Hz, 3 H).

[00612] Compound 244 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]-2-(1-methylpiperidin-4-yl )acetamide): 2-(1-methylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 99.2% purity, Retention Time = 0.99 min. MS: m/z = 225.0 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.94-8.85 (m, 1 H), 8.61 (dt, J = 8.6, 2.0 Hz, 1 H), 8.03- 7.93 (m, 1 H), 7.56-7.60 (m, 1 H), 7.17 (dd, J = 8.0, 2.6 Hz, 1 H), 4.23-4 .13 (m, 1 H), 3.58 (apparent d, J = 9.9 Hz, 1 H), 3.34 (apparent d, J = 11.2 Hz, 1 H), 2.92-2 .76 (m, 2 H), 2.47-2.38 (m, 2 H), 2.24 (s, 3 H), 2.20-1.90 (m, 6 H), 1.80 -1.58 (m, 3 H), 1.36-1.19 (m, 2 H), 1.09 (td, J = 12.2, 12.2 Hz, 1 H), 0.99 ( d, J = 6.5, 3 H).

[00613] Compound 245 (2-(1,4-dimethylpiperidin-4-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3 -yl]acetamide): from 2-(1,4-dimethylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3 -the mine. HPLC: 95.9% purity, Retention Time = 4.37 min. MS: m/z = 463.5 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.83 (dd, J = 4.2, 1.7 Hz, 1 H), 8.55 (dd, J = 8.6, 1.8 Hz, 1 H), 7.92 (d, J = 7.9 Hz, 1 H), 7.52 (dd, J = 8.6, 4.2 Hz, 1 H), 7.11 (d, J = 8 .0 Hz, 1 H), 4.17-4.08 (m, 1 H), 3.57-3.46 (m, 1 H), 3.28 (apparent d, J = 11.6 Hz, 1 H), 2.50-2.20 (m, 6 H), 2.19 (s, 3 H), 2.151.95 (m, 4 H), 1.65-1.49 (m, 2 H ), 1.45-1.32 (m, 2H), 1.15-0.89 (m, 7H).

[00614] Compound 246 (2-[1-(2,2-difluoroethyl)piperidin-4-yl]-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5- yl]piperidin-3-yl]acetamide): from 2-(1,4-dimethylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5- yl]piperidin-3-amine. HPLC: 97.6% purity, Retention Time = 3.21 min. EM: m/z = 499.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.3, 1.7 Hz, 1 H), 8.66- 8.56 (m, 1 H), 7.99 ( d, J = 8.1 Hz, 1 H), 7.58 (dd, J = 8.6, 4.2 Hz, 1 H), 7.17 (d, J = 8.1 Hz, 1 H) , 5.90 (tt, J = 48.6, 4.5 Hz, 1 H), 4.27-4.10 (m, 1 H), 3.59 (d, J = 11.3 Hz, 1 H), 3.35 (d, J = 11.9 Hz, 1 H), 2.98-2.86 (m, 2 H), 2.62-2.74 (m, 2 H), 2, 51-2.36 (m, 2 H), 2.24-2.03 (m, 6 H), 1.79-1.55 (m, 3 H), 1.35-1.21 (m, 2 H), 1.11 (td, J = 12.4, 12.4 Hz, 1 H), 1.03-0.96 (m, 3 H).

[00615] Compound 247 (3,3-difluoro-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]cyclobutane-1-carboxamide ): 2-(1,4-dimethylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 99.9% purity, Retention Time = 1.55 min. MS: m/z = 428.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.3, 1.7 Hz, 1 H), 8.64 (dd, J = 8.6, 1.8 Hz, 1 H), 8.02 (d, J = 8.1 Hz, 1 H), 7.62 (dd, J = 8.6, 4.2 Hz, 1 H), 7.20 (d, J = 8 .0 Hz, 1 H), 4.17-4.25 (m, 1 H), 3.66-3.57 (m, 1 H), 3.42-3.34 (m, 1 H), 2.91-2.84 (m, 1 H), 2.83-2.59 (m, 4 H), 2.50-2.43 (m, 2 H), 2.19-2.09 ( m, 2 H), 1.13 (td, J = 12.3, 12.3 Hz, 1 H), 1.02 (d, J = 6.4 Hz, 3 H).

[00616] Compound 248 (1-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]pyrrolidine-3-carboxamide): of 1-methylpyrrolidine-3-carboxylic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine using HPLC: 92.7% purity, Time Retention = 1.05 min. EM: m/z = 421.3 [M + H]+. 1H NMR (300 MHz, Chloroform-d, ppm) δ 9.01 (dd, J = 4.2, 1.8 Hz, 1 H), 8.56-8.45 (m, 1 H), 7, 92 (d, J = 8.1 Hz, 1 H), 7.49 (dd, J = 8.6, 4.2 Hz, 1 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.83 (d, J = 7.9 Hz, 1 H), 4,294.16 (m, 1 H), 3.64 (apparent d, J = 10.9 Hz, 1 H), 3, 35-3.24 (m, 1H), 2.89-2.82 (m, 3H), 2.52-2.31 (m, 7H), 2.27-1.88 (m, 4 H), 1.11-0.92 (m, 4 H).

[00617] Compound 278 (2-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]propanamide): 2- hydroxypropanoic and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine. HPLC: 96.9% purity, Retention Time = 1.26 min. MS: m/z = 382.2 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.51 (dd, J = 8.6, 1.8 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.51 (dd, J = 8.6, 4.2 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 6.42 (d, J = 8.1 Hz, 1 H), 4.35-4.16 (m, 2 H), 3.70-3.60 (m, 1 H), 3.31 (d, J = 11.6 Hz, 1 H), 2.52-2.32 (m, 2 H), 2.25-2.190(m, 3 H) 1.40 ( d, J = 6.8 Hz, 3 H), 1.14-0.95 (m, 4 H).

[00618] Compound 279 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]-2-(1-methylpiperidin-3-yl )acetamide): from 2-hydroxypropanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine. HPLC: 97.4% purity, Retention Time = 3.49 min. MS: m/z = 449.2 [M + H]+. 1H NMR (300 MHz,CD3OD, ppm) δ 8.89 (dt, J = 4.4, 1.3 Hz, 1 H), 8.61 (dt, J = 8.7, 2.1 Hz, 1 H), 7.98 (d, J = 8.2 Hz, 1 H), 7.64-7.52 (m, 1 H), 7.17 (dd, J = 8.2, 2.4 Hz , 1 H), 4.27-4.10 (m, 1 H), 3.58 (d, J = 11.2 Hz, 1 H), 3.34 (d, J = 11.5 Hz, 1 H), 3.10-2.90 (m, 2 H), 2.51-2.36 (m, 5 H), 2.32-2.17 (m, 1 H), 2.08 (d , J = 9.7 Hz, 6 H), 1.85-1.55 (m, 3 H),1.21-0.95 (m, 5 H).

[00619] Compound 283 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(1-methylpyrrolidin-3) hydrochloride - il)acetamide): 2-(1-methylpyrrolidin-3-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine . HPLC: 99.7% purity, Retention Time = 2.71 min. MS: m/z = 435.2 [M + H]+. 1H NMR (300 MHz,CD3OD, ppm) δ9.27 (d, J = 8.6 Hz, 1 H), 9.12 (d, J = 5.2 Hz, 1 H), 8.31 (d, J = 8.2 Hz, 1 H), 8.07 (dd, J = 8.6, 5.2 Hz, 1 H), 7.52-7.42 (m, 1 H), 4.16 ( d, J = 12.3 Hz, 1 H), 3.78-3.38 (m, 4 H), 3,293.04 (m, 1 H), 2.94-2.72 (m, 4 H) , 2.68-2.59 (m, 3 H), 2.45-2.08 (m, 5 H), 1.86-1.66 (m, 1 H), 1.21 (td, J = 12.3, 12.3 Hz, 1 H), 1.02 (d, J = 6.4 Hz, 3 H).

[00620] Compound 287 (2-(3,3-difluoroazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3 -yl]propanamide): from 2-(3,3-difluoroazetidin-1-yl)propanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3 -the mine. HPLC: 98.4% purity, Retention Time = 1.81 min. MS: m/z = 457.3 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.92 (dd, J = 4.3, 1.7 Hz, 1 H), 8.63 (dt, J = 8.6, 1.6 Hz, 1 H), 8.01 (d, J = 8.1 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (dd, J = 8 .0, 1.9 Hz, 1 H), 4.27-4.18 (m, 1 H), 3.70-3.61 (m, 4 H), 3.56-3.53 (m, 1 H), 3.42-3.20 (m, 2 H), 3.10-2.99 (m, 1 H), 2.61-2.41 (m, 2 H), 2.20- 2.04 (m, 2 H), 1.31-1.14 (m, 4 H), 1.03 (d, J = 6.5 Hz, 3 H).

[00621] Compound 289 (2-(4-hydroxypiperidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl ]propanamide): from 2-(4-hydroxypiperidin-1-yl)propanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine. HPLC: 99.8% purity, Retention Time = 1.75 min. MS: m/z = 465.3 [M + H]+. 1H NMR (300 MHz,CD3OD, ppm) δ8.90 (dd, J = 4.3, 1.7 Hz, 1 H), 8.62 (dt, J = 8.6, 1.7 Hz, 1 H ), 7.99 (d, J = 8.0 Hz, 1 H), 7.59 (dd, J = 8.6, 4.3 Hz, 1 H), 7.19 (d, J = 8, 1 Hz, 1 H), 4.24-4.16 (m, 1 H), 3.58-3.55 (m, 2 H), 3.37-3.32 (m, 1 H), 3 .07-2.96 (m, 1 H), 2.80-2.71 (m, 2 H), 2.55-2.42 (m, 2 H), 2,342.06 (m, 4 H) , 1.89-1.77 (m, 2 H), 1.55-1.50 (m, 2 H), 1.23-1.07 (m, 4 H), 1.01 (d, J = 6.4 Hz, 3 H).

[00622] Compound 472 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-propinoic acid amide): From (3R, 5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine propiolic acid. HPLC: > 99% purity, Retention Time = 3.97 min. MS: m/z = 362.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.8 Hz, 1 H), 8.84 (d, J = 7.4 Hz, 1 H) , 8.50 (dd, J = 8.6, 1.8 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 4.15 (d, J = 0.8 Hz, 1 H), 4.08 (s, 1 H), 3.48 (d, J = 11.0 Hz, 1 H), 2.40 (t, J = 11.3 Hz, 1 H), 2.00 (d, J = 14.0 Hz , 2 H), 1.13 (d, J = 12.1 Hz, 1 H), 0.94 (d, J = 6.5 Hz, 3 H).

[00623] Compound 473 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-but-3-inoic acid amide): From of (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine and 3-butynoic acid. HPLC: > 99% purity, Retention Time = 4.01 min. EM: m/z = 376.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.52 (dd, J = 8.6, 1.8 Hz , 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.97 (d, J = 7.4 Hz, 1 H), 7.66 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 5.74 (t, J = 6.6 Hz, 1 H), 5.29 (d, J = 6.6 Hz, 2 H), 4.08 (s, 1 H), 3.54 (d, J = 11.2 Hz, 1 H), 3.39 - 3.32 (m, 1 H ), 2.48 - 2.36 (m, 2 H), 2.15 - 1.96 (m, 3 H), 1.12 (q, J = 12.0 Hz, 2 H), 0.95 (d, J = 6.5 Hz, 3 H).

[00624] Compound 474 (2-Methanesulfonylamino-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide): From (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine and N-(methylsulfonyl)glycine. HPLC: > 99% purity, Retention Time = 3.52 min. MS: m/z = 445.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz , 1 H), 8.02 (dd, J = 24.1, 7.8 Hz, 2 H), 7.66 (dd, J = 8.6, 4.2 Hz, 1 H), 7.30 (s, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 4.07 (d, J = 6.6 Hz, 1 H), 3.61 (d, J = 4 .1 Hz, 2 H), 3.50 (d, J = 10.2 Hz, 1 H), 3.34 (d, J = 11.0 Hz, 1 H), 2.92 (s, 3 H ), 2.46 - 2.37 (m, 1 H), 2.04 (dd, J = 29.3, 9.1 Hz, 2 H), 1.14 (q, J = 12.0 Hz, 1 H), 0.94 (t, J = 7.1 Hz, 3 H).

[00625] Compound 475 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-1-trifluoromethyl-cyclopropanecarboxylic acid amide): From of (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid. HPLC: > 99% purity, Retention Time = 4.83 min. MS: m/z = 446.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.51 (dd, J = 8.6, 1.8 Hz , 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.67 (dd, J = 8.5, 4.0 Hz, 2 H), 7.20 (d, J = 8.1 Hz, 1 H), 4.08 (s, 1 H), 3.46 - 3.33 (m, 2 H), 2.56 (d, J = 10.9 Hz, 1 H) , 2.39 (t, J = 11.4 Hz, 1 H), 2.15 - 1.89 (m, 2 H), 1.36 - 1.15 (m, 5 H), 0.94 ( d, J = 6.6 Hz, 3 H).

[00626] Compound 515 (2-Cyclopropyl-2-hydroxy-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide) : From cyclopropylhydroxyl-acetic acid and (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dt, J = 4.1, 1.4 Hz, 1 H), 8.54 (dt, J = 8.6, 2.1 Hz, 1 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.76 - 7.62 (m, 1 H), 7.60 (d, J = 7.7 Hz, 1 H) , 7.21 (dd, J = 8.1, 4.3 Hz, 1 H), 5.31 (dd, J = 12.5, 5.4 Hz, 2 H), 3.57 - 3.38 (m, 2 H), 2.59 (t, J = 10.9 Hz, 1 H), 2.43 (t, J = 11.3 Hz, 1 H), 1.98 (d, J = 12 .6 Hz, 2 H), 1.24 (qd, J = 12.1, 2.8 Hz, 1 H), 1.12 - 1.01 (m, 1 H), 0.96 (dt, J = 6.5, 1.5 Hz, 3 H), 0.43 - 0.21 (m, 4 H). MS: m/z = 408 [M + H]+.

[00627] Compound 516 (2-(4-Methyl-piperazin-1-yl)-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3 -yl]-propionamide: From 2-(4-methyl-piperazin-1-yl)-propionic acid and (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl hydrochloride )-piperidin-3-ylamine. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dt, J = 4.1, 1.5 Hz, 1 H), 8.61 - 8.44 (m, 1 H), 8.06 (dt, J = 8.2, 2.7 Hz, 1 H), 7.68 (dtd, J = 9.2, 5.1, 4.6, 1.9 Hz, 2 H), 7.20 (dd, J = 12.5, 8.0 Hz, 1 H), 4.20 (s, 1 H), 3.55 - 3.39 (m, 1 H), 3 .34 (d, J = 8.1 Hz, 3 H), 3.33 - 3.25 (m, 2 H), 3.08 - 2.90 (m, 1 H), 2.44 (dt, J = 11.1, 5.5 Hz, 7H), 2.14 (d, J = 12.0 Hz, 3 H), 2.12 (m, 2 H), 1.99 (d, J = 12 .5Hz, 2H), 1.18 (qd, J = 12.0, 2.5Hz, 1H), 1.08 (dd, J = 6.9, 1.4Hz, 3H), 0.95 (dd, J = 9.9, 6.4 Hz, 3 H).

[00628] Compound 517 (N-[(3R,5S)-5-Methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide): From acetic acid and hydrochloride of (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz, 1 H), 8.05 (d, J = 8.2 Hz, 1 H), 7.90 (d, J = 7.4 Hz, 1 H), 7.67 (dd, J = 8.6, 4 .2 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 3.52 (d, J = 9.2 Hz, 1 H), 2.43 (q, J = 11.4 Hz, 2 H), 2.03 (dd, J = 26.1, 12.3 Hz, 2 H), 1.82 (s, 3 H), 1.08 (q, J = 12, 1 Hz, 1 H), 0.96 (d, J = 6.5 Hz, 3 H). MS: m/z = 352 [M + H]+.

[00629] Compound 519 (2-Cyclopropyl-2-dimethylamino-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide) : From cyclopropyl-dimethylamine-acetic acid hydrochloride and (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride. 1H NMR (400 MHz, Methanol-d4) δ 8.95 (dd, J = 4.2, 1.7 Hz, 1 H), 8.67 (dt, J = 8.6, 1.8 Hz, 1 H), 8.04 (d, J = 8.2 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (dd, J = 8 .0, 1.8 Hz, 1 H), 4.28 (dddd, J = 14.9, 12.0, 5.8, 2.4 Hz, 1 H), 3.60 (m, 1 H) , 3.40 (d, J = 11.6 Hz, 1 H), 2.53 (dtd, J = 25.3, 11.2, 2.9 Hz, 2 H), 2.35 (d, J = 7.9 Hz, 6 H), 2.23 - 2.04 (m, 2 H), 1.86 (dd, J = 9.5, 3.3 Hz, 1 H), 1.20 (q , J = 12.1 Hz, 1 H), 1.09 - 0.89 (m, 4 H), 0.82 - 0.64 (m, 1 H), 0.58 - 0.43 (m, 1 H), 0.35 (tdd, J = 12.5, 9.3, 4.8 Hz, 2 H). MS: m/z = 435 [M + H]+.

[00630] Compound 526 ((S)-2-dimethylamino-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-propionamide) : From (S)-2-dimethylamino-propionic acid and (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.54 (dd, J = 8.6, 1.8 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.79 - 7.64 (m, 2 H), 7.21 (d, J = 8.0 Hz, 1 H) , 4.20-4.15 (m, 2 H), 3.47 (d, J = 9.3 Hz, 1 H), 2.92 (q, J = 6.8 Hz, 1 H), 2 .42 (t, J = 11.4 Hz, 1 H), 2.15 (s, 6 H), 2.13 - 1.88 (m, 2 H), 1.20 (q, J = 12, 0 Hz, 1 H), 1.07 (d, J = 6.9 Hz, 3 H), 0.95 (d, J = 6.6 Hz, 3 H). EM: m/z = 409 [M + H]+.

[00631] Compound 550 (2-(1-Hydroxy-cyclopropyl)-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]- acetamide): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 2-(1-hydroxycyclopropyl)acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.54 (dd, J = 8.6, 1.8 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 7.4 Hz, 1 H), 7.67 (dd, J = 8.6, 4 .1 Hz, 1 H), 7.21 (d, J = 8.1 Hz, 1 H), 4.06 (s, 1 H), 3.54 (d, J = 9.1 Hz, 1 H ), 2.50 - 2.38 (m, 2 H), 2.34 (s, 2 H), 2.14 - 1.93 (m, 2 H), 1.12 (q, J = 12, 0 Hz, 1 H), 0.96 (dd, J = 6.5, 3.6 Hz, 3 H), 0.63 - 0.53 (m, 2 H), 0.53 - 0.38 ( m, 2 H). EM: m/z = 408 [M + H]+.

[00632] Compound 551 (2-(8-methyl-8-aza-bicyclo[3,2,1]oct-3-yl)-N- [(3R,5S)-5-methyl-1-(8- trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-hydrochloride 3-ylamine and 2-(8-methyl-8-azabicyclo[3,2,1]octan-3-yl)acetic acid hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.92 (d, J = 7.3 Hz, 1 H), 7.67 (dd, J = 8.6, 4 .2 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 4.15 (m, 1 H) 3.51 (d, J = 9.9 Hz, 2 H) , 3.34 (d, J = 11.6 Hz, 2 H), 3.14 (s, 2 H), 2.43 (dt, J = 11.3, 5.9 Hz, 1 H), 2 .23 (d, J = 5.7 Hz, 3 H), 2.15 (dd, J = 15.8, 7.9 Hz, 2 H), 2.02 (dd, J = 16.8, 10 .7 Hz, 4 H), 1.68 (d, J = 8.2 Hz, 2 H), 1.22 (dd, J = 13.8, 7.4 Hz, 2 H), 1.10 ( q, J = 12.0 Hz, 1 H), 0.95 (d, J = 6.5 Hz, 3 H). MS: m/z = 475 [M + H]+.

[00633] Compound 572 (2-(1-Isopropyl-piperidin-4-yl)-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3 -yl]-acetamide): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 2-methyl-2-piperidin acid -1-yl-propionic. HPLC: > 99% purity, Retention Time = 3.27 min. EM: m/z = 463.6 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz , 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.68 (dd, J = 8.6, 4.2 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 4.11 - 3.97 (m, 1 H), 3.45 (dd, J = 11 .6, 3.9 Hz, 1 H), 2.56 (t, J = 10.9 Hz, 1 H), 2.45 (t, J = 11.4 Hz, 1 H), 2.33 ( s, 4 H), 2.09 (s, 1 H), 1.97 (d, J = 12.4 Hz, 1 H), 1.54 (s, 4 H), 1.41 (d, J = 6.9 Hz, 2 H), 1.22 (q, J = 12.0 Hz, 1 H), 1.06 (d, J = 9.0 Hz, 6 H), 0.96 (d, J = 6.6 Hz, 3 H).

[00634] Compound 573 (2-(3,3-dimethyl-pyrrolidin-1-yl)-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin -3-yl]-acetamide): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine and (3,3-dimethyl- pyrrolidin-1-yl)-acetic acid. HPLC: > 99% purity, Retention Time = 3.32 min. EM: m/z = 449.5 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz , 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.67 (dd, J = 8.6, 4.2 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 4.13 - 4.06 (m, 1 H), 3.50 - 3.43 (m , 1 H), 3.02 (d, J = 3.0 Hz, 2 H), 2.63 (m, 2 H), 2.56 (t, J = 10.9 Hz, 1 H), 2 .43 (t, J = 11.4 Hz, 1 H), 2.38 - 2.29 (m, 2 H), 2.08 (td, J = 10.4, 9.1, 5.4 Hz , 1 H), 1.99 (dd, J = 12.4, 3.9 Hz, 1 H), 1.53 (t, J = 7.1 Hz, 2 H), 1.21 (q, J = 12.0 Hz, 1 H), 1.05 (d, J = 1.3 Hz, 6 H), 0.96 (d, J = 6.6 Hz, 3 H).

[00635] Compound 574 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-1-cyclopropyl-piperidine-4-carboxylic acid amide ): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 1-cyclopropyl-piperidine-4-carboxylic acid. HPLC: 98% purity, Retention Time = 3.12 min. MS: m/z = 461.5 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.7, 1.8 Hz , 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.76 (d, J = 7.4 Hz, 1 H), 7.67 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 4.02 (s, 0H), 3.48 (d, J = 10.9 Hz, 1 H), 3.36 (d, J = 5.3 Hz, 0H), 2.92 (td, J = 7.9, 3.9 Hz, 1 H), 2.43 (q, J = 11, 2 Hz, 1 H), 2.08 (ddt, J = 11.5, 8.2, 3.7 Hz, 1 H), 1.98 (d, J = 13.0 Hz, 0H), 1, 67 - 1.40 (m, 2 H), 1.10 (q, J = 12.1 Hz, 1 H), 0.95 (d, J = 6.6 Hz, 2 H), 0.38 ( dt, J = 5.2, 2.6 Hz, 1 H), 0.27 (q, J = 3.1, 2.5 Hz, 1 H).

[00636] Compound 575 (N,N-diethyl-N'-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-succinamide): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and N,N-diethyl-succinamic acid. HPLC: > 99% purity, Retention Time = 3.98 min. EM: m/z = 465.5 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz , 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.87 (d, J = 7.4 Hz, 1 H), 7.67 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 4.03 (s, 1 H), 3.51 (d, J = 10.2 Hz, 1 H), 3.30 (d, J = 6.8 Hz, 2 H), 3.28 - 3.18 (m, 2 H), 2.49 (d, J = 6.9 Hz, 2 H ), 2.43 (td, J = 11.1, 4.1 Hz, 2 H), 2.34 (q, J = 7.6, 7.1 Hz, 2 H), 2.06 (s, 1 H), 1.99 (d, J = 13.1 Hz, 1 H), 1.15 - 1.03 (m, 4 H), 0.97 (t, J = 6.8 Hz, 6 H ).Example 58: Synthesis of compound 196 ((3R,5S)-N-(2-methoxyethyl)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine)

[00637] (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine: (3R,5S)-N-( 2-methoxyethyl)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine was prepared from 2-(dimethylamino)acetic acid and (3R,5S)-1-(8- methoxyquinolin-5-yl)-5-methylpiperidin-3-amine using Method N. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 60% gradient in 10 min; detector, UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine was obtained as yellow oil (14 mg, 15%).

[00638] Compound 196: HPLC: 94.9% purity, Retention Time = 2.77 min. EM: m/z = 368.2 [M + H]+. 1H NMR (400 MHz,DMSO-d6, ppm) δ 9.04-8.97 (m, 1 H), 8.48 (dd, J = 8.7, 1.7 Hz, 1 H), 8, 05 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.6, 4.2 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 1 H), 3.57-3.49 (m, 1 H), 3.42-3.28 (m, 2 H), 3.24 (s, 3 H), 2.93 (t, J = 10 .8Hz, 1H), 2.82-2.66 (m, 2H), 2.41-2.33 (m, 2H), 2.12-1.94 (m, 2H), 1.59 (br s, 2 H), 0.97-0.78 (m, 4 H).Example 59: Synthesis of compound 197 and compound 198 ((R)-2-amino-3,3,3- trifluoro-N-((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-yl)propanamide and (S)-2-amino-3,3,3 -trifluoro-N-((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-yl)propanamide)

[00639] (R)-2-amino-3,3,3-trifluoro-N-((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin- 3-yl)propanamide and (S)-2-amino-3,3,3-trifluoro-N-((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin -3-yl)propanamide: 2-amino-3,3,3-trifluoro-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3- yl]propanamide was prepared from (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine and 2-amino-3,3,3-trifluoropropanoic acid using Method J. The two diastereoisomers were separated by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 19 x 150 mm 10 µm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 60% gradient in 10 min; detector, UV 254 nm.Isomer 1: (14 mg, 21%, white solid) HPLC: 93.2% purity, Retention Time = 2.62 min. MS: m/z = 434.9 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz , 1 H), 8.37 (d, J = 7.3 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.68 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 4.09-4.04 (m, 1 H), 3.93-3.84 (m , 1 H), 3.49 (apparent d, J = 11.6 Hz, 1 H), 2.51-2.39 (m, 1 H), 2.31 (apparent d, J = 8.9 Hz , 2 H), 2.10-1.90 (m, 2 H), 1.15 (td, J = 12.0, 12.0 Hz, 1 H), 0.96 (d, J = 6, 5 Hz, 3 H).Isomer 2: (9 mg, 13%, white solid) HPLC: 90.5% purity, Retention Time = 2.71 min. EM: m/z = 434.9 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz, 1 H), 8.37 (d, J = 7.3 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.68 (dd, J = 8.6, 4 .2 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 4.09-4.04 (m, 1 H), 3.93-3.84 (m, 1 H), 3.49 (apparent d, J = 11.6 Hz, 1 H), 2.51-2.39 (m, 1 H), 2.31 (apparent d, J = 8.9 Hz, 2 H), 2.10-1.90 (m, 2 H), 1.15 (td, J = 12.0, 12.0 Hz, 1 H), 0.96 (d, J = 6.5 Hz , 3 H).Example 60: Synthesis of compound 200 (5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinolin-8-ol hydrochloride)

[00640] 5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinolin-8-ol: A - 78°C, to a solution of (3R,5S)-1-(8 -methoxyquinolin-5-yl)-5-methylpiperidin-3-amine (95 mg, 0.35 mmol) in DCM (10 mL) was added a solution of BBr3 (553 mg, 2.19 mmols) in DCM (5 mL ) dropwise. The resulting solution was stirred for one hour at -78°C, warmed to -20°C and stirred for two hours at -20°C. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, Xbridge Shield RP18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% HCl), 35% to 65% gradient in 10 min; detector, UV 254 nm. 5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinolin-8-ol hydrochloride was obtained as brown solid (24 mg, 21%).

[00641] Compound 200: HPLC: 96.6% purity, Retention Time = 1.05 min. EM: m/z = 258.1 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 9.38 (dd, J = 8.5, 1.5 Hz, 1 H), 9.09 (dd, J = 5.2, 1.3 Hz, 1 H), 8.13 (dd, J = 8.6, 5.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.47 (d, J = 8 .5 Hz, 1 H), 3.73-3.67 (m, 1 H), 3.53 (dd, J = 10.8, 3.9 Hz, 1 H), 3.24 (dd, J = 11.6, 3.6 Hz, 1 H), 2.85 (t, J = 10.7 Hz, 1 H), 2.51 (t,J = 11.2 Hz, 1 H), 2, 35-2.17 (m, 2 H), 1.27 (td, J = 11.9, 11.9 Hz, 1 H), 1.08 (d, J = 6.5 Hz, 3 H). Example 61: Synthesis of compound 204 ((2S)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxy-3 -methyl-butanamide)

[00642] (2S)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methyl-piperidin-3-yl]-2-hydroxy-3-methylbutanamide: (2S)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxy-3-methylbutanamide was prepared from acid 2-(dimethylamino)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine using Method J. The crude product was purified by preparative HPLC under the following Conditions: Speaker, XBridge Shield RP18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 25% to 50% gradient in 10 min; detector, UV 254 nm. (2S)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxy-3-methylbutanamide was obtained as a white solid ( 17 mg, 27%).

[00643] Compound 204: HPLC: 91.5% purity, Retention Time = 2.73 min. MS: m/z = 392.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.91 (dd, J = 4.2, 1.7 Hz, 1 H), 8.65 (dd, J = 8.6, 1.8 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.88-7.54 (m, 2 H), 7.27 (d, J = 7.9 Hz, 1 H) , 4.34-4.24 (m, 1 H), 3.85 (d, J = 3.8 Hz, 1 H), 3.58-3.45 (m, 1 H), 3.40- 3.28 (m, 1 H), 2.59 (t, J = 10.8 Hz, 1 H), 2.48 (t, J = 11.2 Hz, 1 H), 2.24-2, 00 (m, 4 H), 1.38-1.18 (m, 1 H), 1.05 (d, J = 6.6 Hz, 3 H), 1.00 (d, J = 6.6 Hz, 3H), 0.84 (d, J = 6.8Hz, 3H).

[00644] The following compounds were synthesized in an analogous manner:

[00645] Compound 205 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): of acid 3, 3-dimethylbutanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 98.9% purity, Retention Time = 1.59 min. EM: m/z = 390.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.91 (dd, J = 4.2, 1.7 Hz, 1 H), 8.64 (dd, J = 8.6, 1.8 Hz, 1 H), 7.95 (dt, J = 7.9, 1.5 Hz, 1 H), 7.85-7.65 (m, 2 H), 7.26 (d, J = 7.9 Hz , 1 H), 4,294.21 (m, 1 H), 3.62-3.53 (m, 1 H), 3.39- 3.36 (m, 1 H), 2.57-2.37 (m, 2 H), 2.23-2.06 (m, 4 H), 1.15 (td, J = 12.1, 12.1 Hz, 1 H), 1.05 (s, 3 H ), 1.03 (s, 9H).

[00646] Compound 209 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(dimethylamino)acetamide): acid 3 ,3-dimethylbutanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 95.9% purity, Retention Time = 2.58 min. MS: m/z = 377.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.91 (dd, J = 4.2, 1.7 Hz, 1 H), 8.64 (dd, J = 8.6, 1.8 Hz, 1 H), 7.95 (dd, J = 7.9, 1.3 Hz, 1 H), 7.86-7.54 (m, 2 H), 7.28 (d, J = 7.9 Hz , 1 H), 4.334.24 (m, 1 H), 3.61-3.54 (m, 1 H), 3.40-3.28 (m, 1 H), 3.10 (s, 2 H), 2,602.40 (m, 2 H), 2.37 (s, 6 H), 2.24-2.09 (m, 2 H), 1.20 (td, J = 12.1, 12 .1 Hz, 1 H), 1.05 (d, J = 6.4 Hz, 3 H).

[00647] Compound 302 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxypropanamide): of 2-hydroxypropanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.0% purity, Retention Time = 2.13 min. EM: m/z = 364.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.62 (dd, J = 8.6, 1.7 Hz, 1 H ), 7.93 (dd, J = 7.9, 1.4 Hz, 1 H), 7.86-7.50 (m, 2 H), 7.26 (d, J = 8.0 Hz, 1 H), 4.28-4.20 (m, 1 H), 4.11 (td, J = 6.8, 6.8 Hz, 1 H), 3.54-3.49 (m, 1 H), 3,383.30 (m, 1 H), 2.56 (t, J = 10.9 Hz, 1 H), 2.45 (t, J = 11.2 Hz, 1 H), 2,212.05 (m, 2 H), 1.32 (d, J = 6.8 Hz, 3 H), 1.22 (td, J = 12.1, 12.1 Hz, 1 H), 1.03 (d , J = 6.4 Hz, 3 H).

[00648] Compound 303 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-3-yl) acetamide): from 2-(1-methylpiperidin-3-yl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 98.8% purity, Retention Time = 1.52 min. MS: m/z = 431.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.62 (dd, J = 8.6, 1.8 Hz, 1 H ), 7.98-7.84 (m, 1 H), 7.73-7.46 (m, 2 H), 7.25 (d, J = 7.8 Hz, 1 H), 4.22 (t, J = 11.4 Hz, 1 H), 3.57 (apparent d, J = 11.6 Hz, 1 H), 3.40-3.30 (m, 1 H), 2.89- 2.72 (m, 2 H), 2.50-2.41 (m, 2 H), 2.25-2.23 (m, 3 H), 2.191.82 (m, 6 H), 1, 81-1.48 (m, 4 H), 1.22-0.87 (m, 5 H).

[00649] Compound 307 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(1-methylpyrrolidin-3-yl) acetamide): from 2-(1-methylpyrrolidin-3-yl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 96.0% purity, Retention Time = 2.82 min. EM: m/z = 417.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ8.86 (dd, J = 4.2, 1.7 Hz, 1 H), 8.58 (dd, J = 8.6, 1.8 Hz, 1 H ), 7.96-7.41 (m, 3 H), 7.21 (d, J = 7.9 Hz, 1 H), 4.26-4.09 (m, 1 H), 3.59 -3.47 (m, 1 H), 3.39-3.29 (m, 1 H), 2.80-2.73 (m, 1 H), 2.67-2.49 (m, 3 H), 2.46-2.37 (m, 2 H), 2.33-2.30 (m, 3 H), 2.28-2.17 (m, 3 H), 2.121.95 (m , 3 H), 1.54-1.40 (m, 1 H), 1.25 (d, J = 1.4 Hz, 1 H), 1.11 (td, J = 12.4, 12, 4 Hz, 1 H), 0.99 (d, J = 6.4 Hz, 3 H).

[00650] Compound 311 (2-(3,3-difluoroazetidin-1-yl)-N-[(3R,5S)-1- [8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3- yl]propanamide): 2-(3,3-difluoroazetidin-1-yl)propanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine . HPLC: 96.8% purity, Retention Time = 2.53 min. EM: m/z = 439.3 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.61 (dt, J = 8.6, 1.7 Hz, 1 H ), 7.93 (dd, J = 8.0, 1.5 Hz, 1 H), 7.85-7.53 (m, 2 H), 7.26 (dd, J = 7.9, 2 .0Hz, 1H), 4.27-4.18 (m, 1H), 3.75-3.56 (m, 4H), 3.53-3.49 (m, 1H), 3.39-3.20 (m, 1 H), 3.10-3.00 (m, 1 H), 2.60-2.40 (m, 2 H), 2.21-2.04 ( m, 2 H), 1.31-1.13 (m, 4 H), 1.03 (d, J = 6.5 Hz, 3 H).

[00651] Compound 313 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(4-hydroxypiperidin-1-yl) propanamide): from 2-(4-hydroxypiperidin-1-yl)propanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 93.5% purity, Retention Time = 1.51 min. MS: m/z = 447.3 [M + H]+. 1H NMR (300 MHz,CD3OD, ppm) δ8.86 (dd, J = 4.2, 1.6 Hz, 1 H), 8.59 (dt, J = 8.6, 1.8 Hz, 1 H ), 7.95-7.44 (m, 3 H), 7.23 (d, J = 7.9 Hz, 1 H), 4.21 (d, J = 11.8 Hz, 1 H), 3.69-3.50 (m, 2 H), 3.40-3.20 (m, 1 H), 3.01 (tt, J = 3.6, 3.3 Hz, 1 H), 2 .82-2.68 (m, 2 H), 2.56-2.02 (m, 6 H), 1.89-1.73 (m, 2 H), 1.58-1.45 (m , 2 H), 1.23-1.05 (m, 4 H), 1.00 (d, J = 6.4 Hz, 3 H).

[00652] Compound 316 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-4-yl) acetamide): from 2-(1-methylpiperidin-4-yl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 98.7% purity, Retention Time = 1.02 min. MS: m/z = 431.3 [M + H]+. 1H NMR (300 MHz,CD3OD, ppm) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1 H), 8.59 (dd, J = 8.6, 1.7 Hz, 1 H), 7.94-7.43 (m, 3 H), 7.21 (d, J = 7.9 Hz, 1 H), 4.24-4.13 (m, 1 H), 3, 60-3.48 (m, 1 H), 3.40-3.20 (m, 1 H), 2.95-2.91 (m, 2 H), 2,462.37 (m, 2 H), 2.29 (s, 3 H), 2.18-2.02 (m, 6 H), 1.83-1.60 (m, 3 H), 1.371.20 (m, 2 H), 1, 07-1.00 (m, 1 H), 0.99 (d, J = 6.3 Hz, 3 H).

[00653] Compound 317 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3-difluorocyclobutane-1-carboxamide: from 3,3-difluorocyclobutane-1-carboxylic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine: 98.6% purity, Time. Retention = 2.25 min MS: m/z = 410.2 [M + H]+. 8 Hz, 1 H), 8.54 (d, J = 8.5 Hz, 1 H), 7.99-7.43 (m, 3 H), 7.12 (d, J = 7.9 Hz , 1 H), 5.38-5.28 (m, 1 H), 4.39-4.23 (m, 1 H), 3.68-3.64 (m, 1 H), 3.31 -3.27 (m, 1 H), 2.94-2.62 (m, 5 H), 2.49-2.29 (m, 2 H), 2.22-2.07 (m, 2 H), 1,030.95 (m, 4 H).

[00654] Compound 318 (N-[(3R,5S)-1-[8-(difluoromethyl) quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-3-yl) acetamide): from 2-(1-methylpiperidin-3-yl)acetic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine. HPLC: 92.0% purity, Retention Time = 2.22 min. MS: m/z = 432.3 [M + H]+. 1H NMR (300 MHz, Chloroform-d, ppm) δ 9.07-8.87 (m, 2 H), 7.94-7.54 (m, 3 H), 7.30 (d, J = 8 .3 Hz, 1 H), 4.12-3.85 (m, 3 H), 2.69-2.40 (m, 4 H), 2.10 (s, 3 H), 2.02- 1.70 (m, 4 H), 1.65-1.35 (m, 3 H), 1.16-0.98 (m, 1 H), 0.95-0.75 (m, 4 H ).

[00655] Compound 319 (N-[(3R,5S)-1-[8-(difluoromethyl) quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(1-methylpyrrolidin-3-yl) acetamide): from 2-(1-methylpyrrolidin-3-yl)acetic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine. HPLC: 91.0% purity, Retention Time = 6.42 min. MS: m/z = 418.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.63 (t, J = 55.8 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 1 H), 4.23-3.92 (m, 3 H), 3.04-2.89 (m, 1 H), 2.85-2.40 (m, 9H), 2.29 (d, J = 7.5 Hz, 2 H), 2.20- 2.00 (m, 3 H), 1, 63-1.49 (m, 1 H), 1.12-1.09 (m, 1 H), 0.97 (d, J = 6.4 Hz, 3 H).

[00656] Compound 323 (2-(3,3-difluoroazetidin-1-yl)-N-[(3R,5S)-1- [8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3- yl]propanamide): from 2-(3,3-difluoroazetidin-1-yl)propanoic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine .HPLC: 94.2% purity, Retention Time = 1.25 min. MS: m/z = 440.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 7.97 (dd, J = 8.2, 1.5 Hz, 1 H), 7.63 ( t, J = 55.9 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 1 H), 4.27-4.13 (m, 1 H), 4.09-3, 95 (m, 2 H), 3.77-3.58 (m, 4 H), 3.11-3.01 (m, 1 H), 2.75-2.68 (m, 1 H), 2.57-2.05 (m, 1 H), 2.14-2.03 (m, 2 H), 1.31-1.13 (m, 4 H), 1.01 (d, J = 6.5Hz, 3H).

[00657] Compound 325 (N-[(3R,5S)-1-[8-(difluoromethyl) quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(4-hydroxypiperidin-1-yl) propanamide): from 2-(4-hydroxypiperidin-1-yl)propanoic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine. HPLC: 90.5% purity, Retention Time = 1.50 minutes. MS: m/z = 448.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.97-8.81 (m, 2 H), 7.97 (d, J = 8.2 Hz, 1 H), 7.63 (t, J = 55.8 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 4.29-3.90 (m, 3 H), 3.65-3.62 (m, 1 H), 3.17-3.09 (m, 1 H), 2.95-2.20 (m, 6 H), 2.19-1.79 (m, 4 H),1.70- 1.50 (m, 2 H), 1.31-1.11 (m, 4 H), 1.02 (d, J = 6.3 Hz, 3 H).

[00658] Compound 328 (N-[(3R,5S)-1-[8-(difluoromethyl) quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-4-yl) acetamide): from 2-(1-methylpiperidin-4-yl)acetic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine. HPLC: 90.4% purity, Retention Time = 1.31 min. MS: m/z = 432.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.81 (m, 2 H), 7.97 (d, J = 8.3 Hz, 1 H), 7.64 (t, J = 55.8 Hz, 1 H), 7.34 (d, J = 8.1 Hz, 1 H), 4.29-3.95 (m, 3 H), 2.97-2.94 (m, 2 H), 2.66-2.46 (m, 2 H), 2.35 (s, 3 H), 2.24-2.03 (m, 6 H), 1.90-1.70 ( m, 3 H), 1.40-1.36 (m, 2 H), 1.14 (td, J = 12.2, 12.2 Hz, 1 H), 1.01 (dd, J = 6 .4, 2.3 Hz, 3 H).

[00659] Compound 329 (N-[(3R,5S)-1-[8-(difluoromethyl) quinoxalin-5-yl]-5-methylpiperidin-3-yl]-3,3-difluorocyclobutane-1-carboxamide): of 3,3-difluorocyclobutane-1-carboxylic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine.HPLC: 91.2% purity, Retention Time = 2.91 min. EM: m/z = 411.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.98-8.85 (m, 2 H), 7.99 (dd, J = 8.2, 1.5 Hz, 1 H), 7.65 ( t, J = 55.6 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 1 H), 4.28-4.11 (m, 2 H), 4.06-3, 98 (m, 1 H), 2.97-2.46 (m, 7H), 2.15-2.07 (m, 2 H), 1.15 (td, J = 12.2, 12.2 Hz, 1 H), 1.02 (d, J = 6.4 Hz, 3 H). Example 62: Synthesis of compound 206 ((3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-N-(2-methoxyethyl)-5-methylpiperidin-3-amine)

[00660] (3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-N-(2-methoxyethyl)-5-methylpiperidin-3-amine): (3R,5S)-1-[ 8-(difluoromethyl)quinolin-5-yl]-N-(2-methoxyethyl)-5-methylpiperidin-3-amine was prepared from 1-bromo-2-methoxyethane and (3R,5S)-1-(8-( difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine using Method N. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 35% to 65% gradient in 8 min; detector, UV 254 nm. (3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-N-(2-methoxyethyl)-5-methylpiperidin-3-amine was obtained as yellow solid (11 mg, 24%).Compound 206: HPLC: 96.4% purity, Retention Time = 1.41 min. EM: m/z = 350.1 [M + H]+. 1H NMR (300 MHz,CD3OD, ppm) δ 8.85 (dd, J = 4.2, 1.8 Hz, 1 H), 8.51 (dd, J = 8.6, 1.8 Hz, 1 H), 7.95-7.85 (m, 1 H), 7.82-7.43 (m, 2 H), 7.22 (d, J = 7.9 Hz, 1 H), 3, 61-3.43 (m, 3 H), 3.35-3.25 (m, 4 H), 3.10-2.98 (m, 1 H), 2.93-2.72 (m, 2 H), 2.50-2.30 (m, 2 H), 2.23-1.96 (m, 2 H), 1.02-0.83 (m, 4 H).Example 63: Synthesis of compound 207 and compound 208 ((R)-2-amino-N-((3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-yl)-3, 3,3-trifluoropropanamide and (S)-2-amino-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3 ,3-trifluoropropanamide)

[00661] (R)-2-amino-N-((3R,5S)-1 -(8-(difluoromethyl)quinoyl-5-yl)- 5-methylpiperidin-3-yl)-3,3,3- trifluoropropanamide and (S)-2-amino-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3,3-trifluoropropanamide : 2-amino-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3,3-trifluoropropanamide was prepared from (3R ,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine and 2-amino-3,3,3-trifluoropropanoic acid using Method J. The two diastereoisomers were separated by HPLC preparative under the following conditions: column, XBridge Shield RP18 OBD, 19 x 150 mm 10 um; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 53% to 55% gradient in 12 min; detector, UV 254 nm.Isomer 1: (11 mg, 16%, white solid) HPLC: 98.5% purity, Retention Time = 1.88 min. MS: m/z = 417.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.87 (dd, J = 4.2, 1.7 Hz, 1 H), 8.58 (dd, J = 8.6, 1.8 Hz , 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.87-7.44 (m, 2 H), 7.22 (d, J = 7.9 Hz, 1 H), 4.30-4.18 (m, 1 H), 3.89 (dt, J = 7.7, 7.7 Hz, 1 H), 3.58-3.47 (m, 1 H ), 3.39-3.28 (m, 1 H), 2.55-2.35 (m, 2 H), 2.3.9-2.08 (m, 2 H), 1.29- 1.05 (m, 1 H), 1.00 (d, J = 6.3 Hz, 3 H).Isomer 2: (13 mg, 19%, yellow solid) HPLC: 93.8% purity, Time Retention = 3.84 min. EM: m/z = 417.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.87 (dd, J = 4.2, 1.7 Hz, 1 H), 8.58 (dd, J = 8.6, 1.8 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.87-7.44 (m, 2 H), 7.22 (d, J = 7.9 Hz, 1 H) , 4.30-4.18 (m, 1 H), 3.89 (dt, J = 7.7, 7.7 Hz, 1 H), 3.58-3.47 (m, 1 H), 3.39-3.28 (m, 1 H), 2.55-2.35 (m, 2 H), 2.3.9-2.08 (m, 2 H), 1.29-1, 05 (m, 1 H), 1.00 (d, J = 6.3 Hz, 3 H). Example 64: Synthesis of compound 210 (8-[(5R)-5-amino-3,3- hydrochloride dimethylpiperidin-1-yl]quinoxaline-5-carbonitrile)

[00662] 1,5-dimethyl (2R)-2-aminopentanedioate: At 0°C, to a solution of (2R)-2-aminopentanedioic acid (19.00 g, 129.14 mmols) in methanol (400 mL ) thionyl chloride (60.95 g, 512.33 mmols) was added dropwise over a period of 20 minutes. The resulting solution was then stirred for 16 hours at room temperature. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (500 mL), and the pH value of the mixture was adjusted to 8 by saturated sodium bicarbonate solution. The resulting mixture was extracted with DCM (300 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1,5-dimethyl(2R)-2-aminopentanedioate as yellow oil (19.80 g, 88%). MS: m/z = 176.0 [M + H]+.

[00663] 1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino]pentanedioate: A solution of 1,5-dimethyl (2R)-2-aminopentanedioate (19.80 g , 119.30 mmols) in dioxane (200 mL) were added 4-dimethylaminopyridine (291 mg, 2.38 mmols), (Boc)2O (29.93 g, 137.16 mmols) and water (200 mL) at temperature environment. The resulting solution was stirred for 16 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (100 mL). The resulting mixture was extracted with DCM (200 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with DCM in hexane (0% to 30% gradient) to yield (2R)-2-[[(tert-butoxy)carbonyl]amino]pentanedioate. 1,5-dimethyl as colorless oil (23.75 g, 72%). EM: m/z = 276.1 [M + H]+.

[00664] 1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpentanedioate: At -78°C, to a solution of (2R)- 2-[[( 1,5-dimethyl tert-butoxy)carbonyl]amino]pentanedioate (3.80 g, 13.80 mmols) in THF (40 mL) was added LiHMDS solution (1 M in THF, 29 mL, 28.98 mmols ) drop by drop over a period of 5 minutes. The resulting mixture was stirred at -78°C for one hour, and then added by Mel (3.13 g, 22.13 mmol) slowly. The resulting solution was stirred for a further 4.5 hours at -78°C. When the reaction was done, it was stopped abruptly by the addition of hydrogen chloride solution (1 M, 40 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 10% gradient) to yield (2R)-2-[[(tert-butoxy)carbonyl]amino]-4 - 1,5-dimethyl methylpentanedioate as white solid (3.33 g, 83%). EM: m/z = 290.1 [M + H]+.

[00665] 1,5-dimethyl (4R)-4-[[(tert-butoxy)carbonyl]amino]-2,2-dimethylpentanedioate: At -78°C, a solution of KHMDS in THF (1 M, 152 mL, 152 mmols) was added to THF (150 mL), to which was added a solution of 1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpentanedioate (3. 52 g, 12.66 mmols) in tetrahydrofuran (50 mL) dropwise over a period of 5 minutes. The resulting solution was stirred for 0.5 hour at -78°C, and then added by MeI (1079 g, 76 mmol) slowly. The resulting solution was then stirred for a further 1 hour at -78°C. When the reaction was carried out, it was stopped abruptly by the addition of saturated NH4Cl solution (100 mL). The resulting mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 5% gradient) to yield (4R)-4-[[(tert-butoxy)carbonyl]amino]-2 1,5-dimethyl ,2-dimethylpentanedioate as light yellow solid (2.00 g, 52%). EM: m/z = 304.1 [M + H]+.

[00666] tert-Butyl N-[(2R)-1,5-dihydroxy-4,4-dimethylpentan-2-yl] carbamate: At 0°C, to a solution of (4R)-4-[[(tert - 1,5-dimethyl butoxy)carbonyl]amino]-2,2-dimethylpentanedioate (1.44 g, 4.75 mmols) in EtOH (18 mL) were added THF (18 mL) and CaCl2 (2.19 g , 19.77 mmols). Then, NaBH4 (1.56 g, 41.18 mmols) was added in portions over a period of 20 minutes at 0°C. The resulting mixture was stirred for 16 hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of Na2CO3 solution (10%, 50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield tert-butyl N-[(2R)-1,5-dihydroxy-4,4-dimethylpentan-2-yl]carbamate as colorless oil (1.42 g, crude). MS: m/z = 248.1 [M + H]+.

[00667] tert-Butyl N-[(2R)-1,5-bis(methanesulfonyloxy)-4,4-dimethylpentan-2-yl]carbamate: At 0°C, to a solution of tert-butyl N-[( 2R)-1,5-dihydroxy-4,4-dimethylpentan-2-yl]carbamate (1.42 g, raw) in DCM (50 mL) was added TEA (2.32 g, 22.91 mmols), to the which MsCl (5.70 g, 49.76 mmols) was added dropwise over a period of 10 minutes. The resulting solution was then stirred for two hours at 0°C. When the reaction was done, it was stopped abruptly by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield tert-butyl N-[(2R)-1,5-bis(methanesulfonyloxy)-4,4-dimethylpentan-2-yl]carbamate as colorless oil (2.60 g, crude). . EM: m/z = 426.1 [M + H]+.

[00668] tert-Butyl N-[(3R)-1-benzyl-5,5-dimethylpiperidin-3-yl] carbamate: at room temperature, tert-butyl N-[(2R)-1,5-bis(methanesulfonyloxy )-4,4-dimethylpentan-2-yl]carbamate (2.60 g, raw) was added to phenylmethanamine (20 mL). The resulting solution was then stirred for 16 hours at 70°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 3% gradient) to yield tert-butyl N-[(3R)-1 -benzyl-5,5-dimethylpiperidin-3-yl]carbamate as colorless oil (740 mg, 49% for 3 steps). MS: m/z = 319.2 [M + H]+.

[00669] tert-Butyl N-[(3R)-5,5-dimethylpiperidin-3-yl]carbamate: In a 30 mL pressure tank reactor, tert-butyl N-[(3R)-1-benzyl- 5,5-dimethylpiperidin-3-yl]carbamate (666 mg, 2.09 mmols) and Pd(OH)2/C (200 mg, 1.42 mmols) were mixed in methanol (5 mL, 123.49 mmols, 291.31 equiv) at room temperature under a nitrogen atmosphere. The reactor was vacuumed and flooded with hydrogen. The reaction mixture was then hydrogenated for 25 hours at 75°C under 15 atm of hydrogen atmosphere. When the reaction was done, the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to yield tert-butyl N-[(3R)-5,5-dimethylpiperidin-3-yl]carbamate as colorless oil (560 mg, raw). MS: m/z = 229.0 [M + H]+.

[00670] tert-Butyl N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]carbamate: A solution of tert-butyl N-[(3R) - 5,5-dimethylpiperidin-3-yl]carbamate (560 mg, raw) in DMF (5 mL) were added 8-bromoquinoxaline-5-carbonitrile (766 mg, 3.27 mmols) and DIEA (904 mg, 7.0 mmol) 00 mmols) at room temperature. The resulting solution was then stirred for 16 hours at 130°C. After cooling to room temperature, the reaction mixture was stopped abruptly by adding water (30 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 14% gradient) to yield tert-butyl N-[(3R)-1-(8-cyanoquinoxalin-5- yl)-5,5-dimethylpiperidin-3-yl]carbamate as yellow solid (477 mg, 60% for two steps). EM: m/z = 382.0 [M + H]+.

[00671] 8-[(5R)-5-amino-3,3-dimethylpiperidin-1-yl] quinoxaline-5-carbonitrile hydrochloride: A solution of tert-butyl N-[(3R)-1-(8 - cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]carbamate (439 mg, 1.15 mmol) in MeOH (5 mL) was added a solution of HCl in dioxane (4 M, 5 mL) in room temperature. The resulting solution was stirred for 3 hours at room temperature. When the reaction was done, the resulting mixture was concentrated under reduced pressure to yield 8-[(5R)-5-amino-3,3-dimethylpiperidin-1-yl]quinoxaline-5-carbonitrile hydrochloride as a yellow solid (450 mg , raw). MS: m/z = 282.2 [M + H]+.

[00672] Compound 210: MS: m/z = 282.1 [M + H]+. Example 65: Synthesis of compound 211 and 212 (((R)-2-amino-N-((R)-1- (8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl)-3,3,3-trifluoropropanamide and (S)-2-amino-N-((R)-1-(8 -cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl)-3,3,3-trifluoropropanamide)

[00673] (R)-2-amino-N-((R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl)-3,3,3-trifluoropropanamide and (S)-2-amino-N-((R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl)-3,3,3-trifluoropro-2-amino -N-((R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl)-3,3,3-trifluoropropanamide was prepared from (R)-8-(5- amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile and 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid using Method J and 6. The two diastereomers were separated by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 19 x 150 mm 10 um; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 40% to 70% gradient in 10 min; detector, UV 254 nm.Isomer 1: (19 mg, 14% for two steps, yellow solid) HPLC: 93.0% purity, Retention Time = 2.39 min. MS: m/z = 407.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 9.01-8.91 (m, 2 H), 8.13 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 4.50-4.38 (m, 1 H), 4.24 (dd, J = 12.1, 4.1 Hz, 1 H), 4.01-3, 90 (m, 2 H), 3.00-2.84 (m, 2 H), 1.86-1.70 (m, 1 H), 1.58-1.48 (m, 1 H), 1.12 (s, 3 H), 1.08 (m, 3 H). Isomer 2: (17 mg, 12% for two steps, yellow solid) HPLC: 93.7% purity, Retention Time = 2 .46 min. EM: m/z = 407.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ9.01-8.91 (m, 2 H), 8.13 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8 .4 Hz, 1 H), 4.50-4.38 (m, 1 H), 4.24 (dd, J = 12.1, 4.1 Hz, 1 H), 4.01-3.90 (m, 2 H), 3.00-2.84 (m, 2 H), 1.86-1.70 (m, 1 H), 1.58-1.48 (m, 1 H), 1 .12 (s, 3 H), 1.08 (m, 3 H).Example 66: Synthesis of compound 213 ((2R)-N-[(3R)-1-(8-cyanoquinoxalin-5-yl)- 5,5-dimethylpiperidin-3-yl]-2-hydroxy-3-methyl-butanamide)

[00674] (2R)-N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-hydroxy-3-methylbutanamide: (2R) -N-[(3R)-1-(8-cyanoquino-xalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-hydroxy-3-methylbutanamide was prepared from acid (2R)-2- hydroxy-3-methylbutanoic acid and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile using Method J. The crude product was purified by preparative HPLC under the following conditions: column , XBridge Prep C18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 35% to 65% gradient in 8 min; detector, UV 254 nm. (2R)-N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-hydroxy-3-methylbutanamide was obtained as yellow solid (18 mg, 33%).

[00675] Compound 213: HPLC: 97.2% purity, Retention Time = 2.51 min. MS: m/z = 382.3 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.94 (dd, J = 8.7, 1.8 Hz, 2 H), 8.11 (d, J = 8.3 Hz, 1 H), 7 .29 (d, J = 8.4 Hz, 1 H), 4.44-4.33 (m, 1 H), 4.01 (dd, J = 12.0, 4.0 Hz, 1 H) , 3.91 (d, J = 3.7 Hz, 1 H), 3.79 (d, J = 12.1 Hz, 1 H), 3.22-3.15 (m, 1 H), 3 .03 (d, J = 12.1 Hz, 1 H), 2.22-2.10 (m, 1 H), 1.82-1.61 (m, 2 H), 1.16-1, 00 (m, 9H), 0.90 (d, J = 6.8 Hz, 3 H).

[00676] The following compounds were synthesized in an analogous manner:

[00677] Compound 214 (N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-(morpholin-4-yl)acetamide): hydrochloride of 8-[(5R)-5-amino-3,3-dimethylpiperidin-1-yl]quinoxaline-5-carbonitrile and 2-(morpholin-4-yl)acetic acid. HPLC: 97.0% purity, room temperature = 1.87 min. EM: m/z = 409.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 15.0 Hz, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.28 (d , J = 6.3 Hz, 1 H), 4.49-4.35 (m, 1 H), 4.16-4.07 (m, 1 H), 3.90 (d, J = 12, 3 Hz, 1 H), 3.77-3.63 (m, 4 H), 3.17-2.95 (m, 4 H), 2.60-2.52 (m, 4 H), 1 .83-1.74 (m, 1 H), 1.62-1.51 (m, 1 H), 1.15-1.05 (m, 6 H).

[00678] Compound 215 (N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-3,3-dimethylbutanamide): 3,3-dimethylbutanoic acid and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.2% purity, Retention Time = 4.17 min. MS: m/z = 380.1 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 4.48-4.36 (m, 1 H), 4.36-4.26 (m, 1 H), 4.11 (d, J = 12.6 Hz, 1 H), 2.90 (d, J = 12.4 Hz, 1 H), 2.80-2.68 (m, 1 H), 2.12 (s, 2 H), 1.85-1 .75 (m, 1 H), 1.44 (t, J = 12.3 Hz, 1 H), 1.13 (s, 3 H), 1.04 (s, 9H), 1.02 (s , 3H).

[00679] Compound 217 (N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-(dimethylamino)acetamide): 2-(dimethylamino) acid )acetic and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 97.9% purity, Retention Time = 2.95 min. MS: m/z = 367.1 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.12-8.04 (m, 1 H), 7.31-7.23 (m, 1 H), 4.46-4.33 (m, 1 H), 4.11 (dd, J = 11.6, 4.1 Hz, 1 H), 3.91 (d, J = 12.2 Hz , 1 H), 3.11-2.92 (m, 4 H), 2.34 (s, 6 H), 1.78 (dd, J = 12.9, 4.3 Hz, 1 H), 1.58 (dd, J = 12.8, 10.5 Hz, 1 H), 1.12 (s, 3 H), 1.07 (s, 3 H).

[00680] Compound 218 (N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-hydroxyacetamide): of 2-hydroxyacetamide and (R)- 8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile.HPLC: 99.6% purity, Retention Time = 2.18 min. MS: m/z = 340.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.11 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.44-4.33 (m, 1 H), 4.10-3.92 (m, 3 H), 3.78 (d, J = 12.1 Hz, 1 H), 3.24 (dd, J = 12.2, 8.5 Hz, 1 H), 3.03 (d, J = 12.1 Hz, 1 H), 1.81-1.67 ( m, 2 H), 1.12 and 1.09 (s, 6 H).

[00681] Compound 220 (N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-3,3,3-trifluoropropanamide): 3,3 acid ,3-trifluoropropanoic and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.0% purity, Retention Time = 2.62 min. MS: m/z = 392.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.11 (dd, J = 8.4, 1.5 Hz, 1 H), 7.30 ( d, J = 8.4 Hz, 1 H), 4.51-4.30 (m, 2 H), 4.13-3.99 (m, 1 H), 3,323.16 (m, 2 H) , 2.94 (d, J = 12.3 Hz, 1 H), 2.82 (t, J = 11.9 Hz, 1 H), 1,901.81 (m, 1 H), 1.47 (t , J = 12.2 Hz, 1 H), 1.15 (s, 3 H), 1.08 (s, 3 H).Example 67: Synthesis of compound 216 (8-[(5R)-5-[ (2-methoxyethyl)amino]-3,3-dimethylpiperidin-1-yl]quinoxaline-5-carbonitrile)

[00682] 8-[(5R)-5-[(2-methoxyethyl)amino]-3,3-dimethylpiperidin-1-yl]quinoxaline-5-carbonitrile: 8-[(5R)-5-[(2- methoxyethyl)amino]-3,3-dimethylpiperidin-1-yl]quinoxaline-5-carbonitrile was prepared from 3,3-dimethylbutanoic acid and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl ) quinoxaline-5-carbonitrile using Method N. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 35% to 65% gradient in 8 min; detector, UV 254 nm. 8-[(5R)-5-[(2-methoxyethyl)amino]-3,3-dimethylpiperidin-1-yl]quinoxaline-5-carbonitrile was obtained as yellow oil (13 mg, 11%).

[00683] Compound 216: HPLC: 95.0% purity, Retention Time = 2.30 min. MS: m/z = 340.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.96-8.86 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 1 H), 4.61-4.52 (m, 1 H), 3.93-3.85 (m, 1 H), 3.63-3.51 (m, 2 H) , 3.40 (s, 3 H), 3.37-3.30 (m, 1 H), 2.98-2.91 (m, 2 H), 2.86 (d, J = 12.1 Hz, 1 H), 2.62 (t, J = 11.2 Hz, 1 H), 1.96-1.87 (m, 1 H), 1.33-1.20 (m, 1 H) , 1.12 (s, 3 H), 1.06 (s, 3 H).

[00684] The following compounds were synthesized in an analogous manner:

[00685] Compound 219 (8-[(5R)-3,3-dimethyl-5-[(1-methyl-2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxaline-5-carbonitrile): of 2-hydroxyacetamide and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.3% purity, Retention Time = 2.46 min. EM: m/z = 379.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.05 (dd, J = 8.3, 0.9 Hz, 1 H), 7.20 ( dd, J = 8.5, 2.1 Hz, 1 H), 4.59 (br s, 1 H), 3.95-3.81 (m, 1 H), 3.70 (t, J = 8.7 Hz, 1 H), 3.48-3.35 (m, 3 H), 2.89-2.80 (m, 4 H), 2.67-2.48 (m, 2 H) , 1.97-1.76 (m, 2 H), 1.31-1.18 (m, 1 H), 1.11 and 1.06 (s, 6 H).Example 68: Synthesis of compound 221 (cis-8-[3-[(2-methoxyethyl)amino]-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5-carbonitrile)

[00686] Cys-8-[3-[(2-methoxyethyl)amino]-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5-carbonitrile: cis-8-[3-[(2-methoxyethyl)amino ]-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5-carbonitrile was prepared from 1-bromo-2-methoxyethane and cis-8-(3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxaline -5-carbonitrile using Method N. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 37% to 57% gradient in 8 min; detector, UV 254 nm. Cys-8-[3-[(2-methoxyethyl)amino]-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5-carbonitrile was obtained as yellow solid (30 mg, 27%).

[00687] Compound 221: HPLC: 99.2% purity, Retention Time = 1.37 min. MS: m/z = 380.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.13 (d, J = 8.3 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4.50-4.33 (m, 2 H), 3.59-3.47 (m, 2 H), 3.36 (s, 3 H), 3.13 -2.79 (m, 5 H), 2.76-2.66 (m, 1 H), 2.45-2.37 (m, 1 H), 1.43 (td, J = 12.1 , 12.1 Hz, 1 H).Example 69: Synthesis of compound 224, compound 225, compound 226 and compound 227 (8-((3R,5S)-3-(((R)-1-methyl-2- oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile, 8-((3R,5S)-3-(((S)-1-methyl-2-oxopyrrolidin -3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile, 8-((3S,5R)- 3-(((R)-1-methyl-2-oxopyrrolidin- 3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile and 8-((3S,5R)-3-(((S)-1-methyl-2-oxopyrrolidin-3 -yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile) Method 16

[00688] 8-((3R,5S)-3-(((R)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5- (trifluoromethyl)piperidin-1-yl)quinoxaline-5- carbonitrile, 8-((3R,5S)- 3-(((S)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile , 8-((3S,5R)-3-(((R)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile and 8-((3S,5R)-3-(((S)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile: A To a solution of cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxaline-5-carbonitrile (228 mg, 0.71 mmol) in tetrahydrofuran (2 mL) TEA (359 .03 mg, 3.55 mmols), KI (353.39 mg, 2.13 mmols), 3-bromo-1-methylpyrrolidin-2-one (377.73 mg, 2.12 mmols) at room temperature. The resulting solution was stirred for 2 days at 100°C. When the reaction was done, it was stopped abruptly by adding water (15 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 35% to 65% gradient in 10 min; detector, UV 254 nm. Then, the four enantiomers of cis-8-(3-(1-methyl-2-oxopyrrolidin-3-ylamino)-5-(trifluoromethyl) piperidin- 1-yl)quinoxaline-5-carbonitrile were obtained by separation on HPLC chiral preparation under the following conditions: column, CHIRAL ADH, 0.46 x 15 cm, 5 µm; mobile phase, EtOH (0.1% DEA) in hexane, 50% isocratic in 20 min; detector, UV 254 nm. Four products were separated and obtained. Isomer 1: (25 mg, 8%, yellow solid) HPLC: 98.4% purity, Retention Time = 0.90 min. EM: m/z = 419.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 4.56-4.46 (m, 1 H), 4.43-4.33 (m, 1 H), 3.71 (t, J = 8.7 Hz, 1 H), 3.48-3.34 (m, 2 H), 3.32-3.25 (m, 1 H), 3.09-2.82 (m, 5 H), 2.77 ( dd, J = 11.9, 10.6 Hz, 1 H), 2.55-2.39 (m, 2 H), 1.93-1.78 (m, 1 H), 1.47 (q , J = 12.1 Hz, 1 H).Isomer 2: (25 mg, 8%, yellow solid) HPLC: 97.4% purity, Retention Time = 1.17 min. EM: m/z = 407.2 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.99 (d, J = 1.7 Hz, 1 H), 8.85 (d, J = 1.8 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 4.56-4.42 (m, 1 H), 4.38-4 .30 (m, 1 H), 4.22-4.06 (m, 1 H), 3.82-3.68 (m, 1 H), 3.603.20 (m, 3 H), 3.10 -2.40 (m, 8 H), 2.15-1.82 (m, 1 H), 1.30-1.20 (s, 1 H). Isomer 3: (25 mg, 8%, yellow solid) HPLC: 97.1% purity, Retention Time = 0.90 min. MS: m/z = 419.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.82 (m, 2 H), 8.13 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 4.49-4.43 (m, 2 H), 3.77-3.63 (m 1 H), 3.49-3.34 (m, 2 H), 3.29-3.01 (m, 1 H), 3.07-2.80 (m, 5 H), 2.79-2.67 (m, 1 H), 2,562.36 (m, 2 H ), 1.93-1.81 (m, 1 H), 1.55-1.41 (m, 1 H). Isomer 4: (25 mg, 8%, yellow solid) HPLC: 93.9% purity, Retention Time = 0.90 min. MS: m/z = 419.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 4.56-4.46 (m, 1 H), 4.43-4.33 (m, 1 H), 3.71 (t, J = 8.7 Hz, 1 H), 3.48-3.34 (m, 2 H), 3.32-3.25 (m, 1 H), 3.09-2.82 (m, 5 H), 2.77 ( dd, J = 11.9, 10.6 Hz, 1 H), 2.55-2.39 (m, 2 H), 1.93-1.78 (m, 1 H), 1.47 (q , J = 12.1 Hz, 1 H).

[00689] The following compounds were synthesized in an analogous manner:

[00690] Compound 237 and compound 238 ((R)-1-methyl-3-(((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-yl )amino)pyrrolidin-2-one and (S)-1-methyl-3-[[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl ]amino]pyrrolidin-2-one):de (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine and 3-bromo-1-methylpyrrolidin-2 -ona. Isomer 1: 14 mg, 11%, yellow solid) HPLC: 97.0% purity, Retention Time = 1.69 min. EM: m/z = 407.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.2, 1.7 Hz, 1 H), 8.59 (dd, J = 8.6, 1.8 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.22 (d, J = 8 .0Hz, 1H), 3.73-3.59 (m, 2H), 3.43-3.24 (m, 4H), 2.85 (s, 3H), 2.54-2 .36 (m, 3 H), 2.28-2.18 (m, 1 H), 2.15-2.07 (m, 1 H), 1.89-1.79 (m, 1 H) , 1.07-0.92 (m, 4 H). Isomer 2: (11 mg, 9%, yellow solid) HPLC: 98.7% purity, Retention Time = 1.46 min. EM: m/z = 407.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.2, 1.7 Hz, 1 H), 8.59 (dd, J = 8.6, 1.8 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.22 (d, J = 8 .0 Hz, 1 H), 3.73-3.59 (m, 2 H), 3.43-3.24 (m, 4 H), 2.85 (s, 3 H), 2.54- 2.36 (m, 3 H), 2.28-2.18 (m, 1 H), 2.15-2.07 (m, 1 H), 1.89-1.79 (m, 1 H ), 1.07-0.92 (m, 4 H).Example 70: Synthesis of compound 231 (8-[(3R,5S)-3-[(1-hydroxy-2-methylpropan-2-yl)amino ]-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile)

[00691] Methyl 2-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-ylamino)-2-methylpropanoate: methyl 2-((3R,5S)-1- (8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-ylamino)-2-methylpropanoate was prepared from methyl 2-bromo-2-methylpropanoate and 8-[(3R,5S)-3-amino-5 -methylpiperidin-1-yl]quinoxaline-5-carbonitrile using Method N. The crude product was purified by flash chromatography eluting with MeOHc in DCM (0% to 5% gradient) to yield methyl 2-[[(3R,5S) -1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]amino]-2-methylpropanoate as yellow solid (190 mg, 61%). EM: m/z = 368.2 [M + H]+.Method 17

[00692] 8-[(3R,5S)-3-[(1-hydroxy-2-methylpropan-2-yl)amino]-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile: At 0°C, to a solution of methyl 2-[[(3R)-1-(8-cyanoquinoxalin-5-yl)piperidin-3-yl]amino]-2-methylpropanoate (143 mg, 0.40 mmol) in tetrahydrofuran ( 5 mL) LiAlH4 (14 mg, 0.37 mmol) was added slowly. The resulting mixture was stirred for 0.5 hours at 0°C. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with DCM (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 32% to 35% gradient in 10 min; detector, UV 254 nm. 8-[(3R,5S)-3-[(1-hydroxy-2-methylpropan-2-yl)amino]-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile was obtained as yellow solid (15 mg, 11%).

[00693] Compound 231: HPLC: 98.9% purity, Retention Time = 0.56 minute. EM: m/z = 340.0 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (d, J = 1.7 Hz, 1 H), 8.87 (d, J = 1.7 Hz, 1 H), 8.10 (d , J = 8.4 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1 H), 4.60-4.50 (m, 1 H), 3,993.90 (m, 1 H), 3.48 (d, J = 10.8 Hz, 1 H), 3.40 (d, J = 10.8 Hz, 1 H), 3,233.11 (m, 1 H), 2.64 -2.52 (m, 2H), 2.14-1.97 (m, 2H), 1.21-1.01 (m, 10H).

[00694] The following compounds were synthesized in an analogous manner:

[00695] Compound 242 (2-methyl-2-[[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]amino]propan-1- ol): from 2-(morpholin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-amine. HPLC: 99.6% purity, Retention Time = 1.54 min. MS: m/z = 382.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.57 (dd, J = 8.6, 1.7 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.55 (dd, J = 8.6, 4.2 Hz, 1 H), 7.17 (d, J = 8 .0Hz, 1H), 3.50-3.21 (m, 4H), 3.20-3.10 (m, 1H), 2.47-2.32 (m, 2H), 2.17-2.01 (m, 2 H), 1.07 (d, J = 9.0 Hz, 6 H), 0.99-0.95 (m, 4 H).

[00696] Compound 252 (2-methyl-2-[[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]amino]propan-1- ol): from 2-(morpholin-4-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl) quinoxalin-5-yl)piperidin-3-amine. HPLC: 99.1% purity, Retention Time = 1.27 min. MS: m/z = 383.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.16-8.86 (m, 2 H), 8.05 (d, J = 8.5 Hz, 1 H), 7.18 (d, J = 8.2 Hz, 1 H), 4.70-4.47 (m, 1 H), 4.23 (d, J = 11.8 Hz, 1 H), 3.88 (dd, J = 11.6, 3.8 Hz, 1 H), 3.49-3.10 (m, 5 H), 3.09-2.89 (m, 1 H), 2.50-2.35 (m , 3 H), 2.03-1.87 (m, 2 H), 1.15-0.80 (m, 7H). Example 71: Synthesis of compound 249 (N-[(3R,5S)-5 -methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide)

[00697] N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide: N- [(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide was prepared from 1-methylpyrrolidine- 3-carboxylic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 44% to 46% gradient in 8 min; detector, UV 254 nm. N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide was obtained as a yellow solid ( 30 mg, 46%).

[00698] Compound 249: HPLC: 99.7% purity, Retention Time = 1.40 min. MS: m/z = 438.3 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.95-8.88 (m, 2 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.29-4.07 (m, 2 H), 4.13-4.05 (m, 1 H), 3.74 (apparent t, J = 4.6 Hz , 4 H), 3.12-2.99 (m, 2 H), 2.77 (t, J = 10.6 Hz, 1 H), 2.65-2.50 (m, 5 H), 2.15-2.06 (m, 2 H), 1.27 (td, J = 12.3, 12.3 Hz, 1 H), 1.04 (d, J = 6.4 Hz, 3 H ).

[00699] The following compounds were synthesized in an analogous manner:

[00700] Compound 250 (2-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide): From acid 2-hydroxyacetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 99.0% purity, Retention Time = 2.60 min. MS: m/z = 369.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.95-8.88 (m, 2 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.31-4.23 (m, 1 H), 4.18 (dd, J = 11.6, 4.3 Hz, 1 H), 4.10-4, 03 (m, 1 H), 3.30-3.20 (m, 2 H), 2.84 (dd, J = 11.5, 10.4 Hz, 1 H), 2.63 (dd, J = 12.1, 10.4 Hz, 1 H), 2.16-2.10 (m, 2 H), 1.33 (td, J = 12.1, 12.1 Hz, 1 H), 1 .05 (d, J = 6.4 Hz, 3 H).

[00701] Compound 251 (1-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]cyclopropane-1-carboxamide): of 1-hydroxycyclopropanecarboxylic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 99.8% purity, Retention Time = 1.46 min. EM: m/z = 395.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.96-8.85 (q, J = 1.7 Hz, 2 H), 8.05 (d, J = 8.3 Hz, 1 H), 7 .29 (d, J = 8.3 Hz, 1 H), 4.28-4.00 (m, 3 H), 2.88 (t, J = 10.9 Hz, 1 H), 2.65 (t, J = 12.0 Hz, 1 H), 2.18-2.06 (m, 2 H), 1.37 (td, J = 12.3, 12.3 Hz, 1 H), 1 .31-1.15 (m, 2 H), 1.09-0.96 (m, 5 H).

[00702] Compound 253 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinoxalin-5-yl]piperidin-3-yl]-2-(1-methylpiperidin-4-yl )acetamide): from 2-(1-methylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 96.5% purity, Retention Time = 2.27 min. MS: m/z = 450.2 [M + H]+. 1H NMR (400 MHz,DMSO-d6, ppm) δ 9.02 (d, J = 1.7 Hz, 1 H), 8.95 (d, J = 1.7 Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 4, 21-4.07 (m, 2 H), 3.99-3.94 (m, 1 H), 2.75-2.50 (m, 4 H), 2.12 (s, 3 H), 2.03-1.87 (m, 4 H), 1.80 (t, J = 11.5 Hz, 2 H), 1.67-1.50 (m, 3 H), 1.23-1 .04 (m, 3H), 0.92 (d, J = 6.3Hz, 3H).

[00703] Compound 254 (2-(dimethylamino)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide): acid 2-(1-methylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 97.4% purity, Retention Time = 0.98 min. EM: m/z = 396.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.88 (m, 2 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.30-4.16 (m, 2 H), 4.11-4.07 (m, 1 H), 3.01 (d, J = 1.6 Hz, 2 H), 2.82-2.71 (m, 1 H), 2.60 (dd, J = 12.2, 10.6 Hz, 1 H), 2.33 (s, 6 H), 2 .18-2.05 (m, 2 H), 1.26 (td, J = 12.4, 12.4 Hz, 1 H), 1.03 (d, J = 6.4 Hz, 3 H) .

[00704] Compound 255 (2-(1,4-dimethylpiperidin-4-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3 -yl]acetamide): from 2-(1-methylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine . HPLC: 93.3% purity, Retention Time = 5.03 min. MS: m/z = 464.5 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.86 (m, 2 H), 8.08-7.99 (m, 1 H), 7.28 (d, J = 8.4 Hz, 1H), 4.28-4.08 (m, 3H), 2.70-2.25 (m, 9H), 2.202.04 (m, 4H), 1.80-1.62 (m, 2H), 1.58-1.40 (m, 2H), 1.25-0.90 (m, 7H).

[00705] Compound 256 (2-[1-(2,2-difluoroethyl)piperidin-4-yl]-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5- yl]piperidin-3-yl]acetamide): from 2-(1-methylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl) piperidin-3-amine. HPLC: 99.1% purity, Retention Time = 2.62 min. MS: m/z = 500.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.88 (m, 2 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 6.15-5.85 (m, 1 H), 4.27-4.08 (m, 3 H), 3.02-2.94 (m, 2 H) , 2.82-2.51 (m, 4 H), 2.27-2.21 (m, 2 H), 2.19-2.05 (m, 4 H), 1.85-1.67 (m, 3 H), 1.43-1.27 (m, 2 H), 1.18 (td, J = 12.5, 12.5 Hz, 1 H), 1.02 (d, J = 6.3Hz, 3H).

[00706] Compound 257 (3,3-difluoro-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]cyclobutane-1-carboxamide ): of 3,3-difluorocyclobutanecarboxylic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 98.3% purity, Retention Time = 1.72 min. MS: m/z = 429.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.89 (m, 2 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.25-4.10 (m, 3 H), 2.97-2.86 (m, 1 H), 2.84-2.54 (m, 6 H) , 2.19-2.03 (m, 2 H), 1.17 (td, J = 12.3, 12.3 Hz, 1 H), 1.02 (d, J = 6.3 Hz, 3 H).

[00707] Compound 258 (1-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]pyrrolidine-3-carboxamide): of 3,3-difluorocyclobutanecarboxylic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 90.4% purity, Retention Time = 1.28 min. EM: m/z = 422.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.93-8.86 (m, 2 H), 8.02 (d, J = 8.3 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 4.25-4.06 (m, 3 H), 3.04-2.89 (m, 2 H), 2.82-2.77 (m, 1 H) , 2.70-2.42 (m, 4 H), 2.37 (s, 3 H), 2.17-1.96 (m, 4 H), 1.16 (td, J = 12.4 , 12.4 Hz, 1 H), 1.00 (d, J = 6.4 Hz, 3 H).

[00708] Compound 259 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinoxalin-5-yl]piperidin-3-yl]-2-(4-methylpiperazin-1-yl )acetamide): 3,3-difluorocyclobutanecarboxylic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 97.1% purity, Retention Time = 1.38 min. MS: m/z = 451.3 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.10-8.95 (m, 2 H), 8.07 (d, J = 8.3 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 4.17-3.93 (m, 3 H), 3.40-3.30 ( m, 1 H), 3.00-2.85 (m, 2 H), 2.78 (t, J = 11.1 Hz, 1 H), 2.62-2.22 (m, 8 H) , 2.16 (s, 3 H), 1.95 (d, J = 11.5 Hz, 2 H), 1.26 (td, J = 12.3, 12.3 Hz, 1 H), 0 .94 (d, J = 6.3 Hz, 3 H).

[00709] Compound 292 (2-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]propanamide): 2- hydroxypropanoic and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 98.9% purity, Retention Time = 2.41 min. EM: m/z = 385.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.86 (m, 2 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.27-4.05 (m, 4 H), 2.83 (t, J = 10.8 Hz, 1 H), 2.62 (t, J = 11, 3 Hz, 1 H), 2.16-2.06 (m, 2 H), 1.41-1.24 (m, 4 H), 1.04 (d, J = 6.4 Hz, 3 H ).

[00710] Compound 293 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(1-methylpiperidin-3-yl )acetamide): 2-(1-methylpiperidin-3-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 99.4% purity, Retention Time = 1.03 min. MS: m/z = 450.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.05-8.95 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 4,254.07 (m, 2 H), 3.99-3.87 (m, 1 H ), 2.59-2.40 (m, 4 H), 2.10 (s, 3 H), 2,021.72 (m, 6 H), 1.65-1.35 (m, 4 H), 1.10 (td, J = 12.0, 12.0 Hz, 1 H), 0.950.78 (m, 4 H).

[00711] Compound 295 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(1-methylpyrrolidin-3-yl )acetamide): from 2-(1-methylpyrrolidin-3-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 92.1% purity, Retention Time = 4.92 min. EM: m/z = 436.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (d, J = 1.7 Hz, 1 H), 8.97 (d, J = 1.7 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.89 (d, J = 7.6 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4, 22-4.07 (m, 2H), 3.99-3.85 (m, 1H), 2.70-2.30 (m, 9H), 2.18 - 2.02 (m, 3 H), 2.00-1.80 (m, 3 H), 1.42 - 1.29 (m, 1 H), 1.20-1.04 (m, 1 H), 0.93 (d , J = 6.3 Hz, 3 H).

[00712] Compound 299 (2-(3,3-difluoroazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3 -yl]propanamide): from 2-(3,3-difluoroazetidin-1-yl)propanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3 -amine.HPLC: 94.2% purity, Retention Time = 2.63 min. MS: m/z = 458.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92-8.88 (m, 2 H), 8.02 (d, J = 8.3 Hz, 1 H), 7.27 (d, J = 8.3 Hz, 1 H), 4.20-4.06 (m, 3 H), 3.76-3.59 (m, 4 H), 3.14-3.02 (m, 1 H) , 2.81-2.70 (m, 1 H), 2.61-2.55 (m, 1 H), 2.14-1.99 (m, 2 H), 1.32-1.18 (m, 4 H), 1.01 (d, J = 6.4 Hz, 3 H).Example 72: Synthesis of compound 260 and compound 261 ((R)-3- (((3R,5S)-1 -(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl)amino)-1-methylpyrrolidin-2-one and (S)-3-[[(3R,5S)-1-(8-chloroquinolin -5-yl)-5-methylpiperidin-3-yl]amino]-1-methylpyrrolidin-2-one)

[00713] (R)-3-(((3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl)amino)-1-methylpyrrolidin-2-one and (S )-3-[[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]amino]-1-methylpyrrolidin-2-one: 3-[[(3R, 5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]amino]-1-methylpyrrolidin-2-one was prepared from (3R,5S)-1-(8-chloroquinolin-5 -yl)-5-methylpiperidin-3-amine and 3-bromo-1-methylpyrrolidin-2-one using Method 16. The crude product was first purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 19 x 150mm 10um; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 20% to 55% gradient in 8 min; detector, UV 254 nm. Then, the two diastereoisomers of 3-[[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]amino]-1-methylpyrrolidin-2-one were obtained by chiral preparative HPLC separation under the following conditions: column, Chiral PAK ID-3, 0.46 x 10 cm, 3 µm; mobile phase, EtOH in hexane, 50% isocratic in 12 min; detector, UV 254/220 nm. Isomer 1: (30 mg, 15%, light yellow solid) HPLC: 99.4% purity, Retention Time = 1.26 min. EM: m/z = 373.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.96 (d, J = 4.3 Hz, 1 H), 8.72-8.65 (m, 1 H), 7.86 (d, J = 8.1 Hz, 1 H), 7.67 (dd, J = 8.5, 4.3 Hz, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 4.09 (t, J = 9.1 Hz, 1 H), 3.83-3.64 (m, 2 H), 3.54-3.40 (m, 2 H), 3.40-3.25 ( m, 1 H), 2.92 (s, 3 H), 2.71 (t, J = 10.5 Hz, 1 H), 2.56 (dt, J = 12.7, 6.9 Hz, 1 H), 2.46 (t, J = 11.3 Hz, 1 H), 2.34 (d, J = 12.4 Hz, 1 H), 2.26-2.14 (m, 1 H ), 2.13-1.97 (m, 1 H), 1.21 (td, J = 12.0, 12.0 Hz, 1 H), 1.07 (d, J = 6.5 Hz, 3 H).Isomer 2: (30 mg, 15%, light yellow solid) HPLC: 99.1% purity, Retention Time = 0.98 min. EM: m/z = 373.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ8.96 (d, J = 4.3 Hz, 1 H), 8.72-8.65 (m, 1 H), 7.86 (d, J = 8 .1 Hz, 1 H), 7.67 (dd, J = 8.5, 4.3 Hz, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 4.09 ( t, J =9.1 Hz, 1 H), 3.83-3.64 (m, 2 H), 3.54-3.40 (m, 2 H), 3.40-3.25 (m , 1 H), 2.92 (s, 3 H), 2.71 (t, J = 10.5 Hz, 1 H), 2.56 (dt, J = 12.7, 6.9 Hz, 1 H), 2.46 (t, J = 11.3 Hz, 1 H), 2.34 (d, J = 12.4 Hz, 1 H), 2.26-2.14 (m, 1 H) , 2.13-1.97 (m, 1 H), 1.21 (td, J = 12.0, 12.0 Hz, 1 H), 1.07 (d, J = 6.5 Hz, 3 H).Example 73: Synthesis of compound 262 (N-[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-(morpholin-4-yl) acetamide)

[00714] N-[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-(morpholin-4-yl)acetamide: N-[(3R, 5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-(morpholin-4-yl)acetamide was prepared from 3,3-difluorocyclobutanecarboxylic acid and (3R,5S)- 1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 20% to 39% (retention to 39.0% in 7 minutes) gradient in 10 min; detector, UV 254 nm. N-[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-(morpholin-4-yl)acetamide was obtained as a light yellow solid (30 mg, 30%).

[00715] Compound 262: HPLC: 99.8% purity, Retention Time = 1.43 min. EM: m/z = 403.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.93 (dd, J = 4.2, 1.7 Hz, 1 H), 8.71 (dd, J = 8.5, 1.7 Hz, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.65 (dd, J = 8.5, 4.2 Hz, 1 H), 7.20 (d, J = 8 .2 Hz, 1 H), 4.31-4.24 (m, 1 H), 3.73 (t, J = 4.6 Hz, 4 H), 3.54-3.44 (m, 1 H), 3.32-3.23 (m, 1 H), 3.04 (s, 2 H), 2.59-2.40 (m, 6 H), 2.23-2.03 (m , 2 H), 1.21 (td, J = 12.0, 12.0 Hz, 1 H), 1.04 (d, J = 6.5 Hz, 3 H).

[00716] The following compounds were synthesized in an analogous manner:

[00717] Compound 263 (N-[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-hydroxyacetamide): of 2-hydroxyacetic acid and (3R, 5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.9% purity, Retention Time = 1.25 min. EM: m/z = 334.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.93 (dd, J = 4.2, 1.6 Hz, 1 H), 8.71 (dd, J = 8.5, 1.6 Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1 H), 7.65 (dd, J = 8.5, 4.2 Hz, 1 H), 7.20 (d, J = 8 .1 Hz, 1 H), 4.35-4.27 (m, 1 H), 3.99 (s, 2 H), 3.52- 3.43 (m, 1 H), 3.31- 3.25 (m, 1 H), 2.58 (t, J = 10.8 Hz, 1 H), 2.45 (t, J = 11.1 Hz, 1 H), 2.24-2, 07 (m, 2 H), 1.24 (td, J = 12.0, 12.0 Hz, 1 H), 1.04 (d, J = 6.5 Hz, 3 H).

[00718] Compound 264 (N-[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-(dimethylamino)acetamide): of 2-hydroxyacetic acid and (3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.4% purity, Retention Time = 1.50 min. EM: m/z = 361.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.91 (dd, J = 4.3, 1.7 Hz, 1 H), 8.74-8.64 (m, 1 H), 7.79 ( dd, J = 8.3, 0.8 Hz, 1 H), 7.62 (dd, J = 8.5, 4.2 Hz, 1 H), 7.23-7.13 (m, 1 H ), 4.29-4.20 (m, 1 H), 3,483.43 (m, 1 H), 3.27-3.22 (m, 1 H), 2.97 (s, 2 H), 2.51 (t, J = 10.8 Hz, 1 H), 2.42 (t, J = 11.2 Hz, 1 H), 2.28 (s, 6 H), 2.17-2, 06 (m, 2 H), 1.17 (td,J = 12.2, 12.2 Hz, 1 H), 1.02 (d, J = 6.4 Hz, 3 H).Example 74: Synthesis of compound 267 (2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]propanamide) Method 18

[00719] Ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin-1-yl) propanoate: A solution of tert-butyl N-(azetidin-3-yl)carbamate (475 mg, 2 .76 mmols) in DCM (40 m) were added triethylamine (418 mg, 4.14 mmols) and ethyl 2-bromopropanoate (749 mg, 4.14 mmols) at room temperature. The resulting solution was stirred for 13 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting solution was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 50% gradient) to yield ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin- 1-yl)propanoate as yellow oil (330 mg, 44%). EM: m/z = 259.3 [M + H]+.Method 19

[00720] Ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin-1-yl): A solution of ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin- 1-yl)propanoate (475 mg, 1.74 mmo) in THF (5 mL) was added to a solution of LiOH (125 mg) in water (15 mL) at room temperature. The resulting mixture was then stirred for 13 hours at room temperature. When the reaction was done, the pH value of the reaction mixture was adjusted to 5 with hydrogen chloride solution (2 M). The resulting mixture was extracted with DCM (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin-1-yl) propanoic acid as a white solid (300 mg, 70%). EM: m/z = 245.1 [M + H]+

[00721] 2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]propanamide: 2-(3 -aminoazetidin-1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]propanamide was prepared from 2-(3-(tert- butoxycarbonylamino)azetidin-1-yl)propanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile using Method J and 6. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 24% to 31% gradient in 6 min; detector, UV 254 nm. 2-(3-Aminoazetidin-1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]propanamide was obtained as a yellow solid (24 mg , 17% for two stages).

[00722] Compound 267: HPLC: 95.6% purity, Retention Time = 1.27 min. EM: m/z = 394.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 4.35-4.05 (m, 3 H), 3.66-3.50 (m, 3 H), 2.96-2.65 (m, 5 H) , 2.07 (d, J = 11.9 Hz, 2 H), 1.33-1.22 (m, 1 H), 1.16 (d, J = 6.7 Hz, 3 H), 1 .02 (d, J = 6.3 Hz, 3 H). Example 75: Synthesis of compound 270 ((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl 2 -(3-hydroxyazetidin-1-yl)acetate)

[00723] (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl 2-(3-hydroxyazetidin-1-yl)acetate: (3R,5S)-1-( 8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl 2-(3-hydroxyazetidin-1-yl)acetate was prepared from 3-(tert-butyldimethylsilyloxy)azetidine, methyl 2-bromoacetate and 8-((3R ,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile using Method 18, 19, and J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 um, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 28% to 32% gradient in 7 min; detector, UV 254 nm. (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl 2-(3-hydroxyazetidin-1-yl)acetate was obtained as yellow solid (22 mg, 10% for 3 steps).

[00724] Compound 270: HPLC: 97.7% purity, Retention Time = 2.43 minutes. MS: m/z = 381.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 4.42-4.21 (m, 3 H), 4.19-4.07 (m, 1 H), 3.77-3.68 (m, 2 H) , 3.18 (d, J = 1.1 Hz, 2 H), 3.08-2.99 (m, 2 H), 2.87-2.76 (m, 1 H), 2.72- 2.60 (m, 1 H), 2.12-1.96 (m, 2 H), 1.26 (td, J = 12.1, 12.1 Hz, 1 H), 1.01 (d , J = 6.3 Hz, 3 H).

[00725] The following compounds were synthesized in an analogous manner:

[00726] Compound 271 2-(3-hydroxyazetidin-1-yl)propanoate ((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl): 3-( tert-butyldimethylsilyloxy)azetidine, ethyl 2-bromopropanoate and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.9% purity, Retention Time = 1.06 min. MS: m/z = 395.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.27 (dd, J = 8.4, 1.1 Hz, 1 H), 4.39-4.23 (m, 3 H), 4.18-4.07 (m, 1 H), 3.66-3.60 (m , 2 H), 3.01-2.76 (m, 4 H), 2.73-2.62 (m, 1 H), 2.08-2.03 (m, 2 H), 1.36 -1.20 (m, 1 H), 1.16 (d, J = 6.8 Hz, 3 H), 1.01 (d, J = 6.4 Hz, 3 H).

[00727] Compound 273 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(3,3-difluoroazetidin-1-yl)propanamide ): of 3,3-difluoroazetidine, ethyl 2-bromopropanoate and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 97.0% purity, Retention Time = 1.50 min. MS: m/z = 415.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 4.34-4.21 (m, 2 H), 4.20-4.06 (m, 1 H), 3.77-3.58 (m, 4 H) , 3.12-3.02 (m, 1 H), 2.90-2.78 (m, 1 H), 2.74-2.62 (m, 1 H), 2.111.98 (m, 2 H), 1.37-1.18 (m, 4 H), 1.01 (d, J = 6.4 Hz, 3 H).

[00728] Compound 275 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4-hydroxypiperidin-1-yl)propanamide): of piperidin-4-ol, ethyl 2-bromopropanoate, and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.7% purity, Retention Time = 1.82 and 1.86 min. EM: m/z = 423.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.28 (dd, J = 8.4, 1.8 Hz, 1 H), 4.39-4.10 (m, 3 H), 3.62 (dd, J = 9.2, 4.9 Hz, 1 H), 3, 15-2.98 (m, 1 H), 2.90-2.63 (m, 4 H), 2.42-2.19 (m, 2 H), 2.15-1.80 (m, 4 H), 1.56 (d, J = 9.7 Hz, 2 H), 1.36-1.19 (m, 4 H), 1.02 (d, J = 6.3 Hz, 3 H ).

[00729] Compound 284 ((3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl 2-(3-hydroxyazetidin-1-yl)acetate): of 2-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)acetic acid. HPLC: 99.9% purity, Retention Time = 1.32 min. EM: m/z = 423.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ8.91 (dd, J = 4.2, 1.7 Hz, 1 H), 8.63 (dd, J = 8.6, 1.8 Hz, 1 H ), 8.01 (d, J = 8.1 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (d, J = 8, 1 Hz, 1 H), 4.40-4.16 (m, 2 H), 3.74-3.65 (m, 2 H), 3.61-3.52 (m, 1 H), 3 .41-3.32 (m, 1 H), 3.15 (s, 2 H), 3.01 (dd, J = 8.2, 6.0 Hz, 2 H), 2.60-2, 40 (m, 2 H), 2.20-2.05 (m, 2 H), 1.19 (td, J = 12.0, 12.0 Hz, 1 H), 1.02 (d, J = 6.4 Hz, 3 H).

[00730] Compound 285 (2-(3-hydroxyazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl ]propanamide): from 2-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)propanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin- 3-amine. HPLC: 98.2% purity, Retention Time = 3.41 min. MS: m/z = 437.2 [M + H]+.1H NMR (400 MHz, CD3OD, ppm) δ 8.94 (dd, J = 4.3, 1.7 Hz, 1 H), 8, 69-8.62 (m, 1 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 4.38-4.31 (m, 1 H), 4.25 (dd, J = 11.7, 4.7 Hz, 1 H ), 3.62 (d, J = 6.4 Hz, 3 H), 3.39 (d, J = 12.0 Hz, 1 H), 2.95 (dt, J = 23.0, 6, 3 Hz, 3 H), 2.62-2.42 (m, 2 H), 2.11-2.16 (m, 2 H), 1.28-1.12 (m, 4 H), 1 .08-1.01 (m, 3H).

[00731] Compound 296 (2-(3-hydroxyazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl ]acetamide): 2-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin- 3-amine. HPLC: 99.1% purity, Retention Time = 1.26 min. MS: m/z = 424.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92-8.85 (m, 2 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.29-7.22 ( m, 1 H), 4.34 (tt, J = 6.1, 6.1 Hz, 1 H), 4.21-416 (m, 2 H), 4.08-4.05 (m, 1 H), 3.71 (dd, J = 8.4, 6.2 Hz, 2 H), 3.17 (s, 2 H), 3.05-3.01 (m, 2 H), 2, 78-2.67 (m, 1 H), 2.57 (t, J = 11.4 Hz, 1 H), 2,092.05 (m, 2 H), 1.22 (td, J = 12.7 , 11.8 Hz, 1 H), 1.01 (d, J = 6.4 Hz, 3 H).

[00732] Compound 297 ((3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinoxalin-5-yl]piperidin-3-yl 2-(3-hydroxyazetidin-1-yl)propanoate): of 2-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)propanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 93.0% purity, Retention Time = 3.18 min. MS: m/z = 438.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.88 (m, 2 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.38-4.34 (m, 1 H), 4.20-4.06 (m, 3 H), 3.69-3.60 (m, 2 H) , 3.00-2.82 (m, 3 H), 2.76-2.74 (m, 1 H), 2.59 (t, J = 11.7 Hz, 1 H), 2.18- 2.04 (m, 2 H), 1.33-1.14 (m, 4 H), 1.03 (d, J = 6.5 Hz, 3 H).

[00733] Compound 308 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(3-hydroxyazetidin-1-yl) acetamide): 2-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine . HPLC: 97.9% purity, Retention Time = 2.52 min. MS: m/z = 405.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.61 (dd, J = 8.6, 1.8 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.83-7.55 (m, 2 H), 7.25 (d, J = 7.9 Hz, 1 H) , 4.40-4.30 (m, 1 H), 4.27-4.18 (m, 1 H), 3.743.65 (m, 2 H), 3.58-3.49 (m, 1 H), 3.35-3.20 (m, 1 H), 3.15 (s, 2 H), 3.052.96 (m, 2 H), 2.58-2.38 (m, 2 H) , 2.18-2.02 (m, 2 H), 1.17 (td, J = 12.0, 12.0 Hz, 1 H), 1.03 (d, J = 6.5 Hz, 3 H).

[00734] Compound 309 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(3-hydroxyazetidin-1-yl) propanamide): from 2-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)propanoic acid and (3R,5S)-1- (8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3- the mine. HPLC: 95.7% purity, Retention Time = 2.47 min. MS: m/z = 419.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.61 (dt, J = 8.6, 1.7 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.85-7.55 (m, 2 H), 7.26 (d, J = 7.9 Hz, 1 H) , 4.36-4.28 (m, 1 H), 4.26-4.17 (m, 1 H), 3.62-3.55 (m, 2 H), 3.55-3.48 (m, 1 H), 3.39-3.20 (m, 1 H), 2.94-2.85 (m, 3 H), 2.562.41 (m, 2 H), 2.20-2 .04 (m, 2 H), 1.23-1.13 (m, 4 H), 1.03 (d, J = 6.5 Hz, 3 H).

[00735] Compound 320 (N-[(3R,5S)-1-[8-(difluoromethyl) quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(3-hydroxyazetidin-1-yl) acetamide): 2-[3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl]acetic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin -3- amine. HPLC: 91.1% purity, Retention Time = 2.97 min. MS: m/z = 406.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.90-8.82 (m, 2 H), 7.96 (d, J = 8.2 Hz, 1 H), 7.63 (t, J = 55.6 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 4.40-4.30 (m, 1 H), 4.25-4.15 (m, 1 H), 4.09 (dd, J = 11.4, 4.1 Hz, 1 H), 3.98 (d, J = 12.0 Hz, 1 H), 3.74-3.70 ( m, 2 H), 3.17 (s, 2 H), 3.05-3.01 (m, 2 H), 2.69 (t, J = 11.0 Hz, 1 H), 2.53 (t, J = 11.4 Hz, 1 H), 2.18-2.04 (m, 2 H), 1.22-1.18 (m, 1 H), 1.01 (d, J = 6.4Hz, 3H).

[00736] Compound 321 (N-[(3R,5S)-1-[8-(difluoromethyl) quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(3-hydroxyazetidin-1-yl) propanamide): 2-[3-[(tert-butyldimethylsilyl)oxy]azetidin-1-yl]propanoic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin -3-amine. HPLC: 94.2% purity, Retention Time = 1.24 min. MS: m/z = 420.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.91-8.80 (m, 2 H), 8.00-7.92 (m, 1 H), 7.63 (t, J = 55.9 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 4.36-4.30 (m, 1 H), 4.22-4.16 (m, 1 H) , 4.11-3.95 (m, 2 H), 3.66-3.60 (m, 2 H), 3.00-2.85 (m, 3 H), 2.72-2.65 (m, 1 H), 2.52 (t, J = 11.5 Hz, 1 H), 2.09 (m, 2 H), 1.31-1.13 (m, 4 H), 1, 01 (d, J = 6.4 Hz, 3 H). Example 76: Synthesis of compound 272 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3- yl]-2-(2,2-difluorocyclopropyl)acetamide)

[00737] 2-(2,2-Difluorocyclopropyl)ethyl benzoate: but-3-en-1-yl benzoate (2.85 g, 16.17 mmols) and trimethylsilyl 2,2-difluoro-2- (fluorosulfonyl )acetate (7.98 g, 31.89 mmol) were mixed in pure condition, to which NaF (36 mg, 0.86 mmol) was added. The resulting mixture was stirred for 12 hours at 110°C. After cooling to room temperature, the reaction was stopped abruptly by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 6% gradient) to give 2-(2,2-difluorocyclopropyl)ethyl benzoate as yellow oil (1.84 g , 50%). MS: m/z = 227.1 [M + H]+.

[00738] 2-(2,2-Difluorocyclopropyl)ethan-1-ol: To a solution of 2-(2,2-difluorocyclopropyl)ethyl benzoate (900 mg, 3.98 mmols) in water (20 mL) was added sodium hydroxide (1.60 g, 40.00 mmols) at room temperature. The resulting mixture was stirred for 16 hours at 100°C. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 2-(2,2-difluorocyclopropyl)ethan-1-ol as a colorless liquid (210 mg, 43%). GCMS: m/z = 122 [M]+.

[00739] 2-(2,2-Difluorocyclopropyl)acetic acid: At 0°C, to a solution of CrO3 (5.70 g, 57.00 mmols) in sulfuric acid (8.3 mL) was added water (92 mL). Then, a solution of 2-(2,2-difluorocyclopropyl)ethan-1-ol (180 mg, 1.47 mmol) in acetone (30 mL) was added dropwise over a period of 20 minutes. The resulting mixture was stirred for 4 hours at room temperature. When the reaction was done, the reaction mixture was extracted with ether (50 mL x 4). The organic layers were combined, washed with 2M sodium hydroxide solution (50 mL x 4) and the aqueous layers were combined. The pH value of the resulting aqueous solution was adjusted to 1 using sulfuric acid and extracted with ether (50 mL x 4). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 2-(2,2-difluorocyclopropyl)acetic acid as colorless oil (117 mg, 58%). GCMS: m/z = 136 [M]+.

[00740] (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl 2- (3-hydroxyazetidin-1-yl)propanoate: N-[(3R,5S)- 1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(2,2-difluorocyclopropyl)acetamide was prepared from 3-(tert-butyldimethylsilyloxy)azetidine, ethyl 2-bromopropanoate, and 8 -((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 one, 19mm x 150mm; mobile phase, acetonitrile in water (with 0.1% NH3.H2O), 30% to 60% gradient in 7 minutes; detector, UV 254 nm. N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(2,2-difluorocyclopropyl)acetamide was obtained as a yellow solid (30 mg , 33%).

[00741] Compound 272: HPLC: 98.5% purity, Retention Time = 1.45 minutes. MS: m/z = 386.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 4.45-4.36 (m, 1 H), 4.32 (d, J = 12.7 Hz, 1 H), 4,214.09 (m, 1 H), 2.82-2.62 (m, 2 H), 2.51-2.30 (m, 2 H), 2.16-1.83 (m, 3 H), 1.62-1.48 ( m, 1 H), 1.33-1.07 (m, 2 H), 1.02 (d, J = 6.4 Hz, 3 H).

[00742] The following compounds were synthesized in an analogous manner:

[00743] Compound 286 (2-(2,2-difluorocyclopropyl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide ): from 2-(2,2-difluorocyclopropyl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine. HPLC: 98.0% purity, Retention Time = 1.77 min. MS: m/z = 428.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.97-8.91 (m, 1 H), 8.74-8.62 (m, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.64 (dd,J = 8.6, 4.2 Hz, 1 H), 7.22 (d,J = 8.0 Hz, 1 H), 4.24 (m, 1 H), 3.69-3.60 (m, 1 H), 3.44-3.35 (m, 1 H), 2.56-2.39 (m, 3 H), 2.33 ( dd, J = 15.4, 7.4 Hz, 1 H), 2.24-2.09 (m, 2 H), 2.00-1.80 (m, 1 H), 1.61-1 .45 (m, 1 H), 1.23-0.97 (m, 5 H).

[00744] Compound 298 (2-(2,2-difluorocyclopropyl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide ): from 2-(2,2-difluorocyclopropyl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 97.0% purity, Retention Time = 1.73 min. MS: m/z = 429.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-.88 (m, 2 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.35 (d, J = 8 .4Hz, 1H), 4.34-4.14 (m, 3H), 2.78-2.28 (m, 4H), 2.22-2.11 (m, 2H), 2.05-1.86 (m, 1 H), 1.66-1.52 (m, 1 H), 1.31-1.13 (m, 2 H), 1.08 (d, J = 6.4Hz, 3H).

[00745] Compound 310 (2-(2,2-difluorocyclopropyl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide) : 2-(2,2-difluorocyclopropyl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.3% purity, Retention Time = 1.46 min. EM: m/z = 410.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.91 (dd, J = 4.1, 1.7 Hz, 1 H), 8.67-8.60 (m, 1 H), 7.95 ( d, J = 7.9 Hz, 1 H), 7.85-7.54 (m, 2 H), 7.26 (d, J = 7.9 Hz, 1 H), 4,284.20 (m, 1 H), 3.65-3.56 (m, 1 H), 3.40-3.34 (m, 1 H), 2.52-2.41 (m, 3 H), 2.32 ( dd, J = 15.6, 7.8 Hz, 1 H), 2.24-2.08 (m, 2 H), 1.96-1.84 (m, 1 H), 1.58-1 .49 (m, 1 H), 1.22-1.01 (m, 5 H).

[00746] Compound 322 (2-(2,2-difluorocyclopropyl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]acetamide) :of 2-(2,2-difluorocyclopropyl)acetic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine. HPLC: 96.9% purity, Retention Time = 3.24 min. EM: m/z = 411.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 7.96 (d, J = 8.2 Hz, 1 H), 7.63 (t, J = 55.9 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 4.27-4.10 (m, 2 H), 4.05-3.97 (m, 1 H), 2.64-2.58 (m, 1 H), 2.55-2.38 (m, 2 H), 2.37-2.26 (m, 1 H), 2.13- 2.06 (m, 2 H), 1.95-1.83 (m, 1 H), 1.59-1.45 (m, 1 H), 1.21-1.04 (m, 2 H ), 1.00 (d, J = 6.3 Hz, 3 H).Example 77: Synthesis of compound 274 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5- methylpiperidin-3-yl]-2-(3,3-difluoroazetidin-1-yl)propanamide)

[00747] tert-butyl 3-([[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamoyl]methyl)azetidine-1-carboxylate: tert-butyl 3-([[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamoyl]methyl)azetidine-1-carboxylate was prepared from 2-(1-( tert-butoxycarbonyl)azetidin-3-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile using Method J. The crude was purified by flash chromatography eluting with EtOAc in hexane (0% to 50% gradient) to produce tert-butyl 3-([[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamoyl ]methyl)azetidine-1-carboxylate as yellow solid (90 mg, 15%). MS: m/z = 465.3 [M + H]+.

[00748] 2-(azetidin-3-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide: At 0°C, terc -butyl 3-([[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamoyl]methyl)azetidine-1-carboxylate (85 mg, 0.18 mmol ) was added by HF-pyridine solution (7 mL) dropwise. The resulting solution was stirred for a further two hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (15 mL). The resulting mixture was extracted with DCM (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0% to 10% gradient) to yield 2-(azetidin-3-yl)-N-[(3R,5S)- 1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide as yellow solid (14 mg, 21%).

[00749] Compound 274: HPLC: 91.4% purity, Retention Time = 2.80 min. EM: m/z = 365.1 [M + H]+. 1H NMR (300 MHz,CD3OD, ppm) δ 8.95-8.80 (m, 2 H), 8.10-7.98 (m, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.28 (t, J = 14.1 Hz, 2 H), 4.13-3.85 (m, 3 H), 3.65 (t, J = 8.4 Hz, 2 H), 3.13 (dt, J = 15.7, 7.8 Hz, 1 H), 2.77-2.42 (m, 4 H), 2,121.92 (m, 2 H), 1 .25-0.92 (m, 4H).Example 78: Synthesis of compound 276 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl] -2-(4-methyl-1,4-diazepan-1-yl)acetamide)

[00750] N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4-methyl-1,4-diazepan-1-yl) acetamide: N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4-methyl-1,4-diazepan-1-yl)acetamide was prepared from 1-methyl-1,4-diazepane, ethyl 2-bromoacetate, and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile using Method N, 19 , and J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 27% to 28% gradient in 10 min; detector, UV 254 nm. N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4-methyl-1,4-diazepan-1-yl)acetamide was obtained as yellow solid (12 mg, 5% for 3 steps).

[00751] Compound 276: HPLC: 96.6% purity, Retention Time = 1.08 min. EM: m/z = 422.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.5Hz, 1H), 4.38-4.12 (m, 3H), 3.15 (s, 2H), 2.90-2.60 (m, 10H), 2.37 ( s, 3 H), 2.14-1.94 (m, 2 H), 1.90-1.74 (m, 2 H), 1.29 (d, J = 12.4 Hz, 1 H) , 1.00 (d, J = 6.4 Hz, 3 H).

[00752] The following compounds were synthesized in an analogous manner:

[00753] Compound 290 (2-(4-methyl-1,4-diazepan-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl ]piperidin-3-yl]acetamide): 2-(4-methyl-1,4-diazepan-1-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin -5-yl)piperidin-3-amine. HPLC: 96.5% purity, Retention Time = 1.47 min. MS: m/z = 464.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.2, 1.8 Hz, 1 H), 8.65 (dd, J = 8.6, 1.8 Hz, 1 H), 8.02 (d, J = 8.1 Hz, 1 H), 7.61 (dd, J = 8.6, 4.2 Hz, 1 H), 7.22 (d, J = 8 .0 Hz, 1 H), 4.28 (t, J = 11.4 Hz, 1 H), 3.58 (d, J = 11.0 Hz, 1 H), 3.38 (d, J = 11.7Hz, 1H), 3.18-3.14 (m, 2H), 2.81-2.30 (m, 13H), 2.23-2.03 (m, 2H), 1.83 (q, J = 5.7 Hz, 2 H), 1.25 (td, J = 11.9, 11.9 Hz, 1 H), 1.04 (d, J = 6.4 Hz , 3H).

[00754] Compound 314 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(4-methyl-1,4- diazepan-1-yl)acetamide): from 2-(4-methyl-1,4-diazepan-1-yl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl) -5-methylpiperidin-3-amine. HPLC: 95.3% purity, Retention Time = 2.46 min. MS: m/z = 446.2 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ8.91 (dd, J = 4.3, 1.8 Hz, 1 H), 8.65 (dd, J = 8.5, 1.8 Hz, 1 H ), 8.00-7.54 (m, 3 H), 7.29 (d, J = 7.9 Hz, 1 H), 4.36-4.24 (m, 1 H), 3.61 -3.52 (m, 1 H), 3.44-3.30 (m, 1 H), 3.18 (s, 2 H), 2.84-2.67 (m, 8 H), 2 .64-2.44 (m, 2 H), 2.41 (s, 3 H), 2.27-2.08 (m, 2 H), 1.87-1.81 (m, 2 H) , 1.26 (td, J = 12.1, 12.0 Hz, 1 H), 1.06 (d, J = 6.4 Hz, 3 H).

[00755] Compound 326 (N-[(3R,5S)-1-[8-(difluoromethyl) quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(4-methyl-1,4- diazepan-1-yl) acetamide): from 2-(4-methyl-1,4-diazepan-1-yl)acetic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl] -5-methylpiperidin-3-amine. HPLC: 87.1% purity, Retention Time = 1.29 min. MS: m/z = 447.5 [M + H]+. 1H NMR (400 MHz,CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 7.97 (d, J = 8.2 Hz, 1 H), 7.63 (t, J = 56.0 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 1 H), 4.32-4.18 (m, 1 H), 4.13-4.09 (m, 1H), 4.00-3.98 (m, 1H), 3.20-2.95 (m, 2H), 2.832.64 (m, 9H), 2.55 (t, J = 11 .3Hz, 1H), 2.39 (s, 3H), 2.13-2.07 (m, 2H), 1.90-1.76 (m, 2H), 1.30- 1.24 (m, 1 H), 1.12-0.99 (m, 3 H).

[00756] Compound 362 (2-(4-methyl-1,4-diazepan-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl ]piperidin-3-yl]acetamide): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine and 2-(4-methyl-1 acid ,4-diazepan-1-yl)acetic acid. HPLC: 93.7% purity, Retention Time = 2.36 min. EM: m/z = 465.1 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.86 (m, 2 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.28 (d, J = 8.3Hz, 1H), 4.23-4.09 (m, 3H), 3.21 (s, 2H), 2.86-2.60 (m, 10H),2.49 ( s, 3 H), 2.12-2.08 (m, 2 H), 1.89-1.85 (m, 2 H), 1.36-1.20 (m, 1 H), 1, 04 (d, J = 6.3 Hz, 3 H). Example 79: Synthesis of compound 280 (2-(3-aminoazetidin-1-yl)-N- [(3R,5S)-5-methyl-1- [8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide)

[00757] 2-Bromo-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide: To a solution of (3R,5S )-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine (266 mg, 0.86 mmol) in N,N-dimethylformamide (10 mL) was added 2-bromoacetic acid (475 mg, 3.42 mmols), T3P (817 mg, 2.57 mmols), DIEA (551 mg, 4.26 mmols) at room temperature. The resulting solution was stirred for 14 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with DCM (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solution was removed under reduced pressure to yield 2-bromo-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide as a solid. yellow (400 mg, raw). (Note: In Method 20, the solvent may also be dichloromethane instead of N,N-dimethylformamide)

[00758] tert-butyl N-[1-([[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]carbamoyl]methyl)azetidin- 3-yl]carbamate: tert-butyl N-[1-([[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl] carbamoyl]methyl )azetidin-3-yl]carbamate was prepared from tert-butyl azetidin-3-ylcarbamate and 2-bromo-N-((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl )piperidin-3-yl)acetamide using Method 18. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 45% gradient in 8 min; detector, UV 254 nm. tert-Butyl N-[1-([[(3R,5S)- 5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamoyl]methyl)azetidin-3-yl ]carbamate was obtained as a white solid (38 mg, 26% for two steps).MS: m/z = 522.3 [M + H]+.Method 21

[00759] 2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide: To a solution of tert-butyl N-[1-([[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamoyl]methyl)azetidin -3-yl]carbamate (18 mg, 0.03 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature. The resulting solution was stirred for 12 hours at room temperature. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3+0.1% NH3.H2O), 30% to 45% gradient in 7 min; detector, UV 254 nm. N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(1-methylpiperidin-3-yl)acetamide was obtained as a solid white (7 mg, 44%).

[00760] Compound 280: HPLC: 92.4% purity, Retention Time = 2.48 min. EM: m/z = 422.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.3, 1.7 Hz, 1 H), 8.64 (dd, J = 8.6, 1.8 Hz, 1 H), 8.02 (d, J = 8.1 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (d, J = 8 .0 Hz, 1 H), 4.30-4.16 (m, 1 H), 3.70-3.53 (m, 4 H), 3.38 (d, J = 11.5 Hz, 1 H), 3.14 (s, 2 H), 2.98-2.90 (m, 2 H), 2.60-2.40 (m, 2 H), 2.22-2.08 (m , 2 H), 1.20 (td, J = 12.0, 12.0 Hz, 1 H), 1.03 (d, J = 6.5 Hz, 3 H).Example 80: Synthesis of compound 281 (2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]propanamide)

[00761] 2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]propanamide: 2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]propanamide was prepared from acid 2-(3-(tert-butoxycarbonylamino)azetidin-1-yl)propanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine using Method J and 6. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 30% to 37% gradient in 7 min; detector, UV 254 nm. 2-(3-Aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]propanamide was obtained as a solid white (17 mg, 17% for two steps).

[00762] Compound 281: HPLC: 99.2% purity, Retention Time = 2.51 min. MS: m/z = 436.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.2, 1.7 Hz, 1 H), 8.63 (dt, J = 8.6, 1.8 Hz, 1 H), 8.02 (d, J = 8.1 Hz, 1 H), 7.61 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (d, J = 8 .0Hz, 1H), 4.29-4.15 (m, 1H), 3.61-3.47 (m, 4H), 3.41-3.33 (m, 1H), 2.91-2.75 (m, 3 H), 2.59-2.41 (m, 2 H), 2.21-2.05 (m, 2 H), 1.31-1.09 ( m, 4 H), 1.03 (d, J = 6.4 Hz, 3 H).

[00763] The following compounds were synthesized in an analogous manner:

[00764] Compound 282 (2-amino-2-cyclopropyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide): of 2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine. HPLC: 96.3% purity, Retention Time = 1.76 min. EM: m/z = 407.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.19-9.04 (m, 2 H), 8.26 (d, J = 6.2 Hz, 1 H), 7.98-7.95 ( m, 1 H), 7.42 (t, J = 7.8 Hz, 1 H), 4.26-4.25 (m, 1 H), 3.69 (d, J = 11.4 Hz, 1 H), 3.48 (d, J = 11.3 Hz, 1 H), 3.15 (dd, J = 9.7, 4.8 Hz, 1 H), 2.77-2.53 ( m, 2 H), 2.25-2.05 (m, 2 H), 1.28-1.23 (m, 2 H), 1.03 (d, J = 6.3 Hz, 3 H) , 0.84-0.58 (m, 3 H), 0.56-0.45 (m, 1 H).

[00765] Compound 288 (2-(azetidin-3-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide ): 2-(3,3-difluoroazetidin-1-yl)propanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine. HPLC: 91.7% purity, Retention Time = 4.98 min. EM: m/z = 407.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.13-9.00 (m, 2 H), 8.23 (d, J = 8.2 Hz, 1 H), 7.92 (dd, J = 8.6, 4.8 Hz, 1 H), 7.40 (d, J = 8.2 Hz, 1 H), 4.28-4.08 (m, 3 H), 3.93 (t, J = 8.9 Hz, 2 H), 3.70 (d, J = 11.1 Hz, 1 H), 3.48 (d, J = 11.7 Hz, 1 H), 3.30-3 .16 (m, 1 H), 2.69-2.52 (m, 4 H), 2.25-2.09 (m, 2 H), 1.21 (td, J = 14.0, 11 .9 Hz, 1 H), 1.04 (d, J = 6.3 Hz, 3 H).

[00766] Compound 291 (4-amino-3,3-dimethyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]butanamide ): 4-[[(tert-butoxy)carbonyl]amino]-3,3-dimethylbutanoic acid and (3R,5S)-5-methyl- 1-(8-(trifluoromethyl)quinolin-5-yl)piperidin- 3-amine. HPLC: 95.1% purity, Retention Time = 1.09 min. EM: m/z = 423.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.3, 1.7 Hz, 1 H), 8.61 (dd, J = 8.6, 1.8 Hz, 1 H), 7.99 (d, J = 8.0 Hz, 1 H), 7.58 (dd, J = 8.6, 4.2 Hz, 1 H), 7.17 (d, J = 8 .0 Hz, 1 H), 4.23-4.16 (m, 1 H), 3.63-3.52 (m, 1 H), 3.35 (apparent d, J = 12.0 Hz, 1 H), 2.64 (s, 2 H), 2.52-2.38 (m, 2 H), 2.18 (s, 2 H), 2.13-2.04 (m, 2 H ), 1.29-0.96 (m, 10H).

[00767] Compound 476 ((S)-2-amino-3-hydroxy-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl ]-propionamide): From (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine and (S)-2-tert-butoxycarbonylamino-3- acid hydroxy-propionic. HPLC: > 99% purity, Retention Time = 2.69 min. EM: m/z = 397.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz , 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.81 (d, J = 7.7 Hz, 1 H), 7.67 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 1 H), 4.67 (t, J = 5.6 Hz, 1 H), 3.48 (dt, J = 10.2, 5.0 Hz, 2 H), 3.42 - 3.33 (m, 2 H), 3.17 (dd, J = 6.2, 4.9 Hz, 1 H), 2.42 (t, J = 11.4 Hz, 1 H), 2.14 - 1.93 (m, 2 H), 1.78 (s, 2 H), 1.16 (q, J = 12 .1 Hz, 1 H), 0.95 (d, J = 6.5 Hz, 3 H).

[00768] Compound 514 (3-amino-3-methyl-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-butyramide) : From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 3-tert-butoxycarbonylamino-3-methyl-butyric acid. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.54 (dd, J = 8.6, 1.8 Hz, 1 H), 8.21 (d, J = 7.5 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.68 (dd, J = 8.6, 4 .2 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 3.61 - 3.46 (m, 1 H), 2.47 - 2.34 (m, 2 H), 2.10 (s, 4 H), 1.68 (s, 2 H), 1.06 (s, 6 H), 0.96 (d, J = 6.5 Hz, 3 H). MS: m/z = 409 [M + H]+.Example 81: Synthesis of compound 294 (2-amino-2-cyclopropyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl )quinoxalin-5-yl]piperidin-3-yl]acetamide)

[00769] 2-Amino-2-cyclopropyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide: 2-amino- 2-Cyclopropyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide was prepared from 2-(1-methylpiperidin-3 -yl)acetic and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine using Method J and 6. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 55% gradient in 8 min; detector, UV 254 nm. 2-Amino-2-cyclopropyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide was obtained as yellow solid (30 mg , 38% for two steps).Compound 294: HPLC: 99.3% purity, Retention Time = 1.46 min. MS: m/z = 408.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ8.95- 8.88 (m, 2 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8 .3 Hz, 1 H), 4.26-4.20 (m, 2 H), 4.11 (dd, J = 12.3, 3.3 Hz, 1 H), 2.77-2.53 (m, 3 H), 2.18-2.05 (m, 2 H), 1.31-1.17 (m, 1 H), 1.11-0.96 (m, 4 H), 0 .64-0.44 (m, 3 H), 0.40-0.31 (m, 1 H).

[00770] The following compounds were synthesized in an analogous manner:

[00771] Compound 300 (2-(azetidin-3-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide ): 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3- the mine. HPLC: 91.9% purity, Retention Time = 5.29 min. MS: m/z = 408.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 1.8 Hz, 1 H), 8.96 (d, J = 1.8 Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.95 (s, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 4.21-4.05 (m , 2 H), 4.00-3.84 (m, 1 H), 3.63-3.40 (m, 4 H), 2.812.48 (m, 3 H), 2.39 (d, J = 7.7 Hz, 2 H), 1.99-1.94 (m, 2 H), 1.12 (td, J = 12.0, 12.0 Hz, 1 H), 0.92 (d , J = 6.3 Hz, 3 H).

[00772] Compound 301 (4-amino-3,3-dimethyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]butanamide ): 4-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 92.8% purity, Retention Time = 1.06 min. EM: m/z = 424.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (d, J = 7.3 Hz, 2 H), 8.05 (d, J =8.3 Hz, 1 H), 7.29 (d , J = 8.3 Hz, 1 H), 4.31-4.05 (m, 3 H), 2.78-2.46 (m, 4 H), 2.19 (s, 2 H), 2.13-2.10 (m, 2H), 1.19 (td, J = 12.2, 12.2Hz, 1H), 1.03 (d, J = 5.1Hz, 9H) . Example 82: Synthesis of compound 304 (2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3- yl]acetamide)

[00773] 2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl) quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide: 2 -(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide was prepared from acid 2-bromoacetic acid, tert-butyl azetidin-3-ylcarbamate, and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine using Method 20, 18, and 6 The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 30% to 60% gradient in 8 min; detector, UV 254 nm. 2-(3-Aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide was obtained as white solid (20 mg, 12% for 3 steps).

[00774] Compound 304: HPLC: 92.6% purity, Retention Time = 2.72 min. MS: m/z = 404.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.88 (dd, J = 4.3, 1.7 Hz, 1 H), 8.66-8.57 (m, 1 H), 8.007.86 ( m, 1 H), 7.85-7.51 (m, 2 H), 7.25 (d, J = 7.9 Hz, 1 H), 4.27-4.19 (m, 1 H) , 3.68-3.61 (m, 2 H), 3.62-3.49 (m, 2 H), 3.42-3.32 (m, 1 H), 3.14 (s, 2 H), 2.98-2.90 (m, 2 H), 2.58-2.38 (m, 2 H), 2.21-2.00 (m, 2 H), 1.18 (td , J = 12.0, 12.0 Hz, 1 H), 1.02 (d, J = 6.4 Hz, 3 H).

[00775] The following compounds were synthesized in an analogous manner:

[00776] Compound 361 (2-(3-aminoazetidin-1-yl)-N-((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-yl )acetamide): From (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine, 2-bromoacetic acid, and tert-butyl azetidin-3- illcarbamate. HPLC: 99.1% purity, Retention Time = 2.27 min. MS: m/z = 423.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (d, J = 1.7 Hz, 1 H), 8.97 (d, J = 1.6 Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 4, 12-3.92 (m, 3 H), 3.5-3.53 (m, 2 H), 3,413.39 (m, 1 H), 3.06-2.90 (m, 2 H), 2.84-2.64 (m, 3 H), 2.58-2.55 (m, 1 H), 1.92-1.88 (m, 2 H), 1.26-1.16 ( m, 1 H), 0.93 (d, J = 6.3 Hz, 3 H).

[00777] Compound 365 (2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl] acetamide): from 2-(azetidin-3-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide and polyformaldehyde. HPLC: 87.4% purity, Retention Time = 1.21 min. MS: m/z = 405.4 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92-8.82 (m, 2 H), 7.96 (d, J = 8.2 Hz, 1 H), 7,807.51 (m, 1 H ),7.33 (d, J = 8.1 Hz, 1 H), 4.28-4.05 (m, 2 H), 4.04-3.94 (m, 1 H), 3.82 -3.68 (m, 3 H), 3.25-3.12 (m, 4 H), 2.69-2.64 (m, 1 H), 2,532.49 (m, 1 H), 2 .09-2.05 (m, 2 H), 1.31-1.12 (m, 1 H), 1.01 (d, J = 6.4 Hz, 3 H).Example 83: Compound Synthesis 305 (2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]propanamide)

[00778] 2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl) quinolin-5-yl]-5-methylpiperidin-3-yl]propanamide: 2 -(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]propanamide was prepared from acid 2- (1-(tert-butoxycarbonyl) azetidin-3-yl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine using Method J and 6. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3), 37% to 39% gradient in 10 min; detector, UV 254 nm. 2-(3-Aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]propanamide was obtained as white solid (29 mg, 23% for two steps).

[00779] Compound 305: HPLC: 94.5% purity, Retention Time = 1.37 min. MS: m/z = 418.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1 H), 8.58 (d, J = 8.6 Hz, 1 H), 7 .95-7.43 (m, 3 H), 7.22 (d, J = 7.9 Hz, 1 H), 4.26-4.12 (m, 1 H), 3.61- 3. 42 (m, 4 H), 3.40-3.20 (m, 1 H), 2.91-2.74 (m, 3 H), 2.56-2.35 (m, 2 H), 2.16-1.96 (m, 2 H), 1.25-1.05 (m, 4 H), 1.00 (d,J = 6.4 Hz, 3 H).

[00780] The following compounds were synthesized in an analogous manner:

[00781] Compound 306 (2-amino-2-cyclopropyl-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide): of 2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 84.9% purity, Retention Time = 2.57 + 2.60 min. MS: m/z = 389.2 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.92 (d, J = 3.7Hz, 1 H), 8.54-8.50(m, 1 H), 7.99-7.56 (m, 2 H), 7.50-7.47 (m, 1 H), 7.19-6.98 (m, 2 H), 4.34-4.26 (m, 1 H), 3 .71-3.59 (m, 1 H), 3.32-3.28 (m, 1 H), 2,852.70 (m, 1 H), 2.42 (apparent q, J = 11.3 Hz , 2 H), 2.22-1.75 (m, 4 H), 1.13-0.92 (m, 5 H), 0.68-0.47 (m, 3 H), 0.32 -0.23 (m, 1 H).

[00782] Compound 312 (2-(azetidin-3-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide) : 2-(3,3-difluoroazetidin-1-yl)propanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 96.7% purity, Retention Time = 6.65 min. EM: m/z = 389.4 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.90 (dd, J = 4.3, 1.8 Hz, 1 H), 8.62 (dd, J = 8.7, 1.8 Hz, 1 H), 7.94 (d, J = 7.9 Hz, 1 H), 7.85-7.50 (m, 2 H), 7.26 (d, J = 7.9 Hz, 1 H) , 4.22 (d, J = 12.4 Hz, 1 H), 3.96-3.75 (m, 2 H), 3.65-3.45 (m, 3 H), 3.24- 3.05 (m, 2 H), 2.63-2.36 (m, 4 H), 2.20-2.08 (m, 2 H), 1.22-0.94 (m, 4 H ).

[00783] Compound 315 (4-amino-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): of 4-[[(tert-butoxy)carbonyl]amino]-3,3-dimethylbutanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine . HPLC: 95.7% purity, Retention Time = 5.17 min. MS: m/z = 405.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1 H), 8.59 (dd, J = 8.6, 1.7 Hz, 1 H), 7.947.45 (m, 3 H), 7.22 (d, J = 7.9 Hz, 1 H), 4.28-4.11 (m, 1 H), 3.55-3, 50 (m, 1 H), 3.40-3.20 (m, 1 H), 2.56 (s, 2 H), 2.53-2.33 (m, 2 H), 2.19- 2.02 (m, 4H), 1.18-1.07 (m, 1H), 0.98-0.88 (m, 9H).

[00784] Compound 324 (2-(azetidin-3-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]acetamide) : 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine. HPLC: 95.8% purity, Retention Time = 1.15 min. EM: m/z = 390.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 7.96 (d, J = 8.1 Hz, 1 H), 7.63 (t, J = 55.9 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 4.22-4.01 (m, 2 H), 3.94-3.90 (m, 2 H), 3.66-3.62 (m, 2 H), 3.23-3.09 (m, 1 H), 2.65-2.44 (m, 4 H), 2.10- 2.03 (m, 2 H), 1.13 (td, J = 12.4, 12.4 Hz, 1 H), 1.00 (d, J = 6.4 Hz, 3 H).

[00785] Compound 327 (4-amino-N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): of 4-[[(tert-butoxy)carbonyl]amino]-3,3-dimethylbutanoic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine . HPLC: 90.8% purity, Retention Time = 1.29 min. EM: m/z = 406.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.93-8.82 (m, 2 H), 7.96 (d, J = 8.1 Hz, 1 H), 7.63 (t, J = 56.0 Hz, 1 H), 7.33 (d, J = 8.2 Hz, 1 H), 4.23-3.95 (m, 3 H), 2.67-2.56 (m, 3 H), 2.50 (t,J = 11.4 Hz, 1 H), 2.19 (s, 2 H), 2.11-2.08 (m, 2 H), 1.21-1 .07 (m, 1H), 1.04-0.94 (m, 9H).Example 84: Synthesis of compound 330 (cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl] piperidin-3-amine)

[00786] cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl] piperidin-3-amine: cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl ]piperidin-3-amine was prepared from 5-bromo-8-(trifluoromethyl)quinoxaline and tert-butyl cis-5-cyclopropylpiperidin-3-ylcarbamate using Method R and 6. The crude product was purified by preparative HPLC under the following conditions : column, XBridge Prep C18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), retention at 36% gradient in 10 min; detector, UV 254 nm. cis-5-Cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine was obtained as yellow solid (20 mg, 6.5% for two steps).

[00787] Compound 330: HPLC: 96.7% purity, Retention Time = 1.62 min. MS: m/z = 337.2 [M + H]+. 1H NMR (400 MHz,DMSO-d6, ppm) δ 9.01 (d, J = 1.8 Hz, 1 H), 8.96 (d, J = 1.7 Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.28-7.16 (m, 1 H), 4.18-4.07 (m, 2 H), 2,972.81 (m, 1 H ), 2.77-2.61 (m, 1 H), 2.60-2.57 (m, 2 H), 2.50-2.20 (m, 1 H), 2.10-2, 03 (m, 1 H), 1.15-0.99 (m, 2 H), 0.63-0.51 (m, 1 H), 0.48-0.34 (m, 2 H), 0.24-0.11 (m, 2 H).

[00788] The following compounds were synthesized in an analogous manner:

[00789] Compound 331 (cis-5-cyclopropyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-amine): of 5-bromo-8-(trifluoromethyl) quinoline and tert-butyl cis- 5-cyclopropylpiperidin-3-ylcarbamate. HPLC: 93.2% purity, Retention Time = 2.71 min. EM: m/z = 336.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.2, 1.8 Hz, 1 H), 8.50 (dd, J = 8.7, 1.8 Hz, 1 H), 8.01 (d, J = 8.1 Hz, 1 H), 7.55 (dd, J = 8.6, 4.2 Hz, 1 H), 7.20 (d, J = 8 .0 Hz, 1 H), 3.55-3.38 (m, 2 H), 3,203.03 (m, 1 H), 2.63-2.44 (m, 2 H), 2.25 ( d, J = 10.9 Hz, 1 H), 1.28-1.03 (m, 2 H), 0.66-0.34 (m, 3 H), 0.28-0.09 (m , 2 H).

[00790] Compound 333 (cis-5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-amine): of 5-bromo-8-fluoroquinoline and tert-butyl cis-5-cyclopropylpiperidin-3- illcarbamate. HPLC: 99.3% purity, Retention Time = 1.20 min. MS: m/z = 286.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.86 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dt, J = 8.6, 1.6 Hz, 1 H), 7.61 (dd, J = 8.6, 4.3 Hz, 1 H), 7.42 (dd, J = 10.7, 8.4 Hz, 1 H), 7.22 (dd , J = 8.4, 4.2 Hz, 1 H), 3.40-3.25 (m, 2 H), 3.22-3.08 (m, 1 H), 2.62-2, 42 (m, 2 H), 2.26 (d, J = 10.7 Hz, 1 H), 1.31-1.07 (m, 2 H), 0.67-0.37 (m, 3 H), 0.29-0.10 (m, 2 H).

[00791] Compound 334 (cis-5-cyclopropyl-1-(8-methoxyquinolin-5-yl)piperidin-3-amine): of 5-bromo-8-fluoroquinoline and tert-butyl cis-5-cyclopropylpiperidin-3- illcarbamate. HPLC: 98.0% purity, Retention Time = 1.11 min. EM: m/z = 298.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ8.80 (dd, J = 4.3, 1.7 Hz, 1 H), 8.57 (dd, J = 8.6, 1.7 Hz, 1 H ), 7.57 (dd, J = 8.5, 4.3 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.15 (d, J = 8, 3 Hz, 1 H), 4.05 (s, 3 H), 3.40-3.10 (m, 3 H), 2.60-2.40 (m, 2 H), 2.27 (d , J = 10.8 Hz, 1 H), 1.28-1.07 (m, 2 H), 0.71-0.56 (m, 1 H), 0.44-0.48 (m, 2 H), 0.18-0.23 (m, 2 H). Example 85: Synthesis of compound 332 (cis-5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin-3-amine)

[00792] tert-Butyl cis-N-[5-cyclopropylpiperidin-3-yl]carbamate: tert-butyl cis-N-[5-cyclopropyl-1-(quinolin-5-yl)piperidin-3-yl]carbamate was prepared from 5-bromoquinoline and tert-butyl cis-5-cyclopropylpiperidin-3-ylcarbamate using Method R. The crude product was purified by flash chromatography eluting with EtOAc in hexane to yield tert-butyl cis-N-[5-methyl-1 -[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate as yellow solid (400 mg, 48%).Method 22

[00793] tert-Butyl cis-N-[5-cyclopropyl-1-(8-iodoquinolin-5-yl) piperidin-3-yl]carbamate: A solution of tert-butyl cis-N-[5-cyclopropyl- 1-(quinolin-5-yl)piperidin-3-yl]carbamate (400 mg, 1.03 mmol) in DMF (10 mL) was added NIS (367 mg, 1.55 mmol) at room temperature. The resulting solution was then stirred for 16 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane to yield tert-butyl cis-N-[5-cyclopropyl-1-(8-iodoquinolin-5-yl)piperidin-3-yl ]carbamate as yellow solid (350 mg, 69%). MS: m/z = 494.2 [M + H]+. Method 23

[00794] tert-Butyl cis-N-[5-cyclopropyl-1-(8-ethenylquinolin-5-yl) piperidin-3-yl]carbamate: A solution of cis-N-[5-cyclopropyl-1-( 8- iodoquinolin-5-yl)piperidin-3-yl]carbamate (350 mg, 0.67 mmol) in toluene (40 mL) were added Pd(PPh3)4 (82 mg, 0.07 mmol) and tributyl(ethenyl )stannan (337 mg, 1.01 mmol) at room temperature. The reaction mixture was then stirred for 3 hours at 120°C. After cooling to room temperature, the reaction mixture was diluted with water (30 mL). The resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane to give cis-N-[5-cyclopropyl-1-(8-ethenylquinolin-5-yl)piperidin-3-yl]carbamate as a yellow solid (200 mg, 75%). EM: m/z = 394.2 [M + H]+.Method 24

[00795] tert-Butyl cis-N-[5-cyclopropyl-1-(8-formylquinolin-5-yl) piperidin-3-yl]carbamate: A solution of cis-N-[5-cyclopropyl-1-( 8-ethenylquinolin-5-yl)piperidin-3-yl]carbamate (200 mg, 0.48 mmol) in THF (10 mL) were added OsO4 (13 mg, 0.05 mmol), NaIO4 (435 mg, 1. 93 mmol), and water (2.3 mL) at room temperature. The reaction mixture was stirred for two hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of saturated Na2S2O3 solution (10 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. This resulted in tert-butyl cis-N-[5-cyclopropyl-1-(8-formylquinolin-5-yl)piperidin-3-yl]carbamate as a yellow solid (150 mg, 79%). EM: m/z = 396.2 [M + H]+.

[00796] tert-Butyl cis-N-[5-cyclopropyl-1-[8-(difluoromethyl) quinolin-5-yl]piperidin-3-yl]carbamate: A solution of tert-butyl cis-N-[5 -cyclopropyl-1-(8-formylquinolin-5-yl)piperidin-3-yl]carbamate (150 mg, 0.36 mmol) in DCM (8 mL) was added BAST (252 mg, 1.08 mmol) at temperature environment. The resulting solution was stirred for two hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of saturated sodium bicarbonate solution (30 mL). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane to give tert-butyl cis-N-[5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin- 3-yl]carbamate as a yellow solid (80 mg, 53%). MS: m/z = 418.2 [M + H]+.

[00797] cis-5-Cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl] piperidin-3-amine: cis-5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl ]piperidin-3-amine was prepared from tert-butyl cis-N-[5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate using Method 6. The crude product was purified by flash chromatography eluting with MeOH in DCM (0% to 10% gradient). cis-5-Cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin-3-amine was obtained as light yellow solid (14 mg, 40%).

[00798] Compound 332: HPLC: 99.3% purity, Retention Time = 1.29 min. EM: m/z = 318.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.51 (dd, J = 8.6, 1.8 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.88-7.48 (m, 2 H), 7.28 (d, J = 7.9 Hz, 1 H) , 3.67-3.38 (m, 2 H), 3.28-3.07 (m, 1 H), 2.61 (t, J = 10.9 Hz, 1 H), 2.52 ( t, J = 10.8 Hz, 1 H), 2.37-2.20 (m, 1 H), 1.29-1.10 (m, 2 H), 0.47-0.60 (m , 1 H), 0.55-0.36 (m, 2 H), 0.23-0.18 (m, 2 H). Example 86: Synthesis of compound 335 cis-(N--5-cyclopropyl- 1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide)

[00799] Cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide: cis-N-[5 -cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide was prepared from 2-(morpholin-4-yl)acetic acid and cis -5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm , 19mm x 150mm; mobile phase, acetonitrile in water (with 0.0.5% NH3.H2O), 46% to 52% gradient in 8 min; detector, UV 254 nm. Cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide was obtained as light yellow solid (11 mg, 13%).

[00800] Compound 335: HPLC: 97.2% purity, Retention Time = 0.90 min. EM: m/z = 464.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.95-8.85 (m, 2 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.29 (d, J = 8.3Hz, 1H), 4.19-4.11 (m,3H), 3.88-3.62 (m, 4H), 3.22-2.98 (m, 2H), 2.94-2.74 (m, 2 H), 2.69-2.42 (m, 4 H), 2.22 (d, J = 12.5 Hz, 1 H), 1.48 (d , J = 11.7 Hz, 1 H), 1.40-1.13 (m, 1 H), 0.67-0.64 (m, 1 H), 0.52-0.49 (m, 2 H), 0.24 (dt, J = 6.7, 2.6 Hz, 2 H).

[00801] The following compounds were synthesized in an analogous manner:

[00802] Compound 336 (cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide): acid 2-(morpholin-4-yl)acetic acid and cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine. HPLC: 99.3% purity, Retention Time = 1.91 min. EM: m/z = 463.2 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.3, 1.7 Hz, 1 H), 8.60 (dt, J = 8.6, 1.6 Hz, 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.26-7.19 (m , 1 H), 4,254.17 (m, 1 H), 3.71 (t, J = 4.7 Hz, 4 H), 3.62-3.53 (m, 1 H), 3.52- 3.43 (m, 1 H), 3.02 (d, J = 1.3 Hz, 2 H), 2.70 (t, J = 11.3 Hz, 1 H), 2.65-2, 47 (m, 5 H), 2.22 (d, J = 12.3 Hz, 1 H), 1.41 (q, J = 12.0 Hz, 1 H), 1.26 (q, J = 10.5Hz, 1H), 0.67-0.60 (m, 1H), 0.51-0.48 (m, 2H), 0.30-0.15 (m, 2H) .

[00803] Compound 338 (cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide): of 2-(4-methylpiperazin-1-yl)acetic acid and cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 96.7% purity, Retention Time = 3.28 min. MS: m/z = 476.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.92 (dd, J = 4.3, 1.7 Hz, 1 H), 8.61 (dd, J = 8.6, 1.7 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (d, J = 8 .0 Hz, 1 H), 4.27-4.14 (m, 1 H), 3.63-3.54 (m, 1 H), 3.47 (d, J = 11.2 Hz, 1 H), 3.04 (d, J = 1.6 Hz, 2 H), 2.75-2.40 (m, 10H), 2.322.20 (m, 4 H), 1.40 (q, J = 11.9 Hz, 1 H), 1.27 (t, J = 10.5 Hz, 1 H), 0.710.58 (m, 1 H), 0.55-0.41 (m, 2 H) , 0.30-0.16 (m, 2 H).Example 87: Synthesis of compound 337 (cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3- yl]-N-methyl-2-(morpholin-4-yl)acetamide)

[00804] Cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl] piperidin-3-yl]-N-methyl-2-(morpholin-4-yl)acetamide: cis- N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-N-methyl-2-(morpholin-4-yl)acetamide was prepared from MeI and cis-N -(5-cyclopropyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-yl)-2-morpholinoacetamide using Method S. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1% NH3.H2O), 52% to 59% gradient in 8 min; detector, UV 254 nm. Cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-N-methyl-2-(morpholin-4-yl)acetamide was obtained as light yellow solid (20 mg, 23%).

[00805] Compound 337: HPLC: 93.0% purity, Retention Time = 2.58 min. MS: m/z = 477.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.94-8.90 (m, 1 H), 8.61-8.55 (m, 1 H), 8.03 (dd, J = 10.8 , 8.0 Hz, 1 H), 7.62-7.57 (m, 1 H), 7.27 (dd, J = 16.4, 8.1 Hz, 1 H), 4.81 (d , J = 12.2 Hz, 1 H), 3.69 (t, J = 4.7 Hz, 2 H), 3.52-3.45 (m, 3 H), 3.40-3.10 (m, 3 H), 3.05 (s, 2 H), 2.90-2.80 (m, 2 H), 2.70-2.40 (m, 5 H), 2.20- 2 .00 (m, 1 H), 1.70 (dt, J = 24.3, 12.0 Hz, 1 H), 1.42-1.22 (m, 1 H), 0.73-0, 59 (m, 1 H), 0.57-0.38 (m, 2 H), 0.33-0.09 (m, 2 H). Example 88: Synthesis of compound 339 and compound 340 ((3R, 5S)-1-(8-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-amine and (3S,5R)-1-(8-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-amine)

[00806] (3R,5S)-1-(8-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-amine and (3S,5R)-1-(8-fluoroquinoxalin-5-yl)-5-methylpiperidin -3- amine: cis-1-(8-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-amine was prepared from 2-bromo-5-fluorobenzenamine, oxalaldehyde, and tert-butyl cis-5-methylpiperidin-3- ylcarbamate using Method 1, 2, 3, 4, 5, R, and 6. The crude product was first purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 19 x 150 mm 10 µm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3+0.1% NH3.H2O), 5% to 47% gradient in 10 min; detector, UV 254 nm. Then, the two enantiomeric isomers were obtained by separation on chiral preparative HPLC under the following conditions: column, CHIRALPAK IE, 2 x 25 cm, 5 µm; mobile phase, EtOH in hexane, 30% isocratic in 25 min; detector, UV 254/220 nm.Isomer 1: (35 mg, 0.13%, yellow solid, for 7 steps) HPLC: 95.2% purity, Retention Time = 2.57 min. EM: m/z = 261.0 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.05-8.93 (m, 2 H), 7.57 (dd, J = 10.2, 8.7 Hz, 1 H), 7, 15 (dd, J = 8.7, 4.9 Hz, 1 H), 3.83-3.64 (m, 2 H), 3.40-3.20 (m, 2 H), 3.03 -2.87 (m, 1 H), 2.31-2.21 (m, 2 H), 1.97-1.87 (m, 2 H), 0.98-0.72 (m, 4 H).Isomer 2: (33 mg, 0.12%, yellow solid, for 7 steps) HPLC: 97.3% purity, Retention Time = 2.58 min. MS: m/z = 261.0 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.05-8.93 (m, 2 H), 7.57 (dd, J = 10.2, 8.7 Hz, 1 H), 7, 15 (dd, J = 8.7, 4.9 Hz, 1 H), 3.83-3.64 (m, 2 H), 3.40-3.20 (m, 2 H), 3.03 -2.87 (m, 1 H), 2.31-2.21 (m, 2 H), 1.97-1.87 (m, 2 H), 0.98-0.72 (m, 4 H).Example 89: Synthesis of compound 341 ((3R,5S)-1-(8-fluoroquinolin-5-yl)-5-methylpiperidin-3-amine)

[00807] (3R,5S)-1-(8-fluoroquinolin-5-yl)-5-methylpiperidin-3-amine: (3R,5S)-1-(8-fluoroquinolin-5-yl)-5-methylpiperidin -3-amine was obtained in 35% production during two steps of 5-bromo-8-fluoroquinoline and tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate, using Method V and 6 .

[00808] Compound 341: HPLC: 97.7% purity, Retention Time = 1.45 min. EM: m/z = 260 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.97 (dd, J = 4.2, 1.6 Hz, 1 H), 8.53 (d, J = 8.5 Hz, 1 H) , 8.19 (s, 3 H), 7.66 (dd, J = 8.6, 4.2 Hz, 1 H), 7.52 (dd, J = 10.8, 8.3 Hz, 1 H), 7.19 (dd, J = 8.4, 4.2 Hz, 1 H), 3.61 - 3.39 (m, 2 H), 3.16 (d, J = 10.0 Hz , 1 H), 2.62 (t, J = 10.7 Hz, 1 H), 2.36 (t, J = 11.2 Hz, 1 H), 2.16 (d, J = 12.3 Hz, 1 H), 2.05 (ddd, J = 16.8, 8.9, 5.2 Hz, 1 H), 1.15 (q, J = 11.7 Hz, 1 H), 0, 96 (d, J = 6.6 Hz, 3 H).

[00809] The following compounds were synthesized in an analogous manner:

[00810] Compound 462 ((3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride): From 5-chloro-8-methyl- quinoline and tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate. HPLC: > 99% purity, Retention Time = 1.37 min. EM: m/z = 256 [M + H]+. 1H NMR (400 MHz, deuterium oxide, ppm) δ 9.35 (d, J = 8.9 Hz, 1 H), 9.09 (dt, J = 5.4, 1.4 Hz, 1 H) , 8.08 (ddd, J = 8.6, 5.5, 1.1 Hz, 1 H), 7.96 (d, J = 8.1 Hz, 1 H), 7.55 (d, J = 7.9 Hz, 1 H), 3.89 - 3.74 (m, 1 H), 3.66 (d, J = 11.3 Hz, 1 H), 3.39 (d, J = 11 .0 Hz, 1 H), 2.98 (t, J = 10.8 Hz, 1 H), 2.80 (s, 3 H), 2.54 (t, J = 11.5 Hz, 1 H ), 2.37 (d, J = 12.7 Hz, 1 H), 2.33 - 2.17 (m, 1 H), 1.33 (q, J = 12.0 Hz, 1 H), 1.05 (d, J = 6.7 Hz, 3 H).

[00811] Compound 586 ((3R,5S)-1-(8-methyl-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-ylamine hydrochloride): From 5-bromo-8-methylquinoline and ((3R,5S)-5-trifluoromethyl-piperidin-3-yl)-carbamic acid tert-butyl ester. HPLC: > 99% purity, Retention Time = 1.60 min. MS: m/z = 310.30 [M + H]+. 1H NMR (400 MHz, Deuterium oxide, ppm) δ 9.34 - 9.29 (m, 1 H), 9.03 (dd, J = 5.5, 1.6 Hz, 1 H), 8, 04 (ddt, J = 8.6, 5.5, 1.4 Hz, 1 H), 7.91 (dd, J = 7.9, 1.1 Hz, 1 H), 7.56 (d, J = 7.9 Hz, 1 H), 3.82 (td, J = 11.3, 5.7 Hz, 1 H), 3.71 (s, 1 H), 3.63 - 3.56 ( m, 1 H), 3.56 - 3.48 (m, 1 H), 3.10 (ddp, J = 11.9, 7.7, 3.9 Hz, 1 H), 2.97 (dt , J = 17.3, 11.2 Hz, 2 H), 2.73 (d, J = 1.0 Hz, 3 H), 2.54 (d, J = 12.2 Hz, 1 H), 1.71 (q, J = 12.2 Hz, 1 H). Example 90: Synthesis of compound 342 (8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-7-fluoroquinoxaline -5-carbonitrile)

[00812] N-(4-fluoro-2-methylphenyl)acetamide: 4-fluoro-2-methylaniline (3.80 g, 30.37 mmol) was added to 100 mL of acetyl anhydride at room temperature. The resulting solution was stirred for 3 hours at room temperature. When the reaction was carried out, it was stopped abruptly by the addition of water (100 mL) and the resulting mixture was extracted with dichloromethane (300 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield N-(4-fluoro-2-methylphenyl)acetamide as a white solid (2.70 g, 50%). EM: m/z = 168.2 [M + H]+.Method 25

[00813] N-(4-fluoro-2-methyl-6-nitrophenyl)acetamide: At 0°C, to a solution of N-(4-fluoro-2-methylphenyl)acetamide (2.70 g, 16.15 mmols) in acetic anhydride (60 mL), HNO3 (65% in water, 3.2 mL, 46.22 mmols) was added dropwise over a period of 20 minutes. The resulting mixture was then stirred for 15 hours at room temperature. After the reaction was carried out, it was stopped abruptly by the addition of ice water (100 mL) and the pH value of the resulting mixture was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (300 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 15% gradient) to give N-(4-fluoro-2-methyl-6-nitrophenyl)acetamide as a brown solid. (1.35 g, 39%). MS: m/z = 213.1 [M + H]+.

[00814] 4-Fluoro-2-methyl-6-nitroaniline: 4-fluoro-2-methyl-6-nitroaniline was prepared from N-(4-fluoro-2-methyl-6-nitrophenyl)acetamide using Method 3. Crude product was purified by flash chromatography eluting with EtOAc in hexane (0% to 17% gradient) to yield 4-fluoro-2-methyl-6-nitroaniline as yellow solid (730 mg, 64%). EM: m/z = 171.1 [M + H]+.Method 26

[00815] 5-Fluoro-3-methylbenzene-1,2-diamine: To a solution of 4-fluoro-2-methyl-6-nitroaniline (730 mg, 4.29 mmols) in methanol (10 mL) was added nickel Raney (95 mg, 11.09 mmols) at room temperature under a nitrogen atmosphere. The reaction flask was vacuum treated and purged with hydrogen. The reaction mixture was then stirred for 30 minutes at room temperature under a hydrogen atmosphere with a hydrogen balloon. When the reaction was done, the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 35% gradient) to give 5-fluoro-3-methylbenzene-1,2-diamine as a yellow solid (631 mg , 97%). MS: m/z = 141.1 [M + H]+.

[00816] 7-Fluoro-5-methylquinoxaline: 7-fluoro-5-methylquinoxaline was prepared from 5-fluoro-3-methylbenzene-1,2-diamine and oxalaldehyde using Method 5. The crude product was purified by flash chromatography eluting with EtOAc in hexane (0% to 25% gradient) to yield 7-fluoro-5-methylquinoxaline as yellow solid (540 mg, 62%). EM: m/z = 163.1 [M + H]+.Method 27

[00817] 5-Bromo-6-fluoro-8-methylquinoxaline: To a solution of 7-fluoro-5-methylquinoxaline (540 mg, 3.33 mmols) in acetonitrile (10 mL) was added NBS (1425 mg, 8. 01 mmols) slowly at room temperature. The resulting solution was stirred for 15 hours at 80°C. When the reaction was done, it was stopped abruptly by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 10% gradient) to give 5-bromo-6-fluoro-8-methylquinoxaline as a white solid (495 mg, 62 %). MS: m/z = 240.8 [M + H]+.Method 28

[00818] 5-Bromo-6-fluoro-8-methylquinoxaline: at room temperature, to a solution of 5-bromo-6-fluoro-8-methylquinoxaline (440 mg, 1.83 mmol) in CCl4 was added NBS (4275 mg, 24.02 mmols) and AIBN (67 mg, 0.40 mmol) slowly in sequence. The resulting solution was stirred for 15 hours at 80°C. When the reaction was done, it was stopped abruptly by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (60 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 15% gradient) to give 5-bromo-8-(dibromomethyl)-6-fluoroquinoxaline as a yellow solid (450 mg , 62%). EM: m/z = 400.5 [M + H]+.Method 29

[00819] 8-Bromo-7-fluoroquinoxaline-5-carbonitrile: To a solution of 5-bromo-8-(dibromomethyl)-6-fluoroquinoxaline (450 mg, 1.13 mmol) in HCOOH (10 mL) formate was added sodium (404 mg, 5.94 mmols), NH2OH.HCl (165 mg, 2.38 mmols), and water (3 mL) at room temperature. The resulting mixture was stirred for 15 hours at 85°C. When the reaction was done, it was stopped abruptly by adding water (50 mL). The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 17% gradient) to give 8-bromo-7-fluoroquinoxaline-5-carbonitrile as a white solid (240 mg, 84 %). MS: m/z = 253.8 [M + H]+.

[00820] 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-7-fluoroquinoxaline-5-carbonitrile: 8-[(3R,5S)-3-amino-5- methylpiperidin-1-yl]-7-fluoroquinoxaline-5-carbonitrile was prepared from 8-bromo-7-fluoroquinoxaline-5-carbonitrile and tert-butyl(3R,5S)-5-methylpiperidin-3-ylcarbamate using Method R and 6 The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmols/L NH4HCO3 and 0.1% NH3.H2O), 5% to 65% gradient in 8 min; detector, UV 254 nm. 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-7-fluoroquinoxaline-5-carbonitrile was obtained as yellow solid (55 mg, 48% for two steps).

[00821] Compound 342: HPLC: 99.2% purity, Retention Time = 1.08 min. MS: m/z = 286.3 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.7 Hz, 1 H), 8.88 (d, J = 1.7 Hz, 1 H), 7.88 (d, J = 12.2 Hz, 1 H), 4.05 (d, J = 12.0 Hz, 1 H), 3.76 (d, J = 12.6 Hz, 1 H), 3, 49-3.32 (m, 1 H), 3.1-3.04 (m, 1 H), 3.02-2.90 (m, 1 H), 2,281.92 (m, 2 H), 1.21-1.16 (m, 1 H), 1.00 (d, J = 6.6 Hz, 3 H).Example 91: Synthesis of compound 343 (N-[(3R,5S)-1- (8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide) Method 30

[00822] N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide: To a solution of 8-[ (3R,5S)-3-amino-5-methylpiperidin-1-yl]-7-fluoroquinoxaline-5-carbonitrile (50 mg, 0.17 mmol) in DMF (3 mL) was added 3,3-dimethylbutanoic acid ( 48 mg, 0.42 mmol), HOBT (29 mg, 0.22 mmol), EDCI (51 mg, 0.27 mmol) and DIEA (107 mg, 0.83 mmol) at room temperature. The resulting solution was stirred for two hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (5 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1% NH3.H2O), 45% to 67% gradient in 7 min; detector, UV 254 nm. N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide was obtained as a yellow solid (35 mg, 52% ).

[00823] Compound 343: HPLC: 99.5% purity, Retention Time = 1.85 min. MS: m/z = 384.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.09-8.95 (m, 2 H), 8.43 (d, J = 12.9 Hz, 1 H), 7.73 (d, J = 7.7 Hz, 1 H), 3.72-3.93 (m,3H), 3.03-2.96 (m, 1 H), 2.87-2.78 (m 1 H) , 1.97-1.94 (m, 4H),1.13-0.89 (m, 13H).Example 92: Synthesis of compound 344 (7-fluoro-8-[(3R,5S)-3 -[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile)

[00824] 7-Fluoro-8-[(3R,5S)-3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile: 7-fluoro-8-[(3R ,5S)-3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidin-1- yl]-7-fluoroquinoxaline-5-carbonitrile and 1-bromo-2-methoxyethane using Method M. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm ; mobile phase, acetonitrile in water (with 10 mmols/L NH4HCO3 and 0.1% NH3.H2O), 42% to 43% gradient in 7 min; detector, UV 254 nm. 7-Fluoro-8-[(3R,5S)-3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile was obtained as yellow oil (13 mg, 22%).

[00825] Compound 344: HPLC: 98.6% purity, Retention Time = 1.39 min. MS: m/z = 344.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.85 (m, 2 H), 8.10 (d, J = 12.7 Hz, 1 H), 4.16-4.11 ( m, 1 H), 3.86-3.76 (m, 1 H), 3.61-3.49 (m, 2 H), 3.38 (s, 3 H), 3.14-2, 83 (m, 5 H), 2.18 (d, J = 12.4 Hz, 1 H), 2.01-1.88 (m, 1 H), 1.13-0.96 (m, 4 H).Example 93: Synthesis of compound 345 and compound 346 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin -3-yl]-3,3,3-trifluoropropanamide and (2S)-2-amino-N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin -3-yl]- 3,3,3-trifluoropropanamide)

[00826] (2R)-2-amino-N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3,3 -trifluoropropanamide and (2S)-2-amino- N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]- 3,3,3 -trifluoropropanamide: cis-2-amino-N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3,3-trifluoropropanamide was prepared from 2-amino-3,3,3-trifluoropropanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-7-fluoroquinoxaline-5-carbonitrile using Method 30. Crude product was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 19 x 150 mm 10 µm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1% NH3.H2O), 40% to 45% gradient in 10 min; detector, UV 254 nm. Two diastereoisomers were separated and obtained. Isomer 1: (34 mg, 16%, yellow solid) HPLC: 97.1% purity, Retention Time = 1.04 min. EM: m/z = 411.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.05-8.95 (m, 2 H), 8.42 (d, J = 12.8 Hz, 1 H), 8.30 (d, J = 7.7 Hz, 1 H), 4.10-3.70 (m, 4 H), 3.11-2.95 (m, 1 H), 2,942.78 (m, 1 H), 2 .38-2.22 (m, 2 H), 2.07-1.91 (m, 2 H), 1.26-1.10 (m, 1 H), 0.92 (d, J = 6 .2 Hz, 3 H).Isomer 2: (34 mg, 16%, yellow solid) HPLC: 96.4% purity, Retention Time = 2.16 min. MS: m/z = 411.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.07-8.97 (m, 2 H), 8.43 (d, J = 12.8 Hz, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 4.05-3.80 (m, 3 H), 3.74 (d, J = 12.8 Hz, 1 H), 3.12-2.96 ( m, 1 H), 2.94-2.78 (m, 1 H), 2.38-2.20 (m, 2 H), 2.06-1.92 (m, 2 H), 1, 22-1.08 (m, 1 H), 0.92 (d, J = 6.3 Hz, 3 H). Example 94: Synthesis of compound 347 (N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(dimethylamino) acetamide)

[00827] N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpi-peridin-3-yl]-2-(dimethylamino)acetamide: N-[( 3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(dimethylamino)acetamide was prepared from 8-[(3R,5S)-3- amino-5-methylpiperidin-1-yl]-7-fluoroquinoxaline-5-carbonitrile and 2-(dimethylamino)acetic acid using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 um, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmols/L NH4HCO3 and 0.1% NH3.H2O), 42% to 43% gradient in 7 min; detector, UV 254 nm. N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(dimethylamino)acetamide was obtained as a yellow solid (23 mg, 37 %).

[00828] Compound 347: HPLC: 97.5% purity, Retention Time = 0.91 min. MS: m/z = 371.1 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.11-8.95 (m, 2 H), 8.41 (d, J = 12.9 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 4.06-3.92 (m, 1 H), 3.83-3.67 (m, 2 H), 3.20-3.04 (m, 1 H), 2.95-2.76 (m, 3 H), 2.19 (s, 6 H), 2.00-1.84 (m, 2 H), 1.32-1.16 (m , 1 H), 0.91 (d, J = 6.3 Hz, 3 H).

[00829] The following compounds were synthesized in an analogous manner:

[00830] Compound 587 (2-(1-methyl-piperidin-4-yl)-N-[(3R,5S)-1-(8-methyl-quinolin-5-yl)-5-trifluoromethyl-piperidin-3 -yl]-acetamide): From (3R,5S)-1-(8-methyl-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-ylamine hydrochloride and (1-methyl-piperidin- 4-yl)-acetic. HPLC: 99% purity, Retention Time = 1.90 min. MS: m/z = 449.30 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.93 (dd, J = 4.1, 1.7 Hz, 1 H), 8.53 (dd, J = 8.5, 1.8 Hz , 1 H), 7.95 (d, J = 7.5 Hz, 1 H), 7.57 (dd, J = 8.5, 4.1 Hz, 1 H), 7.54 (dd, J = 7.6, 1.1 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 4.13 (s, 1 H), 3.13 (d, J = 11 .6 Hz, 2 H), 2.76 (t, J = 11.4 Hz, 2 H), 2.69 (dd, J = 7.4, 3.6 Hz, 2 H), 2.46 ( d, J = 10.9 Hz, 1 H), 2.16 (d, J = 12.0 Hz, 1 H), 2.12 (s, 3 H), 1.99 (d, J = 6, 9 Hz, 2 H), 1.85 - 1.77 (m, 2 H), 1.63 - 1.49 (m, 3 H), 1.44 (q, J = 12.2 Hz, 1 H ), 1.15 (dq, J = 9.1, 5.9, 4.7 Hz, 2 H).

[00831] Compound 588 (3-Hydroxy-3-methyl-N-[(3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-yl]-butyramide) : From (3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 3-hydroxy-3-methyl-butyric acid. HPLC: 98% purity, RT= 2.06 min. MS: m/z = 356.30 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (dd, J = 4.1, 1.8 Hz, 1 H), 8.47 (dd, J = 8.5, 1.8 Hz , 1 H), 7.85 (d, J = 7.7 Hz, 1 H), 7.55 (dd, J = 8.5, 4.1 Hz, 1 H), 7.51 (dd, J = 7.6, 1.1 Hz, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 4.77 (s, 1 H), 3.16 (dd, J = 10 .9, 2.9 Hz, 1 H), 2.65 (d, J = 0.9 Hz, 3 H), 2.38 (t, J = 10.7 Hz, 1 H), 2.30 ( t, J = 11.1 Hz, 1 H), 2.20 (s, 2 H), 2.04 (s, 1 H), 1.99 (d, J = 13.3 Hz, 1 H), 1.13 (d, J = 1.2 Hz, 6 H), 1.04 (q, J = 11.9 Hz, 1 H), 0.94 (d, J = 6.4 Hz, 3 H) .

[00832] Compound 589 (2-Cyclopropyl-2-hydroxy-N-[(3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-yl]-acetamide) : From (3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and cyclopropylhydroxyacetic acid. HPLC: > 99% purity, RT= 2.09 min. MS: m/z = 354.30 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (ddd, J = 4.2, 1.8, 0.8 Hz, 1 H), 8.48 (ddd, J = 8.5, 2.7, 1.8 Hz, 1 H), 7.59 - 7.48 (m, 2 H), 7.08 (dd, J = 7.6, 4.1 Hz, 1 H), 5, 28 (s, 1 H), 4.07 (s, 0H), 3.55 - 3.48 (m, 1 H), 3.28 (d, J = 11.0 Hz, 1 H), 3, 16 (d, J = 10.0 Hz, 1 H), 2.65 (t, J = 0.9 Hz, 2 H), 2.47 (dd, J = 10.7, 2.1 Hz, 1 H), 2.31 (t, J = 11.1 Hz, 1 H), 1.95 (d, J = 12.6 Hz, 1 H), 1.24 - 1.10 (m, 1 H) , 1.11 - 0.91 (m, 3 H), 0.43 - 0.23 (m, 3 H).

[00833] Compound 590 (N-[(3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-yl]-2-(1-methyl-piperidin-4 -yl)-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and (1-methyl-piperidin- 4-yl)-acetic. HPLC: > 99% purity, RT= 1.71 min. MS: m/z = 395.40 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (dd, J = 4.1, 1.8 Hz, 1 H), 8.47 (dd, J = 8.5, 1.8 Hz , 1 H),7.79 (d, J = 7.6 Hz, 1 H), 7.54 (dd, J = 8.5, 4.1 Hz, 1 H), 7.51 (dd, J =7.5, 1.1 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 3.15 (d, J = 10.6 Hz, 1 H),2, 68 (d, J = 3.3 Hz, 2 H), 2.64 (d, J = 1.0 Hz, 3 H), 2.32 (dt, J = 18.2,10.9 Hz, 2 H), 2.10 (s, 3 H), 1.97 (d, J = 6.8 Hz, 2 H), 1.94 (s, 1 H), 1.82 - 1.72 (m, 2 H), 1.62 - 1.48 (m, 3 H), 1.13 (dd, J = 10.2, 6.1 Hz, 2 H), 1.03 (q, J = 12.1 Hz, 1 H), 0.93 (d, J = 6.5 Hz, 3 H).

[00834] Compound 591 (N-[(3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-yl]-2-(1-methyl-pyrrolidin-3 -yl)-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and (1-methyl-pyrrolidin- 3-yl)-acetic. HPLC: > 99% purity, RT= 1.65 min. MS: m/z = 381.40 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (dd, J = 4.1, 1.8 Hz, 1 H), 8.47 (dd, J = 8.5, 1.8 Hz , 1 H), 7.82 (d, J = 7.6 Hz, 1 H), 7.55 (dd, J = 8.5, 4.1 Hz, 1 H), 7.51 (dd, J = 7.6, 1.2 Hz, 1 H), 7.07 (dd, J = 7.7, 1.4 Hz, 1 H), 4.02 (s, 1 H), 3.16 (d , J = 11.4 Hz, 2 H), 2.64 (d, J = 0.9 Hz, 3 H), 2.40 (ddd, J = 9.1, 6.3, 2.7 Hz, 4 H), 2.36 - 2.25 (m, 3 H), 2.20 (d, J = 3.6 Hz, 3 H), 2.12 (dt, J = 7.7, 1.5 Hz, 2 H), 2.10 - 2.04 (m, 2 H), 2.03 (s, 1 H), 1.96 (d, J = 13.2 Hz, 2 H), 1.34 (tdd, J = 13.0, 7.3, 5.8 Hz, 1 H), 1.03 (q, J = 12.0 Hz, 1 H), 0.93 (d, J = 6.5 Hz, 3 H).Example 95: Synthesis of compound 348 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4,4 -difluoropiperidin- 1-yl)acetamide)

[00835] N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4,4-difluoropiperidin-1-yl)acetamide: N- [(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4,4-difluoropiperidin-1-yl) acetamide was prepared from 8-[ (3R,5S)-3-amino-5-methylpiperidin-1-yl] quinoxaline-5-carbonitrile, 4,4-difluoropiperidine, methyl 2-bromoacetate, and 2-(dimethylamino)acetic acid using Method 18, 19, and J The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 42% to 55% gradient in 7 min; detector, UV 254 nm. N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4,4-difluoropiperidin-1-yl)acetamide was obtained as a yellow solid ( 13 mg, 2.7% for 3 steps).

[00836] Compound 348: HPLC: 99.4% purity, Retention Time = 1.51 min. EM: m/z = 429.3 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.97 (d, J = 1.7 Hz, 1 H), 8.86 (d, J = 1.7 Hz, 1 H), 8.02 (d, J = 8.3 Hz, 1 H), 7.21 (d, J = 8.4 Hz, 1 H), 7.18-6.98 (m, 1 H), 4.46-4 .37 (m, 1 H), 4.36-4.21 (m, 2 H), 3.14 (s, 2 H), 2.85-2.68 (m, 6 H), 2.23 -2.00 (m, 6 H), 1.30-1.14 (m, 1 H), 1.03 (d, J = 6.6 Hz, 3 H).

[00837] The following compounds were synthesized in an analogous manner:

[00838] Compound 350 (2-(4,4-difluoropiperidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3 -yl]acetamide):de (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine and 2-(4,4-difluoropiperidin-1-yl acid )acetic. HPLC: 99.1% purity, Retention Time = 2.83 min. MS: m/z = 471.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.1, 1.6 Hz, 1 H), 8.53 (dd, J = 8.6, 1.7 Hz , 1 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.68 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.22 (d, J = 8.1 Hz, 1 H), 4.15-4.05 (m, 1 H), 3.51- 3.30 (m , 2 H), 3.02 (s, 2 H), 2.57-2.35 (m, 6 H), 2.12-1.93 (m, 6 H), 1,251.21 (m, 1 H), 0.96 (d, J = 6.5 Hz, 3 H).

[00839] Compound 354 (2-(4,4-difluoropiperidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3 -yl]acetamide): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine and 2-(4,4-difluoropiperidin-1-yl acid )acetic. HPLC: 99.0% purity, Retention Time = 2.00 min. MS: m/z = 472.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (d, J = 1.7 Hz, 1 H), 8.97 (d, J = 1.7 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4, 19-3.95 (m, 3 H), 3.06-2.97 (m, 2 H), 2.87-2.81 (m, 1 H), 2.58-2.49 (m, 5 H), 2.07-1.58 (m, 6 H), 1.35-1.20 (m, 1 H), 0.94 (d, J = 6.3 Hz, 3 H).Example 96: Synthesis of compound 349 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methyl-2-(1-methylpiperidin-4- il)propanamide)

[00840] Ethyl 2-methyl-2-(pyridin-4-yl)propanoate: To a solution of ethyl 2-(pyridin-4-yl)acetate (1.90 g, 11.50 mmols) in N,N- Dimethylformamide (30 mL) was added to LiHMDS solution (1 M in THF, 14.4 mL, 14.4 mmols) slowly at 0°C. The resulting solution was stirred at room temperature for 0.5 h, and then CH3I (2.61 g, 18.4 mmol) was added slowly. The reaction mixture was stirred at room temperature for one hour. Then, the reaction mixture was added by LiHMDS solution (1 M in THF, 14.4 mL, 14.4 mmols) again at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h, and then CH3I (2.61 g, 18.4 mmol) was added slowly. The reaction mixture was stirred at room temperature for an additional two hours. When the reaction was carried out, it was stopped abruptly by the addition of ice water (50 mL). The resulting mixture was extracted with DCM (150 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 25% gradient) to give ethyl 2-methyl-2-(pyridin-4-yl)propanoate as a yellow solid ( 1.20 g, 54%). MS: m/z = 194.1 [M + H]+.

[00841] Ethyl 2-methyl-2-(piperidin-4-yl)propanoate: To a solution of ethyl 2-methyl-2-(pyridin-4-yl)propanoate (1.14 g, 5.92 mmols) in EtOH (20 mL) was added to Rh/Al2O3 (285 mg, 2.77 mmols) in a pressure tank. The resulting mixture was hydrogenated at room temperature under 4 bars of hydrogen for 12 hours. When the reaction was done, the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0% to 50% gradient) to yield ethyl 2-methyl-2-(piperidin-4-yl)propanoate as yellow oil ( 300 mg, 25%). EM: m/z = 200.1 [M + H]+.Method 32

[00842] Ethyl 2-methyl-2-(1-methylpiperidin-4-yl)propanoate: A solution of ethyl 2-methyl-2-(piperidin-4-yl)propanoate (180 mg, 0.90 mmol) in methanol (10 mL) polyformaldehyde (836 mg, 9.28 mmols), NaOAc (1.56 g, 18.99 mmols) were added at room temperature. The resulting mixture was stirred at room temperature for two hours, and then added by NaBH4 (541 mg, 14.31 mmol) at room temperature. The resulting mixture was stirred for a further 12 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (20 mL). The resulting solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 25% gradient) to give ethyl 2-methyl-2-(1-methylpiperidin-4-yl)propanoate as oil colorless (160 mg, 83%). EM: m/z = 214.1 [M + H]+.Method 33

[00843] Ethyl 2-methyl-2-(1-methylpiperidin-4-yl)propanoate: at room temperature, ethyl 2-methyl-2-(1-methylpiperidin-4-yl)propanoate (160 mg, 0.75 mmol ) was dissolved in EtOH (4 mL), to which a solution of sodium hydroxide (355 mg, 8.86 mmols) in water (2 mL) was added. The resulting mixture was stirred for 12 hours at 80°C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% TFA), 0% to 15% gradient in 9 min; detector, UV 254 nm. 2-Methyl-2-(1-methylpiperidin-4-yl)propanoic acid was obtained as colorless oil (100 mg, 58%). MS: m/z = 186.0 [M + H]+.

[00844] N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methyl-2-(1-methylpiperidin-4-yl)propanamide: N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methyl-2-(1-methylpiperidin-4-yl)propanamide was prepared from 8 -[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile and 2-methyl-2-(1-methylpiperidin-4-yl)propanoic acid using Method 30. The crude product was purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 26% to 45% gradient in 8 min; detector, UV 254 nm. N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methyl-2-(1-methylpiperidin-4-yl)propanamide was obtained as a solid yellow (28 mg, 39%).

[00845] Compound 349: HPLC: 99.9% purity, Retention Time = 0.67 min. MS: m/z = 379.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.82 (m, 2 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.37-4.10 (m, 3 H), 3.00-2.78 (m, 3 H), 2.72-2.65 (m, 1 H) , 2.26 (s, 3 H), 2.04-1.96 (m, 4 H), 1.69-1.25 (m, 6 H), 1.13 (s, 6 H), 1 .00 (d, J = 6.3 Hz, 3 H).

[00846] The following compounds were synthesized in an analogous manner:

[00847] Compound 351 (2-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(1-methylpiperidin -4-yl)propanamide): From 2-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2 -(1-methylpiperidin-4-yl)propanamide and 2-methyl-2-(1-methylpiperidin-4-yl)propanoic acid. HPLC: 96.3% purity, Retention Time = 3.56 min. MS: m/z = 477.2 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.54 (dd, J = 8.6, 1.7 Hz , 1 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.69 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32-7.16 (m, 2 H), 4.20-4.05 (m, 1 H), 3.50-3.30 (m, 2 H), 2.84-2.70 (m, 2 H), 2 .50-2.35 (m, 1 H), 2.15-1.85 (m, 5 H), 1.80-1.65 (m, 2 H), 1.50-1.10 (m , 7H), 1.05-0.90 (m, 9H).

[00848] Compound 355 (2-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(1-methylpiperidin -4-yl)propanamide): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine and 2-methyl-2-(1-methylpiperidin acid -4-yl)propanoic. HPLC: 97.7% purity, Retention Time = 2.35 min. MS: m/z = 478.3 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8.95-8.86 (m, 2 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.3 Hz, 1 H), 4.30-4.05 (m, 3 H), 3.09 (d, J = 11.2 Hz, 2 H), 2.90-2.72 (m, 1 H), 2.66-2.50 (m, 1 H), 2.40 (s, 3 H), 2.30-1.96 (m, 4 H), 1.75-1.60 ( m, 3 H), 1.51-1.26 (m, 4 H), 1.15 (s, 6 H), 1.02 (d, J = 6.4 Hz, 3 H).Example 97: Synthesis of compound 352 and compound 353 ((3S)-1-methyl-3-[[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl] amino]pyrrolidin-2-one and (3R)-1-methyl-3-[[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl] amino]pyrrolidin-2-one)

[00849] (3S)-1-methyl-3-[[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]amino]pyrrolidin -2-one and (3R)-1-methyl-3- [[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]amino]pyrrolidin -2-one: cis-1-methyl-3-[[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]amino]pyrrolidin-2 -one was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine and 3-bromo-1-methylpyrrolidin-2-one using Method 16. The crude product was first purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 19 x 150 mm 10 µm; mobile phase, acetonitrile in water (0.05% NH3.H2O), 36% to 43% gradient in 7 min; detector, UV 254 nm. Then, the two diastereomeric isomers were obtained by separation on chiral preparative HPLC under the following conditions: column, Lux 5 u Cellulose-4, AXIA Packed, 2.12 x 25 cm, 5 µm; mobile phase, EtOH in hexane, 50% isocratic in 12 min; detector, UV 254/220 nm. Isomer 1: (25 mg, 19%, yellow solid) HPLC: 95.4% purity, Retention Time = 2.06 min. MS: m/z = 430.3 [M+Na]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.08-8.95 (m, 2 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.29 (d, J = 11.5 Hz, 1 H), 4.03 (d, J = 11.6 Hz, 1 H), 3.47-3 .21 (m, 4 H), 3.05-2.98 (m, 1 H), 2.74 (s, 3 H), 2.60-2.45 (m, 1 H), 2.38 -2.22 (m, 1 H), 2.18-2.08 (m, 1 H), 1.99-1.85 (m, 2 H), 1,731.58 (m, 1 H), 0 .95-0.92 (m, 4 H).Isomer 2: (24 mg, 18%, yellow solid) HPLC: 94.7% purity, Retention Time = 2.22 min. MS: m/z = 430.3 [M+Na]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.08-8.95 (m, 2 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.29 (d, J = 11.5 Hz, 1 H), 4.03 (d, J = 11.6 Hz, 1 H), 3.47-3 .21 (m, 5 H), 3.05-2.98 (m, 1 H), 2.74 (s, 3 H), 2.60-2.45 (m, 1 H), 2.38 -2.22 (m, 1 H), 2.10-2.00 (m, 1 H), 1.99-1.85 (m, 1 H), 1,731.58 (m, 1 H), 0 .95-0.92 (m, 4 H). Example 98: Synthesis of compound 356 (2-(3-aminoazetidin-1-yl)-N- [(3R,5S)-1-(8-cyanoquinoxalin-5 -yl)-5-methylpiperidin-3-yl]acetamide)

[00850] 2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide: 2-(3 -aminoazetidin-1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide was prepared from 8-((3R,5S)- 3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile, 2-bromoacetic acid, and tert-butyl azetidin-3-ylcarbamate using Method 30, 18, and 6. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 2% to 33% gradient in 10 min; detector, UV 254 nm. 2-(3-Aminoazetidin-1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide was obtained as a yellow solid (34 mg , 29%).

[00851] Compound 356: HPLC: 97.8% purity, Retention Time = 0.96 min. EM: m/z = 380.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 9.10-8.90 (m, 2 H), 8.21 (d, J = 8.4 Hz, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.27 (d, J = 8.5 Hz, 1 H), 4.39-3.85 (m, 3 H),3.70-3.37 (m, 4 H), 3.07-2.60 (m, 7H), 1.98-1.82 (m, 2 H), 1.33-1.24 (m, 1 H), 0.930.76 (m , 3 H).Example 99: Synthesis of compound 357 and 358 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-((1R ,5S,6r)-3-methyl-3-aza-bicyclo[3,1,1]heptan-6-yl)acetamide and N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl) -5-methylpiperidin-3-yl)-2-((1S,5R,6s)-3-methyl-3-aza-bicyclo[3,1,1]heptan-6-yl)acetamide)

[00852] Benzylbis(methoxymethyl)amine: To a solution of phenylmethanamine (95 g, 886.58 mmols) in MeOH (1 L) was added polyformaldehyde (78.4 g, 870.08 mmols) at room temperature. The resulting solution was then stirred overnight at 70°C. When the reaction was carried out, it was stopped abruptly by the addition of water (mL). The solvent was removed under reduced pressure and the residue was purified by distillation under reduced pressure (Hg at 10 mm) and the fraction was collected at 70~72oC to yield benzylbis(methoxymethyl)amine as colorless liquid (104.0 g, 75% ).

[00853] Benzylbis(methoxymethyl)amine: To a solution of benzylbis(methoxymethyl)amine (16.0 g, 81.94 mmols) in DCM (200 mL) cyclobutanone (6.8 g, 96.62 mmols) was added, chlorotrimethylsilane (22.8 g, 210.74 mmols) and ZnBr2 (21.7 g, 96.17 mmols) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. After cooling to room temperature, the reaction mixture was stopped abruptly by adding water (500 mL). The resulting mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 90% gradient) to yield 3-benzyl-6,6-dimethoxy-3-azabicyclo[3,1,1 ]heptane as light yellow oil (6.4 g, 32%). MS: m/z = 248.3 [M + H]+.

[00854] Benzylbis(methoxymethyl)amine: 3-benzyl-6,6-dimethoxy-3-azabicyclo[3,1,1]heptane (3.6 g, 14.56 mmols) was slowly added to trifluoroacetic acid (100 mL ) at room temperature. The resulting solution was then stirred for 13 hours at 50°C. After the reaction was done, the reaction mixture was concentrated under reduced pressure and diluted with H2O (50 mL). The pH value of the resulting mixture was adjusted to 9 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% to 10% gradient) to yield 3-benzyl-3-azabicyclo[3,1,1]heptan-6-one as brown oil (2.5 g, 84%). MS: m/z = 202.0 [M + H]+.

[00855] Ethyl 2-[3-benzyl-3-azabicyclo[3,1,1]heptan-6-ylidene]acetate: At 0°C, to a solution of 3-benzyl-3-azabicyclo[3,1, 1]heptan-6-one (2.0 g, 9.83 mmols) in ethylene glycol dimethyl ether (100 mL) was added sodium hydride (294 mg, 12.25 mmols) slowly. The resulting mixture was stirred at 0°C for 10 min, and then ethyl 2-(diethoxyphosphoryl)acetate (3.9 g, 17.29 mmol) was added. The reaction mixture was then stirred for a further 1.5 hours at 0°C. When the reaction was carried out, it was stopped abruptly by the addition of saturated NH4Cl solution. The resulting mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0% to 10% gradient) to yield ethyl 2-[3-benzyl-3-azabicyclo[3,1,1]heptan -6-ylidene]acetate as light yellow oil (1.4 g, 53%). EM: m/z = 272.1 [M + H]+.

[00856] Ethyl 2-[3-benzyl-3-azabicyclo[3,1,1]heptan-6-ylidene]acetate: A solution of ethyl 2-[3-benzyl-3-azabicyclo[3,1,1 ]heptan-6-ylidene]acetate (1.4 g, 5.16 mmols) in MeOH (100 mL) Pd/C (10%, 400 mg) was added at room temperature under a nitrogen atmosphere. The reaction vial was aspirated and purged with hydrogen. The reaction mixture was then hydrogenated at 0°C for 16 hours under a hydrogen atmosphere under a hydrogen balloon. After the reaction was done, the reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to yield ethyl 2-[3-azabicyclo[3,1,1]heptan-6-yl]acetate as light yellow oil (800 mg, 85%). MS: m/z = 184.2 [M + H]+.

[00857] N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-((1R,5S,6r)-3-methyl-3- aza-bicyclo[3,1,1]heptan-6-yl)acetamide and N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2- ((1S,5R,6s)-3-methyl-3-aza-bicyclo[3,1,1]heptan-6-yl)acetamide: N-((3R,5S)-1-(8-cyanoquinoxalin-5 -yl)-5-methylpiperidin-3-yl)-2-(3-methyl-3-aza-bicyclo[3,1,1]heptan-6-yl)acetamide was prepared from 8-((3R,5S) -3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile, ethyl 2-(3-aza-bicyclo[3,1,1]heptan-6-yl)acetate, and polyformaldehyde using Method 32, 19 , and 30. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 19 x 150 mm 10 µm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1% NH3.H2O), 29% to 33% gradient in 7 min; detector, UV 254 nm. Two diastereoisomers were separated and obtained. Isomer 1: (5 mg, 4% for 3 steps, light yellow solid) HPLC: 96.9% purity, Retention Time = 2.90 min. MS: m/z = 419.1 [M+Na]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.89 (m, 2 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 4.43-4.28 (m, 2 H), 4.17-4.10 (m, 1 H), 3.16-3.07 (m, 2 H) , 2.85-2.63 (m, 4 H), 2.54 (d, J = 8.0 Hz, 2 H), 2.41 (s, 3 H), 2.33-2.31 ( m, 1 H), 2.18-1.99 (m, 5 H), 1.69-1.66 (m, 1 H), 1.30- 1.14 (m, 1 H), 1, 02 (d, J = 6.5 Hz, 3 H).Isomer 2: (6 mg, 4.4% for 3 steps, light yellow solid) HPLC: 97.7% purity, Retention Time = 1.16 min. MS: m/z = 419.5 [M+Na]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.99-8.89 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.38-4.31 (m, 2 H), 4,154.09 (m, 1 H), 3.17-3.04(m, 2 H), 2.92 -2.80 (m, 2 H), 2.79-2.51 (m, 3 H), 2.41 (s, 3 H), 2.37-2.30 (m, 4 H), 2 .11-2.03 (m, 2 H), 1.92-1.75 (m, 2 H), 1.23-1.15 (m, 1 H), 1.02 (d, J = 6 .4 Hz, 3 H).Example 100: Synthesis of compound 359 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1 -methylazetidin-3-yl)acetamide)

[00858] N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylazetidin-3-yl)acetamide: N-[( 3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylazetidin-3-yl)acetamide was prepared from 2-(azetidin-3-yl) -N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide and polyformaldehyde using Method 32. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1% NH3.H2O), 25% to 31% gradient in 7 min; detector, UV 254 nm. N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylazetidin-3-yl)acetamide was obtained as a yellow solid (5 mg , 12%). Compound 359: HPLC: 97.2% purity, Retention Time = 0.84 min. EM: m/z = 379.2 [M + H]+. 1H NMR (300 MHz, CD3OD, ppm) δ 8,998.88 (m, 2 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.26 (d, J = 8.4 Hz , 1 H),4.36- 4.31 (m, 2 H), 4.12-4.04 (m, 1 H),3.55-3.50 (m, 2 H), 3.03 -2.98 (m, 2 H), 2.90-2.60 (m, 3 H), 2.45 (d, J = 7.7 Hz, 2 H), 2.33 (s, 3 H ), 2.15-1.94 (m, 2 H), 1.26-1.10 (m, 1 H), 0.99 (d, J = 6.3 Hz, 3 H).

[00859] The following compounds were synthesized in an analogous manner:

[00860] Compound 360 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinolin-5-yl]piperidin-3-yl]-2-(1-methylazetidin-3-yl )acetamide): from 2-(azetidin-3-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide and polyformaldehyde. HPLC: 94.0% purity, Retention Time = 2.27 min. MS: m/z = 421.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.2, 1.6 Hz, 1 H), 8.52 (dd, J = 8.6, 1.8 Hz , 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.92 (d, J = 7.4 Hz, 1 H), 7.68 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.21 (d, J = 8.1 Hz, 1 H), 4.01-3.99 (m, 1 H), 3,483.21 (m, 3 H) , 2.81-2.70 (m, 2 H), 2.51-2.28 (m, 4 H), 2.16 (s, 3 H), 2.091.95 (m, 3 H), 1 .18-0.91 (m, 4H).

[00861] Compound 363 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl) quinoxalin-5-yl]piperidin-3-yl]-2-(1-methylazetidin-3-yl )acetamide): 2-(azetidin-3-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide and polyformaldehyde. HPLC: 93.5% purity, Retention Time = 5.81 min. EM: m/z = 422.3 [M + H]+. 1H NMR (300 MHz,DMSO-d6, ppm) δ 9.08-8.95 (m, 2 H), 8.07 (d, J = 8.2 Hz, 1 H), 7.91 (d, J = 7.6 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 4.23-4.04 (m, 2 H), 3.92-3.81 ( m, 1 H), 3.43-3.26 (m, 2 H), 2.80-2.65 (m, 5 H), 2.34-2.31 (m, 2 H), 2, 16 (s, 3 H), 1.95-1.83 (m, 2 H), 1.21-1.02 (m, 1 H), 0.93 (d, J = 6.2 Hz, 3 H).

[00862] Compound 364 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(1-methylazetidin-3-yl) acetamide): from 2-(azetidin-3-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide and polyformaldehyde. HPLC: 88.7% purity, Retention Time = 1.24 min. EM: m/z = 403.1 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.89 (dd, J = 4.2, 1.7 Hz, 1 H), 8.60 (dd, J = 8.6, 1.8 Hz, 1 H), 7.93 (dd, J = 7.8, 1.6 Hz, 1 H), 7.83-7.55 (m, 2 H), 7.24 (d, J = 7.9 Hz , 1 H), 4.25-4.12 (m, 1 H), 3.59-3.43 (m, 3 H), 2.98-2.93 (m, 2 H), 2.79 -2.75 (m, 1 H), 2.51-2.36 (m, 4 H), 2.30 (s, 3 H), 2.13-2.07 (m, 2 H), 1 .19-0.97 (m, 5 H). Example 101: Synthesis of compound 366 (cis-5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-amine)

[00863] 5-Bromo-8-fluoroquinoxaline: 5-bromo-8-fluoroquinoxaline was prepared from 2-bromo-5-fluorobenzenamine, acetyl chloride, and oxalaldehyde using Method 1 to 5. The crude product was purified by flash chromatography eluting with EtOAc in hexane (0% to 10% gradient) to yield 5-bromo-8-fluoroquinoxaline as white solid (637 mg, 71%, for 5 steps). MS: m/z = 226.8 [M + H]+. Method 34

[00864] tert-Butyl cis-N-[5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-yl]carbamate: A solution of 5-bromo-8-fluoroquinoxaline (66 mg, 0 .29 mmol) in tert-butanol (10 mL) were added tert-butyl N-(5-cyclopropylpiperidin-3-yl)carbamate (62 mg, 0.26 mmol), RuPhos (29 mg, 0.06 mmol), Cs2CO3 (151.6 mg, 0.44 mmol) and second generation RuPhos precatalyst (23 mg, 0.03 mmol) at room temperature. The resulting mixture was stirred for 3 hours at 100°C. After cooling to room temperature, the reaction mixture was stopped abruptly by adding water (20 mL). The resulting mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was applied to a C18 gel column and purified by reverse phase flash chromatography eluting with acetonitrile in water (with 10 mmol/L NH4HCO3) (0% to 60% gradient in 30 min ) to produce tert-butyl N-[5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-yl]carbamate as yellow solid (32 mg, 29%). EM: m/z = 387.2 [M + H]+.

[00865] cis-5-Cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-amine: cis-5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-amine was prepared of tert-butyl N-[5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-yl]carbamate using method 6. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5um, 19mm x 150mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1% NH3.H2O), 35% to 65% gradient in 7 min; detector, UV 254 nm. Cis-5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-amine was obtained as a yellow solid (7 mg, 29%).

[00866] Compound 366: HPLC: 99.0% purity, Retention Time = 1.78 min. EM: m/z = 278.1 [M + H]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.02-8.92 (m, 2 H), 7.57 (dd, J = 10.2, 8.6 Hz, 1 H), 7, 16 (dd, J = 8.7, 4.9 Hz, 1 H), 3.86-3.72 (m, 2 H), 2.93-2.88 (m, 1 H), 2.50 -2.40 (m, 2 H), 2.33-2.29 (m, 1 H), 2.15-1.90 (m, 2 H), 1.02-1.1 (m, 2 H), 0.65-0.32 (m, 3 H), 0.16-0.14 (m, 2 H). Example 102: Synthesis of compound 367 (cis-N-[5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-yl]-2-(morpholin-4-yl)acetamide)

[00867] Cis-N-[5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-yl]-2-(morpholin-4-yl)acetamide: cis-N-[5-cyclopropyl- 1-(8-fluoroquinolin-5-yl)piperidin-3-yl]-2-(morpholin-4-yl)acetamide was prepared from cis-5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin- 3-amine and 2-(morpholin-4-yl)acetic acid using Method J. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1% NH3.H2O), 36% to 47% gradient in 7 min; detector, UV 254 nm. Cis-N-[5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-yl]-2-(morpholin-4-yl)acetamide was obtained as yellow solid (50 mg, 62%).

[00868] Compound 367: HPLC: 99.9% purity, Retention Time = 1.09 min. MS: m/z = 413.4 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.86 (dd, J = 4.3, 1.6 Hz, 1 H), 8.65 (dt, J = 8.7, 1.6 Hz, 1 H), 7.63 (dd, J = 8.6, 4.3 Hz, 1 H), 7.42 (dd, J = 10.7, 8.4 Hz, 1 H), 7.22 (dd , J = 8.4, 4.2 Hz, 1 H), 4.19-4.12 (m, 1 H), 3.74-3.67 (m, 4 H), 3,453.26 (m, 2 H), 3.02 (s, 2 H), 2.70-2.47 (m, 6 H), 2.26-2.14 (m, 1 H), 1,431.20 (m, 2 H ), 0.63-0.45 (m, 3 H), 0.29-0.12 (m, 2 H).Example 103: Synthesis of compound 368 (cis-N-[5-cyclopropyl-1-( 8-fluoroquinolin-5-yl)piperidin-3-yl]-N-methyl-2-(morpholin-4-yl)acetamide

[00869] Cis-N-[5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-yl]-N-methyl-2-(morpholin-4-yl)acetamide: A solution of cis -N-[5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-yl]-2-(morpholin-4-yl)acetamide (100 mg, 0.24 mmol) in tetra- hydrofuran (15 mL) was added to sodium hydride (17 mg, 0.73 mmol) at room temperature. The mixture was stirred for 10 min at room temperature, and then added by MeI (294 mg, 2.07 mmols). The resulting mixture was stirred for a further 14 hours at room temperature. When the reaction was done, it was stopped abruptly by adding water (20 mL). The resulting mixture was extracted with DCM (50 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 32% to 40% gradient in 8 min; detector, UV 254 nm. Cis-N-[5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-yl]-N-methyl-2-(morpholin-4-yl)acetamide was obtained as light brown solid (10 mg , 9%).Compound 368: HPLC: 95.5% purity, Retention Time = 0.91 min. MS: m/z = 427.3 [M + H]+. 1H NMR (400 MHz, CD3OD, ppm) δ 8.87 (dd, J = 4.2, 1.6 Hz, 1 H), 8.64 (dt, J = 8.7, 1.8 Hz, 1 H), 7.63 (dd, J = 8.7, 4.3 Hz, 1 H), 7.43 (dd, J = 10.6, 8.4 Hz, 1 H), 7.23 (dd , J = 8.4, 4.2 Hz, 1 H), 4.27-4.14 (m, 3 H), 4.03-3.98 (m, 4 H), 3.75-3, 66 (m, 4 H),3.48- 3.47 (m, 1 H), 3.42 (s, 3 H), 2.71-2.51 (m, 2 H), 2.27- 2.21 (m, 1 H), 1,361.25 (m, 3 H), 0.63-0.59 (m, 1 H), 0.53-0.43 (m, 2 H), 0. 21-0.18 (m, 2H).Example 104: Synthesis of compound 369 and compound 370 ((2R)-2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5- methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]propanamide and (2S)-2-(3-aminoazetidin-1-yl)-N-[(3R,5S) -5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]propanamide)

[00870] (2R)-2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3- yl]propanamide and (2S)-2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3 -yl]propanamide: 2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl] Propanamide was prepared from (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine and 2-(3-(tert-butoxycarbonylamino)azetidin-1-yl acid )propanoic using Method J and 6. The crude product was first purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 10 mmol/L NH4HCO3 and 0.1% NH3.H2O), 30% to 50% gradient in 7 min; detector, UV 254 nm. Then, the two enantiomeric isomers were obtained by separation on chiral preparative HPLC under the following conditions: column, CHIRALPAK IC, 2 x 25 cm, 5 µm; mobile phase, EtOH in hexane (0.1% DEA), 30% isocratic in 18 minutes; detector, UV 254/220 nm. Isomer 1: (18 mg, 26%, yellow solid) HPLC: 98.1% purity, Retention Time = 1.31 min. MS: m/z = 437.5 [M+Na]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.06-8.94 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.57 (d, J = 8.0 Hz, 1 H), 7.25 (d, J = 8.3 Hz, 1 H), 4.20-3.85 (m, 3 H), 3.54-3.35 ( m, 3 H), 2.86-2.51 (m, 6 H), 2.02-1.85 (m, 2 H), 1.35-0.85 (m, 8 H). Isomer 2 : (28 mg, 26%, yellow solid) HPLC: 91.6% purity, Retention Time = 1.28 min. MS: m/z = 437.4 [M+Na]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.06-8.94 (m, 2 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 4.14-3.97 (m, 3 H), 3.49-3.32 ( m, 3 H), 2.87-2.52 (m, 4 H), 2.20-1.85 (m, 4 H), 1.31-0.89 (m, 8 H).

[00871] The following compounds were synthesized in an analogous manner:

[00872] Compound 371 and compound 372 ((2R)-2-(4-hydroxypiperidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin- 5-yl]piperidin-3-yl]propanamide and (2s)-2-(4-hydroxypiperidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl )quinoxalin-5-yl]piperidin-3-yl]propanamide): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine and acid 2- (4-hydroxypiperidin-1-yl)propanoic acid. Isomer 1: HPLC: 91.9% purity, Retention Time = 1.44 min. MS: m/z = 466.5 [M+Na]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.06-8.94 (m, 2 H), 8.07 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 7.8 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 4.62-4.46 (m, 1 H), 4.20-3.90 ( m, 3 H), 3.50-3.34 (m, 1 H), 3.14-3.00 (m, 1 H), 2.85-2.50 (m, 4 H), 2, 30-2.05 (m, 2 H), 2.03-1.87 (m, 2 H), 1.79-1.63 (m, 2 H), 1.46-1.17 (m, 3 H), 1.07 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.2 Hz, 3 H). Isomer 2: HPLC: 97.0% purity, Retention Time = 5.48 min. MS: m/z = 466.5 [M+Na]+. 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.09-8.95 (m, 2 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.77-7, 63 (m, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4.62-4.48 (m, 1 H), 4.24-3.90 (m, 3 H), 3.49-3.30 (m, 1 H), 3.03-3.01 (m, 1 H), 2.83-2.53 (m, 4 H), 2.21-2 .12 (m, 2 H), 1.95-1.92 (m, 2 H), 1.79-1.68 (m, 2 H), 1.42-1.38 (m, 2 H) , 1.24-1.20 (m, 1 H), 1.09 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.2 Hz, 3 H). Example 105: Synthesis of compound 373 (1-pyrido[2,3-b]pyrazin-8-yl-piperidine-4-carboxylic acid (2-piperidin-1-yl-ethyl)-amide)

[00873] (2-Piperidin-1-yl-ethyl)-1-pyrido[2,3-b]pyrazin-8-yl-piperidine-4-carboxylic acid amide: (2-piperidin-1-yl-ethyl 1-Pyrido[2,3-b]pyrazin-8-yl-piperidine-4-carboxylic acid)-amide was obtained from 8-chloro-pyrido[2,3-b]pyrazine,1-(2-aminoethyl) piperidine and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid in 11% production during 3 steps, using method 20, Q and V. Compound 373: HPLC: 97.0% purity, Retention Time = 1.13 min. EM: m/z = 369 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.97 (d, J = 1.7 Hz, 1 H), 8.83 (d, J = 5.4 Hz, 1 H), 8.75 (d, J = 1.7 Hz, 1 H), 6.91 (d, J = 5.4 Hz, 1 H), 6.36 (s, 1 H), 4.47 (dt, J = 12 .7, 2.9 Hz, 2 H), 3.38 (q, J = 5.7 Hz, 2 H), 3.30-3.12 (m, 2 H), 2.51-2.38 (m, 6 H), 2.10-2.01 (m, 4 H), 2.00-1.84 (m, 1 H), 1.60 (p, J = 5.6 Hz, 4 H ), 1.53 -1.39 (m, 2 H).

[00874] The following compounds were synthesized in an analogous manner:

[00875] Compound 379 ((2-piperidin-1-yl-ethyl)-1-pyrido[2,3-b]pyrazin-8-yl-piperidine-4-carboxylic acid amide): From 8-chloro - pyrido[2,3-b]pyrazine, N,N-diethylethylenediamine and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid. HPLC: 93.2% purity, Retention Time = 1.06 min. EM: m/z = 357 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.96 (d, J = 1.7 Hz, 1 H), 8.81 (d, J = 5.3 Hz, 1 H), 8.74 (d, J = 1.7 Hz, 1 H), 6.89 (d, J = 5.4 Hz, 1 H), 6.26 (s, 1 H), 4.45 (dt, J = 11 .4, 2.9 Hz, 2 H), 3.32 (q, J = 5.5 Hz, 2 H), 3.17 (ddd, J = 12.7, 8.3, 6.1 Hz, 2 H), 2.70-2.49 (m, 6 H), 2.51-2.38 (m, 1 H), 2.17-1.95 (m, 4 H), 1.03 ( t, J = 7.1 Hz, 6 H).

[00876] Compound 380 (4-[(2-diethylamino-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester): From 8-chloropyrido[2,3-b]pyrazine, 2-(diethylamino)acetic acid hydrochloride and 1-boc-4-(aminomethyl)piperidine. HPLC: > 99% purity, Retention Time = 1.11 min. MS: m/z = 357 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.92 (s, 1 H), 8.77 (dd, J = 5.8, 2.5 Hz, 1 H), 8.70 (s, 1 H), 7.57 (t, J = 6.3 Hz, 1 H), 6.85 (dd, J = 5.8, 2.5 Hz, 1 H), 4.43 (d, J = 12.2 Hz, 3 H), 3.23 (d, J = 6.6 Hz, 4 H), 3.14-2.96 (m, 5 H), 2.54 (q, J = 6, 5 Hz, 7H), 1.85 (d, J = 11.3 Hz, 5 H), 1.55 (q, J = 12.2 Hz, 4 H), 1.01 (t, J = 6, 9Hz, 10H).

[00877] Compound 432 ((2-diethylamino-ethyl)-1-(8-cyano-quinoxalin-5-yl)-piperidine-4-carboxylic acid amide): 8-bromo-quinoxaline-5-carbonitrile , 1-tert-butoxycarbonylpiperidine-4-carboxylic acid and N,N-diethylethylenediamine. HPLC: 91.4% purity, Retention Time = 1.95 min. MS: m/z = 381 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.8 Hz, 1 H), 8.83 (d, J = 1.8 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 4.24 (dt , J = 12.3, 2.6 Hz, 2 H), 3.44 - 3.29 (m, 2 H), 3.19 - 3.07 (m, 2 H), 2.58 (s, 5 H), 2.44 (s, 2 H), 2.21 - 1.95 (m, 4 H), 1.20 - 0.83 (m, 6 H). Example 106: Synthesis of compound 374 (N,N-diethyl-N'-[1-(6-fluoro-2-methyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine )

[00878] Benzyl ester of 4-[(2-diethylamino-ethylamino)-methyl]-piperidine-1-carboxylic acid: a solution of 4-formyl-n-cbz-piperidine (2.0 g; 8.09 mmols) , N,N-diethylethylenediamine (1.4 mL; 9.71 mmols) and sodium triacetoxyborohydride (1.9 g; 8.90 mmols) in anhydrous 1,2-dichloroethane (80 mL) was heated to 65° C for 3 hours. The colorless cloudy solution was cooled, diluted with dichloromethane (250 mL) and washed with saturated aqueous sodium carbonate (2 x 250 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM and purified by chromatography on a 40 g, 30 μm PuriFlash column, eluting with a gradient of methanol in DCM to provide 4-[(2-diethylamino-ethylamino)-methyl]-piperidine acid benzyl ester -1-carboxylic acid (1.5 g, 43%). MS: m/z = 348 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.52-7.17 (m, 5 H), 5.06 (s, 2 H), 3.99 (d, J = 13.2 Hz, 2H), 2.77 (s, 2H), 2.48-2.34 (m, 10H), 1.68 (d, J = 12.6 Hz, 2H), 1.62-1, 47 (m, 1 H), 1.01 (td, J = 12.2, 4.2 Hz, 2 H), 0.93 (t, J = 7.1 Hz, 6 H).

[00879] 4-{[tert-Butoxycarbonyl-(2-diethylamino-ethyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester: a solution of 4-[(2-diethylamino- ethylamino)-methyl]-piperidine-1-carboxylic acid (1.5 g; 4.32 mmols), triethylamine (1.2 mL; 8.63 mmols) and di-tert-butyl dicarbonate (1.2 mL; 5 .18 mmol) in anhydrous THF (15 mL) was stirred overnight at room temperature. The colorless solution was concentrated under reduced pressure, the residue was dissolved in DCM and purified by chromatography on a 40 g, 15 μm PuriFlash column, eluting with a gradient of methanol in DCM to give 4-{[tert- butoxycarbonyl-(2-diethylamino-ethyl)-amino]-methyl}-piperidine-1-carboxylic acid (1.57 g; 68%). EM: m/z = 448 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) d 7.46-7.21 (m, 5 H), 5.06 (s, 2 H), 3.99 (d, J = 13.1 Hz, 2 H), 3.17 (d, J = 4.7 Hz, 2 H), 3.05 (d, J = 7.2 Hz, 2 H), 2.77 (s, 2 H), 2, 45 (q, J = 7.0 Hz, 4 H), 1,861.69 (m, 1 H), 1.56 (d, J = 13.3 Hz, 2 H), 1.38 (s, 9H) , 1.03 (td, J = 12.3, 4.0 Hz, 2 H), 0.94 (t, J = 7.2 Hz, 6 H).

[00880] Benzyl ester of 4-[(2-diethylamino-ethylamino)-methyl]-piperidine-1-carboxylic acid: a solution of benzyl ester of -{[tert-butoxycarbonyl-(2-diethylamino-ethyl)-amino acid ]-methyl}-piperidine-1-carboxylic acid (1.6 g; 3.46 mmols) in methanol (70 mL) was pumped through a H-Cube flow hydrogenator equipped with a Pd(OH) catalyst cartridge 2/C at 20 mol% and heated to 50°C (full hydrogen option, flow rate 1 mL/min). The resulting colorless solution was concentrated under reduced pressure and the colorless oil was dried under vacuum to obtain (2-diethylamino-ethyl)-piperidin-4-ylmethyl-carbamic acid tert-butyl ester (1.06 g, 98%). MS: m/z = 314 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 3.34 (s, 1 H), 3.12 (t, J = 7.4 Hz, 2 H), 3.02 (d, J = 7, 2 Hz, 2 H), 2.92 (d, J = 12.1 Hz, 2 H), 2.48-2.35 (m, 8 H), 1.69-1.55 (m, 1 H ), 1.48 (d, J = 12.4 Hz, 2 H), 1.38 (s, 9H), 1.01 (td, J = 12.0, 3.7 Hz, 2 H), 0 .94 (t, J = 7.1 Hz, 6 H).

[00881] N,N-diethyl-N'-[1-(6-fluoro-2-methyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine: N,N- diethyl-N'-[1-(6-fluoro-2-methyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine was obtained in 43% production during 2 steps of 4 -chloro-6-fluoro-2-methylquinoline and (2-diethylamino-ethyl)-piperidin-4-ylmethyl-carbamic acid tert-butyl ester, using Methods V and Q. Compound 374: HPLC: > 99% purity, Retention Time = 1.33 min. EM: m/z = 373 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 7.96 (dt, J = 8.3, 3.2 Hz, 1 H), 7.56 (d, J = 10.4 Hz, 1 H) , 7.38 (t, J = 8.8 Hz, 1 H), 6.77 (s, 1 H), 3.57 (d, J = 11.8 Hz, 2 H), 2.80 (t , J = 11.7 Hz, 2 H), 2.76-2.69 (m, 2 H), 2.70 -2.63 (m, 4 H), 2.64-2.51 (m, 5 H), 1.96 (d, J = 12.8 Hz, 2 H), 1.80-1.69 (m, 1 H), 1.59 (q, J = 11.9 Hz, 2 H ), 1.05 (t, J = 6.8 Hz, 5 H).

[00882] The following compounds were synthesized in an analogous manner:

[00883] Compound 375 (N,N-diethyl-N'-[1-(6-fluoro-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine): From 4 -chloro-6-fluoroquinoline, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: > 99% purity, Retention Time = 1.23 min. EM: m/z = 359 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.69 (t, J = 3.8 Hz, 1 H), 8.12-7.98 (m, 1 H), 7.61 (dd, J = 10.0, 3.3 Hz, 1 H), 7.42 (td, J = 8.0, 6.8, 3.9 Hz, 1 H), 6.87 (t, J = 3, 8 Hz, 1 H), 3.59 (d, J = 11.7 Hz, 2 H), 2.83 (t, J = 12.0 Hz, 2 H), 2.72 (q, J = 6 .2, 5.7 Hz, 2 H), 2.65 (d, J = 6.1 Hz, 2 H), 2.64-2.47 (m, 6 H), 1.96 (d, J = 12.8 Hz, 2 H), 1.79-1.68 (m, 3 H), 1.60 (q, J = 12.2 Hz, 2 H), 1.05 (t, J = 7 ,0Hz, 6H).

[00884] Compound 376 (N,N-diethyl-N'-[1-(7-trifluoromethyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine): From 4 -chloro-7-(trifluoromethyl)quinolone, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: > 99% purity, Retention Time = 1.65 min. EM: m/z = 409 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.79 (d, J = 5.0 Hz, 1 H), 8.35 (s, 1 H), 8.12 (d, J = 8, 8 Hz, 1 H), 7.64 (dd, J = 8.8, 1.9 Hz, 1 H), 6.93 (d, J = 5.0 Hz, 1 H), 3.64 (d , J = 12.1 Hz, 2 H), 2.88 (td, J = 12.1, 2.3 Hz, 2 H), 2.73 (t, J = 6.2 Hz, 2 H), 2.66 (d, J = 6.6 Hz, 2 H), 2.63-2.40 (m, 6 H), 2.05-1.92 (m, 2 H), 1.77 (ddt , J = 13.9, 6.6, 3.7 Hz, 1 H), 1.61 (qd, J = 12.1, 3.8 Hz, 2 H), 1.05 (t, J = 7 ,1Hz, 6H).

[00885] Compound 377 (N,N-diethyl-N'-[1-(6-trifluoromethyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine): From 4 -chloro-6-(trifluoromethyl)quinolone, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: > 99% purity, Retention Time = 1.59 min. EM: m/z = 409 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.80 (d, J = 5.1 Hz, 1 H), 8.32 (s, 1 H), 8.14 (d, J = 8, 8 Hz, 1 H), 7.82 (dd, J = 8.9, 2.1 Hz, 1 H), 6.92 (d, J = 5.1 Hz, 1 H), 3.64 (d , J = 12.3 Hz, 2 H), 2.90 (td, J = 11.9, 2.0 Hz, 2 H), 2.73 (t, J = 6.2 Hz, 2 H), 2.67 (d, J = 6.6 Hz, 2 H), 2.60 (t, J = 6.0 Hz, 2 H), 2.56 (q, J = 7.1 Hz, 4 H) , 1.99 (d, J = 10.6 Hz, 2 H), 1.77 (ddd, J = 12.9, 8.9, 5.3 Hz, 1 H), 1.64 (td, J = 12.7, 4.0 Hz, 2 H), 1.28 (s, 2 H), 1.05 (t, J = 7.1 Hz, 6 H).

[00886] Compound 378 ([1-(6-Fluoro-quinolin-4-yl)-piperidin-4-ylmethyl]-(2-piperidin-1-yl-ethyl)-amine): From 4-chloro- 6-fluoroquinoline, 4-formyl-n-cbz-piperidine and 1-(2-aminoethyl)piperidine. HPLC: > 99% purity, Retention Time = 1.59 min. MS: m/z = 409 [M + H]+, 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.69 (d, J = 5.0 Hz, 1 H), 8.05 (dd, J = 9.2, 5.6 Hz, 1 H), 7.61 (dd, J = 10.2, 2.9 Hz, 1 H), 7.43 (ddd, J = 9.2, 8, 0, 2.9 Hz, 1 H), 6.88 (d, J = 4.9 Hz, 1 H), 3.59 (d, J = 12.4 Hz, 1 H), 2.83 (td , J = 12.0, 2.3 Hz, 2 H), 2.78 (t, J = 6.3 Hz, 2 H), 2.66 (d, J = 6.6 Hz, 2 H), 2.51 (t, J = 6.3 Hz, 2 H), 2.44 (t, J = 5.3 Hz, 4 H), 2.05 (s, 0H), 1.97 (dd, J = 12.3, 2.8 Hz, 2 H), 1.77 (ddtd, J = 14.1, 10.3, 6.8, 3.6 Hz, 1 H), 1.70-1.52 (m, 6 H), 1.47 (p, J = 5.6, 5.1 Hz, 2 H).

[00887] Compound 381 ([1-(6-Fluoro-2-methyl-quinolin-4-yl)-piperidin-4-ylmethyl]-(2-piperidin-1-yl-ethyl)-amine): From 4-chloro-6-fluoro-2-methylquinoline, 4-formyl-n-cbz-piperidine and 1-(2-aminoethyl)piperidine. HPLC: > 99% purity, Retention Time = 1.34 min. MS: m/z = 385 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 7.94 (dd, J = 9.2, 5.5 Hz, 1 H), 7.54 (dd, J = 10.2, 2.9 Hz , 1 H), 7.36 (ddd, J = 9.2, 8.0, 2.9 Hz, 1 H), 6.75 (s, 1 H), 3.55 (d, J = 12, 3 Hz, 2 H), 2.80 (dd, J = 12.0, 2.4 Hz, 2 H), 2.74 (t, J = 6.3 Hz, 2 H), 2.65 (s , 3 H), 2.63 (d, J = 6.7 Hz, 2 H), 2.47 (t, J = 6.3 Hz, 2 H), 2.40 (s, 4 H), 1 .94 (dd, J = 13.2, 3.5 Hz, 2 H), 1.79-1.67 (m, 1 H), 1.64-1.49 (m, 6 H), 1, 49-1.34 (m, 2 H).

[00888] Compound 382 (N,N-diethyl-N'-[1-(6-methoxy-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine): From 4 -chloro-6-methoxyquinoline, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: > 99% purity, Retention Time = 1.31 min. MS: m/z = 371 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.60 (d, J = 4.9 Hz, 1 H), 7.95 (d, J = 9.1 Hz, 1 H), 7.31 (dd, J = 9.1, 2.9 Hz, 1 H), 7.27 (d, J = 2.8 Hz, 1 H), 6.83 (d, J = 5.0 Hz, 1 H ), 3.94 (s, 3 H), 3.58 (d, J = 11.7 Hz, 2 H), 3.29 (s, 2 H), 3.25 (d, J = 6.8 Hz, 2 H), 2.77 (t, J = 11.8 Hz, 2 H), 2.57 (q, J = 7.1 Hz, 6 H), 1.86 (d, J = 10, 9 Hz, 3 H), 1.68-1.53 (m, 2 H), 1.48 (s, 9H), 1.06 (t, J = 7.1 Hz, 6 H).

[00889] Compound 383 (N,N-diethyl-N'-[1-(7-fluoro-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine: From 4- chloro-7-fluoroquinoline, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: 98.7% purity, Retention Time = 1.20 min. H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.68 (d, J = 5.0 Hz, 1 H), 7.99 (dd, J = 9.3, 6.2 Hz , 1 H), 7.64 (dd, J = 10.2, 2.6 Hz, 1 H), 7.23 (ddd, J = 9.3, 8.0, 2.6 Hz, 1 H) , 6.80 (d, J = 5.1 Hz, 1 H), 3.59 (d, J = 12.4 Hz, 2 H), 2.84 (td, J = 12.1, 2.1 Hz, 2 H), 2.70 (t, J = 6.1 Hz, 2 H), 2.63 (d, J = 6.6 Hz, 2 H), 2.58 (t, J = 6, 1 Hz, 2 H), 2.54 (q, J = 7.1 Hz, 4 H), 1.94 (dd, J = 12.4, 3.2 Hz, 2 H), 1.73 (dtt , J = 14.1, 6.8, 3.9 Hz, 1 H), 1.57 (qd, J = 12.2, 3.8 Hz, 2 H), 1.03 (t, J = 7 ,1Hz, 6H).

[00890] Compound 384 (N,N-diethyl-N'-[1-(6-methyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine): From 4 -chloro-6-methylquinoline, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: > 99% purity, Retention Time = 1.36 min. EM: m/z = 355 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.64 (d, J = 4.9 Hz, 1 H), 7.92 (d, J = 8.6 Hz, 1 H), 7.75 (s, 1 H), 7.46 (dd, J = 8.6, 2.0 Hz, 1 H), 6.80 (d, J = 5.0 Hz, 1 H), 3.61 (d , J = 12.3 Hz, 2 H), 2.80 (td, J = 12.0, 2.3 Hz, 2 H), 2.71 (t, J = 6.1 Hz, 2 H), 2.64 (d, J = 6.6 Hz, 2 H), 2.58 (t, J = 5.8 Hz, 2 H), 2.57-2.49 (m, 7H), 1.94 (dd, J = 12.6, 3.3 Hz, 2 H), 1.73 (ddp, J = 9.8, 6.4, 3.8, 3.3 Hz, 1 H), 1.60 (qd, J = 12.0, 3.8 Hz, 2 H), 1.03 (t, J = 7.1 Hz, 6 H).

[00891] Compound 385 (N,N-diethyl-N'-[1-(6-fluoro-2,3-dimethyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine ): From 4-chloro-6-fluoro-2,3-dimethylquinoline, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: 97.2% purity, Retention Time = 1.33 min. MS: m/z = 387 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 7.93 (dd, J = 9.1, 5.5 Hz, 1 H), 7.74 (s, 1 H), 7.33 (ddd, J = 9.1, 8.0, 2.9 Hz, 1 H), 3.33 (s, 2 H), 3.17 (d, J = 11.8 Hz, 2 H), 2.72 ( t, J = 6.2 Hz, 2 H), 2.68-2.61 (m, 5 H), 2.60 (d, J = 5.8 Hz, 2 H), 2.55 (q, J = 7.1 Hz, 4 H), 2.37 (s, 3 H), 1.86 (d, J = 12.1 Hz, 2 H), 1.73 (s, 1 H), 1, 51 (q, J = 11.7 Hz, 2 H), 1.03 (t, J = 7.1 Hz, 6 H).

[00892] Compound 386 (N,N-diethyl-N'-[1-(7-fluoro-2-methyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine): From 4-chloro-7-fluoro-2-methylquinoline, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: > 99% purity, Retention Time = 1.13 min. EM: m/z = 373 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 7.92 (dd, J = 9.2, 6.2 Hz, 1 H), 7.56 (dd, J = 10.4, 2.6 Hz , 1 H), 7.17 (ddd, J = 9.2, 8.0, 2.6 Hz, 1 H), 6.69 (s, 1 H), 3.57 (d, J = 12, 3 Hz, 2 H), 2.81 (td, J = 12.1, 2.3 Hz, 2 H), 2.70 (t, J = 6.1 Hz, 2 H), 2.64 (s , 3 H), 2.63 (d, J = 6.6 Hz, 2 H), 2.58 (t, J = 6.0 Hz, 2 H), 2.53 (q, J = 7.1 Hz, 4 H), 1.93 (dd, J = 12.6, 2.4 Hz, 2 H), 1.73 (dtd, J = 13.9, 7.5, 6.7, 3.6 Hz, 1 H), 1.56 (qd, J = 12.1, 3.8 Hz, 2 H), 1.03 (t, J = 7.1 Hz, 6 H).

[00893] Compound 387 ((2-Piperidin-1-yl-ethyl)-[1-(6-trifluoromethyl-quinolin-4-yl)-piperidin-4-ylmethyl]-amine): From 4-chloro- 6-(trifluoromethyl)quinolone, 4-formyl-n-cbz-piperidine and 1-(2-aminoethyl)piperidine. HPLC: 89.3% purity, Retention Time = 1.57 min. EM: m/z = 421[M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.78 (d, J = 5.1 Hz, 1 H), 8.29 (s, 1 H), 8.12 (d, J = 8, 8 Hz, 1 H), 7.80 (dd, J = 8.8, 2.1 Hz, 1 H), 6.90 (d, J = 5.1 Hz, 1 H), 3.62 (d , J = 12.6 Hz, 2 H), 2.88 (td, J = 12.2, 2.4 Hz, 2 H), 2.74 (t, J = 6.3 Hz, 2 H), 2.65 (d, J = 6.7 Hz, 2 H), 2.47 (t, J = 6.3 Hz, 2 H), 2.39 (s, 4 H), 1.97 (dd, J = 12.7, 3.2 Hz, 2 H), 1.76 (dt, J = 11.4, 3.0 Hz, 1 H), 1.67-1.50 (m, 6 H), 1.44 (td, J = 6.2, 3.3 Hz, 2 H).

[00894] Compound 389 (N,N-diethyl-N'-[1-(7-methyl-quinolin-4-yl)-piperidin-4-ylmethyl]-ethane-1,2-diamine): From 4 -chloro-7-methylquinoline, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: 96.5% purity, Retention Time = 1.29 min. MS: m/z = 355 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.65 (d, J = 5.0 Hz, 1 H), 7.88 (d, J = 8.5 Hz, 1 H), 7.80 (s, 1 H), 7.29 (dd, J = 8.6, 1.8 Hz, 1 H), 6.77 (d, J = 5.0 Hz, 1 H), 3.62 (d , J = 12.4 Hz, 2 H), 2.81 (td, J = 12.1, 2.3 Hz, 2 H), 2.70 (t, J = 6.1 Hz, 2 H), 2.63 (d, J = 6.6 Hz, 2 H), 2.62-2.44 (m, 9H), 1.93 (dd, J = 12.6, 2.3 Hz, 2 H) , 1.73 (ddq, J = 13.9, 6.7, 3.6 Hz, 1 H), 1.58 (qd, J = 12.0, 3.8 Hz, 2 H), 1.03 (t, J = 7.1 Hz, 6 H).

[00895] Compound 401 (5-{4-[(2-diethylamino-ethylamino)-methyl]-piperidin-1-yl}-quinoline-8-carbonitrile): From 5-bromo-quinoline-8-carbonitrile, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: > 99% purity, Retention Time = 1.67 min. EM: m/z = 366 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.7 Hz, 1 H), 8.43 (dd, J = 8.6, 1.7 Hz , 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = 8.6, 4.2 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 3.50 (d, J = 11.9 Hz, 2 H), 2.87 (td, J = 12.0, 2.3 Hz, 2 H), 2, 71 (t, J = 6.1 Hz, 2 H), 2.64 (d, J = 6.6 Hz, 2 H), 2.62 - 2.46 (m, 6 H), 1.96 ( tt, J = 12.4, 2.1 Hz, 3 H), 1.73 (dtt, J = 14.0, 6.7, 3.7 Hz, 1 H), 1.58 (qd, J = 12.0, 3.8 Hz, 2 H), 1.03 (t, J = 7.1 Hz, 5 H). Example 107: Synthesis of compound 393 (cis-5-(2,6-dimethyl-morpholin - 4-yl)-quinazoline-8-carbonitrile)

[00896] Cis-5-(2,6-dimethyl-morpholin-4-yl)-quinazoline-8-carbonitrile: cis-5-(2,6-dimethyl-morpholin-4-yl)-quinazoline-8-carbonitrile was obtained from 5-bromo-quinazoline-8-carbonitrile and cis-2,6-dimethylmorpholine in 79% production, using method H. Compound 393: HPLC: > 99% purity, Retention Time = 2.70 min. EM: m/z = 269 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.61 (s, 1 H), 9.43 (s, 1 H), 8.16 (d, J = 8.2 Hz, 1 H), 7.07 (d, J = 8.2 Hz, 1 H), 4.03 (dqd, J = 10.2, 6.3, 2.1 Hz, 2 H), 3.41 (dt, J = 11.8, 1.8 Hz, 2 H), 2.77 (dd, J = 12.2, 10.3 Hz, 2 H), 1.28 (d, J = 6.3 Hz, 6 H) .

[00897] The following compounds were synthesized in an analogous manner:

[00898] Compound 455 (cis-5-(2,6-dimethyl-morpholin-4-yl)-8-fluoro-pyrido[3,4-b]pyrazine): From 5-chloro-8-fluoropyrido[ 3,4-b]pyrazine and cis-2,6-dimethylmorpholine. HPLC: > 99% purity, Retention Time = 2.38 min. EM: m/z = 263 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.96 (d, J = 1.9 Hz, 1 H), 8.80 (d, J = 1.8 Hz, 1 H), 8.23 (d, J = 1.3 Hz, 1 H), 4.72 - 4.56 (m, 2 H), 3.91 (dqd, J = 10.4, 6.2, 2.2 Hz, 2 H), 2.81 (dd, J = 12.9, 10.4 Hz, 2 H), 1.27 (d, J = 6.3 Hz, 6 H).Example 108: Synthesis of compound 395 (N -[1-(8-cyano-quinazolin-5-yl)-piperidin-4-ylmethyl]-2-diethylamino-acetamide)

[00899] N-[1-(8-cyano-quinazolin-5-yl)-piperidin-4-ylmethyl]-2-diethylamino-acetamide): N-[1-(8-cyano-quinazolin-5-yl) -piperidin-4-ylmethyl]-2-diethylamino-acetamide) was obtained from 5-bromo-quinazoline-8-carbonitrile, 2-(diethylamino)acetic acid hydrochloride and 1-boc-4-(aminomethyl)piperidine in 40% production during 3 steps, using method 20, Q and H. Compound 395: HPLC: > 99% purity, Retention Time = 1.88 min. EM: m/z = 381 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.54 (s, 1 H), 9.39 (s, 1 H), 8.12 (d, J = 8.2 Hz, 1 H), 7.62 (t, J = 5.9 Hz, 1 H), 7.05 (d, J = 8.2 Hz, 1 H), 3.65 (dt, J = 13.0, 2.8 Hz , 2 H), 3.31 (t, J = 6.5 Hz, 2 H), 3.06 (s, 2 H), 3.01 (td, J = 12.2, 2.4 Hz, 2 H), 2.58 (q, J = 7.1 Hz, 4 H), 1.93 (dd, J = 13.3, 3.1 Hz, 2 H), 1.84 (dtt, J = 14 .4, 6.9, 4.0 Hz, 1 H), 1.62 (qd, J = 12.4, 3.9 Hz, 2 H), 1.05 (t, J = 7.1 Hz, 6 H).

[00900] The following compounds were synthesized in an analogous manner:

[00901] Compound 397 (2-diethylamino-ethyl)-amide) of (1-(8-cyano-quinazolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo-quinazoline-8-carbonitrile , 1-tert-butoxycarbonylpiperidine-4-carboxylic acid and N,N-diethylethylenediamine: > 99% purity, Retention Time = 1.75 min. NMR (400 MHz, Chloroform-d, ppm) δ 9.58 (s, 1 H), 9.41 (s, 1 H), 8.13 (d, J = 8.2 Hz, 1 H), 7 .06 (d, J = 8.2 Hz, 1 H), 6.28 (s, 1 H), 3.69 (dt, J = 12.1, 2.4 Hz, 2 H), 3.34 (q, J = 5.1 Hz, 2 H), 3.06 (ddd, J = 12.3, 10.3, 3.8 Hz, 2 H), 2.63-2.47 (m, 6 H), 2.39 (tt, J = 10.2, 5.1 Hz, 1 H), 2.19-2.03 (m, 4 H), 1.03 (t, J = 7.1 Hz , 6H).

[00902] Compound 398 (N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-2-diethylamino-acetamide): From 5-bromo-quinoline-8-carbonitrile, 2-(diethylamino)acetic acid hydrochloride and 2-(diethylamino)acetic acid hydrochloride. HPLC: 98.8% purity, Retention Time = 2.13 min. EM: m/z = 380 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1 H), 8.41 (dd, J = 8.5, 1.7 Hz , 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.60 (s, 1 H), 7.47 (dd, J = 8.5, 4.2 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 3.50 (d, J = 11.9 Hz, 2 H), 3.32 (t, J = 6.5 Hz, 2 H), 3.07 (s, 2 H), 2.86 (td, J = 12.0, 2.2 Hz, 2 H), 2.59 (q, J = 7.1 Hz, 4 H ), 1.90 (d, J = 12.6 Hz, 2 H), 1.78 (dtt, J = 14.4, 6.8, 3.6 Hz, 1 H), 1.62 (qd, J = 12.1, 3.8 Hz, 2 H), 1.06 (t, J = 7.1 Hz, 6 H).

[00903] Compound 403 ((2-piperidin-1-yl-ethyl)-1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid amide): From 5-bromoquinoline -8-carbonitrile, 1-tert-butoxycarbonylpiperidine-4-carboxylic acid and 1-(2-aminoethyl)piperidine. HPLC: 96.7% purity, Retention Time = 2.07 min. EM: m/z = 392 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.06 (dd, J = 4.2, 1.7 Hz, 1 H), 8.45 (dd, J = 8.6, 1.7 Hz , 1 H), 8.02 (d, J = 8.0 Hz, 1 H), 7.49 (dd, J = 8.5, 4.2 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.22 (s, 1 H), 3.54 (d, J = 12.3 Hz, 2 H), 3.37 (q, J = 5.6 Hz, 2 H), 2.91 (td, J = 11.9, 2.8 Hz, 2 H), 2.76 - 2.23 (m, 7H), 2.13 (qd, J = 12.2, 11.3, 3.8 Hz, 2 H), 2.08 - 1.94 (m, 2 H), 1.73 - 1.52 (m, 4 H), 1.53 - 1.36 (m , 2 H).

[00904] Compound 407 (2-diethylamino-ethyl)-amide (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid: From 5-bromo-quinoline-8-carbonitrile, 1-tert-butoxycarbonylpiperidine-4-carboxylic acid and N,N-diethylethylenediamine. HPLC: 98.2% purity, Retention Time = 2.01 min. NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1 H), 8.44 (dd, J = 8.5, 1.7 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H), 7.49 (dd, J = 8.6, 4.2 Hz, 1 H), 7.05 (d, J = 8.0 Hz, 1 H), 6.25 (s, 1 H), 3.53 (d, J = 12.6 Hz, 2 H), 3.34 (q, J = 5.5 Hz, 2 H), 2.90 (td, J = 11.8, 2.8 Hz, 2 H), 2.69 - 2.44 (m, 6 H), 2.35 (tt, J = 11.1, 4.3 Hz, 1 H), 2.22 - 1.92 (m, 4 H), 1.03 (t, J = 7.1 Hz, 6 H).Example 109: Synthesis of compound 404 (2- (3-Methoxy-phenylamino)-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide) Method 36

[00905] 2-(3-Methoxy-phenylamino)-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide: a solution of 2-[(3) - methoxyphenyl)amino]acetic acid (77.7 mg; 0.429 mmol) and 1,1'-carbonyldiimidazole (69.6 mg; 0.429 mmol) in anhydrous THF (2.0 mL) was stirred at room temperature for 15 minutes before C-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-yl)-methylamine hydrochloride (80.0 mg, 0.286 mmol) will be added. The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The residue was dissolved in DCM and purified by chromatography on a 35 g, 30 μm Puri Flash NH2 column, eluting with a gradient of methanol in DCM to provide 2-(3-methoxy-phenylamino)-N-(1-pyrido[ 2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide (63 mg; 54.2%).(Note: In Method 36, the solvent may also be DMF instead of THF) Compound 404 : HPLC: > 99% purity, Retention Time = 1.93 min. MS: m/z = 407 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1 H), 8.79 (d, J = 5.4 Hz, 1 H), 8.71 (d, J = 1.7 Hz, 1 H), 7.11 (t, J = 8.1 Hz, 1 H), 6.87 (s, 1 H), 6.85 (d, J = 5 .5 Hz, 1 H), 6.37 (ddd, J = 8.2, 2.3, 0.8 Hz, 1 H), 6.24 (ddd, J = 8.1, 2.3, 0 .9 Hz, 1 H), 6.18 (t, J = 2.3 Hz, 1 H), 4.40 (d, J =12.4 Hz, 2 H), 3.82 (s, 2 H ), 3.76 (s, 3 H), 3.27 (t, J = 6.4 Hz, 2 H), 3.02 (td, J = 12.4, 2.4 Hz, 2 H), 1.95 - 1.73 (m, 3 H), 1.51 (qd, J = 12.0, 3.9 Hz, 2 H).

[00906] The following compounds were synthesized in an analogous manner:

[00907] Compound 406 (2-tert-Butylamino-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide): From C-(1) hydrochloride -pyrido[2,3-b]pyrazin-8-yl-piperidin-4-yl)-methylamine and 2-(tert-butylamino)acetic acid hydrochloride. HPLC: 98.1% purity, Retention Time = 1.11 min. MS: m/z = 357 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J = 1.7 Hz, 1 H), 8.79 (d, J = 5.4 Hz, 1 H), 8.72 (d, J = 1.7 Hz, 1 H), 7.67 (s, 1 H), 6.87 (d, J = 5.4 Hz, 1 H), 4.44 (d, J = 12 .1 Hz, 2 H), 3.33 - 3.19 (m, 4 H), 3.07 (td, J = 12.5, 2.3 Hz, 2 H), 1.90 - 1.84 (m, 2 H), 1.73 - 1.64 (m, 1 H), 1.57 (qd, J = 12.3, 11.8, 3.8 Hz, 2 H), 1.09 ( s, 8H).

[00908] Compound 413 (2-tert-Butylamino-N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide): From 5-bromo-quinoline-8- carbonitrile, 4-(boc-aminomethyl)piperidine and 2-(tert-butylamino)acetic acid hydrochloride. HPLC: 97.7% purity, Retention Time = 2.19 min. EM: m/z = 380 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J = 4.2, 1.7 Hz, 1 H), 8.41 (dd, J = 8.6, 1.7 Hz , 1 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.73 (s, 1 H), 7.47 (dd, J = 8.5, 4.2 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 3.50 (d, J = 12.3 Hz, 3 H), 3.32 (t, J = 6.5 Hz, 2 H), 3.29 (s,2 H), 2.85 (td, J = 12.0, 2.3 Hz, 2 H), 1.91 (d, J = 12.0 Hz, 2 H ), 1.78 (dddd, J = 17.6, 10.3, 6.8, 3.1 Hz, 1 H), 1.62 (qd, J = 12.0, 3.8 Hz, 2 H ), 1.12 (s, 9 H). Example 110: Synthesis of compound 425 (N-[1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylamino-acetamide)

[00909] N-[1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylamino-acetamide: N-[1-(8-cyano-quinolin -5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylamino-acetamide was obtained from 5-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoline hydrochloride -8-carbonitrile and N,N- dimethylglycine in 39% production, using method 20.

[00910] Compound 425: HPLC: 96.6% purity, Retention Time = 2.16 min. MS: m/z = 374 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.11 (dd, J = 4.2, 1.7 Hz, 1 H), 8.65 (dd, J = 8.6, 1.7 Hz , 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.87 (s, 1 H), 7.57 (dd, J = 8.6, 4.2 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 4.63 (s, 1 H), 3.51 (q, J = 10.7, 10.3 Hz, 1 H) , 3.41 (q, J = 12.4 Hz, 1 H), 3.37 - 3.16 (m, 2 H), 3.06 - 2.84 (m, 2 H), 2.45 - 2.31 (m, 1 H), 2.28 (s, 6 H), 1.56 (s, 1 H).Example 111: Synthesis of compound 436 ([2-(ethyl-methyl-amino)-ethyl ]- 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid amide)

[00911] [2-(Ethyl-methyl-amino)-ethyl]-amide trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid: From [2- (ethyl-methyl-amino)-ethyl]- 1-(8-Trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid amide was obtained from 5-bromo-8-(trifluoromethyl)quinolone, ethyl piperidine-4-carboxylate and (2-aminoethyl)(ethyl) )methylamine at 48% production during 3 steps, using method V, I and 20. Compound 436: HPLC: 98.3% purity, Retention Time = 2.55 min. MS: m/z = 409 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.8 Hz, 1 H), 8.50 (dd, J = 8.6, 1.8 Hz , 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = 8.6, 4.2 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.25 (s, 1 H), 3.47 (dt, J = 12.6, 3.5 Hz, 2 H), 3.40 (d, J = 6 .2 Hz, 2 H), 2.86 (td, J = 11.9, 2.7 Hz, 2 H), 2.53 (s, 4 H), 2.42 - 2.20 (m, 4 H), 2.13 (qd, J = 12.1, 11.3, 3.8 Hz, 2 H), 2.04 (dd, J = 12.8, 3.6 Hz, 2 H), 1 .10 (t, J = 5.9 Hz, 3 H).

[00912] The following compounds were synthesized in an analogous manner:

[00913] Compound 441 ((2-piperidin-1-yl-ethyl)-1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid amide): From 5-bromo-8 -(trifluoromethyl)quinolone, ethyl piperidine-4-carboxylate and 1-(2-aminoethyl)piperidine. HPLC: 98.0% purity, Retention Time = 2.63 min. EM: m/z = 435 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.03 (dd, J = 4.2, 1.8 Hz, 1 H), 8.50 (dd, J = 8.6, 1.8 Hz , 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = 8.6, 4.2 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.24 (s, 1 H), 3.47 (dt, J = 11.9, 2.6 Hz, 2 H), 3.37 (td, J = 6 ,1, 4.8 Hz, 2 H), 2.86 (td, J = 11.8, 2.7 Hz, 2 H), 2.47 (t, J = 6.0 Hz, 2 H), 2.44 - 2.27 (m, 5 H), 2.13 (qd, J = 12.1, 11.3, 3.8 Hz, 2 H), 2.08 - 1.96 (m, 2 H), 1.59 (p, J = 5.6 Hz, 4 H), 1.52 - 1.38 (m, 2 H).

[00914] Compound 442 ((1-methyl-pyrrolidin-2-ylmethyl)-1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid amide): From 5-bromo-8 -(trifluoromethyl)quinolone, ethyl piperidine-4-carboxylate and (1-methylpyrrolidin-2-yl)methanamine. HPLC: 98.7% purity, Retention Time = 2.55 min. EM: m/z = 421 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.8 Hz, 1 H), 8.50 (dd, J = 8.6, 1.8 Hz , 1 H), 7.97 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = 8.6, 4.2 Hz, 1 H), 7.06 (d, J = 7.9 Hz, 1 H), 6.12 (d, J = 7.8 Hz, 1 H), 3.66 (ddd, J = 13.7, 7.9, 2.5 Hz, 1 H ), 3.47 (dt, J = 12.1, 3.3 Hz, 2 H), 3.13 (ddd, J = 13.7, 4.1, 2.4 Hz, 1 H), 3, 07 (ddd, J = 9.3, 6.8, 2.5 Hz, 1 H), 2.86 (tt, J = 11.8, 3.2 Hz, 2 H), 2.46 - 2, 38 (m, 1 H), 2.33 (s, 3 H), 2.24 (td, J = 9.4, 7.5 Hz, 1 H), 2.14 (qt, J = 11.3 , 3.3 Hz, 2 H), 2.03 (dd, J = 13.5, 3.6 Hz, 2 H), 1.96 - 1.83 (m, 1 H), 1.80 - 1 .65 (m, 2 H), 1.60 - 1.47 (m, 2 H).

[00915] Compound 446 ((2-diethylamino-ethyl)-1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid amide): From 5-bromo-8-(trifluoromethyl) quinolone, ethyl piperidine-4-carboxylate en,n-diethylethylenediamine. HPLC: > 99% purity, Retention Time = 2.63 min. MS: m/z = 423 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.8 Hz, 1 H), 8.49 (dd, J = 8.6, 1.8 Hz , 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 7.47 (dd, J = 8.6, 4.2 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 6.25 (s, 1 H), 3.47 (dt, J = 11.8, 2.8 Hz, 2 H), 3.34 (q, J = 5 .3 Hz, 2 H), 2.86 (td, J = 11.8, 2.8 Hz, 2 H), 2.63 - 2.49 (m, 6 H), 2.34 (tt, J = 11.2, 4.3 Hz, 1 H), 2.12 (qd, J = 12.2, 11.2, 3.8 Hz, 2 H), 2.07 - 1.97 (m, 2 H), 1.04 (t, J = 7.1 Hz, 6 H). Example 112: Synthesis of compound 443 (2-diethylamino-N-[1-(8-trifluoromethyl-quinolin-5-yl)-piperidin -4-ylmethyl]-acetamide)

[00916] 2-Diethylamino-N-[1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide: 2-diethylamino-N-[1-(8-trifluoromethyl-quinolin-5 -yl)-piperidin-4-ylmethyl]-acetamide was obtained from 5-bromo-8-trifluoromethyl-quinoline, 4-(boc-aminomethyl)piperidine and 2-(diethylamino)acetic acid hydrochloride at 55% production during 3 steps, using method V, Q and 20. Compound 443: HPLC: > 99% purity, Retention Time = 2.76 min. MS: m/z = 423 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.02 (dd, J = 4.2, 1.8 Hz, 1 H), 8.45 (dd, J = 8.6, 1.8 Hz , 1 H), 7.95 (d, J= 8.1 Hz, 1 H), 7.60 (s, 1 H), 7.44 (dd, J = 8.6, 4.2 Hz, 1 H), 7.04 (d, J =8.0 Hz, 1 H), 3.43 (dt, J = 12.7, 2.9 Hz, 2 H), 3.32 (t, J = 6 .5 Hz, 2 H), 3.06 (s, 2 H), 2.81 (td, J = 11.9, 2.3 Hz, 2 H), 2.58 (q, J = 7.2 Hz, 4H),1.89 (dd, J = 12.8, 3.0Hz, 2H), 1.77 (ddtd, J = 13.6, 10.0, 6.6, 3.6 Hz, 1 H), 1.62 (qd, J = 11.9, 3.8 Hz, 2 H), 1.05 (t, J = 7.2 Hz, 6 H).

[00917] The following compounds were synthesized in a similar way:

[00918] Compound 448 (2-Piperidin-1-yl-N-[1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide): From 5-bromo-8- trifluoromethyl-quinoline, 4-(boc-aminomethyl)piperidine and piperidin-1-yl-acetic acid. HPLC: 97.6% purity, Retention Time = 2.79 min. MS: m/z = 435 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.03 (dd, J = 4.2, 1.8 Hz, 1 H), 8.46 (dd, J = 8.6, 1.8 Hz , 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.45 (dd, J = 8.6, 4.2 Hz, 2 H), 7.05 (d, J = 8.0 Hz, 1 H), 3.44 (dt, J = 11.7, 2.4 Hz, 2 H), 3.33 (t, J = 6.5 Hz, 2 H), 2, 99 (s, 2 H), 2.82 (td, J = 11.9, 2.3 Hz, 2 H), 2.49 (t, J = 5.3 Hz, 4 H), 1.89 ( dd, J = 12.3, 2.6 Hz, 2 H), 1.77 (tdd, J = 10.0, 8.6, 5.0 Hz, 1 H), 1.70 - 1.54 ( m, 6 H), 1.54 - 1.42 (m, 2 H). Example 113: Synthesis of compound 444 and compound 445 ((R)-1-cyclopropylmethyl-pyrrolidin-3-yl)-amide acid ( 1-(8-Trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid and ((S)-1-cyclopropylmethyl-pyrrolidin-3-yl)-amide) 1-(8-trifluoromethyl-quinolin-5 -yl)- piperidine-4-carboxylic acid

[00919] ((R)-1-cyclopropylmethyl-pyrrolidin-3-yl)-amide of 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid and ((S)-1-cyclopropylmethyl -pyrrolidin-3-yl)-amide 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid: ((R)-1-cyclopropylmethyl-pyrrolidin-3-yl)-amide 1-(8-Trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid and ((S)-1-cyclopropylmethyl-pyrrolidin-3-yl)-amide 1-(8-trifluoromethyl-quinolin-5- yl)-piperidine-4-carboxylic acid were prepared from 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid and 1-(cyclopropylmethyl)pyrrolidin-3-amine at 62% production using method 20 Enantiomers were isolated using chiral SFC chromatography. (Column: 1.0 x 25.0 cm Lux Amylose-1); CO2 Co-Solvent (Solvent B): ethanol with 0.5% dimethylamine; Isocratic Method: 55% Co-Solvent at 10 mL/min; System pressure: 100 bar; Column temperature: 40°C).Isomer 1: HPLC: 98.6% purity, Retention Time = 2.84 min. EM: m/z = 447 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.8 Hz, 1 H), 8.49 (dd, J = 8.6, 1.8 Hz , 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = 8.6, 4.2 Hz, 1 H), 7.06 (d, J = 7.9 Hz, 1 H), 5.95 (s, 1 H), 4.50 (dddd, J = 10.6, 8.5, 4.5, 2.8 Hz, 1 H), 3 .47 (d, J = 12.5 Hz, 2 H), 3.02 (td, J = 8.7, 3.5 Hz, 1 H), 2.84 (td, J = 11.8, 2 .6 Hz, 2 H), 2.77 (dd, J = 10.1, 2.4 Hz, 1 H), 2.53 (dd, J = 10.0, 6.5 Hz, 1 H), 2.41 - 2.19 (m, 5 H), 2.12 (qd, J = 12.0, 11.5, 3.7 Hz, 2 H), 2.06 - 1.96 (m, 2 H), 1.63 (dtd, J = 11.9, 7.9, 3.7 Hz, 1 H), 0.89 (dddd, J = 11.5, 8.1, 4.8, 2, 4 Hz, 1 H), 0.58 - 0.45 (m, 2 H), 0.13 (ddd, J = 6.7, 4.9, 3.7 Hz, 2 H). Isomer 2: HPLC: > 99% purity, Retention Time = 2.84 min. MS: m/z = 447 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.8 Hz, 1 H), 8.49 (dd, J = 8.6, 1.8 Hz , 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.47 (dd, J = 8.6, 4.2 Hz, 1 H), 7.06 (d, J = 8.0 Hz, 1 H), 5.96 (s, 1 H), 4.52 (s, 1 H), 3.47 (d, J = 11.9 Hz, 2 H), 3.04 (s, 1 H), 2.84 (td, J = 11.9, 2.7 Hz, 2 H), 2.78 (d, J = 8.2 Hz, 1 H), 2.54 (dd , J = 10.1, 6.5 Hz, 1 H), 2.47 - 2.19 (m, 4 H), 2.12 (qd, J = 11.9, 11.4, 3.7 Hz , 2 H), 2.02 (d, J = 12.8 Hz, 2 H), 1.62 (s, 2 H), 0.98 - 0.82 (m, 1 H), 0.65 - 0.41 (m, 2 H), 0.14 (q, J = 5.0 Hz, 2 H).Example 114: Synthesis of compound 447 (N-[(3R,5S)-1-(8-cyano - quinazolin-5-yl)-5-methyl-piperidin-3-yl]-2-dimethylamino-acetamide)

[00920] N-[(3R,5S)-1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-2-dimethylamino-acetamide: N-[(3R,5S )-1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-2-dimethylamino-acetamide was prepared from 5-[(3R,5S)-3-amino-hydrochloride 5-methyl-1-piperidyl]quinazoline-8-carbonitrile and N,N-dimethylglycine in 77% production, using method 20.

[00921] Compound 447: HPLC: 97.2% purity, Retention Time = 2.01 min. EM: m/z = 353 [M + H]+. 1H NMR (400 MHz, Chloroform-d, pppm) δ 9.61 (s, 1 H), 9.41 (s, 1 H), 8.11 (d, J = 8.2 Hz, 1 H), 7.14 (d, J = 8.9 Hz, 1 H), 7.11 (d, J = 8.2 Hz, 1 H), 4.34 - 4.20 (m, 1 H), 3, 92 (ddt, J = 11.7, 4.0, 1.9 Hz, 1 H), 3.61 (ddd, J = 12.3, 4.0, 2.0 Hz, 1 H), 2, 96 (s, 2 H), 2.76 - 2.59 (m, 2 H), 2.30 (s, 6 H), 2.26 - 2.05 (m, 2 H), 1.18 ( q, J = 11.9 Hz, 1 H), 1.01 (d, J = 6.5 Hz, 3 H).

[00922] The following compounds were synthesized in an analogous manner:

[00923] Compound 460 (2-dimethylamino-N-[(3R,5S)-1-(8-fluoro-pyrido[3,4-b]pyrazin-5-yl)-5-methyl-piperidin-3-yl ]-acetamide): From (3R,5S)-1-(8-fluoro-pyrido[3,4-b]pyrazin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride and N, N-dimethylglycine. HPLC: > 99% purity, Retention Time = 1.65 min. MS: m/z = 347 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J = 1.8 Hz, 1 H), 8.82 (d, J = 1.8 Hz, 1 H), 8.21 (d, J = 1.4 Hz, 1 H), 7.12 (d, J = 8.5 Hz, 1 H), 4.90 (ddt, J = 12.3, 4.1, 1.8 Hz, 1 H), 4.66 (ddt, J = 12.7, 3.8, 1.8 Hz, 1 H), 4.25 - 4.13 (m, 1 H), 3.01 - 2 .89 (m, 2 H), 2.79 (dd, J = 12.3, 10.7 Hz, 1 H), 2.61 (dd, J = 12.7, 11.0 Hz, 1 H) , 2.30 (s, 6 H), 2.22 - 2.14 (m, 1 H), 2.08 (dddt, J = 14.9, 10.8, 7.8, 3.6 Hz, 1 H), 1.13 (q, J = 11.8 Hz, 1 H), 1.00 (d, J = 6.7 Hz, 3 H).

[00924] Compound 466 (N-[(3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-yl]-2-morpholin-4-yl-acetamide) : From (3R,5S)-5-methyl-1-(8-methyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 2-morpholinoacetic acid hydrochloride. HPLC: > 99% purity, Retention Time = 1.62 min. EM: m/z = 383 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.93 (dd, J = 4.2, 1.8 Hz, 1 H), 8.54 (dd, J = 8.5, 1.8 Hz , 1 H), 7.48 - 7.38 (m, 2 H), 7.02 (d, J = 7.6 Hz, 1 H), 6.98 (s, 1 H), 4.42 - 4.26 (m, 1 H), 3.71 (t, J = 4.6 Hz, 4 H), 3.52 (ddt, J = 10.8, 4.1, 1.7 Hz, 1 H ), 3.22 (ddt, J = 11.4, 3.7, 1.7 Hz, 1 H), 3.08 - 2.93 (m, 2 H), 2.74 (d, J = 0 .9 Hz, 3 H), 2.60 - 2.44 (m, 4 H), 2.39 (td, J = 10.8, 2.1 Hz, 2 H), 2.24 - 2.07 (m, 2 H), 1.11 - 0.93 (m, 4 H).

[00925] Compound 469 (2-dimethylamino-N-[(3R,5S)-1-(8-fluoro-quinolin-5-yl)-5-methyl-piperidin-3-yl]-acetamide): from hydrochloride (3R,5S)-1-(8-fluoro-quinolin-5-yl)-5-methyl-piperidin-3-ylamine and N,N-dimethylglycine. HPLC: 94.0% purity, Retention Time = 1.70 min. MS: m/z = 345 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (dd, J = 4.2, 1.7 Hz, 1 H), 8.55 (dt, J = 8.6, 1.7 Hz , 1 H), 7.50 (dd, J = 8.6, 4.2 Hz, 1 H), 7.29 (dd, J = 10.4, 8.3 Hz, 1 H), 7.07 (d, J = 8.5 Hz, 1 H), 7.02 (dd, J = 8.3, 4.2 Hz, 1 H), 4.32 (dddd, J = 14.6, 10.5 , 8.4, 4.1 Hz, 1 H), 3.52 (ddt, J = 10.9, 4.1, 1.8 Hz, 1 H), 3.20 (ddt, J = 11.3 , 3.7, 1.8 Hz, 1 H), 2.93 (d, J = 2.2 Hz, 2 H), 2.39 (q, J = 10.9 Hz, 2 H), 2, 28 (s, 6 H), 2.21 - 2.04 (m, 2 H), 1.11 - 0.92 (m, 4 H).

[00926] Compound 470 (N-[(3R,5S)-1-(8-Fluoro-quinolin-5-yl)-5-methyl-piperidin-3-yl]-2-morpholin-4-yl-acetamide) : From (3R,5S)-1-(8-fluoro-quinolin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride and 2-morpholinoacetic acid hydrochloride. HPLC: > 99% purity, Retention Time = 1.73 min. MS: m/z = 387 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (dd, J = 4.1, 1.7 Hz, 1 H), 8.55 (dt, J = 8.6, 1.7 Hz , 1 H), 7.50 (dd, J = 8.6, 4.2 Hz, 1 H), 7.29 (dd, J = 10.4, 8.3 Hz, 1 H), 7.03 (dd, J = 8.3, 4.2 Hz, 1 H), 6.99 (s, 1 H), 4.41 - 4.23 (m, 1 H), 3.71 (s, 4 H ), 3.55 - 3.46 (m, 1 H), 3.25 - 3.16 (m, 1 H), 3.00 (s, 2 H), 2.51 (s, 4 H), 2.44 - 2.27 (m, 2 H), 2.22 - 2.05 (m, 2 H), 1.11 - 0.90 (m, 4 H).

[00927] Compound 471 (N-[(3R,5S)-1-(8-Fluoro-quinolin-5-yl)-5-methyl-piperidin-3-yl]-2-(1-methyl-piperidin-4 -yl)-acetamide): From (3R,5S)-1-(8-fluoro-quinolin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride and 1-methyl-4-piperidineacetic acid . HPLC: > 99% purity, Retention Time = 1.84 min. MS: m/z = 399 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (dd, J = 4.2, 1.7 Hz, 1 H), 8.55 (dt, J = 8.6, 1.7 Hz , 1 H), 7.51 (dd, J = 8.6, 4.2 Hz, 1 H), 7.29 (dd, J = 10.4, 8.3 Hz, 1 H), 7.01 (dd, J = 8.3, 4.2 Hz, 1 H), 5.25 (d, J = 8.0 Hz, 1 H), 4.31 (ddq, J = 16.1, 8.3 , 4.1 Hz, 1 H), 3.63 - 3.48 (m, 1 H), 3.26 - 3.08 (m, 1 H), 2.81 (t, J = 10.3 Hz , 2 H), 2.35 (dt, J = 17.8, 10.8 Hz, 2 H), 2.25 (s, 3 H), 2.21 - 2.07 (m, 2 H), 1.93 (tdd, J = 11.7, 5.4, 2.6 Hz, 2 H), 1.80 (dp, J = 11.2, 3.5 Hz, 1 H), 1.74 - 1.64 (m, 2 H), 1.34 - 1.21 (m, 2 H), 1.04 - 0.91 (m, 4 H).Example 115: Synthesis of compound 449 and compound 450 (N -[(R)-1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylamino-acetamide and N-[(S)-1-(8 -cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylamino-acetamide)

[00928] N-[(R)-1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylamino-acetamide and N-[(S)- 1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylamino-acetamide: N-[(R)-1-(8-cyano-quinolin-5 -yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylamino-acetamide and N-[(S)-1-(8-cyano-quinolin-5-yl)-5,5-difluoro- piperidin-3-yl]-2-dimethylamino-acetamide were prepared from 5-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and N,N-dimethylglycine in 25 % production, using method 20. Enantiomers were isolated using chiral SFC chromatography. (Column: 1.0 x 25.0 cm Chiralpak IA; CO2 Co-Solvent (Solvent B): Methanol with 0.5% dimethylamine; Isocratic Method: 45% Co-Solvent at 6 mL/min; system: 100 bar; Column temperature: 30°C).Isomer 1: HPLC: > 99% purity, Retention Time = 2.06 min. EM: m/z = 374 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.11 (dd, J = 4.2, 1.7 Hz, 1 H), 8.65 (dd, J = 8.6, 1.7 Hz , 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.87 (s, 1 H), 7.57 (dd, J = 8.6, 4.2 Hz, 1 H), 7.14 (d, J = 7.9 Hz, 1 H), 4.63 (s, 1 H), 3.51 (dd, J = 21.5, 10.2 Hz, 1 H) , 3.43 (d, J = 11.9 Hz, 1 H), 3.35 - 3.18 (m, 2 H), 3.04 - 2.90 (m, 2 H), 2.46 - 2.30 (m, 2 H), 2.28 (s, 6 H). Isomer 2: HPLC: > 99% purity, Retention Time = 2.08 min. MS: m/z = 374 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.11 (dd, J = 4.2, 1.7 Hz, 1 H), 8.65 (dd, J = 8.6, 1.7 Hz , 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.86 (s, 1 H), 7.57 (dd, J = 8.6, 4.2 Hz, 1 H), 7.14 (d, J = 7.9 Hz, 1 H), 4.63 (s, 1 H), 3.51 (q, J = 10.4 Hz, 1 H), 3.43 (d, J = 11.9 Hz, 1 H), 3.37 - 3.17 (m, 2 H), 3.04 - 2.90 (m, 2 H), 2.46 - 2.29 ( m, 2 H), 2.28 (s, 6 H). Example 116: Synthesis of compound 451 (Methyl- [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-) hydrochloride il)-piperidin-3-yl]-amine)

[00929] Methyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine hydrochloride: methyl-[(3R,5S) hydrochloride )-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine was prepared from acid tert-butyl ester [(3R,5S)-5-methyl-1- (8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-carbamic acid and iodomethane at 68% production during 2 steps, using method 35 and Q.

[00930] Compound 451: HPLC: 98.8% purity, Retention Time = 2.74 min. MS: m/z = 324 [M + H]+. 1H NMR (400 MHz, Deuterium oxide, ppm) δ 9.21 (dt, J = 8.7, 1.3 Hz, 1 H), 9.13 (dt, J = 5.2, 1.4 Hz , 1 H), 8.41 (d, J = 8.3 Hz, 1 H), 8.08 (ddd, J = 8.5, 5.2, 1.1 Hz, 1 H), 7.55 (d, J = 8.3 Hz, 1 H), 3.86 (d, J = 11.2 Hz, 1 H), 3.72 (tt, J = 7.7, 3.8 Hz, 1 H ), 3.51 (d, J = 12.1 Hz, 1 H), 3.07 (t, J = 11.0 Hz, 1 H), 2.85 (s, 3 H), 2.62 ( t, J = 11.8 Hz, 1 H), 2.47 (d, J = 12.5 Hz, 1 H), 2.36 - 2.21 (m, 1 H), 1.34 (q, J = 12.0 Hz, 1 H), 1.07 (d, J = 6.6 Hz, 3 H).Example 117: Synthesis of compound 452 (2-dimethylamino-N-methyl-N-[(3R, 5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide)

[00931] 2-dimethylamino-N-methyl-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide: dimethylamino -N-methyl-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide was prepared from methyl-[(3R) hydrochloride ,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine and N,N-dimethylglycine in 56% production, using method 20.

[00932] Compound 452: HPLC: 95.0% purity, Retention Time = 3.11 min. MS: m/z = 409 [M + H]+.Example 118: Synthesis of compound 453 ((2-diethylamino-ethyl)-amide acid 4-(8-cyano-quinoxalin-5-yl)-piperazine-1- carboxylic)

[00933] (2-Diethylamino-ethyl)-amide of 4-(8-cyano-quinoxalin-5-yl)-piperazine-1-carboxylic acid: (2-diethylamino-ethyl)-amide of 4-(8- cyano-quinoxalin-5-yl)-piperazine-1-carboxylic acid was prepared from 8-bromo-quinoxaline-5-carbonitrile, 1-boc-piperazine and N,N-diethylethylenediamine at 11% production during 3 steps using method H , Q and 36.

[00934] Compound 453: HPLC: 96.4% purity, Retention Time = 1.85 min. MS: m/z = 382 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.98 (d, J = 1.8 Hz, 1 H), 8.84 (d, J = 1.8 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.05 (d, J = 8.3 Hz, 1 H), 5.36 (s, 1 H), 3.77 - 3.59 (m , 8 H), 3.37 - 3.25 (m, 2 H), 2.56 (s, 6 H), 1.03 (s, 6 H).

[00935] The following compound was synthesized in an analogous manner:

[00936] Compound 463 ((2-dimethylamino-ethyl)-4-(8-cyano-quinoxalin-5-yl)-piperazine-1-carboxylic acid amide): HPLC: > 99% purity, Retention Time = 1.62 min. EM: m/z = 354 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.98 (d, J = 1.8 Hz, 1 H), 8.83 (d, J = 1.8 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.05 (d, J = 8.3 Hz, 1 H), 5.28 (s, 1 H), 3.79 - 3.67 (m , 4 H), 3.67 - 3.57 (m, 4 H), 3.35 (dt, J = 5.9, 4.8 Hz, 2 H), 2.47 (t, J = 5, 8 Hz, 2 H), 2.26 (s, 6 H). Example 119: Synthesis of compound 458 (5-((3R,5S)-3-amino-5-methyl-piperidin-1-yl) hydrochloride -pyrido[4,3-d]pyrimidine-8-carbonitrile)

[00937] 8-Iodo-6H-pyrido[4,3-d]pyrimidin-5-one: A mixture of 5H,6H-pyrido[4,3-d]pyrimidin-5-one (500 mg; 3.40 mmols) and iodine (863 mg; 3.40 mmols) in a 0.4 N sodium hydroxide solution (15 mL) was heated at reflux for 3 hours. The light yellow suspension was cooled to room temperature, water (30 mL) was added and the suspension was stirred at room temperature for 15 min. The suspension was filtered, the solid was rinsed with water and dried under vacuum to provide 8-iodo-6H-pyrido[4,3-d]pyrimidin-5-one (727 mg, 76%) as a pale yellow solid. EM: m/z = 274 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 12.15 (s, 1 H), 9.42 (s, 1 H), 9.33 (s, 1 H), 8.13 (s, 1 H).

[00938] [(3R,5S)-1-(8-iodo-pyrido[4,3-d]pyrimidin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-Butyl ester : a solution of 8-iodo-6H-pyrido[4,3-d]pyrimidin-5-one (300 mg; 1.10 mmol), tert-butyl N-[(3R,5S)-5-methylpiperidin-3 -yl]carbamate (283 mg; 1.32 mmol), pybop (858 mg; 1.65 mmol) and DIPEA (574 μl; 3.30 mmols) in anhydrous DMSO (9 mL) was placed in a sealed tube and heated at 40°C overnight. The light yellow solution was cooled to room temperature, poured into a saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phase was washed with brine (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a PuriFlash column (25 g, 30 μm), eluting with hexanes and ethyl acetate to provide acid tert-butyl ester [(3R,5S)-1-(8-Iodo-pyrido[4 ,3-d]pyrimidin-5-yl)-5-methyl-piperidin-3-yl]-carbamic (212 mg; 41%) as a yellow solid. MS: m/z = 470 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.41 (s, 1 H), 9.38 (s, 1 H), 8.77 (s, 1 H), 4.45 (s, 1 H), 4.33 (ddt, J = 12.4, 4.2, 1.9 Hz, 1 H), 4.02 (ddt, J = 12.9, 4.0, 1.8 Hz, 1 H), 3.87 (s, 1 H), 2.74 (dd, J = 12.3, 10.8 Hz, 1 H), 2.66 (t, J = 12.1 Hz, 1 H) , 2.19 (d, J = 12.6 Hz, 1 H), 2.06 (s, 1 H), 1.45 (s, 9 H), 1.13 - 0.95 (m, 4 H ).

[00939] Tert-Butyl ester of [(3R,5S)-1-(8-cyano-pyrido[4,3-d]pyrimidin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid : a mixture of acid tert-butyl ester [(3R,5S)-1-(8-iodo-pyrido[4,3-d]pyrimidin-5-yl)-5-methyl-piperidin-3-yl]- carbamic (100 mg; 0.213 mmol), zinc cyanide (62.6 mg; 0.533 mmol), tris(dibenzylideneacetone)dipalladium(0) (19.5 mg; 0.021 mmol) and 1,1'-bis(diphenylphosphine)ferrocene (5.9 mg; 0.011 mmol) in anhydrous DMF (3 mL) was microwaved at 120°C for two hours. The black suspension was filtered over celite, washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by chromatography on a Puri Flash column (12 g, 30 μm), eluting with hexanes and ethyl acetate to provide acid tert-butyl ester [(3R,5S)-1-(8-cyano-pyrido[4 ,3-d]pyrimidin-5-yl)-5-methyl-piperidin-3-yl]-carbamic (50 mg; 64%) as a yellow solid. EM: m/z = 369 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.54 (s, 1 H), 9.40 (s, 1 H), 8.66 (s, 1 H), 4.70 (d, J = 12.7 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 2 H), 3.81 (s, 1 H), 2.89 (dd, J = 12.6, 11 .0 Hz, 1 H), 2.75 (t, J = 12.4 Hz, 1 H), 2.21 (d, J = 12.5 Hz, 1 H), 1.99 (s, 1 H ), 1.45 (s, 9H), 1.15 (q, J = 12.0 Hz, 1 H), 1.05 (d, J = 6.6 Hz, 3 H).

[00940] 5-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-pyrido[4,3-d]pyrimidine-8-carbonitrile hydrochloride: A solution of hydrochloric acid (692 μl; 2.77 mmols) at 4 M in dioxane was added to a solution of acid tert-butyl ester [(3R,5S)-1-(8-cyano-pyrido[4,3- d]pyrimidin-5- yl)-5-methyl-piperidin-3-yl]-carbamic acid (34.0 mg; 0.092 mmol) in methanol (2 mL) and the reaction mixture was stirred at room temperature overnight. The yellow solution was concentrated under reduced pressure, the residue was dissolved in methanol (1 ml) and ethyl acetate was added (10 ml). The yellow suspension was filtered, the yellow solid was washed with ethyl acetate and dried under vacuum to give 5-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-pyrido[4] hydrochloride ,3-d]pyrimidine-8-carbonitrile (18 mg; 64%) as a yellow solid.

[00941] Compound 453: HPLC: > 99% purity, Retention Time = 1.42 min. EM: m/z = 269 [M + H]+. 1H NMR (400 MHz, Deuterium oxide, ppm) δ 9.58 (s, 1 H), 9.32 (s, 1 H), 8.79 (s, 1 H), 4.85 (d, J = 12.5 Hz, 1 H), 4.38 (d, J = 13.7 Hz, 1 H), 3.73 - 3.62 (m, 1 H), 3.42 - 3.33 (m , 1 H), 3.22 (t, J = 12.5 Hz, 1 H), 2.37 (d, J = 12.8 Hz, 1 H), 2.08 (s, 1 H), 1 .51 (q, J = 12.2 Hz, 1 H), 1.06 (d, J = 6.7 Hz, 3 H).Example 119: Synthesis of compound 461 (cis-5-methyl-1-( 8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ol)

[00942] Cis-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ol: cis-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin -3-ol was obtained from 5-bromo-8-(trifluoromethyl)quinolone and cis-5-methyl-piperidin-3-ol in 7% production using method V.

[00943] Compound 461: HPLC: 95.7% purity, Retention Time = 3.67 min. EM: m/z = 311 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J = 4.2, 1.8 Hz, 1 H), 8.44 (dd, J = 8.6, 1.8 Hz , 1 H), 7.98 (dd, J = 8.0, 0.9 Hz, 1 H), 7.47 (dd, J = 8.5, 4.2 Hz, 1 H), 7.08 (d, J = 8.0 Hz, 1 H), 4.18 - 4.03 (m, 1 H), 3.57 (ddt, J = 11.0, 4.4, 1.9 Hz, 1 H), 3.30 (ddt, J = 11.7, 3.7, 1.7 Hz, 1 H), 2.59 (dd, J = 11.0, 10.0 Hz, 1 H), 2 .38 (t, J = 11.3 Hz, 1 H), 2.26 (dtd, J = 11.8, 3.9, 1.8 Hz, 1 H), 2.10 (dddt, J = 11 .9, 10.6, 6.6, 4.0 Hz, 1 H), 1.12 (td, J = 12.1, 10.8 Hz, 1 H), 1.02 (d, J = 6 .7 Hz, 3 H).Example 120: Synthesis of compound 464 (((3R,4S)-4-fluoro-pyrrolidin-3-yl)-amide hydrochloride 1-(8-trifluoromethyl-quinolin-5- il)-piperidine-4-carboxylic acid)

[00944] 1-(8-Trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid ((3R,4S)-4-fluoro-pyrrolidin-3-yl)-amide hydrochloride: (( hydrochloride 1-(8-Trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid 3R,4S)-4-fluoro-pyrrolidin-3-yl)-amide was prepared from 5-bromo-8-(trifluoromethyl) quinolone, ethyl piperidine-4-carboxylate and tert-butyl ester of (3R,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylic acid in 45% production during 4 steps, using method V, I, 20 and Q.

[00945] Compound 464: HPLC: > 99% purity, Retention Time = 2.45 min. MS: m/z = 411 [M + H]+. 1H NMR (400 MHz, Deuterium oxide, ppm) δ 8.97 (dd, J = 4.7, 1.6 Hz, 1 H), 8.79 (dd, J = 8.6, 1.7 Hz , 1 H), 8.19 (d, J = 8.2 Hz, 1 H), 7.79 (dd, J = 8.6, 4.7 Hz, 1 H), 7.32 (d, J = 8.2 Hz, 1 H), 5.42 (dt, J = 52.4, 3.3 Hz, 1 H), 4.92 - 4.81 (m, 1 H), 3.95 - 3 .76 (m, 3 H), 3.52 (d, J = 12.2 Hz, 2 H), 3.35 (t, J = 11.4 Hz, 1 H), 3.02 - 2.87 (m, 2 H), 2.73 - 2.59 (m, 1 H), 2.17 - 1.92 (m, 4 H).Example 121: Synthesis of compound 465 (3-amino-3,N -dimethyl-N- [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-butyramide)

[00946] 3-Amino-3,N-dimethyl-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-butyramide: 3 -amino-3,N-dimethyl-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-butyramide was prepared from methyl hydrochloride -[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine and 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid in 13% production during 2 steps, using method 20 and Q.

[00947] Compound 465: HPLC: 93.2% purity, Retention Time = 3.29 min. MS: m/z = 423 [M + H]+.Example 121: Synthesis of compound 477 (1-(2-dimethylamino-ethyl)-3- [(3R,5S)-5-methyl-1-(8- trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-urea)

[00948] 1-(2-dimethylamino-ethyl)-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-urea: a To a solution of (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine (1.0 eq.) in THF was added DIEA (5.0 eq.) . The solution was stirred at room temperature for 10 minutes, then the vial was charged with (2-isocyanatoethyl)dimethylamine. The reaction was stirred for 16 hours. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC under the following conditions: column, XBridge Prep C18 OBD, 5 µm, 19 mm x 150 mm; mobile phase, acetonitrile in water (with 0.05% NH3.H2O), 30% to 65% gradient in 7 min; detector, UV 254 nm.

[00949] Compound 477: HPLC: > 99% purity, Retention Time = 2.86 min. EM: m/z = 424.2 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.00 (dd, J = 4.2, 1.7 Hz, 1 H), 8.52 (dd, J = 8.6, 1.8 Hz , 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 7.65 (dd, J = 8.6, 4.2 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 1 H), 6.09 (d, J = 7.4 Hz, 1 H), 5.71 (t, J = 5.4 Hz, 1 H), 3.56 (d, J = 9.2 Hz, 1 H), 3.14 - 2.98 (m, 2 H), 2.46 - 2.33 (m, 2 H), 2.23 (t, J = 6.3 Hz, 2 H), 2.12 (s, 6 H), 1.98 (d, J = 20.5 Hz, 2 H), 1.03 - 0.88 (m, 4 H). Example 122: Synthesis of compound 478 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(1-methyl-piperidin-4-yl )-acetamide)

[00950] cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(1-methyl-piperidin-4-yl)-acetamide: a cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride solution (100 mg; 0.28 mmol), acid (1-methyl-piperidin-4-yl )-acetic acid (53 mg; 0.34 mmol) and DIPEA (0.2 mL; 0.84 mmol) in DMSO (2 mL) was stirred at room temperature for 5 min, and then bop (149 mg; 0 .34 mmol). The mixture was stirred at room temperature for one hour and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (XBridge column), eluting with acetonitrile in water (0.1% NH3.H2O), 30% to 70% gradient to give cis-N-[1-(8-cyano -quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(1-methyl-piperidin-4-yl)-acetamide as white solid (70 mg, 54%).

[00951] Compound 478: 1H NMR (400 MHz, Methanol-d4, ppm) δ 9.01 (dd, J = 4.3, 1.6 Hz, 1 H), 8.67 (dd, J = 8, 6, 1.7 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.3 Hz, 1 H), 7 .32 (d, J = 8.0 Hz, 1 H), 4.32 (tt, J = 11.3, 4.3 Hz, 1 H), 3.76 - 3.62 (m, 2 H) , 3.16 - 2.94 (m, 2 H), 2.87 (t, J = 10.8 Hz, 2 H), 2.60 (t, J = 11.2 Hz, 1 H), 2 .35 (d, J = 12.5 Hz, 1 H), 2.27 (s, 3 H), 2.21 - 2.11 (m, 2 H), 2.02 (ddt, J = 14, 5, 9.0, 2.9 Hz, 2 H), 1.90 - 1.46 (m, 4 H), 1.32 (dt, J = 11.9, 5.4 Hz, 2 H). EM: m/z = 460 [M + H]+.

[00952] The following compounds were synthesized in an analogous manner:

[00953] Compound 481 (cis-N-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3-hydroxy-3-methyl-butyramide): From hydrochloride of cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile and 3-hydroxy-3-methyl-butyric acid. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.07 (dd, J = 4.2, 1.6 Hz, 1 H), 8.59 (dd, J = 8.6, 1.7 Hz , 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 7.5 Hz, 1 H), 7.73 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.33 (d, J = 8.1 Hz, 1 H), 4.70 (s, 1 H), 4.19 (s, 1 H), 3.57 (d, J = 9.3 Hz, 2 H), 3.21 (s, 1 H), 2.95 (t, J = 11.6 Hz, 1 H), 2.65 (t, J = 11 .3 Hz, 1 H), 2.22 (s, 2 H), 1.53 (q, J = 12.2 Hz, 1 H), 1.16 (s, 6 H). EM: m/z = 421 [M + H]+.

[00954] Compound 484 (2-(1-Hydroxy-cyclohexyl)-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl ]-acetamide): from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and (1-tbutoxycarbonylamino-cyclohexyl)-acetic acid . 1H NMR (400 MHz, Methanol-d4, ppm) δ 8.95 (d, J = 4.2 Hz, 1 H), 8.66 (d, J = 8.6 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.63 (dd, J = 8.7, 4.1 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H ), 4.25 (s, 1 H), 3.63 (d, J = 11.4 Hz, 1 H), 3.40 (d, J = 11.6 Hz, 1 H), 2.50 ( q, J = 11.4 Hz, 2 H), 2.31 (s, 2 H), 2.14 (d, J = 12.6 Hz, 2 H), 1.67 - 1.35 (m, 11H), 1.16 (q, J = 12.4 Hz, 1 H), 1.05 (d, J = 6.2 Hz, 3 H). EM: m/z = 449 [M + H]+.

[00955] Compound 485 (2-(1-Hydroxy-cyclohexyl)-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl ]-acetamide): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine and 3-hydroxy-3-methyl-butyric hydrochloride, 1H NMR (400 MHz, Methanol-d4, ppm) δ 8.94 (dd, J = 4.2, 1.7 Hz, 1 H), 8.67 (dd, J = 8.6, 1.8 Hz , 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 4.26 (ddt, J = 17.3, 13.6, 6.9 Hz, 1 H), 3.68 - 3.59 (m, 1 H), 3 .47 - 3.36 (m, 2 H), 2.55 - 2.37 (m, 2 H), 2.36 (s, 2 H), 2.17 (s, 2 H), 1.27 (d, J = 0.9 Hz, 6 H), 1.17 (q, J = 12.6 Hz, 1 H), 1.05 (d, J = 6.4 Hz, 3 H). EM: m/z = 410 [M + H]+.

[00956] Compound 490 (cis-N-[(1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(1-methyl-azetidin-3-yl) -acetamide): From cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (1-methyl-azetidin-3-yl)- acid hydrochloride acetic. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.57 (dd, J = 8.6, 1.7 Hz , 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 7.4 Hz, 1 H), 7.72 (dd, J = 8.6 , 4.2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 4.12 (s, 2 H), 3.56 (t, J = 8.9 Hz, 2 H), 3.24 (tdd, J = 7.2, 4.0, 2.1 Hz, 2 H), 2.93 (t, J = 11.6 Hz, 1 H), 2.82 - 2.68 (m, 2 H), 2.64 - 2.53 (m, 2 H), 2.43 - 2.28 (m, 2 H), 2.15 (s, 3 H), 1, 50 (q, J = 12.3 Hz, 1 H). EM: m/z = 432 [M + H]+.

[00957] Compound 491 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(1-methyl-azetidin-3-yl)- acetamide): From cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (1-hydroxy-cyclohexyl)-acetic acid. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (dd, J = 4.2, 1.6 Hz, 1 H), 8.59 (dd, J = 8.6, 1.7 Hz, 1 H), 8.26 (d, J = 8.0 Hz, 1 H), 8.06 (d, J = 7.4 Hz, 1 H), 7.73 (dd, J = 8.6, 4 .2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 4.25 (m, 1 H), 4.57 (s, 1 H), 3.70 - 3 .48 (m, 2 H), 3.21 (d, J = 11.2 Hz, 1 H), 2.95 (t, J = 11.6 Hz, 1 H), 2.64 (t, J = 11.2 Hz, 1 H), 2.21 (s, 3 H), 1.65 - 1.28 (m, 9H), 1.19 (q, J = 10.7, 10.1 Hz, 1 H). MS: m/z = 461 [M + H]+.

[00958] Compound 496 (cis-N-[-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-4-(4-methyl-piperazin-1-yl) -4-oxo-butyramide): From cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid and 1-methyl methyl ester -piperazine. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 7.3 Hz, 1 H), 7.72 (dd, J = 8.6, 4 .2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 4.13 (d, J = 8.2 Hz, 1 H), 3.57 (d, J = 11.7 Hz, 1 H), 3.41 (d, J = 5.0 Hz, 3 H), 3.19 (s, 1 H), 2.95 (t, J = 11.6 Hz, 1 H), 2.70 - 2.54 (m, 2 H), 2.41 - 2.24 (m, 3 H), 2.15 (s, 3 H), 1.51 (q, J = 12 .3Hz, 1H). MS: m/z = 503 [M + H]+.

[00959] Compound 554 (N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-yl]-2-(1- methyl-piperidin-4-yl)-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3- dihydrochloride ylamine and 1-methyl-4-piperidineacetic acid. MS: m/z = 396 [M + H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (dd, J = 4.1, 1.7 Hz, 1 H), 8.44 (dd, J = 8.5, 1.7 Hz, 1 H), 8.10 (s, 1 H), 7.87 - 7.76 (m, 2 H), 4.06 - 3.97 (m, 1 H),3.45 - 3.36 (m , 1 H), 3.26 - 3.19 (m, 1 H), 2.88 (s, 3 H), 2.74 - 2.63 (m, 2 H), 2.42 (q, J = 11.0 Hz, 2 H), 2.11 (s, 3 H), 2.08 - 1.91 (m, 4 H), 1.85 - 1.72 (m, 2 H), 1, 65 - 1.48 (m, 3 H), 1.22 - 1.06 (m, 2 H), 1.05 (q, J = 11.8 Hz, 1 H), 0.95 (d, J = 6.5 Hz, 3 H).

[00960] Compound 555 (3-Hydroxy-3-methyl-N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3- yl]-butyramide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and beta-hydroxy acid -isovaleric. MS: m/z = 357 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J = 4.1, 1.7 Hz, 1 H), 8.45 (dd, J = 8.5, 1.7 Hz , 1 H), 8.11 (s, 1 H), 7.88 (d, J = 7.6 Hz, 1 H), 7.80 (dd, J = 8.5, 4.1 Hz, 1 H), 4.77 (s, 1 H), 4.13 - 3.95 (m, 1 H), 3.47 - 3.37 (m, 1 H), 3.28 - 3.18 (m , 1 H), 2.88 (s, 3 H), 2.43 (dd, J = 23.0, 11.1 Hz, 2 H), 2.21 (s, 2 H), 2.12 - 1.91 (m, 2 H), 1.14 (s, 3 H), 1.13 (s, 3 H), 1.12 - 1.00 (m, 1 H), 0.95 (d, J = 6.4 Hz, 3 H).

[00961] Compound 556 (2-(1-methyl-azetidin-3-yl)-N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl )-piperidin-3-yl]-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3- dihydrochloride ylamine and (1-methyl-azetidin-3-yl)-acetic acid hydrochloride. MS: m/z = 357 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.43 (dd, J = 8.5, 1.7 Hz , 1 H), 8.10 (s, 1 H), 7.85 (d, J = 7.6 Hz, 1 H), 7.79 (dd, J = 8.5, 4.1 Hz, 1 H), 4.03 - 3.95 (m, 1 H), 3.44 - 3.35 (m, 1 H), 3.23 (ddt, J = 8.4, 4.6, 2.4 Hz, 3 H), 2.88 (s, 3 H), 2.73 (td, J = 6.3, 2.2 Hz, 2 H), 2.61 - 2.52 (m, 1 H) , 2.41 (dt, J = 15.1, 11.0 Hz, 2 H), 2.32 (dd, J = 7.7, 1.6 Hz, 2 H), 2.14 (s, 3 H), 2.05 - 1.93 (m, 2 H), 1.05 (q, J = 12.0 Hz, 1 H), 0.94 (d, J = 6.5 Hz, 3 H) .

[00962] Compound 557 (3-{[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylcarbamoyl acid tert-butyl ester ]-methyl}-azetidine-1-carboxylic acid): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3- dihydrochloride ylamine and 3-carboxymethyl-azetidine-1-carboxylic acid tert-butyl ester. MS: m/z = 454 [M + H]+. 1H NMR (400 MHz, Methanol-d4, ppm) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.60 (dd, J = 8.6, 1.7 Hz , 1 H), 8.05 (s, 1 H), 7.79 (dd, J = 8.6, 4.2 Hz, 1 H), 4.25 - 4.13 (m, 1 H), 4.05 (q, J = 8.0 Hz, 2 H), 3.69 - 3.58 (m, 2 H), 3.56 - 3.52 (m, 1 H), 2.96 (s , 3 H), 2.96 - 2.82 (m, 1 H), 2.55 - 2.43 (m, 4 H), 2.18 - 2.07 (m, 2 H), 1.42 (s, 9H), 1.41 - 1.35 (m, 1H), 1.14 (q, J = 12.6 Hz, 1 H), 1.04 (d, J = 6.4 Hz, 3H).

[00963] Compound 558 ((R)-2-Cyclopropyl-2-hydroxy-N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)- piperidin-3-yl]-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and cyclopropylhydroxyacetic acid. EM: m/z = 355 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J = 4.1, 1.7 Hz, 1 H), 8.46 (dd, J = 8.5, 1.7 Hz , 1 H), 8.11 (s, 1 H), 7.80 (dd, J = 8.5, 4.1 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 5.28 (s, 1 H), 4.13 - 4.00 (m, 1 H), 3.51 (d, J = 6.2 Hz, 1 H), 3.37 - 3, 33 (m, 1 H), 3.26 - 3.22 (m, 1 H), 2.88 (s, 3 H), 2.57 (t, J = 10.8 Hz, 1 H), 2 .41 (t, J = 11.2 Hz, 1 H), 2.09 - 2.01(m, 1 H), 1.99 - 1.90 (m, 1 H), 1.19 (q, J = 12.1 Hz, 1 H), 1.09 - 0.98 (m, 1 H), 0.95 (d, J = 6.6 Hz, 3 H), 0.42 - 0.23 ( m, 4 H).

[00964] Compound 559 ((S)-2-Cyclopropyl-2-hydroxy-N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)- piperidin-3-yl]-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and cyclopropylhydroxyacetic acid. MS: m/z = 355 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J = 4.1, 1.7 Hz, 1 H), 8.45 (dd, J = 8.5, 1.8 Hz , 1 H), 8.10 (s, 1 H), 7.80 (dd, J = 8.5, 4.1 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 5.32 (s, 1 H), 4.11 - 4.03 (m, 1 H), 3.53 (d, J = 6.0 Hz, 1 H), 3.40 - 3, 34 (m, 1 H), 3.27 - 3.20 (m, 1 H), 2.88 (s, 3 H), 2.57 (t, J = 10.8 Hz, 1 H), 2 .41 (t, J = 11.2 Hz, 1 H), 2.08 - 2.03 (m, 1 H), 1.99 - 1.94 (m, 1 H), 1.20 (q, J = 12.0 Hz, 1 H), 1.10 - 0.98 (m, 1 H), 0.95 (d, J = 6.5 Hz, 3 H), 0.42 - 0.25 ( m, 4 H).

[00965] Compound 560 (N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-yl]-2-(1- methyl-pyrrolidin-3-yl)-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3- dihydrochloride ylamine and (1-methyl-pyrrolidin-3-yl)-acetic acid hydrochloride. MS: m/z = 382 [M + H]+. 1H NMR (400 MHz, Methanol-d4, ppm) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.60 (dd, J = 8.6, 1.7 Hz , 1 H), 8.05 (s, 1 H), 7.79 (dd, J = 8.5, 4.2 Hz, 1 H), 4.24 - 4.17 (m, 1H), 3 .60 - 3.50 (m, 1 H), 2.96 (s, 3 H), 2.85 (dt, J = 9.8, 7.4 Hz, 1 H), 2.75 - 2, 56 (m, 3 H), 2.49 (td, J = 10.9, 6.8 Hz, 2 H), 2.40 (d, J = 4.0 Hz, 3 H), 2.35 - 2.25 (m, 3 H), 2.22 - 1.99 (m, J = 5.1 Hz, 4 H), 1.53 (dp, J = 14.3, 7.0 Hz, 1 H ), 1.14 (q, J = 12.5 Hz, 1 H), 1.04 (d, J = 6.4 Hz, 3 H). Example 123: Synthesis of compound 479 (cis-5- hydrochloride (3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile)

[00966] Cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride: cis-5-(3-amino-5-trifluoromethyl-piperidin-1- hydrochloride yl)-quinoline-8-carbonitrile was prepared from cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (1-tert-butoxycarbonylamino-cyclohexyl acid )-acetic, using method 37 and Q.Compound 479: 1H NMR (400 MHz, Methanol-d4, ppm) δ 9.01 (dd, J = 4.3, 1.6 Hz, 1 H), 8.68 (dd, J = 8.6, 1.7 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.3 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.42 - 4.22 (m, 1 H), 3.78 - 3.57 (m, 2 H) , 3.15 - 2.86 (m, 2 H), 2.62 (t, J = 11.2 Hz, 1 H), 2.42 - 2.24 (m, 3 H), 1.70 - 1.21 (m, 11H). EM: m/z = 460 [M + H]+.

[00967] The following compounds were synthesized in an analogous manner:

[00968] Compound 483 (2-(1-amino-cyclohexyl)-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl ]-acetamide): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 2-(1-{[(tert -butoxy)carbonyl]amino}cyclohexyl)acetic acid. 1H NMR (400 MHz, Methanol-d4, ppm) δ 8.95 (d, J = 4.2 Hz, 1 H), 8.66 (d, J = 8.6 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.63 (dd, J = 8.7, 4.1 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H ), 4.25 (s, 1 H), 3.63 (d, J = 11.4 Hz, 1 H), 3.40 (d, J = 11.6 Hz, 1 H), 2.50 ( q, J = 11.4 Hz, 2 H), 2.31 (s, 2 H), 2.14 (d, J = 12.6 Hz, 2 H), 1.67 - 1.35 (m, 11H), 1.16 (q, J = 12.4 Hz, 1 H), 1.05 (d, J = 6.2 Hz, 3 H). MS: m/z = 449 [M + H]+.

[00969] Compound 486 and compound 487 (rac-(R)-2-amino-N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3- yl]-2-cyclopropyl-acetamide and rac-(S)-2-amino-N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3- yl]-2-cyclopropyl-acetamide): From cis-5-((3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and tert-butoxycarbonylamino-cyclopropyl-acetic acid . 1.7 Hz, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 7.71 (dd, J = 8.6, 4.3 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 1 H), 4.34 (dq, J = 11.3, 5.2, 4.3 Hz, 1 H), 3.68 (d, J = 10.5 Hz, 2 H), 3.12 - 2.84 (m, 2 H), 2.73 - 2.50 (m, 2 H), 1.65 (q, J = 12.2 Hz, 1 H) , 0.99 (dtd, J = 13.2, 8.3, 4.9 Hz, 1 H), 0.68 - 0.23 (m, 3 H). H]+. .6, 1.7 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.3 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.34 (ddd, J = 15.4, 11.1, 4.2 Hz, 1 H), 3.82 - 3.60 ( m, 2 H), 3.18 - 2.87 (m, 2 H), 2.69 - 2.52 (m, 2 H), 2.38 (d, J = 12.5 Hz, 1 H) , 1.63 (q, J = 12.2 Hz, 1 H), 1.03 (qt, J = 8.3, 4.9 Hz, 1 H), 0.72 - 0.51 (m, 2 H), 0.41 (ddq, J = 45.4, 9.3, 5.0 Hz, 2 H). MS: m/z = 418 [M + H]+.

[00970] Compound 493 (2-(4-amino-tetrahydro-pyran-4-yl)-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3 hydrochloride -yl]-acetamide): From cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (4-tert-butoxycarbonylamino-tetrahydro- pyran-4-yl)-acetic acid, 1H NMR (400 MHz, DMSO-d6) δ 9.08 (dd, J = 4.2, 1.6 Hz, 1 H), 8.78 (d, J = 7 .1 Hz, 1 H), 8.59 (dd, J = 8.6, 1.7 Hz, 1 H), 8.28 (d, J = 8.0 Hz, 1 H), 8.16 ( s, 3 H), 7.72 (dd, J = 8.6, 4.2 Hz, 1 H), 7.35 (d, J = 8.1 Hz, 1 H), 3.91 - 3, 66 (m, 3 H), 3.67 - 3.42 (m, 4 H), 3.33 - 3.11 (m, 1 H), 2.98 (t, J = 11.5 Hz, 1 H), 2.78 - 2.56 (m, 3 H), 2.25 (d, J = 12.3 Hz, 1 H), 1.88 - 1.41 (m, 5 H). MS: m/z = 462 [M + H]+.

[00971] Compound 561 ((R)-2-amino-2-cyclopropyl-N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)- piperidin-3-yl]-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and tert-butoxycarbonylamino-cyclopropyl-acetic acid. MS: m/z = 354 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.51 (dd, J = 8.5, 1.8 Hz , 1 H), 8.30 (s, 1 H), 8.14 (s, 1 H), 7.67 (dd, J = 8.5, 4.1 Hz, 1 H), 7.14 ( d, J = 8.1 Hz, 1 H), 4.35 - 4.27 (m, 1 H), 3.66 - 3.61 (m, 2 H), 3.35 - 3.23 (m , 1 H), 3.04 (s, 3 H), 2.88 (d, J = 8.9 Hz, 1 H), 2.50 (td, J = 10.9, 6.6 Hz, 2 H), 2.20 - 2.09 (m, 2 H), 1.16 - 1.06 (m, 1 H), 1.03 (d, J = 6.5 Hz, 3 H), 0, 72 - 0.53 (m, 3 H), 0.37 - 0.33 (m, 1 H).

[00972] Compound 562 ((S)-2-amino-2-cyclopropyl-N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)- piperidin-3-yl]-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and tert-butoxycarbonylamino-cyclopropyl-acetic acid. MS: m/z = 354 [M + H]+. 1H NMR (400 MHz, Chloroform-d, ppm) δ 8.99 (dd, J = 4.2, 1.7 Hz, 1 H), 8.41 (dd, J = 8.5, 1.8 Hz , 1 H), 8.10 (s, 1 H), 7.68 - 7.48 (m, 2 H), 4.96 (bs, 3 H), 4.25 (bs, 1 H), 3 .62 - 3.45 (m, 1 H), 3.28 - 3.22 (m, 1 H), 3.01 (s, 3 H), 2.61 - 2.43 (m, 1 H) , 2.39 (t, J = 11.1 Hz, 1 H), 2.19 - 2.04 (m, 2 H), 1.18 - 1.05 (m, 2 H), 0.99 ( d, J = 6.3 Hz, 3 H), 0.57 (bs, 3 H), 0.38 (bs, 1 H).

[00973] Compound 563 (2-(1-amino-cyclohexyl)-N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)- piperidin-3-yl]-acetamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and (1-tert-butoxycarbonylamino-cyclohexyl)-acetic acid, followed by de-Boc using Method Q. MS: m/z = 396 [M + H]+. 1H NMR (400 MHz, Methanol-d4, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.59 (dd, J = 8.5, 1.8 Hz , 1 H), 8.55 (bs, 1 H), 8.06 (s, 1 H), 7.78 (dd, J = 8.6, 4.2 Hz, 1 H), 4.28 - 4.21 (m, 1 H), 3.61 - 3.53 (m, 1 H), 3.37 - 3.35 (m, 1 H), 2.97 (s, 3 H), 2 .70 - 2.41 (m, 4H), 2.20 - 2.08 (m, 2H), 1.88 - 1.47 (m, 9H), 1.45 - 1.35 (m, 1 H), 1.16 (q, J = 12.6 Hz, 1 H), 1.04 (d, J = 6.4 Hz, 3 H). Example 124: Synthesis of compound 480 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamide)

[00974] cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid methyl ester: cis-N-[(3R) acid methyl ester ,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic was prepared from 5-((3R,5S)-3-amino-5- hydrochloride trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile and succinic acid monomethyl ester using method 37. Method 38

[00975] cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamide: a solution of cis-N-[1-( 8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid (55 mg; 0.13 mmol) in 7.0 M ammonia in methanol (2.00 mL; 14.00 mmol) was stirred at 60°C for one hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (XBridge column), eluting with acetonitrile in water (0.1% NH3.H2O), 20% to 70% gradient, to give cis-N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamide (5 mg, 9%). Compound 480: 1H NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 7.3 Hz, 1 H), 7.72 (dd, J = 8, 6, 4.2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 7.25 (s, 1 H), 6.70 (s, 1 H), 4, 23 (d, J = 10.5 Hz, 1 H), 3.57 (d, J = 11.5 Hz, 2 H), 2.94 (t, J = 11.6 Hz, 1 H), 2 .60 (t, J = 11.2 Hz, 1 H), 2.35 - 2.25 (m, 3 H), 2.18 (d, J = 12.3 Hz, 1 H), 1.50 (q, J = 12.3 Hz, 1 H). EM: m/z = 420 [M + H]+.

[00976] The following compounds were synthesized in an analogous manner:

[00977] Compound 482 (cis-4-Azetidin-1-yl-N-[(1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-4-oxo-butyramide ): From cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid methyl ester and azetidine, 1H NMR (400 MHz, DMSO -d6) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz, 1 H), 8.25 ( d, J = 8.0 Hz, 1 H), 8.04 (d, J = 7.3 Hz, 1 H), 7.72 (dd, J = 8.6, 4.2 Hz, 1 H) , 7.32 (d, J = 8.1 Hz, 1 H), 4.10 (t, J = 7.6 Hz, 3 H), 3.79 (td, J = 7.8, 2.8 Hz, 2 H), 3.56 (d, J = 11.7 Hz, 2 H), 3.20 (d, J = 10.9 Hz, 1 H), 2.95 (t, J = 11, 6 Hz, 1 H), 2.60 (t, J = 11.2 Hz, 1 H), 2.38 - 1.99 (m, 7H), 1.50 (q, J = 12.3 Hz, 1 H). MS: m/z = 460 [M + H]+.

[00978] Compound 492 cis-(N--1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-N'-methyl-succinamide): From methyl ester of cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid and methylamine. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 7.3 Hz, 1 H), 7.72 (dd, J = 8.6, 4 .2 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 1 H), 4.15 (m, 1 H), 3.68 - 3.50 (m, 2 H), 3 .20 (d, J = 10.0 Hz, 1 H), 2.94 (t, J = 11.6 Hz, 1 H), 2.54 (d, J = 4.6 Hz, 3 H), 2.30 (qd, J = 6.7, 6.0, 4.2 Hz, 4 H), 2.18 (d, J = 12.1 Hz, 1 H), 1.50 (q, J = 12.3 Hz, 1 H).MS: m/z = 434 [M + H]+.

[00979] Compound 564 (N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-yl]-succinamide): From of (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and mono-methyl succinate, followed by reaction with ammonia in methanol at 50°C overnight. MS: m/z = 356 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.44 (dd, J = 8.5, 1.7 Hz , 1 H), 8.10 (s, 1 H), 7.84 (d, J = 7.5 Hz, 1 H), 7.79 (dd, J = 8.5, 4.1 Hz, 1 H), 7.24 (s, 1 H), 6.69 (s, 1 H), 4.05 - 3.95 (m, 1 H),3.48 - 3.36 (m, 1 H) , 3.24 (d, J = 10.5 Hz, 1 H), 2.88 (s, 3 H), 2.41 (q, J = 11.3 Hz, 2 H), 2.36 - 2 .21 (m, 4 H), 2.10 - 1.92 (m, 2 H), 1.05 (q, J = 12.0 Hz, 1 H), 0.95 (d, J = 6, 5Hz, 3H).

[00980] Compound 565 (N-methyl-N'-[(3R,5S)-5-methyl-1-(8-methyl- [1,7]naphthyridin-5-yl)-piperidin-3-yl]- succinamide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and mono-methyl succinate, followed by reaction with methylamine in ethanol at room temperature overnight. MS: m/z = 370 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.44 (dd, J = 8.5, 1.7 Hz , 1 H), 8.10 (s, 1 H), 7.86 (d, J = 7.5 Hz, 1 H), 7.79 (dd, J = 8.5, 4.1 Hz, 1 H), 7.71 (d, J = 5.4 Hz, 1 H), 4.05 - 3.94 (m, 1 H), 3.43 - 3.37 (m, 1 H), 3, 24 (d, J = 10.1 Hz, 1 H), 2.88 (s, 3 H), 2.54 (d, J = 4.6 Hz, 3 H), 2.41 (q, J = 11.2 Hz, 2 H), 2.35 - 2.24 (m, 4 H), 2.07 - 1.93 (m, 2 H), 1.05 (q, J = 12.0 Hz, 1 H), 0.95 (d, J = 6.4 Hz, 3 H).

[00981] Compound 566 (4-Azetidin-1-yl-N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3- yl]-4-oxo-butyramide): From (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and mono-methyl succinate, followed by reaction with azetidine in ethanol at room temperature overnight. MS: m/z = 396 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J = 4.1, 1.7 Hz, 1 H), 8.44 (dd, J = 8.5, 1.7 Hz , 1 H), 8.41 (s, 1 H), 8.10 (s, 1 H), 7.88 (d, J = 7.4 Hz, 1 H), 7.80 (dd, J = 8.5, 4.1 Hz, 1 H), 4.09 (t, J = 7.7 Hz, 2 H), 4.04 - 3.96 (m, 1 H), 3.78 (td, J = 7.8, 2.2 Hz, 2 H), 3.42 - 3.38 (m, 1 H), 3.25 - 3.22 (m, 1 H), 2.88 (s, 3 H), 2.41 (td, J = 10.9, 7.6 Hz, 2 H), 2.35 - 2.26 (m, 2 H), 2.26 - 2.18 (m, 2 H ), 2.18 - 2.08 (m, 2 H), 2.08 - 1.90 (m, 2 H), 1.05 (q, J = 12.0 Hz, 1 H), 0.95 (d, J = 6.5 Hz, 3 H). Example 125: Synthesis of compound 488 ((3R,5S)-1-(7-fluoro-8-methyl-quinolin-5-yl)-5- hydrochloride methyl-piperidin-3-ylamine)

[00982] 5-Bromo-7-fluoro-8-methyl-quinoline: a mixture of 5-bromo-3-fluoro-2-methyl-phenylamine (2.91 g; 14.3 mmols), glycerol (4.20 mL; 57.1 mmols), iron(II) sulfate heptahydrate (793 mg; 2.85 mmols) and sulfuric acid (4.66 mL; 85.6 mmols) was stirred at 120°C for two hours. . After the reaction mixture was cooled to room temperature, ice (50 g) and solid sodium hydroxide (4.5 g) were added, the mixture was stirred for 30 minutes and extracted with dichloromethane (70 mL X 3). The combined organic layer was washed with brine (10 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column, eluting ethyl acetate and hexanes, to give 5-bromo-7-fluoro-8-methyl-quinoline (1.10 g, 32%), 1H NMR (400 MHz , Chloroform-d, ppm) δ 8.99 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.5, 1.7 Hz, 1 H), 7.68 (d, J = 8.8 Hz, 1 H), 7.50 (dd, J = 8.5, 4.2 Hz, 1 H), 2.70 (d, J = 2.5 Hz , 3 H). EM: m/z = 239 [M + H]+.

[00983] [(3R,5S)-1-(7-fluoro-8-methyl-quinolin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-Butyl ester: tert-butyl [(3R,5S)-1-(7-fluoro-8-methyl-quinolin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid ester was prepared from 5-bromo-7-fluoro -8-methyl-quinoline and tert-butyl ester of ((3R,5S)-5-methyl-piperidin-3-yl)-carbamic acid in 56% production using V. 1H NMR method (400 MHz, DMSO-d6 , ppm) δ 8.94 (dd, J = 4.2, 1.7 Hz, 1 H), 8.43 (dd, J = 8.5, 1.7 Hz, 1 H), 7.53 ( s, 1 H), 7.04 (d, J = 11.5 Hz, 1 H), 6.93 (d, J = 7.6 Hz, 1 H), 3.73 (s, 1 H), 3.36 (s, 1 H), 3.18 (d, J = 11.5 Hz, 1 H), 2.54 (d, J = 2.3 Hz, 3 H), 2.34 (dt, J = 27.7, 10.9 Hz, 2 H), 2.08 - 1.80 (m, 2 H), 1.39 (s, 8 H), 1.03 (q, J = 12.2 Hz, 1 H), 0.93 (d, J = 6.4 Hz, 3 H). MS: m/z = 374 [M + H]+.

[00984] (3R,5S)-1-(7-fluoro-8-methyl-quinolin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride: (3R,5S)-1-( hydrochloride 7-fluoro-8-methyl-quinolin-5-yl)-5-methyl-piperidin-3-ylamine was prepared from acid tert-butyl ester [(3R,5S)-1-(7-fluoro-8-methyl -quinolin-5-yl)-5-methyl-piperidin-3-yl]- carbamic in 88% production, using method Q.Compound 388: 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.4, 1.7 Hz, 1 H), 8.56 (d, J = 8.3 Hz, 1 H), 8.29 (s, 3 H), 7.61 (dd, J = 8.5, 4.4 Hz, 1 H), .16 (d, J = 11.4 Hz, 1 H), 3.27 - 3.11 (m, 1 H), 2.71 - 2.59 (m, 1 H), 2.57 (d, J = 2.3 Hz, 3 H), 2.43 (t, J = 11.3 Hz, 1 H), 2.18 (d, J = 12 .4 Hz, 1 H), 2.06 (s, 1 H), 1.18 (q, J = 11.9 Hz, 1 H), 0.98 (d, J = 6.6 Hz, 3 H ). MS: m/z = 274 [M + H]+.

[00985] The following compounds were synthesized in a similar way:

[00986] Compound 389 ((3R,5S)-1-(6-Fluoro-8-methyl-quinolin-5-yl)- 5-methyl-piperidin-3-ylamine): From 5-bromo-6- fluoro-8-methyl-quinoline and tert-butyl ((3R,5S)-5-methyl-piperidin-3-yl)-carbamic acid ester. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (dd, J = 4.1, 1.8 Hz, 1 H), 8.58 (dd, J = 8.5, 1.8 Hz, 1 H), 7.65 - 7.54 (m, 1 H), 7.51 (dd, J = 13.1, 1.2 Hz, 1 H), 3.06 (d, J = 11.1 Hz , 1 H), 2.95 (d, J = 11.3 Hz, 2 H), 2.78 - 2.58 (m, 5 H), 2.02 - 1.83 (m, 2 H), 1.60 (s, 2 H), 0.97 - 0.84 (m, 3 H). MS: m/z = 274 [M + H]+.Example 126: Separation of compound 494 and compound 495 (4-azetidin-1-yl-N-[(3R,5S)-1-(8-cyano-quinolin -5-yl)-5-trifluoromethyl-piperidin-3-yl]-4-oxo-butyramide and 4-azetidin-1-yl-N-[(3S,5R)-1-(8-cyano-quinolin-5 -yl)-5-trifluoromethyl-piperidin-3-yl]-4-oxo-butyramide)

[00987] The title compounds were isolated using chiral SFC chromatography of compound 482. (Column: Fenomenex 250 x 21.20 mm Lux Cellulose-2; CO2 Co-Solvent (Solvent B): Methanol; Isocratic Method: 40 % Co-Solvent at 70 mL/min; System pressure: 100 bar; Column temperature: 40°C). Isomer 1: EM: m/z = 460 [M + H]+. /z = 460 [M + H]+.

[00988] The following compounds were synthesized in a similar way:

[00989] Compound 497 and compound 498 (2-(1-amino-cyclohexyl)- N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin- 3-yl]-acetamide and 2-(1-amino-cyclohexyl)-N-[(3S,5R)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3- yl]-acetamide): From compound 479 (Column: CHIRALPAK 10 x 250 mm IC; CO2 Co-Solvent (Solvent B): Ethanol with 0.5% dimethylethylamine; Isocratic Method: 55% Co-Solvent a 9 mL/min; System pressure: 100 bar; Column temperature: 30°C). Isomer 1: EM: m/z = 460 [M + H]+. Isomer 2: EM: m/z = 460 [M + H]+.

[00990] Compound 520 and compound 521 ((R)-2-Cyclopropyl-2-hydroxy-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin- 3-yl]-acetamide and (S)-2-cyclopropyl-2-hydroxy-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3- yl]-acetamide): From compound 515 (Column: CHIRALPAK 10 x 250 mm ADH; CO2 Co-Solvent (Solvent B): Methanol with 0.5% dimethylethylamine; Isocratic Method: 40% Co-Solvent a 8 mL/min; System pressure: 100 bar; Column temperature: 35°C). Isomer 1: MS: m/z = 408 [M + H]+. Isomer 2: MS: m/z = 408 [M + H]+.

[00991] Compound 522 and compound 523 (N-[(S)-1-(8-cyano-quinoxalin-5-yl)-5, 5-difluoro-piperidin-3-yl]-2-(1-methyl- piperidin-4-yl)-acetamide and N-[(R)-1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-(1-methyl- piperidin-4-yl)-acetamide): From compound 504 (Column: CHIRALPAK 10 x 250 mm IF; CO2 Co-Solvent (Solvent B): Ethanol with 0.5% dimethylethylamine; Isocratic Method: 55% Co-Solvent at 8 mL/min; System pressure: 100 bar; Column temperature: 35°C). Isomer 1: EM: m/z = 429 [M + H]+. Isomer 2: EM: m/z = 429 [M + H]+.

[00992] Compound 527 and compound 528 ((S)-5,5-difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine and (R)-5,5-difluoro-1 - (8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine): From compound 510 (Column: CHIRALPAK 10 x 250 mm IF; CO2 Co-Solvent (Solvent B): Ethanol with 0.5 % dimethylethylamine; Isocratic Method: 55% Co-Solvent at 4 mL/min; Isomer 1: MS: m/z = 332 [M + H]+. Isomer 2: MS: m/z = 332 [M + H]+.Example 127: Synthesis of compound 499 (8-((3R,5S)-3-amino-5-fluoro-piperidin-1-yl hydrochloride) -quinoxaline-5-carbonitrile)

[00993] [(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-carbamic acid tert-Butyl ester: a mixture of 8-bromo- quinoxaline-5-carbonitrile (84 mg; 0.36 mmol), ((S)-5-fluoro-piperidin-3-yl)-carbamic acid tert-butyl ester (94 mg; 0.43 mmol), carbonate dipotassium (64 mg; 0.47 mmol) and DMSO (2mL) was microwaved at 120°C for one hour. The reaction mixture was purified by reversed-phase chromatography (XBridge column), eluting with acetonitrile in water (0.1% NH3.H2O), to provide acid tert-butyl ester [(3R,5S)-1-( 8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-carbamic, 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.8 Hz, 1 H ), 8.99 (d, J = 1.8 Hz, 1 H), 8.25 (d, J = 8.4 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.02 (d, J = 7.6 Hz, 1 H), 4.85 (dt, J = 9.2, 4.7 Hz, 1 H), 4.49 (s, 1 H) , 3.93 (d, J = 12.1 Hz, 1 H), 3.73 (s, 1 H), 3.17 (ddd, J = 13.2, 9.1, 4.9 Hz, 1 H), 3.04 (t, J = 10.9 Hz, 1 H), 1.76 (q, J = 11.1 Hz, 1 H), 1.40 (s, 9H). MS: m/z = 373 [M + H]+.

[00994] 8-((3R,5S)-3-amino-5-fluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride: 8-((3R,5S)-3-amino- hydrochloride 5-fluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile was prepared from acid tert-butyl ester [(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-fluoro- piperidin-3-yl]- carbamic using Q method.

[00995] Compound 499: 1H NMR (400 MHz, DMSO-d6) δ 9.20 - 9.07 (m, 1 H), 9.03 (d, J = 1.8 Hz, 1 H), 8, 42 - 8.12 (m, 4 H), 7.38 (d, J = 8.4 Hz, 1 H), 5.19 - 4.93 (m, 1 H), 3.93 (ddd, J = 33.2, 13.0, 8.3 Hz, 2 H), 3.78 (dd, J = 12.6, 3.0 Hz, 1 H), 2.46 - 2.29 (m, 1 H), 2.22 - 2.07 (m, 1 H). EM: m/z = 273 [M + H]+.

[00996] The following compounds were synthesized in a similar way:

[00997] Compound 500 ([(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-fluoro-piperidin-3-yl]-carbamic acid tert-Butyl ester): From 5-bromo-quinoline-8-carbonitrile and tert-butyl ester of ((3R,5S)-5-fluoro-piperidin-3-yl)-carbamic acid. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.55 (d, J = 8.6 Hz, 1 H), 8 .25 (d, J = 8.1 Hz, 1 H), 7.71 (dd, J = 8.7, 4.2 Hz, 1 H), 7.30 (d, J = 8.1 Hz, 1 H), 6.97 (d, J = 7.4 Hz, 1 H), 4.99 (s, 1 H), 3.85 (s, 1 H), 3.63 (s, 1 H) , 3.44 (d, J = 11.8 Hz, 1 H), 3.00 (s, 1 H), 2.71 (t, J = 10.9 Hz, 1 H), 2.37 (t , J = 11.9 Hz, 1 H), 1.70 (t, J = 11.1 Hz, 1 H), 1.39 (s, 5 H). MS: m/z = 372 [M + H]+.

[00998] Compound 501 (8-((3S,5R)-3-amino-5-fluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride): From tert-butyl acid ester [( 3S,5R)-1-(8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-carbamic, 1H NMR (400 MHz, Methanol-d4) δ 9.06 (d, J = 1.8 Hz, 1 H), 8.99 (d, J = 1.8 Hz, 1 H), 8.23 (d, J = 8.2 Hz, 1 H), 7.41 (d, J = 8.2 Hz, 1 H), 5.16 (dt, J = 46.0, 2.7 Hz, 1 H), 4.55 - 4.38 (m, 1 H), 4.05 - 3.89 (m, 1 H), 3.81 (s, 1 H), 3.59 (ddd, J = 36.7, 13.4, 1.8 Hz, 1 H), 3.38 (dd , J = 13.5, 1.9 Hz, 1 H), 2.58 - 2.43 (m, 1 H), 2.39 (ddd, J = 15.8, 4.4, 3.1 Hz , 1 H), 2.28 (ddd, J = 15.8, 4.5, 3.1 Hz, 1 H). EM: m/z = 273 [M + H]+. Example 128: Synthesis of compound 502 (N-[(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-2-(4-methyl-piperazin -1-yl)-acetamide):

[00999] N-[(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-2-(4-methyl-piperazin-1-yl) -acetamide: N-[(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-2-(4-methyl-piperazin-1-yl) - acetamide was prepared from (4-methyl-piperazin-1-yl)-acetic acid and 8-((3R,5S)-3-amino-5-fluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride using method J. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 1.8 Hz, 1 H), 8.96 (d, J = 1.8 Hz, 1 H), 8 .24 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 7.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 5.00 (s, 1 H), 4.20 - 4.01 (m, 2 H), 3.98 (d, J = 14.5 Hz, 1 H), 3.82 (dd, J = 29 .6, 12.7 Hz, 1 H), 3.52 (d, J = 11.8 Hz, 1 H), 2.97 - 2.75 (m, 2 H), 2.33 (d, J = 24.5 Hz, 4 H), 2.11 (d, J = 4.5 Hz, 3 H), 2.01 (s, 3 H). MS: m/z = 412 [M + H]+.Example 129: Synthesis of compound 503 (N-[1-(8-cyano-quinoxalin-5-yl)-5, 5-difluoro-piperidin-3-yl ]-2-(4-methyl-piperazin-1-yl)-acetamide)

[001000] N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-(4-methyl-piperazin-1-yl)-acetamide: N -[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-(4-methyl-piperazin-1-yl)-acetamide was prepared from acid (4 -methyl-piperazin-1-yl)-acetic acid and 8-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride using method J.

[001001] Compound 503: 1H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 1.8 Hz, 1 H), 9.01 (d, J = 1.8 Hz, 1 H) , 8.30 (d, J = 8.4 Hz, 1 H), 8.21 (d, J = 7.6 Hz, 1 H), 7.41 (d, J = 8.4 Hz, 1 H ), 4.32 - 4.11 (m, 2 H), 3.98 (s, 1 H), 3.87 - 3.62 (m, 2 H), 2.39 (d, J = 13, 8Hz, 5H), 2.14 (s, 3H), 2.02 (s, 3H). MS: m/z = 430 [M + H]+.

[001002] The following compounds were synthesized in a similar way:

[001003] Compound 504 (N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-(1-methyl-piperidin-4-yl)- acetamide (racemic)): From (1-methyl-piperidin-4-yl)-acetic acid and 8-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoxaline-5- hydrochloride carbonitrile, 1H NMR (400 MHz, DMSO-d6) δ 9.09 (d, J = 1.8 Hz, 1 H), 8.99 (d, J = 1.8 Hz, 1 H), 8.30 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 6.9 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 4, 80 (s, 1 H), 4.20 (s, 1 H), 4.07 (d, J = 13.4 Hz, 1 H), 3.79 (dd, J = 29.1, 13.5 Hz, 2 H), 3.16 (dd, J = 13.0, 10.2 Hz, 2 H), 2.71 (d, J = 11.4 Hz, 2 H), 2.41 (m, 2 H), 2.13 (s, 3 H), 2.06 (d, J = 6.8 Hz, 1 H), 1.82 (t, J = 11.2 Hz, 2 H), 1, 60 (d, J = 12.9 Hz, 2 H), 1.18 (q, J = 11.9, 11.3 Hz, 2 H). EM: m/z = 429 [M + H]+.

[001004] Compound 506 (2-chloro-N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide): From 2-chloro acid -propionic and 8-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.8 Hz, 1 H), 9.00 (d, J = 1.8 Hz, 1 H), 8.56 (d , J = 6.9 Hz, 1 H), 8.31 (d, J = 8.3 Hz, 1 H), 7.44 (dd, J = 8.4, 3.6 Hz, 1 H), 4.75 - 4.45 (m, 2 H), 4.21 (s, 1 H), 3.97 (t, J = 11.3 Hz, 1 H), 3.82 (dd, J = 25 .6, 13.4 Hz, 1 H), 3.41 - 3.32 (m, 1 H), 2.44 (d, J = 13.2 Hz, 1 H), 2.26 (s, 1 H), 1.59 (dd, J = 6.8, 2.4 Hz, 3 H). EM: m/z = 380 [M + H]+. Example 130: Synthesis of compound 505 (3-amino-N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-3-methyl-butyramide hydrochloride)

[0065] 3-Amino-N-[1-(8-cyano-quinoxalin-5-yl)-5, 5-difluoro-piperidin-3-yl]-3-methyl-butyramide hydrochloride: 3-amino hydrochloride -N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-3-methyl-butyramide was prepared from 3-tert-butoxycarbonylamino-3-methyl-acid butyric hydrochloride and 8-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride using J and Q method.

[001005] Compound 505: 1H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.8 Hz, 1 H), 9.01 (d, J = 1.8 Hz, 1 H) , 8.64 (d, J = 7.0 Hz, 1 H), 8.29 (d, J = 8.4 Hz, 1 H), 8.00 (s, 2 H), 7.42 (d , J = 8.5 Hz, 1 H), 4.72 (s, 1 H), 4.26 (s, 1 H), 4.11 (d, J = 12.9 Hz, 1 H), 3 .81 (dd, J = 28.3, 13.6Hz, 2H), 3.25 (dd, J = 12.9, 10.0Hz, 2H), 2.50 (s, 2H), 2.19 (dtd, J = 30.2, 12.3, 6.4 Hz, 1 H), 1.31 (s, 6 H). MS: m/z = 389 [M + H]+. Example 131: Synthesis of compound 507 and compound 508 (2-Azetidin-1-yl-N-[(R)-1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3- yl]-propionamide and 2-azetidin-1-yl-N-[(R)-1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide)

[00918] Cis-2-azetidin-1-yl-N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide and trans-2-azetidin -1-yl-N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide: a mixture of 2-chloro-N-[1-( 8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide (30 mg; 0.08 mmol) and azetidine (45 mg; 0.79 mmol) in acetonitrile was stirred at 100°C for two hours. The reaction mixture was purified by reversed-phase chromatography (XBridge column), eluting with acetonitrile in water (0.1% NH3.H2O), to provide cis-2-azetidin-1-yl-N-[1-( 8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide and trans-2-azetidin-1-yl-N-[1-(8-cyano-quinoxalin-5- yl)-5,5-difluoro-piperidin-3-yl]-propionamide. Isomer 1: 1H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J = 1.8 Hz, 1 H), 9 .02 (d, J = 1.8 Hz, 1 H), 8.31 (d, J = 8.3 Hz, 1 H), 7.96 (d, J = 7.5 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H), 4.50 - 4.32 (m, 1 H), 4.21 (s, 1 H), 3.89 - 3.68 (m , 2 H), 3.62 (dd, J = 12.9, 7.7 Hz, 1 H), 3.21 (q, J = 6.8 Hz, 2 H), 3.09 (q, J = 6.8 Hz, 2 H), 2.79 (q, J = 6.8 Hz, 1 H), 2.33 (s, 2 H), 1.96 (p, J = 6.9 Hz, 2 H), 1.02 (d, J = 6.8 Hz, 3 H). MS: m/z = 401 [M + H]+. Isomer 2: 1H NMR (400 MHz, DMSO-d6) δ 9.13 (d, J = 1.8 Hz, 1 H), 9.04 (d, J = 1.8 Hz, 1 H), 8, 31 (dd, J = 7.7, 4.0 Hz, 2 H), 7.42 (d, J = 8.3 Hz, 1 H), 4.31 (td, J = 15.0, 14, 5, 6.6 Hz, 1 H), 4.19 (d, J = 7.2 Hz, 1 H), 3.81 (s, 1 H), 3.65 (d, J = 5.0 Hz , 1 H), 3.28-3.19 (m, 1 H), 3.18 (q, J = 6.9 Hz, 2 H), 3.09 (q, J = 6.8 Hz, 2 H), 2.77 (q, J = 6.8 Hz, 1 H), 2.39 - 2.16 (m, 2 H), 1.83 (p, J = 6.9 Hz, 2 H) , 1.07 (d, J = 6.8 Hz, 3 H). MS: m/z = 401 [M + H]+.

[00919] The following compounds were synthesized in an analogous manner:

[00920] Compound 509 (N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-morpholin-4-yl-propionamide): From 2-chloro-N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide and morphine. 1H NMR (400 MHz, DMSO-d6) δ 9.11 (t, J = 1.9 Hz, 1 H), 9.01 (dd, J = 8.7, 1.8 Hz, 1 H), 8 .37 - 8.16 (m, 2 H), 7.43 (dd, J = 8.4, 3.9 Hz, 1 H), 4.44 - 4.14 (m, 2 H), 4, 01 - 3.85 (m, 1 H), 3.82 - 3.71 (m, 1 H), 3.65 (dt, J = 13.2, 6.8 Hz, 1 H), 3.46 (q, J = 4.3 Hz, 4 H), 2.97 (q, J = 6.9 Hz, 1 H), 2.51 - 2.23 (m, 6 H), 1.14 (dd , J = 10.9, 7.0 Hz, 3 H). MS: m/z = 431 [M + H]+.Example 132: Synthesis of compound 518 (1-Cyclopropyl-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5- il)-piperidin-3-yl]-urea)

[00921] 1-Cyclopropyl-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-urea: a mixture of (3R) hydrochloride ,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine (60 mg; 0.17 mmol), ethyl-diisopropyl-amine (0.04 mL; 0. 21 mmol) and isocyanatocyclopropane (28 mg; 0.35 mmol) in DMSO (1 mL) was stirred at room temperature overnight. The mixture was purified by reverse phase chromatography (XBridge column), eluting with acetonitrile in water (0.1% NH3.H2O), to provide 1-cyclopropyl-3-[(3R,5S)-5-methyl-1 -(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-urea as white solid.

[00922] Compound 518: 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.54 (dd, J = 8.6, 1.8 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.67 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (d, J = 8.1 Hz, 1 H), 6.09 (d, J = 2.7 Hz, 1 H), 5.80 (d, J = 7.5 Hz, 1 H), 3, 56 (d, J = 8.9 Hz, 1 H), 2.48 - 2.35 (m, 3 H), 2.14 - 1.82 (m, 2 H), 1.06 (q, J = 11.9 Hz, 1 H), 0.95 (d, J = 6.4 Hz, 3 H), 0.56 (dd, J = 7.0, 2.1 Hz, 2 H), 0, 32 (dd, J = 3.7, 2.3 Hz, 2 H). MS: m/z = 293 [M + H]+.Example 133: Synthesis of compound 525 (8-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-3-methyl- quinoxaline-5-carbonitrile)

[00923] 4-Bromo-7-dibromomethyl-benzo[1,2,5]thiadiazole: a mixture of 4-bromo-7-methyl-benzo[1,2,5]thiadiazole (5.00 g; 21.8 mmols), N-bromosuccinimide (8.24 g; 45.8 mmols) and 2,2'-azobis(2-methylpropionitrile) (0.54 g; 3.27 mmols) in tetrachlorocarbon (150 mL) was stirred at 80°C. °C at night. The suspension was filtered, the filtrate diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to provide 4-bromo-7-dibromomethyl-benzo[1,2,5]thiadiazole (8.36 g quantitative yield) as a yellow solid. EM: m/z = 386 [M + H]+.

[00924] 7-Bromo-benzo[1,2,5]thiadiazol-4-carbaldehyde: a solution of 4-bromo-7-dibromomethyl-benzo[1,2,5]thiadiazole (8.36 g; 21.61 mmols) and silver nitrate (9.18 g; 54.02 mmols) in acetone (100 mL) and water (20 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, the resulting solid was washed with water and dried to provide 7-bromo-benzo [1,2,5]thiadiazol-4-carbaldehyde. EM: m/z = 242 [M + H]+.

[00925] 7-Bromo-benzo[1,2,5]thiadiazol-4-carbaldehyde oxime: a mixture of 7-bromo-benzo[1,2,5]thiadiazol-4-carbaldehyde (5.25 g; 21 .6 mmols) and sodium acetate (1.95 g; 23.77 mmols) in ethanol (200 mL) and ammonium chloride solution (1.58 mg; 22.7 mmols) was stirred at 70°C for one hour. The reaction mixture was cooled, filtered and the solid was washed with ethanol. The filtrate was concentrated under reduced pressure to provide 7-bromobenzo[1,2,5]thiadiazol-4-carbaldehyde oxide (4.30 g, 78%) as a yellow solid. MS: m/z = 257 [M + H]+.

[00926] 7-Bromo-benzo[1,2,5]thiadiazol-4-carbonitrile: a mixture of 7-bromo-benzo[1,2,5]thiadiazol-4-carbaldehyde oxime (4.30 g; 16 .7 mmols), copper(II) acetate (302 mg; 1.67 mmol) and acetic acid (2.00 mL; 35.0 mmols) in acetonitrile (20 mL) was refluxed over the weekend. The reaction mixture was cooled, water (20 mL) and slowly 2 M sodium hydroxide solution (17.5 mL) added. The mixture was concentrated to 1/3 under reduced pressure, diluted with water (20 mL) and filtered. The solid was washed with water and dried to provide 7-bromo-benzo[1,2,5]thiadiazol-4-carbonitrile (3.0 g, 75%) as a light green solid. EM: m/z = 239 [M + H]+.

[00927] [(3R,5S)-1-(7-cyano-benzo[1,2,5] thiadiazol-4-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-Butyl ester : a mixture of 7-bromo-benzo[1,2,5]thiadiazol-4-carbonitrile (1.80 g; 7.50 mmols), tert-butyl N-[(3R,5S)-5-methylpiperidin-3 -yl]carbamate (1.80 g; 8.25 mmols) and ethyl-diisopropyl-amine (1.61 mL; 9.00 mmols) in DMSO (2 mL) was microwaved at 120°C for 60 min. The reaction mixture was diluted with methanol (10 mL). A precipitated brown solid was filtered to provide acid tert-butyl ester [(3R,5S)-1-(7-cyano-benzo[12.5]thiadiazol-4-yl)-5-methyl-piperidin-3-yl ]-carbamic (2.16 mg, 77%). MS: m/z = 374 [M + H]+.

[00928] [(3R,5S)-1-(2,3-diamino-4-cyano-phenyl)-5-methyl-piperidin-3-yl]-carbamic acid tert-Butyl ester: a mixture of tert- [(3R,5S)-1-(7-cyano-benzo[1,2,5]thiadiazol-4-yl)-5-methyl-piperidin-3-yl]-carbamic acid butyl ester (2.16 g ; 5.78 mmols) and sodium borohydride (0.24 g; 6.36 mmols) in ethanol (130mL) was refluxed for 2 days. More sodium borohydride was added during the course of the reaction to completion. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure, diluted with ether and washed with brine. The organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide acid tert-butyl ester [(3R,5S)-1-(2,3-diamino-4-cyano-phenyl)-5-methyl- piperidin-3-yl]-carbamic acid (1.6 g, 80%) as brown solid. EM: m/z = 346 [M + H]+.

[00929] 8-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-3-methyl-quinoxaline-5-carbonitrile: A solution of tert-butyl acid ester [ (3R,5S)-1-(2,3-diamino-4-cyano-phenyl)-5-methyl-piperidin-3-yl]-carbamic acid (70.0 mg; 0.20 mmol) in ethanol (2 mL ) hydrogen chloride (0.10 mL; 0.41 mmol) and 2-oxo-propionaldehyde (0.03 mL; 0.20 mmol) were added. The mixture was stirred at 70°C for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (XBridge column), eluting with acetonitrile in water (0.1% NH3.H2O) to give 8-((3R,5S)- 3-amino-5-methyl-piperidin-1-yl)-3-methyl-quinoxaline-5-carbonitrile as white solid.

[00930] Compound 525: 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1 H), 8.08 (dd, J = 9.7, 8.4 Hz, 1 H), 7, 13 (t, J = 8.7 Hz, 1 H), 4.21 (s, 2 H), 3.01 - 2.79 (m, 1 H), 2.73 (d, J = 2.8 Hz, 3 H), 2.57 (dt, J = 11.3, 5.5 Hz, 1 H), 2.02 - 1.47 (m, 4 H), 0.99 - 0.75 (m , 3H). MS: m/z = 282 [M + H]+. Example 134: Synthesis of (1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid) compound 529

[00931] 1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid methyl ester: 1-(8-cyano-quinoxalin-5-yl) acid methyl ester -5,5-difluoro-piperidine-3-carboxylic acid was prepared from 8-bromo-quinoxaline-5-carbonitrile and 5,5-difluoro-piperidine-3-carboxylic acid methyl ester hydrochloride using H. 1H NMR method (400 MHz, DMSO-d6) δ 9.09 (d, J = 1.8 Hz, 1 H), 9.01 (d, J = 1.8 Hz, 1 H), 8.27 (d, J = 8 .4 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 4.39 (d, J = 12.5 Hz, 1 H), 3.83 - 3.72 ( m, 1 H), 3.69 (s, 3 H), 3.49 - 3.33 (m, 1 H), 3.20 (s, 1 H), 2.31 (dtd, J = 31, 9, 12.8, 6.4 Hz, 1 H). EM: m/z = 333 [M + H]+.

[00932] 1-(8-Cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid lithium: a mixture of 1-(8-cyano-quinoxalin-5- il)-5,5-difluoro-piperidine-3-carboxylic acid (25 mg; 0.08 mmol) and lithium hydroxide (7 mg; 0.30 mmol) in THF (1.0 mL) and water (1.0 mL) was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure and the resulting solid was dried to provide 1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid lithium as a yellow solid. EM: m/z = 319 [M + H]+.

[00933] 1-(8-Cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-carboxylic acid (1-Methyl-piperidin-4-yl)-amide: (1-methyl-piperidin 1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid-4-yl)-amide was prepared from 1-(8-cyano-quinoxalin-5) acid lithium -yl)-5,5-difluoro-piperidine-3-carboxylic acid and 4-amino-1-methylpiperidine as a white solid, using Method J.

[00934] Compound 529: 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 1.8 Hz, 1 H), 8.99 (d, J = 1.8 Hz, 1 H) , 8.26 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 1 H ), 4.73 (s, 2 H), 4.16 (d, J = 13.3 Hz, 1 H), 3.77 - 3.40 (m, 4 H), 3.01 (s, 2 H), 2.71 (s, 2 H), 2.33 (s, 1 H), 2.15 (s, 3 H), 1.93 (t, J = 11.1 Hz, 2 H), 1.73 (d, J = 12.3 Hz, 2 H), 1.53 - 1.32 (m, 2 H). MS: m/z = 415 [M + H]+.

[00935] The following compounds were synthesized in an analogous manner:

[00936] Compound 530 (1-Methyl-piperidin-4-yl)-amide) (1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid: from 5 -bromo-quinoline-8-carbonitrile, 5,5-difluoro-piperidine-3-carboxylic acid methyl ester hydrochloride and 4-amino-1-methylpiperidine 1H NMR (400 MHz, DMSO-d6) δ 9.08 (. dd, J = 4.2, 1.6 Hz, 1 H), 8.56 (dd, J = 8.6, 1.7 Hz, 1 H), 8.28 (d, J = 8.0 Hz , 1 H), 8.04 (d, J = 7.6 Hz, 1 H), 7.75 (dd, J = 8.6, 4.2 Hz, 1 H), 7.36 (d, J = 8.1 Hz, 1 H), 3.67 (s, 1 H), 3.55 - 3.34 (m, 3 H), 3.18 - 2.93 (m, 2 H), 2, 77 - 2.58 (m, 2 H), 2.37 (d, J = 12.3 Hz, 1 H), 2.30 (s, 1 H), 2.13 (s, 3 H), 1 .92 (tdd, J = 10.9, 5.3, 2.2 Hz, 2 H), 1.78 - 1.60 (m, 2 H), 1.47 - 1.26 (m, 2 H ).MS: m/z = 414 [M + H]+.

[00937] Compound 531 (1-methyl-piperidin-4-ylmethyl)-amide) (1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid: From of 5-bromo-quinoline-8-carbonitrile, 5,5-difluoro-piperidine-3-carboxylic acid methyl ester hydrochloride and C-(1-methyl-piperidin-4-yl)-methylamine. , Methanol-d4) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.69 (dd, J = 8.6, 1.7 Hz, 1 H), 8, 18 (d, J = 8.0 Hz, 1 H), 7.69 (dd, J = 8.6, 4.3 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 3.79 - 3.52 (m, 2 H), 3.26 - 3.07 (m, 4 H), 2.88 (d, J = 11.8 Hz, 2 H), 2, 46 (s, 1 H), 2.33 (dd, J = 13.6, 6.1 Hz, 1 H), 2.27 (s, 3 H), 2.07 - 1.91 (m, 2 H), 1.71 (dd, J = 13.3, 3.2 Hz, 2 H), 1.52 (dtd, J = 14.3, 7.6, 6.5, 4.1 Hz, 1 H),1.29 (qd, J = 12.1, 3.9 Hz, 2 H). EM: m/z = 428 [M + H]+.

[00938] Compound 532 (1-ethyl-piperidin-4-yl)-amide) (1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid: From of 5-bromo-quinoline-8-carbonitrile, 5,5-difluoro-piperidine-3-carboxylic acid methyl ester hydrochloride and 1-ethyl-piperidin-4-ylamine 1H NMR (400 MHz, Methanol-d4) δ. 9.02 (dd, J = 4.3, 1.7 Hz, 1 H), 8.69 (dd, J = 8.6, 1.7 Hz, 1 H), 8.18 (d, J = 8.0 Hz, 1 H), 7.69 (dd, J = 8.6, 4.3 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 3.77 - 3.64 (m, 2 H), 3.60 (d, J = 10.2 Hz, 1 H), 3.26 - 3.09 (m, 3 H), 2.98 (d, J = 25.7 Hz, 3 H), 2.45 (q, J = 7.2 Hz, 3 H), 2.39 - 2.17 (m, 1 H), 2.10 (dp, J = 7, 0, 3.5, 3.0 Hz, 2 H), 1.90 (t, J = 13.7 Hz, 2 H), 1.57 (dd, J = 12.4, 8.9 Hz, 2 H), 1.12 (t, J = 7.2 Hz, 3 H).

[00939] Compound 537 and compound 538 [2-(4-methyl-piperazin-1-yl)-ethyl]-acid amide (cis-1-(8-cyano-quinoxalin-5-yl)-5-methyl- piperidine-3-carboxylic acid and trans-1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidine-acid [2-(4-methyl-piperazin-1-yl)-ethyl]-amide). 3-carboxylic: From 8-bromo-quinoxaline-5-carbonitrile, 5-methyl-piperidine-3-carboxylic acid methyl ester hydrochloride and 2-(1-methyl-piperidin-4-yl)-ethylamine. Isomer 1: 1H NMR (400 MHz, Methanol-d4) δ 8.92 (dd, J = 19.8, 1.8 Hz, 2 H), 8.10 (d, J = 8.4 Hz, 1 H ), 7.24 (d, J = 8.4 Hz, 1 H), 4.41 (ddt, J = 12.3, 3.6, 1.7 Hz, 1 H), 4.17 (ddd, J = 10.4, 4.5, 2.5 Hz, 1 H), 3.37 (d, J = 6.8 Hz, 2 H), 3.09 (dd, J = 12.3, 11, 3 Hz, 1 H), 2.90 - 2.75 (m, 1 H), 2.67 (dd, J = 12.5, 10.9 Hz, 2 H), 2.54 (q, J = 10.2, 6.8 Hz, 8 H), 2.29 (s, 3 H), 2.13 - 1.98 (m, 2 H), 1.45 (q, J = 13.1, 12 .7 Hz, 1 H), 1.03 (d, J = 6.4 Hz, 3 H). EM: m/z = 422 [M + H]+. Isomer 2: 1H NMR (400 MHz, Methanol-d4) δ 9.03 (dd, J = 24.4, 1.8 Hz, 2 H), 8.22 (d, J = 8.3 Hz, 1 H ), 7.40 (d, J = 8.3 Hz, 1 H), 4.60 - 4.48 (m, 1 H), 3.67 - 3.46 (m, 2 H), 3.46 - 3.34 (m, 3 H), 3.14 (dd, J = 13.2, 3.3 Hz, 1 H), 2.96 - 2.83 (m, 1 H), 2.75 ( s, 1 H), 2.49 (td, J = 6.5, 1.3 Hz, 3 H), 2.43 - 2.27 (m, 4 H), 2.10 (s, 5 H) , 1.50 (ddd, J = 13.2, 11.3, 5.1 Hz, 1 H), 1.06 (dd, J = 10.1, 6.7 Hz, 3 H).

[00940] Compound 539 (1-methyl-piperidin-4-ylmethyl)-amide) of (1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidine-3-carboxylic acid: 8-bromo -quinoxaline-5-carbonitrile, 5-methyl-piperidine-3-carboxylic acid methyl ester hydrochloride and C-(1-methyl-piperidin-4-yl)-methylamine 1H NMR (400 MHz, Methanol-d4) δ. 9.06 (d, J = 1.8 Hz, 1 H), 8.98 (d, J = 1.9 Hz, 1 H), 8.20 (d, J = 8.3 Hz, 1 H) , 7.39 (d, J = 8.3 Hz, 1 H), 4.39 (dd, J = 13.3, 3.5 Hz, 1 H), 3.62 - 3.38 (m, 2 H), 3.17 - 3.05 (m, 2 H), 2.97 - 2.85 (m, 2 H), 2.85 - 2.71 (m, 2 H), 2.24(s , 3 H). 1.37 - 1.18 (m, 2 H), 1.08 (d, J = 6.6 Hz, 3 H). EM: m/z = 407 [M + H]+.

[00941] Compound 540 ((1-ethyl-piperidin-4-yl)-1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidin-3-carboxylic acid amide): From 8 -bromo-quinoxaline-5-carbonitrile, 5-methyl-piperidine-3-carboxylic acid methyl ester hydrochloride and 1-ethyl-piperidin-4-ylamine. 1H NMR (400 MHz, Methanol-d4) δ 9.07 (s, 2 H), 8.20 (d, J = 8.3 Hz, 1 H), 7.39 (d, J = 8.4 Hz , 1 H), 4.45 (d, J = 12.4 Hz, 1 H), 3.85 (ddd, J = 15.5, 11.4, 4.3 Hz, 1 H), 3.59 - 3.46 (m, 1 H), 3.13 (dd, J = 13.1, 3.2 Hz, 1 H), 3.01 (d, J = 10.2 Hz, 1 H), 2 .91 (dd, J = 11.4, 9.8 Hz, 2 H), 2.75 (t, J = 4.3 Hz, 1 H), 2.44 (q, J = 7.2 Hz, 2 H), 2.18 - 1.91 (m, 4 H), 1.82 (d, J = 13.0 Hz, 1 H), 1.65 (qd, J = 12.0, 3.9 Hz, 1 H), 1.57 - 1.39 (m, 2 H), 1.18 - 1.00 (m, 5 H). MS: m/z = 407 [M + H]+.

[00942] Compound 541 and compound 542 (cis-1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidine-3-carboxylic acid methylamide and trans-1-(8-cyano- quinoxalin-5-yl)-5-methyl-piperidine-3-carboxylic acid): From 8-bromo-quinoxaline-5-carbonitrile, 5-methyl-piperidine-3-carboxylic acid methyl ester hydrochloride and methylamine hydrochloride . Isomer 1: 1H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 1.8 Hz, 1 H), 8.96 (d, J = 1.8 Hz, 1 H), 8, 18 (d, J = 8.4 Hz, 1 H), 7.84 (d, J = 5.1 Hz, 1 H), 7.24 (d, J = 8.5 Hz, 1 H), 4 .34 (d, J = 12.8 Hz, 1 H), 4.18 (d, J = 12.2 Hz, 1 H), 3.05 (t, J = 12.0 Hz, 1 H), 2.76 - 2.63 (m, 2H), 2.58 (d, J = 4.6Hz, 3H), 1.91 (t, J = 15.5Hz, 2H), 1.35 (q, J = 12.1 Hz, 1 H), 1.04 - 0.86 (m, 3 H). EM: m/z = 310 [M + H]+. Isomer 2: 1H NMR (400 MHz, DMSO-d6) δ 9.12 - 9.03 (m, 1 H), 8.99 (d, J = 1.8 Hz, 1 H), 8.43 (d , J = 5.2 Hz, 1 H), 8.23 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1 H), 3.92 (dd , J = 12.9, 6.4 Hz, 1 H), 3.48 (ddd,J = 20.3, 12.5, 3.6 Hz, 2 H), 2.82 - 2.68 (m , 1 H), 2.64 (d, J = 4.4 Hz, 3 H), 2.20 - 1.91 (m, 2 H), 1.48 (ddd, J = 12.5, 7, 7, 4.7 Hz, 1 H), 1.00 (d, J = 6.7 Hz, 3 H). MS: m/z = 310 [M + H]+.

[00943] Compound 543 and compound 544 (cis-1-(8-cyanoquinoxalin-5-yl)-5-methyl-N-(1-methyl-3-piperidyl)piperidine-3-carboxamide and trans-1-(8 -cyanoquinoxalin-5-yl)-5-methyl-N-(1-methyl-3-piperidyl)piperidine-3-carboxamide): From 8-bromo-quinoxaline-5-carbonitrile, acid methyl ester hydrochloride 5 -methyl-piperidine-3-carboxylic acid and 1-methyl-piperidin-3-ylamine. Isomer 1: 1H NMR (400 MHz, DMSO-d6) δ 9.04 (dd, J = 1.8, 0.7 Hz, 1 H), 8.95 (t, J = 1.8 Hz, 1 H ), 8.18 (dd, J = 8.5, 1.3 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H), 7.24 (d, J = 8, 5 Hz, 2 H), 4.30 (s, 1 H), 4.19 (d, J = 12.3 Hz, 1 H), 3.69 (s, 1 H), 3.07 (t, J = 12.0 Hz, 1 H), 2.75 - 2.59 (m, 3 H), 2.55 (s, 2 H), 2.14 (d, J = 1.5 Hz, 2 H ), 1.89 (s, 3 H), 1.64 (s, 3 H), 1.43 (d, J = 31.3 Hz, 1 H), 1.13 (d, J = 11.1 Hz, 2H), 0.94 (d, J = 6.0Hz, 3H). EM: m/z = 393 [M + H]+. Isomer 2: 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 1.8 Hz, 1 H), 8.97 (d, J = 1.8 Hz, 1 H), 8, 22 (d, J = 8.4 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.26 (d, J = 8.5 Hz, 1 H), 4 .11 - 3.99 (m, 1 H), 3.71 (d, J = 9.5 Hz, 2 H), 3.57 - 3.44 (m, 2 H), 2.73 (s, 2 H), 2.60 (s, 1 H), 2.08 (s, 4 H), 1.93 - 1.62 (m, 3 H), 1.45 (d, J = 47.0 Hz , 4 H), 1.01 (d, J = 6.6 Hz, 3 H). EM: m/z = 393 [M + H]+.

[00944] Compound 547 and compound 548 ((1-methyl-piperidin-4-ylmethyl)-cis-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-3-carboxylic acid amide and trans-5-methyl-1(8-trifluoromethyl-quinolin-5-yl)-piperidine-3-carboxylic acid (1-methyl-piperidin-4-ylmethyl)-amide): From 5-bromo-8- trifluoromethyl-quinoline, 5,5-difluoro-piperidine-3-carboxylic acid methyl ester hydrochloride and C-(1-methyl-piperidin-4-yl)-methylamine. Isomer 1: : 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.65 (dd, J = 8.6, 1, 8 Hz, 1 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.85 (t, J = 5.9 Hz, 1 H), 7.66 (dd, J = 8 .5, 4.2 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 3.21 - 3.05 (m, 2 H), 2.98 (hept, J = 6.4 Hz, 2 H), 2.79 (s, 2 H), 2.66 - 2.56 (m, 2 H), 2.26 (s, 1 H), 2.05 - 1, 96 (m, 1 H), 1.64 (dt, J = 22.8, 11.5 Hz, 2 H), 1.51 (t, J = 13.0 Hz, 1 H), 1.29 ( dt, J = 7.7, 4.1 Hz, 1 H), 1.12 (d, J = 6.9 Hz, 1 H), 1.10 - 0.98 (m, 1 H). Isomer 2: 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.52 (dd, J = 8.6, 1.8 Hz, 1 H), 8.06 (d, J = 8.1 Hz, 1 H), 7.90 (t, J = 5.8 Hz, 1 H), 7.66 (dd, J = 8, 6, 4.1 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 3.45 - 3.32 (m, 2 H), 3.06 - 2.86 ( m, 2 H), 2.82 (t, J = 11.7 Hz, 2 H), 2.71 (d, J = 11.3 Hz, 2 H), 2.41 (t, J = 11, 3 Hz, 1 H), 2.12 (s, 3 H), 1.99 (t, J = 14.9 Hz, 2 H), 1.76 (td, J = 11.6, 2.5 Hz , 2 H), 1.57 (d, J = 12.9 Hz, 2 H), 1.30 (dd, J = 16.6, 8.1 Hz, 2 H), 1.12 (tt, J = 13.0, 6.5 Hz, 2 H), 0.95 (dd, J = 6.5, 3.9 Hz, 3 H). EM: m/z = 449 [M + H]+.

[00945] Compound 549 (4-methyl-piperazin-1-yl)-[5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-methanone): From 5 - bromo-8-trifluoromethyl-quinoline, 5-methyl-piperidine-3-carboxylic acid methyl ester hydrochloride and 1-methyl-piperazine. 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.7 Hz, 1 H), 8.62 (ddd, J = 48.2, 8.6, 1, 8 Hz, 1 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.67 (ddd, J = 8.6, 4.1, 1.7 Hz, 1 H), 7 .23 (d, J = 8.0 Hz, 1 H), 3.68 - 3.40 (m, 4 H), 3.12 - 3.01 (m, 1 H), 2.85 (t, J = 11.3 Hz, 1 H), 2.44 (t, J = 11.5 Hz, 1 H), 2.32 (d, J = 5.3 Hz, 4 H), 2.18 (d , J = 1.7 Hz, 3 H), 2.10 (s, 1 H), 1.93 (d, J = 13.3 Hz, 1 H), 1.56 (d, J = 13.5 Hz, 1 H), 1.23 (d, J = 7.2 Hz, 2 H), 0.95 (d, J = 6.6 Hz, 3 H). MS: m/z = 421 [M + H]+.Example 135: Synthesis of compound 533 and compound 534 (cis-5-[3-methyl-5-(4-methyl-piperazin-1-ylmethyl)-piperidin- 1-yl]-8-trifluoromethyl-quinoline and trans-5-[3-methyl-5-(4-methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-8-trifluoromethyl-quinoline)

[00946] [5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]- methanol: to a solution of 5-methyl-1-(8-trifluoromethyl- quinolin-5-yl)-piperidine-3-carboxylic acid (200 mg; 0.57 mmol) in anhydrous THF (2 mL) was added a 2N solution of sodium borohydride (1.14 mL; 2.27 mmols) in THF and the reaction mixture was stirred at room temperature for 48 hours. A 10% citric acid solution (3 mL) was added, the resulting mixture was brought to pH > 8 and extracted with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide [5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-methanol as a light yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 9.06 (dd, J = 4.2, 1.8 Hz, 1 H), 8.50 (dd, J = 8.6, 1.8 Hz, 1 H), 7.99 (ddd, J = 8.0, 4.1, 0.9 Hz, 1 H), 7.49 (ddd, J = 8.5, 4.2, 1.0 Hz, 1 H), 7.11 (t, J = 7.4 Hz, 1 H), 4.07 - 3.80 (m, 1 H), 3.73 - 3.61 (m, 1 H), 3, 58 (ddd, J = 8.4, 7.2, 3.2 Hz, 1 H), 3.39 (ddt, J = 11.7, 3.9, 1.8 Hz, 1 H), 3, 28 - 3.05 (m, 1 H), 2.27 - 2.16 (m, 1 H), 2.16 - 2.05 (m, 1 H), 2.06 - 1.93 (m, 1 H), 1.38 (s, 1 H), 1.11 (d, J = 6.7 Hz, 1 H), 1.01 (d, J = 6.6 Hz, 2 H), 0, 88 (q, J = 12.2 Hz, 1 H). MS: m/z = 325 [M + H]+.

[00947] 5-Methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylmethyl methane sulfonic acid ester: a mixture of [5-methyl-1-(8-trifluoromethyl-quinolin-5 -yl)-piperidin-3-yl]-methanol (175 mg; 0.54 mmol), methane sulfonyl chloride (0.05 mL; 0.70 mmol) and ethyl-diisopropyl-amine (0.15 mL; 0 .81 mmol) in THF (2 mL) was stirred at room temperature for one hour. The reaction mixture was directly taken to the next step without any further purification. MS: m/z = 403 [M + H]+.

[00948] Cis-5-[3-methyl-5-(4-methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-8-trifluoromethyl-quinoline and trans-5-[3-methyl-5- (4-methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-8-trifluoromethyl-quinoline: a mixture of 5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3- methanesulfonic acid ylmethyl ester (100 mg; 0.25 mmol) and 1-methyl-piperazine (0.31 mL; 2.48 mmol) in THF (1 mL) and DMSO (1 mL) was heated at 80°C for at night. The reaction mixture was purified by reversed-phase chromatography (XBridge column), eluting with acetonitrile in water (0.1% NH3.H2O), to provide cis-5-[3-methyl-5-(4- methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-8-trifluoromethyl-quinoline and trans-5-[3-methyl-5-(4-methyl-piperazin-1-ylmethyl)-piperidin-1-yl ]-8-trifluoromethyl-quinoline as a mixture of 2 enantiomers. Isomer 1: Isomer 1 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.2, 1.6 Hz, 1 H) , 8.48 (dd, J = 8.6, 1.8 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.64 (dd, J = 8.6 , 4.1 Hz, 1 H), 7.18 (d, J = 8.1 Hz, 1 H), 3.60 - 3.45 (m, 1 H), 2.49 - 2.33 (m , 3 H), 2.28 (q, J = 16.3, 13.4 Hz, 5 H), 2.21 - 2.15 (m, 2 H), 2.12 (s, 3 H), 2.01 (d, J = 12.3 Hz, 1 H), 1.88 (d, J = 12.8 Hz, 1 H), 0.94 (dd, J = 6.6, 1.9 Hz , 3 H), 0.74 (q, J = 11.8, 11.3 Hz, 1 H). MS: m/z = 407 [M + H]+.Isomer 2: 1H NMR (400 MHz, DMSO-d6) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8 .73 (dd, J = 8.6, 1.8 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.63 (dd, J = 8.6, 4 .1 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 3.18 (d, J = 9.0 Hz, 1 H), 2.95 (d, J = 11.5 Hz, 1 H), 2.73 (s, 2 H), 2.42 - 2.17 (m, 6 H), 2.15 (s, 3 H), 1.60 (d, J = 13.0 Hz, 1 H), 1.40 (s, 1 H), 1.04 (d, J = 6.6 Hz, 3 H). MS: m/z = 407 [M + H]+.

[00949] The following compounds were synthesized in an analogous manner:

[00950] Compound 535 and compound 536 (cis-5-[3-methyl-5-(4-morpholin-4-yl-piperidin-1-ylmethyl)-piperidin-1-yl]-8-trifluoromethyl-quinoline and trans -5-[3-methyl-5-(4-morpholin-4-yl-piperidin-1-ylmethyl)-piperidin-1-yl]-8-trifluoromethyl-quinoline): from 5-bromo-8-trifluoromethyl-quinoline , 5-methyl-piperidine-3-carboxylic acid methyl ester hydrochloride and 4-piperidin-4-yl-morpholine. Isomer 1: 1H NMR (400 MHz, Methanol-d4) δ 8.93 (dd, J = 4.2, 1.7 Hz, 1 H), 8.60 (dd, J = 8.6, 1.8 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.60 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 3.70 (t, J = 4.7 Hz, 4 H), 3.62 (d, J = 11.5 Hz, 1 H), 3.41 (d , J = 11.5 Hz, 1 H), 3.14 (d, J = 11.7 Hz, 1 H), 2.94 (d, J = 11.7 Hz, 1 H), 2.57 ( t, J = 4.7 Hz, 4 H), 2.40 (dt, J = 16.9, 11.1 Hz, 2 H), 2.33 - 2.15 (m, 4 H), 2, 15 - 1.79 (m, 6 H), 1.60 - 1.40 (m, 2 H), 1.01 (d, J = 6.6 Hz, 3 H), 0.82 (q, J = 11.7 Hz, 1 H). EM: m/z = 477 [M + H]+. Isomer 2: 1H NMR (400 MHz, Methanol-d4) δ 8.93 (dd, J = 4.2, 1.7 Hz, 1 H), 8.79 (dd, J = 8.6, 1.8 Hz, 1 H), 8.03 (d, J = 8.1 Hz, 1 H), 7.61 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 3.79 - 3.63 (m, 3 H), 3.26 (d, J = 12.9 Hz, 1 H), 3.10 (s, 2 H ), 2.96 (d, J = 11.7 Hz, 1 H), 2.75 (s, 2 H), 2.58 (t, J = 4.7 Hz, 3 H), 2.41 - 2.11 (m, 4 H), 2.07 (t, J = 11.5 Hz, 1 H), 1.92 (d, J = 10.7 Hz, 2 H), 1.72 (d, J = 12.8 Hz, 1 H), 1.60 - 1.40 (m, 3 H), 1.11 (d, J = 6.6 Hz, 3 H). MS: m/z = 477 [M + H]+.Example 136: Separation of compound 545 and compound 546 (1-methyl-piperidin-4-ylmethyl)-amide acid ((R)-1-(8-cyano -quinolin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid and (1-methyl-piperidin-4-ylmethyl)-amide) (S)-1-(8-cyano-quinolin-5 -yl)-5,5-difluoro-piperidine-3-carboxylic acid

[00951] The title compounds were isolated using chiral SFC chromatography of compound 531. (Column: CHIRALPAK 10 x 250 mm ADH; CO2 Co-Solvent (Solvent B): Methanol with 0.5% dimethylethylamine; Isocratic Method : 45% Co-Solvent at 5 mL/min; System pressure: 100 bar; Column temperature: 35°C).Isomer 1: MS: m/z = 428 [M + H]+. Isomer 2: MS: m/z = 428 [M + H]+.Example 137: Synthesis of compound 552 (7-((3R,5S)-3-amino-5-methyl-piperidin-1-yl hydrochloride) -benzo[1,2,5]thiadiazol-4-carbonitrile)

[00952] 7-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-benzo[1,2,5]thiadiazol-4-carbonitrile hydrochloride: 7-((3R) hydrochloride ,5S)-3-amino-5-methyl-piperidin-1-yl)-benzo[1,2,5]thiadiazol-4-carbonitrile was prepared from acid tert-butyl ester [(3R,5S)-1- (7-cyano-benzo[1,2,5]thiadiazol-4-yl)-5-methyl-piperidin-3-yl]-carbamic acid using Q method.

[00953] Compound 552: 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 2 H), 8.16 (dd, J = 8.3, 1.2 Hz, 1 H), 6, 95 (d, J = 8.3 Hz, 1 H), 4.94 (d, J = 12.1 Hz, 1 H), 4.65 (d, J = 11.9 Hz, 1 H), 3 .13 (q, J = 12.6, 11.8 Hz, 1 H), 2.75 (t, J = 12.3 Hz, 1 H), 2.16 (d, J = 12.3 Hz, 1 H), 1.88 (s, 1 H), 1.33 (q, J = 12.0 Hz, 1 H), 0.99 (d, J = 6.5 Hz, 3 H). MS: m/z = 354 [M + H]+.Example 138: Synthesis of compound 567 (N-[(3R,5S)-5-methyl- 1-(8-methyl-[1,7]naphthyridin- acid 5-yl)-piperidin-3-yl]-succinamic)

[00954] N-[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-yl]-succinamic acid: N-[( 3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-yl]-succinamic was prepared from (3R,5S)-5-methyl dihydrochloride -1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine and mono-methyl succinate using Method 37, followed by ester saponification to carboxylic acid using Method I to provide N- [(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-yl]-succinamic acid in 71% production during two steps.

[00955] Compound 567: EM: m/z = 357 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.44 (dd, J = 8.5, 1.8Hz, 1 H), 8.10 (s, 1 H), 7.90 (d, J = 7.5 Hz, 1 H), 7.80 (dd, J = 8.5, 4.1 Hz, 1 H ), 4.04 - 3.97 (m, 1 H), 3.42 - 3.37 (m, 1 H), 3.27 - 3.20 (m, 1 H), 2.88 (s, 3 H), 2.47 - 2.35 (m, 4 H), 2.35 - 2.25 (m, 2 H), 2.09 - 1.91 (m, 2 H), 1.06 ( q, J = 12.1 Hz, 1 H), 0.95 (d, J = 6.4 Hz, 3 H). Example 139: Synthesis of compound 568 (1-Azetidin-1-yl-2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]- ethanone)

[00956] [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-carbamic acid tert-Butyl ester: a mixture of 5-bromo- 8-trifluoromethyl-quinoline (600 mg; 2.0 mmols), tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (486 mg; 2.27 mmols), cesium carbonate ( 1345 mg; 4.1 mmols), 2-dicyclohexylphosphine-2',6'-di-i-propoxy-1,1'-biphenyl (48 mg; 0.1 mmol), chloro(2-dicyclohexylphosphine - 2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (84 mg; 0.1 mmol) and tBuOH (15 mL) in a 20 mL microwave tube was degassed and microwaved at 85°C for 8 hours. The reaction mixture was filtered. The filtrate was concentrated. The crude was purified by silica gel chromatography, eluting with ethyl acetate and hexanes, to provide acid tert-butyl ester [(3R5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin -3-yl]- carbamic (764 mg; 90%). MS: m/z = 410[M + H]+.

[00957] {tert-Butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid methyl ester: bis Lithium (trimethylsilyl)amide (2.3 mL; 2.38 mmol) was added to a solution of acid tert-butyl ester [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5 -yl)-piperidin-3-yl]-carbamic acid (750 mg; 1.8 mmol) and potassium iodide (30 mg; 0.18 mmol) in THF (2 mL) and the reaction mixture was stirred at room temperature for 30 min. Methyl bromoacetate (0.8 mL; 9.1 mmols) was added to the reaction mixture. The resulting mixture was stirred at 60°C for 2 days. After cooling to room temperature, the reaction mixture was stopped abruptly with a saturated ammonium chloride solution and extracted with ethyl acetate. The separated organic layer was washed with brine, dried and concentrated. The crude was purified by preparative HPLC (XBridge Prep C18 column, 10 μM, OBD 30 x 250 mm, 50-95% ACN in water with 0.1% NH4OH) to give acid methyl ester {tert-butoxycarbonyl-[ (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid (160 mg; 19%). EM: m/z = 482 [M + H]+.

[00958] acid tert-Butyl ester (2-azetidin-1-yl-2-oxo-ethyl)- [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)- piperidin-3-yl]-carbamic acid: a mixture of {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3- acid methyl ester yl]-amino}-acetic acid (25 mg; 0.05 mmol) and azetidine (0.14 mL; 2.0 mmol) in methanol (1 mL) was stirred at room temperature for 2 days. The reaction mixture was concentrated to dryness to give acid tert-butyl ester (2-azetidin-1-yl-2-oxo-ethyl)-[(3R,5S)-5-methyl-1-(8 - crude trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-carbamic acid (25 mg), which was used directly for the following reaction. MS: m/z = 507 [M + H]+.

[00959] 1-Azetidin-1-yl-2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-ethanone: 1-Azetidin -1-yl-2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-ethanone was prepared from acid tert-butyl ester ( 2-azetidin-1-yl-2-oxo-ethyl)-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-carbamic using Method Q. The crude was purified by preparative HPLC (XBridge Prep C18 column, 10 μM, OBD 30 x 250 mm, 10-60% ACN in water with 0.1% NH4OH) to give 1-azetidin-1-yl- 2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-ethanone (18 mg; 90%).

[00960] Compound 568: EM: m/z = 407 [M + H]+. 1H NMR (400 MHz, Methanol-d4, ppm) δ 8.96 (dd, J = 4.2, 1.8 Hz, 1 H), 8.59 (dd, J = 8.6, 1.8 Hz , 1 H), 8.49 (s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 1 H), 4.24 (t, J = 7.7 Hz, 2 H), 4.08 (t, J = 7.8 Hz, 2 H), 3.74 - 3.65 (m, 1 H), 3.62 (s, 2 H), 3.45 - 3.35 (m, 2 H), 2.69 (t, J = 10.9 Hz, 1 H), 2.47 (t, J = 11.4 Hz, 1 H), 2.38 (q, J = 7.8 Hz, 2 H), 2.34 - 2.26 (m, 1 H), 2.23 - 2.06 (m, 1 H), 1.15 (q, J = 11.9 Hz, 1 H), 1.06 (d, J = 6.6 Hz , 3H).

[00961] The following compounds were synthesized in an analogous manner:

[00962] Compound 569 (1-Azetidin-1-yl-2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-ethanone) : From {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid methyl ester and methylamine. MS: m/z = 381 [M + H]+. 1H NMR (400 MHz, Methanol-d4, ppm) δ 8.95 (dd, J = 4.3, 1.7 Hz, 1 H), 8.58 (dd, J = 8.6, 1.8 Hz , 1 H), 8.46 (s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.62 (dd, J = 8.6, 4.2 Hz, 1 H), 7.26 (d, J = 8.0Hz, 1H), 3.72 - 3.63 (m, 1H), 3.59 (bs, 2H), 3.43 - 3.35 (m, 1 H), 3.32 - 3.27 (m, 1 H),2.80 (s, 3 H), 2.67 (t, J = 10.9 Hz, 1 H), 2, 46 (t, J = 11.4 Hz, 1 H), 2.28 (d, J = 12.4 Hz, 1 H), 2.22 - 2.07 (m, 1 H), 1.13 ( q, J = 11.8 Hz, 1 H), 1.05 (d, J = 6.6 Hz, 3 H).

[00963] Compound 570 (1-Azetidin-1-yl-2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-ethanone) : From {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid methyl ester and ammonia. MS: m/z = 367 [M + H]+. 1H NMR (400 MHz, Methanol-d4, ppm) δ 8.96 (dd, J = 4.2, 1.7 Hz, 1 H), 8.59 (dd, J = 8.6, 1.8 Hz , 1 H), 8.46 (s, 2 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H), 3.78 - 3.56 (m, 3 H), 3.39 (dd, J = 11.9, 4.0 Hz , 2 H), 2.69 (t, J = 10.8 Hz, 1 H), 2.47 (t, J = 11.4 Hz, 1 H), 2.30 (d, J = 12.3 Hz, 1 H), 2.22 - 2.10 (m, 1 H), 1.15 (q, J = 11.9 Hz, 1 H), 1.06 (d, J = 6.6 Hz , 3 H).Example 140: Synthesis of compound 571 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid)

[00964] [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid methyl ester dihydrochloride: a solution of acid methyl ester {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid (18 mg; 0.04 mmol) and 4.0 M HCl in dioxane (186 μL; 0.75 mmol) in methanol (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to dryness to give acid methyl ester dihydrochloride [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino] -raw acetic acid (17 mg; > 99%), which was used for the following reaction directly. MS: m/z = 382 [M + H]+.

[00965] [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid: a solution of acid methyl ester dihydrochloride [(3R ,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid (17 mg, 0.04 mmol) and lithium hydroxide monohydrate (9, 4 mg; 0.2 mmol) in THF (1 mL) and water (1 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated and then purified by preparative HPLC (XBridge Prep C18 column, 10 μM, OBD 30 x 250 mm, 5-60% ACN in water with 0.1% formic acid) to provide acid [( 3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid (11 mg; 80%).Compound 571: MS: m/z = 368 [ M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J = 4.2, 1.7 Hz, 1 H), 8.49 (dd, J = 8.6, 1.8 Hz , 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.67 (dd, J = 8.6, 4.1 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 3.73 - 3.64 (m, 1 H), 3.48 - 3.41 (m, 1 H), 3.34 - 3.30 (m, 1 H ), 3.28 (d, J = 4.6 Hz, 2 H), 2.62 (t, J = 11.0 Hz, 1 H), 2.41 (t, J = 11.4 Hz, 1 H), 2.20 (d, J = 12.3 Hz, 1 H), 2.07 - 1.95 (m, 1 H), 1.09 (q, J = 12.0 Hz, 1 H) , 0.96 (d, J = 6.6 Hz, 3 H). Example 141: Synthesis of compound 580 (1-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5 -trifluoromethyl-piperidin-3-yl]-3-(3,3-difluorocyclobutylmethyl)-urea)

[00966] 1-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3-(3,3-difluoro-cyclobutylmethyl)-urea : a solution of 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride (60 mg; 0.17 mmol) and 1,1'- carbonyldiimidazole (30 mg, 0.18 mmol) in DMF (1 mL) was stirred for one hour and then C-(3,3-difluoro-cyclobutyl)-methylamine hydrochloride (32 mg, 0.20 mmol) was added and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep, 5 µm, 19 mm x 250 mm; Mobile phase, acetonitrile in water (with 10 mmol/L NH4OH), 10% to 80% gradient for 25 min; Detector, UV 254 nm, to provide 1-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3-(3,3-difluoro -cyclobutylmethyl)-urea (6.8 mg, 9%) as a white solid.

[00967] Compound 580: HPLC: <99% purity, Retention Time = 4.03 min. MS: m/z = 468.3 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz , 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.71 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 6.13 (d, J = 7.7 Hz, 2 H), 3.99 (s, 1 H), 3.58 (t, J = 10.3 Hz, 2 H), 3.12 (qt, J = 13.2, 6.0 Hz, 3 H), 2.93 (t, J = 11.5 Hz, 1 H), 2.64 - 2.54 ( m, 2 H), 2.35 - 2.16 (m, 4 H), 1.46 (q, J = 12.2 Hz, 1 H).

[00968] The following compounds were synthesized in a similar manner:

[00969] Compound 581 ([(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-acid amide (3R,4S)-3,4 -difluoro-pyrrolidine-1-carboxylic): From 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (3R, 4S)-3,4-difluoropyrrolidine. HPLC: <99% purity, Retention Time = 3.73 min. MS: m/z = 454.5 [M + H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J = 4.2, 1.6 Hz, 1 H), 8.59 (dd, J = 8.6, 1.7 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.72 (dd, J = 8.6, 4.2 Hz, 1 H), 7.33 (d, J = 8 .1 Hz, 1 H), 6.39 (d, J = 7.4 Hz, 1 H), 5.40 - 5.18 (m, 3 H), 4.06 (s, 2 H), 3 .68 (dd, J = 12.6, 5.9 Hz, 2 H), 3.64 - 3.55 (m, 3 H), 3.47 - 3.35 (m, 3 H), 2, 92 (t, J = 11.6 Hz, 2 H), 2.64 (t, J = 11.3 Hz, 1 H), 2.20 (d, J = 12.0 Hz, 1 H), 1 .63 (q, J = 12.4 Hz, 2 H).

[00970] Compound 582 (1-(3,3-difluoro-cyclobutylmethyl)-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl ]-urea): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and C-(3,3-difluoro - cyclobutyl)-methylamine. HPLC: <99% purity, Retention Time = 4.39 min. MS: m/z = 457.4 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz , 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.66 (dd, J = 8.6, 4.2 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 6.02 (t, J = 5.9 Hz, 1 H), 5.93 (d, J = 7.5 Hz, 1 H), 3.61 - 3, 51 (m, 1 H), 3.35 (s, 1 H), 3.11 (qt, J = 13.3, 6.1 Hz, 2 H), 2.62 - 2.52 (m, 2 H), 2.41 (t, J = 11.0 Hz, 2 H), 2.32 - 2.16 (m, 3 H), 2.02 (s, 2 H), 1.02 (q, J = 11.9 Hz, 1 H), 0.95 (d, J = 6.4 Hz, 3 H).

[00971] Compound 583 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acid amide (3R,4S)-3,4 -difluoro-pyrrolidine-1-carboxylic): From (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and (3R, 4S)-3,4-difluoropyrrolidine. HPLC: <99% purity, Retention Time = 4.08 min. MS: m/z = 44,3,4 [M + H]+. 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz , 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.67 (dd, J = 8.6, 4.2 Hz, 1 H), 7.21 (d, J = 8.1 Hz, 1 H), 6.23 (d, J = 7.5 Hz, 1 H), 5.21 (dd, J = 9.6, 5.5 Hz, 2 H), 3, 94 (s, 1 H), 3.73 - 3.49 (m, 3 H), 3.49 - 3.32 (m, 4 H), 2.48 (s, 3 H), 2.40 ( t, J = 11.3 Hz, 1 H), 2.12 - 1.96 (m, 2 H), 1.20 (q, J = 12.1 Hz, 1 H), 0.96 (d, J = 6.4 Hz, 3 H).

Example 142: HEK Cell Assay

[00972] In 384 Culture Plates (Corning 3707) 5000 c/w of HEK TLR7/NFKb cells were placed in 30 uL of DMEM without phenyl red (gibco#31053) and 10% a.i. FCS and 2 mM L-ZGLutamine. The cells were incubated for 24 hours at 37°C, 10% carbon dioxide and 90% relative humidity. 3 uL of controls, standards, and compounds were dispensed into wells, incubated for 30 minutes, then 3 uL of 20 mM Hepes R*48 agonist was added. After incubation for 5 hours, they were allowed to rest at room temperature for 15 min. To this was added 10 uL of Steady-Glo substrate reagent and the assay plate was shaken for 5 minutes at 1500 rpm. The assay plate was allowed to settle for 30 minutes at room temperature and then the plate was read in EnVision.

[00973] The results are provided in the following table. A: IC50 < 1 uM B: IC50: 1 uM -10 uM C: IC50 > 10 uM Table 1

Example 77. Pharmaceutical Preparations

[00974] (A) Injection vials: a solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water is adjusted to pH 6.5 using hydrochloric acid at 2 N, sterile filtered, transferred into injection vials, is lyophilized under sterile conditions and is sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

[00975] (B) Suppositories: a mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

[00976] (C) Solution: a solution is prepared from 1 g of an active ingredient according to the invention, 9.38 g of NaH2PO4^2 H2O, 28.48 g of Na2 HPO4 • 12 H2O and 0.1 g of benzalkonium chloride in 940 mL of double-distilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

[00977] (D) Ointment: 500 mg of an active ingredient according to the invention are mixed with 99.5 g of petroleum jelly under aseptic conditions.

[00978] (E) Tablets: a mixture of 1 kg of an active ingredient according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of stearate of magnesium is pressed to provide tablets in a conventional manner in such a way that each tablet contains 10 mg of active ingredient.

[00979] (F) Coated tablets: tablets are pressed analogously to Example E and are subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

[00980] (G) Capsules: 2 kg of an active ingredient according to the invention are introduced into hard gelatin capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

[00981] (H) Ampoules: a solution of 1 kg of an active ingredient according to the invention in 60 l of double-distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

[00982] (I) Inhalation spray: 14 g of an active ingredient according to the invention are dissolved in 10 l of isotonic NaCl solution, and the solution is transferred into commercially available spray containers with a pump mechanism. The solution can be sprayed into the mouth or nose. One jet of spray (approximately 0.1 mL) corresponds to a dose of approximately 0.14 mg.

[001006] While some embodiments of this invention are described here, it is apparent that the basic examples can be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention should be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims (13)

1. Compound, characterized by the fact that it presents Formula I, or a pharmaceutically acceptable salt thereof, in which Ring A is Ring B is R1 is absent, -H, -CHF2, -CF3, -OMe, or -CN; X is CH2; R4 is -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2, each of which is optionally substituted; R5 is -haloalkyl; each R is independently hydrogen, C1-6 aliphatic, C3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally replaced; or two R groups on the same atom are taken together with the atom to which they are bonded to form a C3-10 aryl, a 3- to 8-membered saturated or partially unsaturated carbocyclic ring, a 3- to 7-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5 to 6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally replaced; k is 1; n is 0; p is 0; r is 1; et is 1; with the proviso that the following compounds are excluded: 2. Compound, according to claim 1, characterized by the fact that ring A is 3. Compound according to claim 1 or 2, characterized by the fact that ring B is 4. Compound according to any one of claims 1 to 3, characterized by the fact that R4 is -N(R)2, which is optionally substituted. 5. Compound according to any one of claims 1 to 4, characterized by the fact that R4 is -NH2. 6. Compound according to any one of claims 1 to 5, characterized by the fact that R4 is 7. Compound according to any one of claims 1 to 6, characterized by the fact that R5 is -CF3. 8. Compound according to any one of claims 1 to 7, characterized in that it is selected from: or a pharmaceutically acceptable salt thereof. 9. Pharmaceutical composition, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 8, and a pharmaceutically acceptable adjuvant, carrier, or vehicle. 10. Use of the compound, as defined in any one of claims 1 to 8, or a physiologically acceptable salt thereof, characterized by the fact that it is for preparing a pharmaceutical composition and/or medicament for inhibiting TLR7/8 activity, or a mutant thereof, in a patient or in a biological sample. 11. Use of the compound as defined in any one of claims 1 to 8, or a physiologically acceptable salt thereof, characterized in that it is for preparing a pharmaceutical composition and/or medicament for treating a TLR7/mediated disorder. 8 in a patient in need of it. 12. Use according to claim 11, characterized in that the disorder is selected from rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, diabetes type I, type II diabetes, inflammatory bowel disease (Cronh's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, periodic syndromes associated with cryopyrin, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease , Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Parkinson's disease, and cancer. 13. Use of the compound, as defined in any one of claims 1 to 8, or a physiologically acceptable salt thereof, characterized by the fact that it is for preparing a pharmaceutical composition and/or medicine for the treatment of cancer in an individual .