RU2783748C2 - Polycyclic antagonists of tlr7/8 and their use in treatment of immune disorders - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a compound of the formula (1) or its pharmaceutically acceptable salt. The invention relates to a pharmaceutical composition inhibiting activity of TLR7/8, including effective amount of the compound, according to the invention, or its pharmaceutically acceptable salt and a pharmaceutically acceptable adjuvant, carrier, or filler. The invention also relates to a method for inhibition of activity of TLR7/8 and a method for the treatment of TLR7/8-mediated disorder selected from lupus, polymyositis, dermatomyositis, Sjogren’s disease, and rheumatoid arthritis in a patient, who needs it, including a stage of administration to the specified patient of the compound, according to the invention, or its pharmaceutically acceptable salt.

EFFECT: compound of the formula (1) as antagonists of toll-like receptor 7/8 (TLR7/8).

5 cl, 2 tbl, 141 ex

Description

Related Applications

This application claims priority under U.S. Provisional Application No. 62/268,765, filed December 17, 2015, and U.S. Provisional Application No. 62/353,603, filed June 23, 2016. The contents of the above applications are incorporated into this application by reference in their entirety.

The field of technology to which the invention belongs

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 associated with overexpression of TLR7/8.

Prerequisites for the creation of the invention

Toll-like receptors (TLRs), which currently include a gene family of 10 receptors with different specificities, are part of a cellular pathogenic pattern recognition system that has evolved to protect against various infections (bacteria, viruses, fungi). Activation of TLRs results in cytokine responses, for example, with the release of interferons and activation of specific immune cells. The functional expression of certain TLRs in tissues varies greatly. Some receptors are located on the cell surface, such as TLR4 (LPS-stimulated E. coli LPS), for example, on epithelial cells, or TLR3, 7, 8 and 9, located on endosomal membranes in certain immune cells. The latter are all activated by nucleic acids, but recognize different 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.

TLRs are implicated in various autoimmune and inflammatory diseases, with the most prominent example being the role played by TLR7 in the pathogenesis of systemic lupus erythematosus (Barrat and Coffman, Immunol Rev, 223:271-283, 2008). In addition, TLR8 polymorphism is associated with rheumatoid arthritis (Enevold et al., J Rheumatol, 37:905-10, 2010). Although various inhibitors of TLR7, TLR8 and TLR9 have been described, additional TLR inhibitors are desirable. In particular, polynucleotides containing inhibitory motifs for one or more of TLR7, TLR8, and TLR9 are required to specifically inhibit an immune response in a subject (eg, a patient having an autoimmune disease or an inflammatory disorder).

For several years there has been an active worldwide effort to use the strong immune activation induced by TLR7, 8 or 9 agonists for the treatment of cancer. However, cancer immunotherapy has had a long history of failure. However, therefore, in recent years, knowledge of immunosurveillance for cancer detection and the function of immune cell subpopulations have been greatly improved. TLR7 or TLR9 agonists are under clinical trials for mono- or combination therapies for cancer or as a vaccine adjuvant. The approach using TLR agonists for cancer immunotherapy differs from previous attempts using, for example, cytokines, interferons, or monovalent vaccines. TLR agonist-mediated immune activation is pleiotropic through specific immune cells (mainly dendritic cells and B cells, and then other cells) that generates an innate and adaptive immune response. In addition, not only one interferon is induced, but many different isoforms all together, and not only type I (alpha, beta), but also (indirectly) type II (gamma, NK cells).

The essence of the invention

In one aspect, the invention provides compounds of formula (I):

and their pharmaceutically acceptable derivatives, solvates, salts, hydrates and stereoisomers.

In another aspect, the invention provides compounds of formula (I) which are dual TLR7 and TLR8 antagonists. In another aspect, the invention provides compounds of formula (I) which are useful in the treatment and/or prevention of disorders associated with TLR7/8. In another aspect, the invention provides compounds that are capable of modulating, eg inhibiting, TLR7/8 activity or function in disease states in mammals, especially humans.

In accordance with another aspect of the invention, methods are provided for the treatment and/or prevention of autoimmune disorders.

According to another aspect, the present invention provides compounds of formula (I) which are selective for TLR7 or TLR8.

According to another aspect, the present invention provides compounds of formula (I) which are selective for TLR7 and TLR8.

Detailed description of some embodiments

1. General description of the compounds according to the invention

In some aspects, the present invention provides TLR7/8 antagonists. In some embodiments, such compounds include compounds of the formulas described in this application, or their pharmaceutically acceptable salts, where each variable has the meaning defined and described in this application.

2. Compounds and definitions

The compounds of the present invention include those described generally above and further illustrated by the classes, subclasses and species disclosed in this application. In the context of this application, the following definitions apply, unless otherwise indicated. For the purposes of the present invention, the chemical elements are specified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed. In addition, the 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, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated into this application by reference.

The term "aliphatic" or "aliphatic group", in the context of this application, means a linear (i.e. straight) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or a bicyclic hydrocarbon which is fully saturated or which contains one or more units of unsaturation, but which is not aromatic (also referred to in this application as "carbocycle", "cycloaliphatic" or "cycloalkyl"), which has one point of attachment to the rest of the molecule. Unless otherwise indicated, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, the implementation of aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, the implementation of aliphatic groups contain 1-4 aliphatic carbon atoms. In some other embodiments, the implementation of the aliphatic groups contain 1-3 aliphatic carbon atoms, and in some embodiments, the implementation of the aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C ₃ -C ₆ hydrocarbon that is fully saturated or that contains one or more units of unsaturation, but that is not aromatic, that has a single dot attachment to the rest of the molecule. Examples of aliphatic groups include linear or branched, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl groups, and combinations thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl )alkenyl.

The term "lower alkyl" refers to a C _1-4 linear or branched alkyl group. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl.

The term “lower haloalkyl” refers to a C _1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

азота или; замещаемый азот гетероциклического кольца, например, N (как в 3,4-дигидро-2H-пирролиле), NH (как в пирролидиниле) или NR⁺ (как в N-замещенном пирролидиниле)).The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, or phosphorus (including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any

nitrogen or; the displaceable nitrogen of the heterocyclic ring, eg N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)).

The term "unsaturated", in the context of this application, means that the group has one or more units of unsaturation.

In the context of this application, the term "divalent C _1-8 (or C _1-6 ) saturated or unsaturated, linear or branched hydrocarbon chain" refers to divalent alkylene, alkenylene and alkynylene chains that are linear or branched, as defined in this application .

The term "alkylene" refers to a divalent alkyl group. "Alkylene chain" is a polymethylene group, ie. -(CH ₂ ) _n - where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. The substituted alkylene chain is a polymethylene group, in which one or more hydrogen atoms of the methylene are replaced by a substituent. Suitable substituents include those described below for the substituted aliphatic group.

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 have been replaced by a substituent. Suitable substituents include those described below for the substituted aliphatic group.

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

The term "aryl", whether used alone or as part of a larger group, as in "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems containing a total of five to fourteen ring members, where at least at least one ring in the system is aromatic, and where each ring in the system contains three to seven ring members. The term "aryl" is used interchangeably with the term "aryl ring". In some embodiments of the present invention, “aryl” refers to an aromatic ring system. Examples of aryl groups include phenyl, biphenyl, naphthyl, anthracyl, and the like, which optionally include one or more substituents. Also encompassed 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.

азота. Гетероарильные группы включают, без ограничения, тиенил, фуранил, пирролил, имидазолил, пиразолил, триазолил, тетразолил, оксазолил, изоксазолил, оксадиазолил, тиазолил, изотиазолил, тиадиазолил, пиридил, пиридазинил, пиримидинил, пиразинил, индолизинил, пуринил, нафтиридинил и птеридинил. Термины “гетероарил” и “гетероар-“, в контексте настоящей заявки, также включают группы, в которых гетероароматическое кольцо конденсировано с одним или несколькими арильными, циклоалифатическими или гетероциклильными кольцами, где радикал или точка присоединения находится на гетероароматическом кольце. Неограничивающие примеры включают индолил, изоиндолил, бензотиенил, бензофуранил, дибензофуранил, индазолил, бензимидазолил, бензтиазолил, хинолил, изохинолил, циннолинил, фталазинил, хиназолинил, хиноксалинил, 4H-хинолизинил, карбазолил, акридинил, феназинил, фенотиазинил, феноксазинил, тетрагидрохинолинил, тетрагидроизохинолинил и пиридо[2,3-b]-1,4-оксазин-3(4H)-он. Гетероарильная группа необязательно является моно- или бициклической. Термин “гетероарил” используется взаимозаменяемо с терминами “гетероарильное кольцо”, “гетероарильная группа” или “гетероароматический”, при этом любой из этих терминов включает кольца, которые необязательно замещены. Термин “гетероаралкил” относится к алкильной группе, замещенной гетероарилом, где алкильная и гетероарильная части независимо являются необязательно замещенными.The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger group, such as “heteroaralkyl” or “heteroaralkoxy”, refer to groups containing 5-10 ring atoms, preferably 5, 6 or 9 ring atoms; containing 6, 10 or 14 π electrons distributed in a cyclic structure; and containing, 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

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. Неограничивающие примеры включают индолил, изоиндолил, бензотиенил, бензофуранил, дибензофуранил, индазолил, бензимидазолил, бензтиазолил, хинолил, изохинолил, циннолинил, фталазинил, хиназолинил, хиноксалинил, 4H-хинолизинил, карбазолил, акридинил, феназинил, фенотиазинил, феноксазинил, тетрагидрохинолинил, тетрагидроизохинолинил и пиридо [2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group is optionally mono- or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic", any of these terms including rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted with heteroaryl, where the alkyl and heteroaryl moieties are independently optionally substituted.

In the context of this application, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic group that is either saturated or partially unsaturated, and contains, in addition to carbon atoms, one or more, preferably one to four heteroatoms as defined above. When used in connection with a heterocycle ring atom, the term "nitrogen" includes a substituted nitrogen. By way of example, in a saturated or partially unsaturated ring containing 0-3 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).

A heterocyclic ring may be linked to its side group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may 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, thiazepinyl, quinuclidinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic fragment" and "heterocyclic radical" are used interchangeably in this application 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, wherein the radical or point of attachment is on the heterocyclyl ring. The heterocyclyl group is optionally mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with heterocyclyl, where the alkyl and heterocyclyl moieties are independently optionally substituted.

In the context of this application, the term "partially unsaturated" refers to a ring group that includes at least one double or triple bond. The term "partially unsaturated" is intended to cover rings containing multiple sites of unsaturation, but is not meant to include aryl or heteroaryl groups as defined herein.

относится к по меньшей мере

; и

относится к по меньшей мере

,

или

. Если не указано иное, “необязательно замещенная” группа содержит подходящий заместитель в каждом замещаемом положении группы, и когда более чем одно положение в какой-либо конкретной структуре замещено более чем одним заместителем, выбранным из указанной группы, заместители в каждом положении являются либо одинаковыми, либо отличными друг от друга. Комбинации заместителей, предусматриваемые настоящим изобретением, предпочтительно являются такими, которые приводят к образованию стабильных или химически возможных соединений. Термин “стабильный”, в контексте настоящей заявки, относится к соединениям, которые по существу не изменяются, когда их подвергают условиям, делающим возможными их получение, детекцию и, в некоторых вариантах осуществления, их выделение, очистку и применение по одному или нескольким из назначений, раскрытых в настоящей заявке.As described in this application, some compounds according to the invention contain "optionally substituted" groups. In general, the term "substituted", whether preceded by the term "optional" or not, means that one or more hydrogens of the indicated group are substituted with a suitable substituent. "Substituted" refers to one or more hydrogens that are either specifically specified or implied from the structure (e.g.,

applies to at least

; and

applies to at least

,

or

. Unless otherwise indicated, an “optionally substituted” group contains a suitable substituent at each substitutable position of the group, and when more than one position in any particular structure is substituted by more than one substituent selected from the specified group, the substituents at each position are either the same, or different from each other. The combinations of substituents contemplated by the present invention are preferably those which lead to the formation of stable or chemically feasible compounds. The term "stable", in the context of this application, refers to compounds that are essentially unchanged when they are subjected to conditions that enable their production, detection and, in some embodiments, their isolation, purification and use for one or more of the purposes. disclosed in this application.

Suitable monovalent substituents on the substituted carbon atom of the "optionally substituted" group are independently deuterium; halogen; -(CH₂)_0-4R°; -(CH₂)_0-4OR°; -O(CH₂)_0-4R^o, -O-(CH₂)_0-4C(O)OR°; -(CH₂)_0-4CH(OR°)₂; -(CH₂)_0-4SR°; -(CH₂)_0-4Ph which are optionally substituted with R°; -(CH₂)_0-4O(CH₂)_0-1Ph, which is optionally substituted by R°; -CH=CHPh which is optionally substituted with R°; -(CH₂)_0-4O(CH₂)_0-1-pyridyl which is optionally substituted with R°; -NO₂; -CN; -N₃; -(CH₂)_0-4N(R°)₂; -(CH₂)_0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH₂)_0-4N(R°)C(O)NR°₂; -N(R°)C(S)NR°₂; -(CH₂)_0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°₂; -N(R°)N(R°)C(O)OR°; -(CH₂)_0-4C(O)R°; -C(S)R°; -(CH₂)_0-4C(O)OR°; -(CH₂)_0-4C(O)SR°; -(CH₂)_0-4C(O)OSiR°₃; -(CH₂)_0-4OC(O)R°; -OC(O)(CH₂)_0-4SR°, SC(S)SR°; -(CH₂)_0-4SC(O)R°; -(CH₂)_0-4C(O)NR°₂; -C(S)NR°₂; -C(S)SR°; -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)_0-4SSR°;-(CH₂)_0-4S(O)₂R°; -(CH₂)_0-4S(O)₂OR°; -(CH₂)_0-4OS(O)₂R°; -S(O)₂NR°₂; -(CH₂)_0-4S(O)R°; -N(R°)S(O)₂NR°₂; -N(R°)S(O)₂R°; -N(OR°)R°; -C(NH)NR°₂; -P(O)₂R°; -P(O)R°₂; -OP(O)R°₂; -OP(O)(OR°)₂; SiR°₃; -(C_1-4 linear or branched alkylene)O-N(R°)₂; or -(C_1-4 linear or branched alkylene)C(O)O-N(R°)₂where each R° is optionally substituted as defined below and is independently hydrogen, C_1-6 aliphatic group, -CH₂Ph, -O(CH₂)_0-1Ph, -CH₂-(5-6 membered heteroaryl ring) or 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the definition above, two independently present R °, taken together with their intermediate atom(s), form a 3-12-membered saturated, partially unsaturated or aryl mono- or bicyclic ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which is optionally substituted, as defined below.

Suitable monovalent substituents on R° (or the ring formed by two independently present R° taken together with their intermediates) are independently deuterium, halogen, -(CH ₂ ) _0-2 R ^• , -(haloR ^• ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^• , -(CH ₂ ) _0-2 CH(OR ^• ) ₂ ; -O(haloR ^• ), -CN, -N ₃ , -(CH ₂ ) _0-2 C(O)R ^• , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _{0- 2} C(O)OR ^• , -(CH ₂ ) _0-2 SR ^• , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^• , -(CH ₂ ) _0-2 NR ^• ₂ , -NO ₂ , -SiR ^• ₃ , -OSiR ^• ₃ , -C(O)SR ^• , -(C _1-4 linear or branched alkylene)C(O) OR ^• or -SSR ^• where each R ^• is unsubstituted or, if preceded by the term "halo", substituted with only one or more halogens, and is independently selected from the C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom R° include ═O and ═S.

Suitable divalent substituents on the saturated carbon of the “optionally substituted” group include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) ₂ R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3 O- or -S(C(R ^* ₂ )) _2-3 S-, where in each independent case R ^* is selected from hydrogen, a C _1-6 aliphatic group which is substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents that are linked to the vicinal substitutable carbons of the "optionally substituted" group include: -O(CR ^* ₂ ) _2-3 O-, where in each independent case R ^* is selected from hydrogen, C _1-6 aliphatic group, which optionally substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

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

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

Suitable substituents on the aliphatic group R ^† are independently halogen, -R ^• , -(haloR ^• ), -OH, -OR ^• , -O(haloR ^• ), -CN, -C(O)OH, -C(O )OR ^• , -NH ₂ , -NHR ^• , -NR ^• ₂ , or -NO ₂ , where each R ^• is unsubstituted or, if preceded by the term “halogen”, is substituted with only one or more halogens, and is independently C _{1 -4} aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, the terms “optionally substituted”, “optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted carbocyclic group”, “optionally substituted aryl”, “optionally substituted heteroaryl”, “optionally substituted "heterocyclic group" and any other optionally substituted group as used herein refer to groups that are unsubstituted or substituted by independent substitution of one, two or three or more hydrogen atoms on them with exemplary substituents, including but not limited to:

-F, -Cl, -Br, -I, deuterium,

-OH protected by hydroxy, alkoxy, oxo, thiooxo,

-NO ₂ , -CN, CF ₃ , N ₃ ,

-NH ₂ protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -NH cycloalkyl, -NH -aryl, -NH -heteroaryl, -NH-heterocyclic group, -dialkylamino, -diarylamino, -

diheteroarylamino,

-O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclic group,

-C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)- carbocyclyl, -C(O)-aryl, -C(O)-heteroaryl, -C (O)-heterocyclyl,

-CONH ₂ , -CONH- alkyl, -CONH- alkenyl, -CONH- alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl,

-OCO ₂ -alkyl, -OCO ₂ -alkenyl, -OCO ₂ -alkynyl, -OCO ₂ -carbocyclyl, -OCO ₂ -aryl, -OCO ₂ -heteroaryl, -OCO ₂ -heterocyclyl, -OCONH ₂ , -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, -NHCO ₂ -alkyl, -NHCO ₂ -alkenyl, -NHCO ₂ -alkynyl, -NHCO ₂ -carbocyclyl, -NHCO ₂ -aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ -heterocyclyl, -NHC (O)NH ₂ , -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)NH ₂ , -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)NH ₂ , -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 -SO ₂ NH ₂ , -SO ₂ NH-alkyl, -SO ₂ NH-alkenyl, -SO ₂ NH-alkynyl, -SO ₂ NH- carbocyclyl, -SO ₂ NH-aryl, -SO ₂ NH -heteroaryl, -SO ₂ NH- heterocyclyl,

-NHSO ₂ -alkyl, -NHSO ₂ -alkenyl, -NHSO ₂ -alkynyl, -NHSO ₂ - carbocyclyl, -NHSO ₂ -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocyclyl,

-CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ ,

-mono-, di- or tri-alkylsilyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic group, -heterocyclic group, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S - alkyl, -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S-heteroaryl, -S-heterocyclyl or methylthiomethyl.

In the context of the present application, the term "pharmaceutically acceptable salt" refers to those salts which, within sound medical judgment, are suitable for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, and the like, and are commensurate with reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge 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 the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, phenylpropionate, phosphate, pivalate , propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

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

Unless otherwise indicated, structures provided herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, the scope of the invention includes individual stereochemical isomers, as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the present compounds. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In addition, unless otherwise indicated, the structures presented in this application are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures shown, including replacement of hydrogen with deuterium or tritium, or replacement of carbon ¹³ C or ¹⁴ C with enriched carbon, are within the scope of the present invention. In some embodiments, the group includes one or more deuterium atoms.

In addition, the compound of formula I is contemplated to include isotopically labeled forms. The isotopically labeled form of a compound of formula I is identical to that compound, except that one or more atoms of the compound are replaced by an atom or atoms having an atomic mass or mass number that is different from the atomic mass or mass number of that atom normally found in nature. Examples of isotopes which are readily commercially available and which can be incorporated into the compound of formula I by known methods include the isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ CI, respectively. The compound of formula I, its prodrug or its pharmaceutically acceptable salt, which contain one or more of the above isotopes and/or other isotopes of other atoms, are part of the present invention. An isotopically labeled compound of formula I can be advantageously used for a variety of purposes. For example, an isotopically labeled compound of formula I, which includes, for example, a radioisotope such as ³ H or ¹⁴ C, is suitable for drug and/or substrate distribution assays. These radioisotopes, i.e. tritium ( ³ H) and carbon-14 ( ¹⁴ C) are particularly preferred due to ease of preparation and excellent detectability. The incorporation of heavier isotopes, eg deuterium ( ² H), into a compound of formula I has therapeutic advantages due to the higher metabolic stability of this isotopically labeled compound. Higher metabolic stability translates directly into increased in vivo half-life or lower doses, which in most cases will be the preferred embodiment of the present invention. An isotopically labeled compound of formula I can generally be prepared by following the procedures disclosed in the synthetic schemes and in the corresponding description in the examples section and in the preparation section of this text, replacing the non-isotopically labeled reagent with a readily available isotopically labeled reagent.

Deuterium ( ² H) can also be included in the compound of formula I for the purpose of manipulating the oxidative metabolism of the compound through a primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of a chemical reaction resulting from the exchange of isotopic nuclei, which, in turn, is due to a change in the ground state energies required for the formation of covalent bonds after this isotopic exchange. The exchange of a heavier isotope generally results in a decrease in the ground state energy for a chemical bond, and therefore leads to a decrease in the rate-limiting bond cleavage. If the bond break occurs in or near the saddle point region along the multiproduction reaction coordinate, then the distribution coefficients of the products can be significantly changed. To explain: if deuterium is bonded to a carbon atom in a non-exchangeable position, then the rate differences k _M /k _D =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 that compound can be radically modified and result in improved pharmacokinetic properties.

When discovering and developing therapeutic agents, one skilled in the art can optimize pharmacokinetic parameters while maintaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Current in vitro liver microsomal assays provide valuable information on the course of this type of oxidative metabolism, which in turn allows the rational design of deuterated compounds of formula I with improved stability due to resistance to such oxidative metabolism. Thus, a significant improvement in the pharmacokinetic profiles of the compounds of formula I is achieved, and this can be quantified as an increase in in vivo half-life (t/2), concentration at maximum therapeutic effect (C _max ), area under the dose-response curve (AUC) and F ; and as a reduction in clearance, dose, and cost of materials.

To illustrate the above, the following is given: a compound of formula I, which has many potential attack sites for oxidative metabolism, for example, benzyl hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms. , so that some, most, or all of these hydrogen atoms are replaced by deuterium atoms. Half-life determinations provide an advantageous and accurate indication of the extent to which an improvement in resistance to oxidative metabolism has occurred. Thus, it is determined that the half-life of the parent compound can be increased up to 100% by this type of deuterium-hydrogen exchange.

Deuterium-hydrogen exchange in a compound of formula I can also be used to achieve a favorable modification of the metabolite spectrum of the parent compound to reduce or eliminate unwanted toxic metabolites. For example, if a toxic metabolite is due to oxidative cleavage of a carbon-hydrogen (CH) bond, it is reasonable to assume that the deuterated analog will significantly reduce or eliminate the production of the unwanted metabolite, even if the particular oxidation is not the rate-determining step. Further information on the prior art relating to deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55 , 3992-3997, 1990, Reider et al., J. Org. Chem. 52 , 3326-3334, 1987, Foster, Adv. DrugRes. 14 , 1-40, 1985, Gillette et al, Biochemistry 33 (10) 2927-2937, 1994 and Jarman et al. Carcinogenesis 16 (4), 683-688, 1993.

In the context of this application, the term "modulator" is defined as a compound that binds and/or inhibits a target with a measurable affinity. In some embodiments, the modulator has an IC ₅₀ and/or a binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

The terms "measurable affinity" and "measurable inhibition", in the context of this application, mean a measurable change in TLR7/8 activity between a sample containing the compound of the present invention or its composition and TLR7/8, and an equivalent sample, including TLR7/8 in the absence of the specified compounds or compositions thereof.

The combinations of substituents and variables contemplated by the present invention are only those that lead to the formation of stable compounds. The term "stable", in the context of this application, refers to compounds that have a stability sufficient to enable them to receive, and which maintains the integrity of the connection for a sufficient period of time to be useful for the purposes detailed in this application (for example, therapeutic or prophylactic administration to a subject).

The listing of chemical groups in any definition of a variable includes definitions of that variable as any single group or combination of the listed groups. The description of an embodiment for a variable includes that embodiment as any single embodiment or in combination with any other embodiments or parts thereof.

3. Description of exemplary compounds

According to one aspect, the present invention provides a compound of formula I ,

or a pharmaceutically acceptable salt thereof, where:

Ring A is aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted;

Ring B is aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted;

R ¹ is absent or represents -H, -CHF ₂ , -CF ₃ , -OMe or -CN;

each R ² is independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

each R ³ is independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

X is C(R ⁴ ) ₂ , O, NR ⁴ , S, S(R ⁴ ) or S(R ⁴ ) ₂ ;

each R ⁴ is independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

each R ⁵ is independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

each R is independently hydrogen, C _1-6 aliphatic, C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of these groups is optionally substituted; or

two R groups on the same atom are taken together with the atom to which they are attached to form a C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of these groups is optionally substituted;

k is 0 or 1;

n is 0, 1, or 2;

p is 0, 1, or 2;

r is 0, 1, or 2; and

t is 0, 1, or 2.

представляет собой

и X представляет собой CH₂; тогда R⁴ не является H, метилом или гидроксилом.In some embodiments, when

represents

and X is CH ₂ ; then R ⁴ is not H, methyl or hydroxyl.

представляет собой

и X представляет собой O, тогда R⁴ не является -C(O)N(R)₂.In some embodiments, when

represents

and X is O, then R ⁴ is not -C(O)N(R) ₂ .

In some embodiments, R ¹ is absent.

In some embodiments, R ¹ is -H.

In some embodiments, R ¹ is -CHF ₂ .

In some embodiments, R ¹ is -CF ₃ .

In some embodiments, R ¹ is -OMe.

In some embodiments, R ¹ is -CN.

In some embodiments, Ring A is C ₆ aryl or a 6-membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In some embodiments, Ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; each of which is optionally substituted.

In some embodiments, Ring A is phenyl, pyridyl, or pyrimidinyl; each of which is optionally substituted.

In some embodiments, ring A is

In some embodiments, ring A is

In some embodiments, Ring B is C ₆ aryl or a 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted.

In some embodiments, Ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of which is optionally substituted.

In some embodiments, Ring B is

In some embodiments, Ring B is

In some embodiments, each R ² is independently -H.

In some embodiments, each R ² is independently C _1-6 aliphatic, C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of these groups is optionally substituted.

In some embodiments, each R ² is independently methyl, ethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of which is optionally substituted.

In some embodiments, each R ² 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]бициклооктанил, флуоренил, инданил, тетрагидронафтил, акридинил, азоцинил, бензимидазолил, бензофуранил, бензотиофуранил, бензотиофенил, бензоксазолил, бензтиазолил, бензтриазолил, бензтетразолил, бензизоксазолил, бензизотиазолил, бензимидазолинил, карбазолил, NH-карбазолил, карболинил, хроманил, хроменил, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadia zolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, пиразолидинил, пиразолинил, пиразолил, пиридазинил, пиридооксазол, пиридоимидазол, пиридотиазол, пиридинил, пиридил, пиримидинил, пирролидинил, пирролинил, 2H-пирролил, пирролил, хиназолинил, хинолинил, 4H-хинолизинил, хиноксалинил, хинуклидинил, тетрагидрофуранил, тетрагидроизохинолинил, тетрагидрохинолинил, 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 substituted.

In some embodiments, each R ² is independently halo, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, - C(O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ .

In some embodiments, each R ³ is independently -H.

In some embodiments, each R ³ is independently C _1-6 an aliphatic group, a C _3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of these groups is optionally substituted.

In some embodiments, each R ³ is independently methyl, ethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of which is optionally substituted.

In some embodiments, each R ³ is independently methyl.

In some embodiments, each R ³ 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]бициклооктанил, флуоренил, инданил, тетрагидронафтил, акридинил, азоцинил, бензимидазолил, бензофуранил, бензотиофуранил, бензотиофенил, бензоксазолил, бензтиазолил, бензтриазолил, бензтетразолил, бензизоксазолил, бензизотиазолил, бензимидазолинил, карбазолил, NH-карбазолил, карболинил, хроманил, хроменил, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadia zolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl , piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl-quinolinyl , 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 substituted.

In some embodiments, each R ³ is independently halo, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C (O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ .

In some embodiments, X is C(R ⁴ ) ₂ or O.

In some embodiments, X is C(R ⁴ ) ₂ . In some embodiments, X is CH ₂ .

In some embodiments, X is O.

In some embodiments, each R ⁴ is independently -H.

In some embodiments, each R ⁴ is independently C _1-6 an aliphatic group, C _3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of these groups is optionally substituted.

In some embodiments, each R ⁴ is independently methyl, ethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of which is optionally substituted.

In some embodiments, each R ⁴ 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]бициклооктанил, флуоренил, инданил, тетрагидронафтил, акридинил, азоцинил, бензимидазолил, бензофуранил, бензотиофуранил, бензотиофенил, бензоксазолил, бензтиазолил, бензтриазолил, бензтетразолил, бензизоксазолил, бензизотиазолил, бензимидазолинил, карбазолил, NH-карбазолил, карболинил, хроманил, хроменил, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadia zolyl, 1,2,4-oxadiazolyl;- 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl , piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl-quinolinyl , 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 substituted.

In some embodiments, each R ⁴ is independently halo, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C (O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ .

In some embodiments, each R ⁴ is independently -H, C _1-6 aliphatic, -OR, -C(O)R, -CO ₂ R, -C(O)N(R) ₂ , -NRC(O )R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ; each of which is optionally substituted.

In some embodiments, each R ⁴ is independently -H, C _1-6 aliphatic, -C(O)N(R) ₂ , -NRC(O)R or -N(R) ₂ ; each of these groups is optionally substituted.

In some embodiments, each R ⁴ is independently

In some embodiments, each R ⁴ is independently

In some embodiments, each R ⁵ is independently -H.

In some embodiments, each R ⁵ is independently C _1-6 aliphatic, C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of these groups is optionally substituted.

In some embodiments, each R ⁵ is independently methyl, ethyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of which is optionally substituted.

In some embodiments, each R ⁵ 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]бициклооктанил, флуоренил, инданил, тетрагидронафтил, акридинил, азоцинил, бензимидазолил, бензофуранил, бензотиофуранил, бензотиофенил, бензоксазолил, бензтиазолил, бензтриазолил, бензтетразолил, бензизоксазолил, бензизотиазолил, бензимидазолинил, карбазолил, NH-карбазолил, карболинил, хроманил, хроменил, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H- indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadia zolyl, 1,2,4-oxadiazolyl; -1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl , пиразолидинил, пиразолинил, пиразолил, пиридазинил, пиридооксазол, пиридоимидазол, пиридотиазол, пиридинил, пиридил, пиримидинил, пирролидинил, пирролинил, 2H-пирролил, пирролил, хиназолинил, хинолинил, 4H-хинолизинил, хиноксалинил, хинуклидинил, тетрагидрофуранил, тетрагидроизохинолинил, тетрагидрохинолинил, 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 substituted.

In some embodiments, each R ⁵ is independently halo, -haloalkyl, -OR, -SR, -CN, -NO ₂ , -SO ₂ R, -SOR, -C(O)R, -CO ₂ R, -C (O)N(R) ₂ , -NRC(O)R, -NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ .

In some embodiments, each R ⁵ is independently methyl, cyclopropyl, -F, or -CF ₃ .

In some embodiments, each R ⁵ is independently

-F или -CF₃.

-F or -CF ₃ .

In some embodiments, each of X, ring A, ring B, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , k, m, n, p, r, and t has the meaning defined above and described in the embodiments , classes and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Ia ,

I-a;

or a pharmaceutically acceptable salt thereof, wherein each of X, rings A, R^one, R², R³, R^four, R⁵, k, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Ib

or a pharmaceutically acceptable salt thereof, wherein each of X, rings A, R^one, R², R³, R^four, R⁵, k, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Ic

or a pharmaceutically acceptable salt thereof, wherein each of X, rings A, R^one, R², R³, R^four, R⁵, k, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Id

or a pharmaceutically acceptable salt thereof, wherein each of X, rings A, R^one, R², R³, R^four, R⁵, k, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Ie

or a pharmaceutically acceptable salt thereof, wherein each of X, rings A, R^one, R², R³, R^four, R⁵, k, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula If

or a pharmaceutically acceptable salt thereof, wherein each of X, rings B, R^one, R², R³, R^four, R⁵, k, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Ig

or a pharmaceutically acceptable salt thereof, wherein each of X, rings B, R², R³, R^four, R⁵, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Ih

or a pharmaceutically acceptable salt thereof, wherein each of X, R^one, R², R³, R^four, R⁵, k, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Ij

or a pharmaceutically acceptable salt thereof, wherein each of X, R², R³, R^four, R⁵, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Im

or a pharmaceutically acceptable salt thereof, wherein each of X, R², R³, R^four, R⁵, n, p, r and t, has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula In

or a pharmaceutically acceptable salt thereof, wherein each of X, R^one, R², R³, R^four, R⁵, k, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the present invention provides a compound of formula Ip

or a pharmaceutically acceptable salt thereof, wherein each of X, R², R³, R^four, R⁵, n, p, r and t has the meaning defined above and described in the embodiments, classes, and subclasses above and below, alone or in combination.

In some embodiments, the invention provides a compound selected from Table 1:

Table 1 Connection number Example number Chemical structure one one

2 one

3 2

four 3

5 four

6 5

7 6

eight 7

9 eight

ten 9

eleven 9

12 9

13 ten

fourteen ten

fifteen ten

16 eleven

17 eleven

eighteen 12

19 12

twenty ten

21 ten

22 ten

23 ten

24 13

25 13

26 13

27 13

28 13

29 13

thirty 13

31 13

32 ten

33 ten

34 13

35 13

36 ten

37 ten

38 12

39 12

40 ten

41 ten

42 fourteen

43 fifteen

44 16

45 16

46 17

47 eighteen

48 19

49 twenty

fifty 21

51 22

52 22

53 22

54 22

55 22

56 22

57 22

58 22

59 22

60 22

61 23

62 24

63 25

64 25

65 25

66 26

67 27

68 28

69 29

70 29

71 thirty

72 31

73 31

74 32

75 33

76 33

77 34

78 35

79 36

80 37

81 38

82 39

83 39

84 39

85 40

86 40

87 41

88 41

89 41

90 41

91 42

92 42

93 42

94 42

95 42

96 42

97 ten

98 43

99 43

100 43

101 43

102 13

103 13

104 13

105 13

106 13

107 13

108 ten

109 ten

110 ten

111 ten

112 44

113 44

114 44

115 44

116 13

117 13

118 13

119 13

120 ten

121 12

122 12

123 45

124 46

125 46

126 12

127 45

128 13

129 13

130 ten

131 ten

132 ten

133 ten

134 ten

135 42

136 42

137 42

138 42

139 42

140 ten

141 ten

142 ten

143 ten

144 ten

145 ten

146 41

147 41

148 41

149 41

150 41

151 41

152 41

153 41

154 41

155 41

156 41

157 41

158 41

159 41

160 41

161 41

162 47

163 ten

164 ten

165 ten

166 ten

167 ten

168 ten

169 ten

170 ten

171 ten

172 ten

173 41

174 41

175 ten

176 12

177 48

178 48

179 ten

180 49

181 fifty

182 fifty

183 51

184 52

185 52

186 42

187 53

188 54

189 54

190 55

191 56

192 56

193 54

194 57

195 57

196 58

197 59

198 59

199 57

200 60

201 27

202 27

203 27

204 61

205 61

206 62

207 63

208 63

209 61

210 64

211 65

212 65

213 66

214 66

215 66

216 67

217 66

218 66

219 67

220 66

221 68

222 40

223 40

224 69

225 69

226 69

227 69

228 40

229 40

230 ten

231 70

232 ten

233 ten

234 ten

235 ten

236 ten

237 69

238 69

239 57

240 57

241 57

242 70

243 57

244 57

245 57

246 57

247 57

248 57

249 71

250 71

251 71

252 70

253 71

254 71

255 71

256 71

257 71

258 71

259 71

260 72

261 72

262 73

263 73

264 73

265 ten

266 ten

267 74

268 13

269 ten

270 75

271 75

272 76

273 75

274 77

275 75

276 78

277 13

278 57

279 57

280 79

281 80

282 80

283 57

284 75

285 75

286 76

287 57

288 80

289 57

290 78

291 80

292 71

293 71

294 81

295 71

296 75

297 75

298 76

299 71

300 81

301 81

302 61

303 61

304 82

305 83

306 83

307 61

308 75

309 75

310 76

311 61

312 83

313 61

314 78

315 83

316 61

317 61

318 61

319 61

320 75

321 75

322 76

323 61

324 83

325 61

326 78

327 83

328 61

329 61

330 84

331 84

332 85

333 84

334 84

335 86

336 86

337 87

338 86

339 88

340 88

341 89

342 90

343 91

344 95

345 93

346 93

347 94

348 95

349 96

350 95

351 96

352 97

353 98

354 95

355 96

356 98

357 99

358 99

359 100

360 100

361 82

362 78

363 100

364 100

365 82

366 101

367 102

368 103

369 104

370 104

371 104

372 104

373 105

374 106

375 106

376 106

377 106

378 106

379 105

380 105

381 106

382 106

383 106

384 106

385 106

386 106

387 106

388 7

389 106

390 7

391 7

392 7

393 107

394 7

395 108

396 7

397 108

398 108

399 7

400 7

401 106

402 7

403 108

404 109

405 7

406 109

407 108

408 7

409 7

410 7

411 7

412 7

413 109

414 one

415 one

416 one

417 7

418 7

419 one

420 one

421 one

422 one

423 thirty

424 40

425 110

426 40

427 one

428 40

429 41

430 41

431 40

432 105

433 one

434 one

435 one

436 111

437 41

438 41

439 one

440 one

441 111

442 111

443 112

444 113

445 113

446 111

447 114

448 112

449 115

450 115

451 116

452 117

453 118

454 one

455 107

456 one

457 32

458 119

459 32

460 114

461 119

462 89

463 118

464 120

465 121

466 114

467 22

468 25

469 114

470 114

471 114

472 57

473 57

474 57

475 57

476 80

477 121

478 122

479 123

480 124

481 122

482 124

483 123

484 122

485 122

486 123

487 123

488 125

489 125

490 122

491 122

492 124

493 123

494 126

495 126

496 122

497 126

498 126

499 127

500 127

501 127

502 128

503 129

504 129

505 130

506 129

507 131

508 131

509 131

510 thirty

511 40

512 40

513 40

514 80

515 57

516 57

517 57

518 132

519 57

520 126

521 126

522 126

523 126

524 thirty

525 133

526 57

527 126

528 126

529 134

530 134

531 134

532 134

533 135

534 135

535 135

536 135

537 134

538 134

539 134

540 134

541 134

542 134

543 134

544 134

545 136

546 136

547 134

548 134

549 134

550 57

551 57

552 137

553 thirty

554 122

555 122

556 122

557 122

558 122

559 122

560 122

561 123

562 123

563 123

564 124

565 124

566 124

567 138

568 139

569 139

570 139

571 140

572 57

573 57

574 57

575 57

576 40

577 40

578 40

579 40

580 141

581 141

582 141

583 141

584 40

585 40

586 89

587 94

588 94

589 94

590 94

591 94

In some embodiments, the present invention provides a compound selected from the compounds described above, or a pharmaceutically acceptable salt thereof.

подразумевает

).Various structural images may show a heteroatom with no attached group, radical, charge, or counterion. Those skilled in the art will appreciate that such images suggest that the heteroatom is bonded to hydrogen (e.g.,

implies

).

In some embodiments, the implementation of the compounds according to the invention were synthesized in accordance with the schemes presented in the Examples below.

4. Applications, formulation and introduction

Pharmaceutically acceptable compositions

According to another embodiment, the invention relates to a composition comprising a compound of the present invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or excipient. The amount of the compound in the compositions of the present invention is that which is effective for measurable inhibition of TLR7/8 or its mutant in a biological sample or in a patient. In some embodiments, the amount of the compound in the compositions of the present invention is such that it is effective to measurable inhibition of TLR7/8 or its mutant in a biological sample or in a patient. In some embodiments, a composition of the present invention is formulated for administration to a patient in need of such a composition.

The term "patient" or "subject", in the context of this application, means an animal, preferably a mammal and most preferably a human.

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

A "pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of a compound of the present invention which, when administered to a recipient, can provide, directly or indirectly, a compound of the present invention or an inhibitory active metabolite or residue thereof.

The compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" in the context of this application includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, 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 the present invention include an aqueous or oily suspension. These suspensions are formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example 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. In addition, sterile fixed oils are usually used as a solvent or suspending medium.

For this purpose, any bland fixed oil used includes synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are suitable for the preparation of injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oily solutions or suspensions also contain a long chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersants that are commonly used to formulate pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifiers or bioavailability enhancers that are commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms are also used for formulation purposes.

The pharmaceutically acceptable compositions of the present invention are administered orally in any orally acceptable dosage form. Examples of oral dosage forms are capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and cornstarch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous oral suspensions are required, the active ingredient is combined with emulsifiers and suspending agents. If desired, some sweetening, flavoring or coloring agents are also optionally added.

Alternatively, the pharmaceutically acceptable compositions of the present invention are administered in the form of rectal suppositories. They 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 therefore melts in the rectum to release the drug. Such substances include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable compositions of the present invention are also administered topically, especially when the target of treatment includes areas or organs readily accessible through topical application, including diseases of the eyes, skin, or lower intestinal tract. Suitable compositions for topical administration are readily prepared for each of these areas or organs.

Topical application to the lower intestinal tract can be done using the rectal suppository form (see above) or a suitable enema formulation. Topically applied transdermal patches are also used.

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

The pharmaceutically acceptable compositions of the present invention are optionally administered by nasal spray or inhalation. Such compositions are prepared according to methods well known in the art of pharmaceutical formulation and are prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, bioavailability absorption promoters, fluorocarbons and/or other conventional solubilizing or dispersing agents.

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

The number of compounds of the present invention, which are optionally combined with carrier materials to obtain a composition in a single dosage form, will vary depending on the host being treated, the particular route of administration. Preferably, the present compositions should be formulated so that a dose of 0.01 to 100 mg/kg of body weight per day can be administered to a patient receiving these compositions.

It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combinations. and the judgment of the attending physician and the severity of the particular disease being treated. The amount of a compound of the present invention in a composition will also depend on the particular compound in the composition.

Use of Compounds and Pharmaceutically Acceptable Compositions

The present invention also provides a method of treating a subject suffering from a TLR7/8 related disorder, comprising administering to said subject an effective amount of a compound of Formula I and related formulas.

The compounds of the present invention are useful as anticancer agents for the treatment of cancer that responds to TLR7 activation. In some embodiments, cancer includes, but is not limited to, cancer of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver , lungs, larynx and hypopharynx, mesothelioma, sarcoma, ovaries, pancreas, prostate, rectum, kidneys, small intestine, soft tissues, male gonads, stomach, skin, ureter, vagina and vulva; hereditary 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, cancer of unknown primary site, and AIDS-associated malignancies.

In some embodiments, the compounds of the invention are used to treat skin or kidney cancer. The sensitivity of a given cancer to TLR7 activation can be assessed, but not limited to, by measuring a reduction in primary or metastatic tumor burden (minor, partial, or complete regression), changes in hemogram, changes in blood hormone or cytokine concentrations, inhibition of a further increase in tumor burden, stabilization disease in a patient by evaluating disease-relevant biomarkers or surrogate markers to prolong overall patient survival, prolong patient progression to disease progression, prolong patient progression-free survival, prolong patient disease-free survival, improve patient quality of life, or modulation of the accompanying disease state (eg, but not limited to pain, cachexia, mobilization, hospitalization, altered hemogram, weight loss, wound healing, fever).

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

Provided herein are methods for inhibiting an immune response in a subject, comprising administering to the subject an effective amount of a TLR7 and/or TLR8 inhibitor (eg, a TLR inhibitor) using the compounds described herein. In some embodiments, the TLR inhibitor inhibits a TLR7-dependent immune response. In some embodiments, the TLR inhibitor inhibits a TLR8-dependent immune response. In some embodiments, the TLR inhibitor inhibits the TLR7-dependent and TLR8-dependent immune response. In some embodiments, the TLR inhibitor inhibits a TLR7-dependent, TLR8-dependent, and other TLR-dependent immune response. Unless otherwise indicated, the term TLR inhibitor refers to any of the TLR inhibitors disclosed in this application. In some preferred embodiments, the individual is a patient, such as a human.

Methods of immunoregulation are presented in the present disclosure and include those that suppress and/or inhibit the immune response, including, but not limited to, the immune response. The present disclosure also provides methods for improving 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 in this application can be practiced on subjects, including those suffering from a disorder associated with unwanted activation of the immune response. The present disclosure also provides methods for inhibiting a TLR7 and/or TLR8-induced response (eg, in vitro or in vivo). In some embodiments, the cell is contacted with a TLR inhibitor in an amount effective to inhibit a response from a cell that promotes an immune response.

Inhibition of TLR7 and/or TLR8 is useful for the treatment and/or prevention of various diseases or disorders that respond to cytokines. Conditions for which TLR7 and/or TLR8 inhibitors can be used include, but are not limited to, autoimmune diseases and inflammatory disorders. Methods provided herein for treating or preventing a disease or disorder in an individual comprise administering to the individual an effective amount of a TLR7 and/or TLR8 inhibitor. Also provided are methods of alleviating symptoms associated with a disease or disorder, comprising administering an effective amount of a TLR7 and/or TLR8 inhibitor to an individual having the disease or disorder. Also provided herein are methods for preventing or slowing the development of a disease or disorder, comprising administering an effective amount of an inhibitor of one or more TLR7 and/or TLR8 to an individual having the disease or disorder. In some embodiments, the implementation of the inhibitor is a compound described in this application.

Provided herein are methods for inhibiting an immune response in a subject, comprising administering to the subject at least one TLR inhibitor disclosed herein in an amount effective to inhibit the immune response in the subject. In some embodiments, the immune response is associated with an autoimmune disease. In other aspects, the inhibition of the immune response is an improvement in one or more symptoms of an autoimmune disease. In other aspects, the inhibition of the immune response is different in that it treats an autoimmune disease. In still other aspects, the inhibition of an immune response is characterized in that it prevents or delays the development of an autoimmune disease. In some embodiments, the TLR inhibitor inhibits a TLR7-dependent immune response. In some embodiments, the TLR inhibitor inhibits a TLR8-dependent immune response. In some embodiments, the TLR inhibitor inhibits the TLR7-dependent and TLR8-dependent immune response. In some aspects, at least one TLR inhibitor is administered in an amount effective to inhibit an immune response in an individual.

The present application also provides methods for 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 rash, or discoid rash. In some aspects, the autoimmune disease is associated with the skin, muscle tissue and/or connective tissue. In some embodiments, the individual has no symptoms of an autoimmune disease in the skin, muscle tissue, and/or connective tissue. In some embodiments, the autoimmune disease is systemic. Autoimmune diseases include, without limitation, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type I diabetes mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic arthritis, inflammatory bowel disease (IBD), scleroderma, Sjögren'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, without limitation, polyangiitis cross syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cryopathies.

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

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.

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 aspects, the autoimmune disease is glomerulonephritis. In some aspects, the autoimmune disease is pyelitis. In some aspects, the autoimmune disease is sclerosing cholangitis. In some aspects, the autoimmune disorder is psoriasis. In some aspects, the 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 disease or disorder. In some aspects, an autoimmune disease is different in that it is associated with RNA-containing immune complexes. In some aspects, the autoimmune disease is Sjögren's disease.

Provided herein are methods for inhibiting an immune response in a subject, which comprises administering to the subject at least one TLR inhibitor disclosed herein in an amount effective to inhibit the immune response in the subject. In some embodiments, the immune response is associated with an inflammatory disorder. As used herein, the term "inflammatory disorder" encompasses autoimmune diseases as well as inflammatory conditions without a known autoimmune component (eg arteriosclerosis, asthma, etc.). In other aspects, inhibition of the immune response improves one or more symptoms of an inflammatory disease. In yet another aspect, inhibition of the immune response treats an inflammatory disorder. In still other aspects, inhibition of the immune response prevents or delays the development of an inflammatory disorder. In some aspects, the inflammatory disease is selected from the group consisting of non-rheumatoid arthritis, renal fibrosis, and liver fibrosis. In some aspects, the inflammatory disease is marginal dermatitis. In some other aspects, marginal dermatitis is selected from the group consisting of lichen planus, lichenoid dermatosis, lichen planus-like keratosis, lichen linear, chronic lichenoid keratosis, erythema multiforme, segmental drug rash, lichenoid parapsoriasis, phototoxic dermatitis, radiation dermatitis, viral exanthems , dermatomyositis, secondary syphilis, lichen sclerosus, fungal mycoses, bullous pemphigoid, lichen aureus, porokeratosis, chronic atrophic acrodermatitis and regressing melanoma. In some aspects, the inflammatory disease is a skin disease such as atopic dermatitis (eczema). In some aspects, the inflammatory disease is a sterile inflammatory disease, such as drug-induced inflammation of the liver and/or pancreas. In some other aspects, the inflammatory disease is an inflammatory liver disease. In some other aspects, the inflammatory disease is an inflammatory disease of the pancreas.

Provided herein are methods for inhibiting an immune response in a subject, which comprises administering to the subject at least one TLR inhibitor disclosed herein in an amount effective to inhibit the immune response in the subject. In some embodiments, the immune response is associated with chronic pathogenic stimulation. In some embodiments, the immune response is associated with HIV infection. In other aspects, the inhibition of the immune response is characterized in that it improves one or more symptoms of a viral disease or disorder caused by infection with HIV. In other aspects, the inhibition of the immune response is different in that it treats a viral disease or disorder caused by HIV infection. In several other aspects, the inhibition of the immune response is different in that it prevents or delays the development of a viral disease or disorder caused by HIV infection. Other options presented in this application relate to immunoinhibitory therapy of subjects exposed to or infected with HIV. Administration of a TLR inhibitor to an individual 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.

Provided herein are methods for inhibiting a TLR7- and/or TLR8-dependent immune response in an individual, which comprises administering to the individual a TLR inhibitor in an amount effective to inhibit the immune response in the individual. In some embodiments, the immune response is associated with an autoimmune disease. In some aspects, the autoimmune disease is rheumatoid arthritis. In some aspects, a TLR inhibitor is effective in suppressing one or more symptoms of rheumatoid arthritis. In some aspects, the autoimmune disease is multiple sclerosis. In some aspects, a TLR inhibitor is effective in suppressing one or more symptoms of multiple sclerosis. In some aspects, the autoimmune disease is lupus. In some aspects, a TLR inhibitor is effective in suppressing one or more of the symptoms of lupus. In some aspects, the autoimmune disease is pancreatitis. In some aspects, a TLR inhibitor is effective in suppressing one or more symptoms of pancreatitis. In some aspects, the autoimmune disease is diabetes. In some aspects, a TLR inhibitor is effective in suppressing one or more symptoms of diabetes. In some aspects, the disease is Sjögren's disease. In some aspects, a TLR inhibitor is effective in suppressing one or more symptoms of Sjögren's disease. In some embodiments, the immune response is associated with an inflammatory disorder. In some aspects, a TLR inhibitor is effective in suppressing one or more symptoms of an inflammatory disorder. In some embodiments, the immune response is associated with chronic pathogenic stimulation. In some aspects, a TLR inhibitor is effective in suppressing one or more symptoms of chronic pathogen stimulation. In some embodiments, the immune response is associated with a viral disease caused by HIV infection. In some aspects, a TLR inhibitor is effective in suppressing one or more symptoms of a viral disease caused by an HIV infection. In any embodiment, the TLR inhibitor is a polynucleotide comprising an inhibitory motif for one or more TLR7, TLR8 and TLR9.

In some embodiments of any of the methods comprising administering a TLR inhibitor to an individual (eg, methods for inhibiting an immune response, treating or preventing an autoimmune disease or inflammatory disorder, etc.), the TLR inhibitor has a therapeutically acceptable safety profile. The TLR inhibitor may, for example, have a therapeutically acceptable histological profile, including acceptably low, if any, toxicity to the liver, kidneys, pancreas, or other organs. Occasionally, polynucleotides have been associated with toxicity in certain organs such as the liver, kidneys, and pancreas. In some embodiments, the TLR inhibitor has a safety profile that is unexpected and beneficial. In some embodiments, the implementation of the safety profile includes an assessment of toxicity, histological profile and/or necrosis (eg, liver, kidney and/or heart). In some embodiments, the implementation of the TLR inhibitor has a therapeutically acceptable level of toxicity. In some embodiments, a TLR inhibitor has a reduced level of toxicity compared to another TLR inhibitor. In some embodiments, the implementation of the TLR inhibitor induces a therapeutically acceptable decrease in body weight compared with the initial body weight of the individual receiving treatment. In some embodiments, the implementation of the TLR inhibitor causes less than 5%, 7.5%, 10%, 12.5 or 15% reduction in total body weight. In some embodiments, the implementation of the TLR inhibitor has a therapeutically acceptable histological profile. In some embodiments, the TLR inhibitor has, for example, a better (eg, lower severity score) histological profile compared to a reference TLR inhibitor. In some embodiments, the TLR inhibitor has a better (eg, lower severity score) histological profile, eg, in liver, kidney, and/or heart assessment. In some embodiments, the TLR inhibitor has a therapeutically acceptable necrosis rate. In some embodiments, the TLR inhibitor has reduced necrosis and/or better (eg, lower) necrosis score, eg, compared to a reference TLR inhibitor. In some embodiments, the TLR inhibitor has lower renal and/or hepatocellular necrosis and/or a better score for renal and/or hepatocellular necrosis, for example, compared to a reference TLR inhibitor.

Accordingly, the invention provides a method for activating TLR7 in an animal, in particular a mammal, preferably a human, comprising administering to the animal an effective amount of a compound of Formula I. depending on the individual, the condition being treated, and other factors obvious to a person skilled in the art. The effective amount of the compound will vary according to factors known in the art, but is expected to be about 0.1-10 mg/kg, 0.5-10 mg/kg, 1-10 mg/kg, 0. 1-20 mg/kg, 0.1-20 mg/kg or 1-20 mg/kg.

The invention also provides a method of treating a viral infection in an animal, comprising administering to the animal an effective amount of a compound of formula I. An amount effective to treat or inhibit a viral infection is an amount that will reduce one or more manifestations of a viral infection, such as burden, virus production rate and mortality compared to untreated control animals. The exact amount will vary depending on factors known in the art, but is expected to be the dose indicated above for TLR7 activation, or a dose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg up to 5 mg/kg.

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

The method of the invention can be carried out both in vitro and in vivo. The susceptibility of a particular cell to treatment with the compounds of the invention can in particular be determined by in vitro tests, either in research or for clinical use. Typically, the cell culture is combined with a compound of the invention at various concentrations for a period of time that is sufficient for the active agents to inhibit TLR7/8 activity, typically from about one hour to one week. In vitro processing can be performed using cultured cells from a biopsy sample or cell line.

The host or patient may be any mammalian species such as, for example, primates, in particular humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental research, providing a model for the treatment of human diseases.

Appropriate models or model systems have been developed by different scientists to identify the signaling pathway and to detect interactions between different signaling pathways, such as cell culture models and transgenic animal models. Interacting junctions can be used to modulate the signal to determine certain stages of the signal transduction cascade. The compounds of the invention can also be used as reagents for testing TLR7/8-dependent signal transduction pathways in animals and/or in cultured cell models or in the clinical diseases described herein.

In addition, the following disclosure in this specification regarding the use of compounds of formula (I) and their derivatives for the preparation of a medicament for prophylactic or therapeutic treatment and/or monitoring is considered valid and applicable without limitation to the use of a compound to inhibit TLR7/8 activity if it is expedient.

The invention also relates to the use of compounds of formula (I) and/or their physiologically acceptable salts for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or the development of which is associated with the activity of TLR7/8. In addition, the invention relates to the use of compounds of formula (I) and/or their physiologically acceptable salts for the preparation of a medicament for the prophylactic or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or the development of which is associated with TLR7/8 activity. In some embodiments, the present invention relates to the use of a compound of Formula I, or physiologically acceptable salts thereof, for the manufacture of a medicament for the prophylactic or therapeutic treatment of a TLR7/8-mediated disorder.

The compounds of formula (I) and/or their physiologically acceptable salts can also be used as an intermediate for the preparation of other active drug ingredients. The drug is preferably prepared in a non-chemical manner, for example by combining the active ingredient with at least one solid, liquid and/or semi-liquid carrier or excipient and optionally in combination with one or more other active agents in an appropriate dosage form.

The compounds of formula (I) according to the invention can be administered before or after the onset of the disease one or more times as a therapy. The above compounds and medical products of the present invention are especially used for therapeutic treatment. A therapeutically significant effect alleviates to some extent one or more symptoms of the disorder or returns to normal, partially or completely, one or more physiological or biochemical parameters associated with or causing the disease or pathological condition. Monitoring is considered as a form of treatment, provided that the compounds are administered at certain intervals, for example, to induce a response and complete elimination of pathogens and/or symptoms of the disease. Either the same connection or different connections can be used. 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 emerging and persistent symptoms.

According to the invention, prophylactic treatment is appropriate if the subject has any predisposition to the aforementioned physiological or pathological conditions, such as a hereditary predisposition, a genetic defect or a previous disease.

Furthermore, the invention relates to a medicament comprising at least one compound according to the invention and/or pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all proportions. In some embodiments, the invention relates to a drug comprising at least one compound according to the invention and/or its physiologically acceptable salts.

"Drug", within the meaning of the invention, is any agent in the field of medicine, which includes one or more compounds of formula (I) or their preparations (for example, a pharmaceutical composition or a pharmaceutical preparation) and can be used for the prevention, treatment, monitoring or follow-up of patients suffering from diseases that are associated with the activity of TLR7/8, so that the pathogenic modification of their general condition or the condition of specific areas of the body can be established at least temporarily.

In various embodiments, the active ingredient may be administered alone or in combination with other treatments. A synergistic effect can be achieved when more than one compound is used in a pharmaceutical composition, i.e. a compound of formula (I) is combined with at least another agent as an active ingredient, which is either another compound of formula (I) or a compound with another structural framework. The active ingredients may be used simultaneously or sequentially.

The TLR inhibitors of the present invention may be administered in combination with one or more additional therapeutic agents. As described in this application, TLR inhibitors can be combined with a physiologically acceptable carrier. The methods described in this application can be practiced in combination with other therapies that constitute the standard of care for this disorder, such as the administration of anti-inflammatory drugs.

In some embodiments, a TLR inhibitor as described herein is administered in combination with a corticosteroid. In some embodiments, the implementation of the corticosteroid is a glucocorticosteroid. In some embodiments, the corticosteroid is a mineralocorticoid. Corticosteroids include, but are not limited to, corticosterone and its derivatives, prodrugs, isomers and analogs, cortisone and its derivatives, prodrugs, isomers and analogs (i.e. Corton), aldosterone and its derivatives, prodrugs, isomers and analogs, dexamethasone and its derivatives , prodrugs, isomers and analogs (e.g. Decadron), prednisone and its derivatives, prodrugs, isomers and analogs (e.g. Prelon), fludrocortisones and their derivatives, prodrugs, isomers and analogs, hydrocortisone and its derivatives, prodrugs, isomers and analogs ( i.e. cortisol or Cortef), hydroxycortisone and its derivatives, prodrugs, isomers and analogs, betamethasone and its derivatives, prodrugs, isomers and analogs (e.g. Celeston), budesonide and its derivatives, prodrugs, isomers and analogs (i.e. Entocort EC), methylprednisolone and its derivatives, prodrugs, isomers and analogues (eg Medrol), prednisolone and its derivatives, prodrugs, isomers and analogues (eg Deltazone, Kart an, Meticorten, Orazone or Sterapred), triamcinolone and its derivatives, prodrugs, isomers and analogues (i.e. Kenacort or Kenalog), etc. In some embodiments, the corticosteroid is fludrocortisone or a derivative, prodrug, isomer, or analog thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is hydroxycortisone, or a derivative, prodrug, isomer, or analog thereof. In some embodiments, the corticosteroid is hydroxycortisone.

In some embodiments, the corticosteroid is administered at a dose ranging from about 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 up 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 at a dose ranging from about 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.

In some embodiments, the delivered amount of the TLR inhibitor used in the combination therapy may be, for example, 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.

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 (serial administration). In some embodiments, sequential administration comprises administering a TLR inhibitor or then an additional therapeutic agent at about one minute, five minutes, 30 minutes, one hour, five hours, 24 hours, 48 hours, or a week later. In some embodiments, the TLR inhibitor is administered by the same route of administration as the additional therapeutic agent. In some embodiments, the TLR inhibitor is administered by a different route of administration than that of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered parenterally (e.g., by injection into a central venous line, intraarterially, intravenously, intramuscularly, intraperitoneally, intradermally, or subcutaneously), orally, intraperitoneally, topically, naso-pharyngeally, and intrapulmonaryly (e.g., by inhalation or intranasally ). In some embodiments, the additional therapeutic agent is a corticosteroid.

The disclosed compounds of Formula I may be administered in combination with other known therapeutic agents, including anti-cancer agents. Used in this application, the term "anticancer agent" refers to any agent that is administered to a patient suffering from cancer to treat the patient.

The anti-cancer treatment as defined above may be used as monotherapy, or it may include, in addition to the described compounds of formula I, conventional surgery or radiation therapy or drug therapy. Such drug therapy, such as chemotherapy or targeted therapy, may include one or more, but preferably one, of the following anticancer agents:

Alkylating agents : such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobrontite, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glufosfamide, palyphosfamide, piprobroman, trofosfamide, uramustine, TH-302 ⁴ , VAL-083 ⁴ ;

Platinum compounds : such as carboplatin, cisplatin, eptaplatin, myriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA modifying agents : such as amrubicin, bisantren, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine ^1.3 ;

Topoisomerase inhibitors : such as etoposide, irinotecan, razoxane, sobuxane, teniposide, topotecan; amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule modifiers : such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tezetexel;

Antimetabolites : such as asparaginase ³ , azacitidine, calcium levophenylate, capecitabine, cladribine, cytarabine, enocytabin, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed, sapacitabine, tegafur ^2,3 , trimetrexate;

Anticancer antibiotics : such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romadepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plixamycin; aclarubicin, peplomycin, pyrarubicin;

Hormones/antagonists : such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisen, degarelix, dexamethasone, estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nizotrelin, nizotamide , raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifen, danazol, dezlorelin, epitiostanol, orterol, enzalutamide ^1.3 ;

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, dinacyclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motsanib, neratinib, orantinib, perifosin, ponanib, radotinib, rigosertib, tipifarnib, tivanibranib, tivozanibalani, tivozanibal ^{; _ _ _ _ _ _ _ _ _}

Photosensitizers : such as methoxsalen ³ ; sodium porfimer, talarfin, temoporfin;

Antibodies: as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab ^2.3 ; catumaxomab, elotuzumab, epratuzumab, farotuzumab, mammulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, ^zalutumumab , ^zanolimumab , ^matuzumab , dalotuzumab ^1.3 , EMD-525797 ⁴ , nivolumab ^1.3 ;

Cytokines : such as aldesleukin, interferon alfa ² , interferon alfa 2a ³ , interferon alfa 2b ^2.3 ; celloleukin, tasonermin, teceleukin, oprelvekin ^1,3 , recombinant interferon beta-1a ⁴ ;

Drug conjugates : such as denileukin-diftitox, ibritumomab tiuxetan, iobenguan I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; cintredikin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab ^1.3 , vintafolid ^1.3 ;

Vaccines : such as sipuleucel ³ ; witespen ³ , emepepimut-S ³ , oncoVAX4, rindopepimut ³ , troVax4, MGN-16014, MGN-17034; as well as

Others : alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleisel ³ , sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxyl, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazole, ridaphorolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, ^{pibanilspodar4} , reolisin ⁴ , retaspimycin hydrochloride ^1,3 , trebananib ^2,3 , virulizin ⁴ , carfilzomib ^1,3 , endostatin ⁴ , immucotel ⁴ , belinostat ³ , MGN-1703 ⁴ .

( ¹ Prop. INN (Proposed International Nonproprietary Name); ² Rec. INN (Recommended International Nonproprietary Names); ³ USAN (U.S. Adopted Name); ⁴ no INN).

In some embodiments, the combination of a TLR inhibitor with one or more additional therapeutic agents reduces the effective amount (including, but not limited to, dose volume, concentration, and/or total drug dose) of the TLR inhibitor and/or one or more additional therapeutic agents administered. to achieve the same result as compared to the effective amount administered when the TLR inhibitor or additional therapeutic agent is administered alone. In some embodiments, the combination of a TLR inhibitor with a corticosteroid reduces the effective amount of the corticosteroid administered compared to the corticosteroid administered alone. In some embodiments, the combination of a TLR inhibitor with additional therapeutic agents reduces the frequency of administration of the therapeutic agent compared to the administration of only one additional therapeutic agent. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces the overall duration of treatment compared to the administration of only one additional therapeutic agent. In some embodiments, the combination of a TLR inhibitor with an additional therapeutic agent reduces the side effects associated with administering an 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 analog thereof. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the combination of an effective amount of a TLR inhibitor with an additional therapeutic agent is more effective than an effective amount of a TLR inhibitor alone or an additional therapeutic agent alone.

TLR inhibitors may also be useful as a vaccine adjuvant for use in combination with any substance that modulates a humoral and/or cell-mediated immune response, such as, for example, live viral, bacterial or parasitic immunogens; inactivated viral, tumor-derived, protozoal, body-produced, fungal or bacterial immunogens, toxoids, toxins; autoantigens; polysaccharides; proteins; glycoproteins; peptides; cell vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides; etc. In some aspects, a combination therapy, including but not limited to a combination of a TLR inhibitor and a vaccine, is used to treat an autoimmune disease or inflammatory disorder. In some aspects, a combination therapy, including but not limited to a combination of a TLR inhibitor and a vaccine, is used to treat an infectious disease.

In some embodiments, a combination therapy, including but not limited to a combination of a TLR inhibitor and a corticosteroid, is used to treat an autoimmune disease or 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 Sjögren's disease.

Also provided herein are kits comprising the TLR inhibitor provided herein and instructions for use in methods of inhibiting a TLR7- and/or TLR8-dependent immune response.

Kits may include one or more containers containing a TLR inhibitor (or a composition containing a TLR inhibitor) described herein and a set of instructions, usually written instructions, although electronic media (eg, a magnetic floppy disk or optical disc) containing instructions, are also acceptable regarding the use and dosage of a TLR inhibitor or drug for the intended treatment (e.g. suppression of response to TLR7 and/or TLR8 agonists, suppression of TLR7- and/or TLR8-dependent immune response, improvement of one or more symptoms of an autoimmune disease, improvement of symptoms of a chronic inflammatory disease, reducing cytokine production in response to a virus, and/or treating and/or preventing one or more symptoms of a disease or disorder mediated by TLR7 and/or TLR8). The instructions included in the kit usually include information about the dosage, schedule of administration and route of administration for the intended treatment. Containers for a TLR inhibitor (or compositions comprising a TLR inhibitor) can be in unit doses, bulk packs (eg, multi-dose packs), or divided doses. The kits may further include a container containing an adjuvant.

In another aspect, the invention provides a kit consisting of individual packs of an effective amount of a compound of the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally, an effective amount of an additional active ingredient. The kit includes suitable containers such as boxes, individual bottles, bags or ampoules. The kit may include, for example, individual ampoules, each containing an effective amount of a compound of the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of the additional active ingredient in dissolved or lyophilized form. .

In the context of this application, the terms "treating", "treating" and "treating" refer to reversing, alleviating, delaying the onset or inhibiting the development of a disease or disorder or one or more of its symptoms described in this application. In some embodiments, the treatment is administered after the onset of one or more symptoms. In other embodiments, the treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible subject prior to the onset of symptoms (eg, in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after the symptoms have been eliminated, for example, to prevent or delay their recurrence.

Compounds and compositions according to the method of the present invention are administered using any amount and by any route of administration effective to treat or lessen the severity of the disorder described above. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, route of administration, and the like. The compounds of the invention are preferably formulated in unit dosage form for ease and uniformity of administration. The expression "unit dosage form", in the context of this application, refers to a physically discrete unit of funds suitable for the treatment of the patient to be treated. However, it should be understood that the total daily use of the compounds and compositions of the present invention will be determined by the attending physician within the limits of sound medical judgment. The specific effective dosage 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 particular compound used; the particular composition used; age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound used; duration of treatment; drugs used in combination with or simultaneously with the specific compound used, and like factors well known in medicine.

Pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as powders, ointments or drops), bucally, as an oral or nasal spray, or the like, in depending on the severity of the infection to be treated. In some embodiments, the compounds of the invention are administered orally or parenterally at doses of from about 0.01 to about 100 mg/kg, and preferably from about 1 mg/kg to about 50 mg/kg of body weight per day, one or more times a day for obtaining the desired therapeutic effect.

In some embodiments, the therapeutically effective amount of the compound of formula (I) and related formulas and the other active ingredient depends on a number of factors, including, for example, the age and body weight of the animal, the exact condition of the disease that requires treatment and its severity, the nature of the composition and method administration, and is ultimately determined by the attending physician or veterinarian. However, an effective amount of the compound is typically in the range of 0.1 to 100 mg/kg body weight of the recipient (mammal) per day, and particularly typically in the range of 1 to 10 mg/kg body weight per day. Thus, the actual amount per day for a 70 kg adult mammal is typically 70 to 700 mg, and this amount can be administered as a single dose per day or usually as a series of divided doses (e.g., two, three, four, five or six) per day so that the total daily dose is the same. An effective amount of a salt or solvate or a physiologically functional derivative can be defined as the proportion of the effective amount of a compound per se.

In some embodiments, pharmaceutical compositions may be administered in the form of dosage units that contain a predetermined amount of the active ingredient per dosage unit. Such a unit may contain, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, particularly preferably from 5 mg to 100 mg of the compound according to the invention, depending on the state of the disease, treatment, route of administration and age, weight the body and condition of the patient, or the pharmaceutical preparations may be administered in the form of dosage units which contain a predetermined amount of the active ingredient per dosage unit. Preferred dosage forms are compositions which contain a daily dose, or portion of the dose as indicated above, or an appropriate proportion thereof, of the active ingredient. In addition, pharmaceutical compositions of this type can be obtained using a method that is well known in the pharmaceutical industry.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to active compounds, 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, ethyl acetate, benzyl alcohol, benzyl benzoate , propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavors and flavors.

Injectable preparations, for example, sterile injectable aqueous or oily suspensions, are formulated according to the known art using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation is also a sterile injectable solution, suspension or emulsion 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 may be used are water, Ringer's solution U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium. Any bland fixed oil can be used for this purpose, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used to make injectables.

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

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

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

Solid dosage forms for oral administration 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) excipients or bulking agents such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, c) humectants, such as glycerol, d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate e) dissolution retardants such as paraffin f) absorption accelerators such as quaternary ammonium compounds g) wetting agents such as cetyl alcohol and glycerol monostearate h) absorbents , such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form also optionally includes buffering agents.

Solid compositions of a similar type are also used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, 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 formulated so that the active ingredient(s) are released only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of drug dipping compositions that can be used include polymeric materials and waxes. Solid compositions of a similar type are also used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more excipients as described above. Solid dosage forms in the form of tablets, dragees, 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 admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms also include, as a common practice, additional substances other than inert diluents, for example tabletting lubricants and other tabletting agents such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, dosage forms optionally also include buffering agents. They optionally contain opacifying agents and may also be formulated so that the active ingredient(s) are released only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of drug dipping compositions that can be used include polymeric materials and waxes.

Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as needed. Ophthalmic composition, ear drops and eye drops are also considered to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added benefit of providing controlled delivery of a compound to the body. Such dosage forms can be prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of a 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.

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

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

The compounds of the invention are useful in vitro as unique tools for understanding the biological role of TLR7/8, including the evaluation of many factors that are believed to influence, and may be influenced by, TLR7/8 production and TLR7/8 interaction. The compounds of the present invention are also useful in the development of other compounds that interact with TLR7/8, as the compounds of the invention provide important structure-activity relationship (SAR) information that facilitates this development. Compounds of the present invention that bind to TLR7/8 can be used as reagents for the detection of TLR7/8 in live cells, fixed cells, biological fluids, tissue homogenates, purified natural biological materials, etc. For example, by labeling such compounds, cells expressing TLR7/8 can be identified. In addition, based on their ability to bind to TLR7/8, the compounds of the present invention can be used in in-situ staining, FACS (fluorescence activated cell sorting), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), ELISA (solid-phase enzyme immunoassay), etc., in the purification of enzymes or in the purification of cells expressing TLR7/8 inside permeabilized cells. The compounds of the invention can also be used as commercial research reagents for various medical research and diagnostic purposes. Such uses may include, but are not limited to: use as a calibration standard to quantify the activity of candidate TLR7/8 inhibitors in various functional assays; use as blocking reagents in randomized screening of compounds, ie when searching for new families of TLR7/8 ligands, compounds can be used to block the isolation of the TLR7/8 compounds claimed in the present invention; use in co-crystallization with TLR7/8, ie the compounds of the present invention will allow the formation of crystals of the compound associated with TLR7/8, which will allow the structure of the enzyme/compound to be determined by X-ray crystallography; other studies and diagnostic applications where TLR7/8 is preferably activated, or such activation is conveniently calibrated against a known amount of TLR7/8 inhibitor, etc.; use in assays as probes to determine the expression of TLR7/8 in cells; and developing assays to detect compounds that bind to the same site as TLR7/8 binding ligands.

The compounds of the invention can be used alone and/or in combination with physical measurements to diagnose the effectiveness of a treatment. Pharmaceutical compositions containing these compounds, and the use of these compounds for the treatment of conditions mediated by TLR7/8, represent a promising new approach to a wide range of therapies that cause direct and immediate improvement in health in both humans and animals. The orally bioavailable and active novel chemistries of the invention improve patient comfort and adherence to drug recommendations.

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 cost and ease of handling. These features serve as the basis for a reproducible action, which includes the absence of cross-reactivity, as well as for reliable and safe interaction with the target structure.

The term "biological sample", in the context of this application, includes, without limitation, cell cultures or their extracts; biopsy material obtained from a mammal, or its extracts; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

Modulation of the activity of TLR7/8 or a mutant thereof in a biological sample is useful for a variety of purposes, which are known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, storage of biological specimens, and biological assays.

Illustrative examples

As shown in the examples below, in some exemplary embodiments, compounds are prepared according to the following general procedures. It is understood that while the general methods illustrate the synthesis of some of the compounds of the present invention, the following general methods and other methods known to those skilled in the art can be applied to all compounds and subclasses and species of each of these compounds as described herein.

The symbols and conventions used in the following descriptions of methods, schemes, and examples are consistent with those used in current scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

Unless otherwise noted, all temperatures are in °C (degrees Celsius).

All solvents used were commercially available and were used without further purification. The reactions were usually carried out using anhydrous solvents under an inert nitrogen atmosphere. Flash column chromatography was typically performed using silica gel 60 (particle size 0.035-0.070 mm).

All NMR experiments were performed 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 spectrometer Bruker Avance III 400 NMR fitted with a Bruker PABBO BB-1H/DZ GRD probe at 400 MHz for proton NMR. Most deuterated solvents contained typically 0.03 to 0.05% v/v tetramethylsilane, which was used as a reference signal (set at d 0.00 for both ¹ H and ¹³ C). In cases where the deuterated solvents did not contain tetramethylsilane, the residual non-deuterated solvent peaks were used as a reference signal, in accordance with published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997).

LC-MS analysis was performed using one of the following two devices:

- SHIMADZU LC/MS device consisting of UFLC 20-AD system and LCMS 2020 MS detector. An XR-ODS Shim-pack, 2.2 µm, 3.0 x 50 mm column was used. A linear gradient was applied starting at 95% A (A: 0.05% TFA in water) to 100% B (B: 0.05% TFA in acetonitrile) over 2.2 min, with a total cycle time of 3, 6 min. The column temperature was 40° C., with a flow rate of 1.0 ml/min. The diode array detector operated at 200-400 nm. The mass spectrometer was equipped with an electrospray ion source (ES) operating in positive or negative mode. The mass spectrometer was operated in a scan mode between m/z 90-900 with a scan time of 0.6 sec.

- Agilent 1200 Series Mass Spectrometers from Agilent Technologies using either atmospheric pressure chemical ionization (APCI) or electrospray ionization (ESI). The diode array detector operated at 200-400 nm. The mass spectrometer was operated in a scan mode between m/z 90-900 with a scan time of 0.6 sec. Column: XBridge C8, 3.5 µm, 4.6 × 50 mm; Solvent A: water + 0.1% TFA; Solvent B: ACN+0.1% TFA; Flow rate: 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 LC/MS Waters ZMD (ESI).

HPLC data were obtained using either a SHIMAZU LC-MS instrument or an Agilent 1200 Series HPLC 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. Gradient method: 0 min: 5% B; 8 min: 100% B; 8.1 min: 100% B; 8.5 min: 5% B; 10 min. 5% B unless otherwise noted.

In general, compounds according to formula (I) and related formulas of the present invention can be prepared from readily available starting materials. If such starting materials are not commercially available, they can be obtained by standard synthetic methods. In general, synthetic routes for any particular compound of formula (I) and related formulas will depend on the specific substituents of each molecule, such factors being understood by those skilled in the art. The following general methods and procedures, described below in the examples, can be used to obtain compounds of formula (I) and related formulas. The reaction conditions shown in the following schemes, such as temperatures, solvents, or co-reagents, are given as examples only and are not restrictive. It should be understood that when typical or preferred experimental conditions (ie, reaction temperatures, times, moles of reactants, solvents, etc.) are indicated, other experimental conditions may be used unless otherwise indicated. Optimum reaction conditions may vary with particular reagents or solvents, but such conditions can be determined by those skilled in the art using routine optimization procedures. See Philip J. Kocienski "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994, and Theodora W. Greene and Peter GM Wuts "Protective Groups in Organic Synthesis", Wiley Interscience, 3 for all methods of protection and deprotection. ^rd Edition 1999.

Intermediate 1: 8-chloropyrido[2,3-b]pyrazine

Method A

8-Chloropyrido[2,3-b]pyrazine: To a solution of 4-chloropyridine-2,3-diamine (1.90 g, 13.20 mmol) in THF (100 ml) was added oxaldehyde (1.00 g, 17. 20 mmol) at room temperature. The resulting solution was then stirred for 6 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-50% gradient) to give 8-chloropyrido[2,3-b]pyrazine as yellow solids (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

4-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine: To 4-chloro-1H- pyrrolo [2,3-b]pyridine solution (2.85 g, 18.68 mmol) in DCM (100 ml) were added benzenesulfonyl chloride (4.95 g, 28.02 mmol), 4-dimethylaminopyridine (228 mg, 1.87 mmol) and triethylamine (5.67 g, 56.04 mmol) at room temperature. The resulting solution was then stirred for 3 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-50% gradient) to give 1-(benzenesulfonyl)-4-chloro-1H- pyrrolo [ 2,3-b]pyridine as a white solid (4.98 g, 91%). MS: m/z=292.9 [M+H] ⁺ .

Method C

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 mmol) in THF (35 ml) was added a solution of n-BuLi (2.5 M in THF, 5 ml, 12.80 mmol) dropwise over 5 minutes. The resulting solution was stirred for 1 hour at -78° C. and then iodoethane (2.20 g, 14.10 mmol) was added slowly. Then the reaction mixture was slowly heated from -78°C to 0°C for 3 hours with stirring. When the reaction was complete, it was quenched by adding a saturated solution of NH ₄ Cl (20 ml) and the resulting mixture was extracted with ethyl acetate (60 ml ×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-5% gradient) to give 1-(benzenesulfonyl)-4-chloro-2-ethyl-1H- pyrrolo [2, 3-b]pyridine as a white solid (591 mg, 29%). MS: m/z=320.8 [M+H] ⁺ .

Method D

4-Chloro-2-ethyl-1H-pyrrolo[2,3-b]pyridine: To 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 off and the filtrate was concentrated under reduced pressure to give 4-chloro-2-ethyl-1H- pyrrolo [2,3-b]pyridine as a yellow solid (443 mg, crude). MS: m/z=180.9 [M+H] ⁺ .

Method E

4-Chloro-1,2-diethyl-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-chloro-2-ethyl-1H- pyrrolo [2,3-b]pyridine (443 mg, crude) in acetonitrile (23 ml) was added Cs ₂ CO ₃ (1.40 g, 4.30 mmol) and iodoethane (676 mg, 4.30 mmol) at room temperature. The resulting mixture was then stirred for 3.5 hours at 40°C. When the reaction was complete, 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 off and the filtrate was concentrated under reduced pressure to give 4-chloro-1,2-diethyl-1H- pyrrolo [2,3-b]pyridine as a yellow oil (333 mg, 89% for 2 steps). MS: m/z=209.0 [M+H] ⁺ .

Intermediate 3: 4-chloro-1,2-dimethyl-1H-pyrrolo[2,3-b]pyridine

Method F

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 mmol) in tetrahydrofuran (30 ml) was added a solution of LDA (2 M in THF, 3.4 ml, 6.85 mmol) dropwise. The resulting solution was stirred for 1 hour at -78° C. and then iodomethane (0.97 g, 6.85 mmol) was slowly added. The resulting mixture was then stirred for 5 hours at -78°C. When the reaction was complete, it was quenched with H ₂ O (30 ml) and the resulting mixture was extracted with ethyl acetate (50 ml ×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 1-(benzenesulfonyl)-4-chloro-2-methyl-1H- pyrrolo [2,3-b]pyridine as a brown oil (2.50 g, crude).

4-Chloro-2-methyl-1H-pyrrolo[2,3-b]pyridine: 4-chloro-2-methyl-1H- pyrrolo [2,3-b]pyridine was obtained 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%-10% gradient) to give 4-chloro-2 -methyl-1H- pyrrolo [2,3-b]pyridine as a yellow solid (900 mg, 79% for 2 steps). MS: m/z=166.9 [M+H] ⁺ .

Method G

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 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydroxide (240 mg, 6.00 mmol). 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 completed, the reaction mixture was diluted with DCM (100 ml) and the resulting mixture was washed with water (30 ml × 3). The organic phase was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-10% gradient) to give 4-chloro-1,2-dimethyl-1H- pyrrolo [2,3-b] pyridine as a yellow solid (300 mg, 82%). MS: m/z=181.0 [M+H] ⁺ .

Intermediate 4: tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate

tert-Butyl 5-methylpyridin-3-ylcarbamate: At room temperature, a solution of NaHMDS (2 M in THF, 110 ml, 220.0 mmol) drop by drop over 10 minutes. The resulting solution was stirred for 1 hour at room temperature. Boc ₂ O (21.14 g, 92.4 mmol) was then added. The reaction mixture was stirred for an additional 2 hours at room temperature. When the reaction was complete, it was quenched by adding a saturated solution of NH ₄ Cl (100 ml). The resulting mixture was extracted with ethyl acetate (150 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-35% gradient) to give t-butyl N-(5-methylpyridin-3-yl)carbamate as a yellow solid (15.18 g, 83%). MS: m/z=209.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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).

tert-Butyl 5-methylpiperidin-3-ylcarbamate: tert-Butyl N-(5-methylpyridin-3-yl)carbamate (14.22 g, 68.43 mmol), PtO ₂ (2 .50 g, 11.01 mmol) and Rh/C (5%, 2.50 g, 1.21 mmol) in AcOH (250 ml) at room temperature. The mixture was hydrogenated at 70°C under a hydrogen pressure of 15 atm for 24 hours. When the reaction was complete, the reaction mixture was cooled to room temperature. Insoluble solids in the reaction mixture were filtered off and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (100 ml) and the mixture was adjusted to pH 12 with sodium hydroxide solution (20%). The resulting mixture was extracted with DCM (100 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give tert-butyl N-(5-methylpiperidin-3-yl)carbamate as a light brown solid (14.19, 97%). MS: m/z=215.2 [M+H] ⁺ .

tert-Butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate: To a solution of tert-butyl N-(5-methylpiperidin-3-yl)carbamate (11.70 g, 54.60 mmol) in acetone (200 ml ) was added a solution of (2R,3R)-2,3-bis[(4-methoxyphenyl)carbonyloxy]butanedioic acid (28.95 g, 69.19 mmol) in isopropanol (13 ml) at room temperature. The resulting mixture was stirred for 24 hours at room temperature, a precipitate formed. When the reaction was complete, the precipitated substances were collected by filtration to give a white solid, which was added to a solution of potassium carbonate (29.06 g, 210.27 mmol) in water (15 ml) in portions at 0°C. The resulting mixture was then mixed with dichloromethane (100 ml) at 0°C and stirred for 2.5 hours at room temperature. The mixture was then extracted with dichloromethane (100 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate as a white solid (2.93 g, 25%). MS: m/z=215.2 [M+H] ⁺ .

Intermediate 5: 8-chloroquinoxaline-5-carbonitrile

4-Chloro-2,3-dinitrobenzoic acid: At room temperature, HNO ₃ (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 mmol) in H ₂ SO ₄ (80 ml) dropwise over 30 minutes. The resulting solution was then stirred for 1 hour at 130°C. After cooling to room temperature, the reaction mixture was poured into ice water (300 ml). The pH of the resulting mixture was adjusted to 7 with sodium hydroxide solution (6M). The mixture was then concentrated under reduced pressure and insoluble solids were filtered off from the remaining mixture. The pH of the filtrate was then adjusted to 3 with hydrochloric acid solution (6 M) and a precipitate formed. The precipitates were collected by filtration and dried in an oven under vacuum to give 4-chloro-2,3-dinitrobenzoic acid as a light yellow solid (4.8 g, crude). MS: m/z=247.0 [M+H] ⁺ .

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

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

8-Chloroquinoxaline-5-carboxylic acid: 8-Chloroquinoxaline-5-carboxylic acid (1.70 g, crude) was added to thionyl chloride (30 ml, 0.39 mol) at room temperature. The resulting solution was stirred for 2 hours at 60°C. When the reaction was complete, 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 a solution of NH ₄ OH (28%, 14.8 mol/l, 20 ml, 0.30 mol) was added dropwise over 5 minutes. The resulting mixture was then stirred for 1 hour at room temperature. When the reaction was complete, the reaction mixture was diluted with 20 ml of H ₂ O and was extracted with ethyl acetate (50 ml ×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-50% gradient) to give 8-chloroquinoxaline-5-carboxamide as a yellow oil (1.20 g, 6% for 4 stages). MS: m/z=208.1 [M+H] ⁺ .

8-chloroquinoxaline-5-carbonitrile: To a solution of 8-chloroquinoxaline-5-carboxamide (0.78 g, 3.77 mmol) in N,N-dimethylformamide (10 ml) was added POCl ₃ (4.00 g, 22.88 mmol) at room temperature. The resulting solution was stirred for 2 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×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-2% gradient) to give 8-chloroquinoxaline-5-carbonitrile as an off-white solid (555 mg, 78% ). MS: m/z=189.9 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.24 (s, 2H), 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 mmol) in CH ₃ CN (80 ml) was added 1-bromopyrrolidine-2,5-dione (27.00 g, 151. 74 mmol) 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). Insoluble solids in the mixture were filtered off and the filtrate was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 5-bromo-8-methylquinoxaline as a brown solid (6.00 g, 41%). MS: m/z=222.9 [M+H] ⁺ .

5-Bromo-8-(dibromomethyl)quinoxaline: To a solution of 5-bromo-8-methylquinoxaline (6.00 g, 27.02 mmol) in CCl ₄ (200 ml) was added NBS (19.23 g, 108.08 mmol ) and AIBN (0.71 g, 4.32 mmol) 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). Insoluble solids in the mixture were filtered off and then the filtrate was washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-5% gradient) to give 5-bromo-8-(dibromomethyl)quinoxaline as a light yellow solid (7. 15 g, 70%). MS: m/z=378.7 [M+H] ⁺ .

8-Bromoquinoxaline-5-carbaldehyde: To a solution of 5-bromo-8-(dibromomethyl)quinoxaline (13.50 g, 35.71 mmol) in ethanol (290 ml) was added a solution of AgNO ₃ (24.27 g, 142.86 mmol) in water (90 ml) dropwise at room temperature. The resulting mixture was then stirred for 1 hour at room temperature. When the reaction was complete, the reaction mixture was diluted with CH ₃ CN (300 ml) and a precipitate formed. The precipitate was filtered off and the filtrate was concentrated under reduced pressure to give 8-bromoquinoxaline-5-carbaldehyde as a yellow solid (10.00 g, crude). MS: m/z=236.8 [M+H] ⁺ .

(E)-8-Bromoquinoxaline-5-carbaldehyde oxime: To a solution of 8-bromoquinoxaline-5-carbaldehyde (10 g, crude) in ethanol (100 ml) was added NaOAc (6.34 g, 73.42 mmol) and NH ₂ Oh ^. HCl (3.12 g, 42.65 mmol) at room temperature. The resulting mixture was stirred for 3 hours at 70°C. When the reaction was completed, the insoluble solids present in the reaction mixture were filtered off at 70°C, and then the filtrate was cooled to 0°C, a precipitate formed. The precipitates were collected by filtration and dried in an oven to give (E)-N-[(8-bromoquinoxalin-5-yl)methylidene]hydroxylamine as a yellow solid (2.96 g, 33% over 2 steps). MS: m/z=253.9 [M+H] ⁺ .

8-Bromoquinoxaline-5-carbonitrile: Cu(OAc ) ₂ (577 mg, 3.18 mmol) and acetic acid (1.24 g, 20.73 mmol) 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). Insoluble solids in the mixture were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-15% gradient) to give 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

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 round bottom flask equipped with a mechanical stirrer. The reaction mixture was heated at 180°C for 3 hours. The completion of the reaction was monitored by LCMS. When the reaction was complete, the reaction mixture was cooled to room temperature and diluted with 2N NaOH solution (300 ml). After stirring at the same temperature for 15 minutes, the reaction mixture was neutralized with a 1.5N HCl solution. The solid was filtered off, washed with ice water and dried under vacuum to give 8-methyl-3H-quinazolin-4-one (125 g, 94%) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 12.2 (br s, 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).

4-Chloro-8-methylquinazoline: Phosphorus oxychloride (800 ml) was charged to a 2 L round bottom flask under nitrogen atmosphere. Then 8-methylquinazolin-4(3H)-one (125 g) was added in portions. The reaction mixture was refluxed at 120°C for 12 hours. The completion of the reaction was monitored by TLC and LCMS. When the reaction was complete, the reaction mixture was cooled to room temperature and evaporated to dryness under reduced pressure. The resulting residue was dissolved in DCM (500 ml) and slowly quenched in ice-cold saturated K ₂ CO ₃ solution with constant stirring. The organic layer was then separated and washed with brine, dried over sodium sulfate and concentrated in vacuo to give 4-chloro-8-methylquinazoline (120 g, 86%) as a yellow solid. This material was used in the next step without further purification. MS: m/z=179/181 [M+H] ⁺ .

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. The completion of the reaction was monitored by LCMS and TLC. When the reaction was complete, the reaction mixture was cooled to room temperature, the solvent was evaporated to dryness, the resulting residue was dissolved in EtOH (500 ml), 5N NaOH solution (500 ml) was added and refluxed for 6 hours. The completion of the reaction was monitored by LCMS. When the reaction was complete, the reaction mixture was cooled to room temperature and was extracted with MTBE (3×600 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 (60-120 mesh) and eluted with petroleum ether/ethyl acetate to give 8-methylquinazoline (60 g, 61%) as a low melting yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ , 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).

5-Bromo-8-methylquinazoline: To a stirred solution of silver sulfate (151.5 g, 0.486 mol) in concentrated sulfuric acid (700 ml), 8-methylquinazoline (50 g, 0.347 mol) was added portionwise 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. After 16 hours, LCMS analysis indicated 40% starting material, 7% isomer, 10% dibromo compound and 40% product. The reaction mixture was quenched with ice, filtered and made basic with ammonium hydroxide solution. The aqueous layer was extracted with MTBE (4×500 ml), washed with water and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by column chromatography using neutralized silica gel (60-120 mesh) and eluted with petroleum ether/ethyl acetate to give 5-bromo-8-methylquinazoline (16 g, 20%) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ , 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] ⁺ .

5-Bromo-8-dibromomethylquinazoline: To a stirred solution of 5-bromo-8-methylquinazoline (53 g, 0.237 mol) in CCl ₄ (800 ml) under nitrogen was added N-bromosuccinimide (94.1 g, 0.522 mol) followed by adding AIBN (7.8 g, 0.048 mol) at room temperature. The reaction mixture was heated at 90°C for 12 hours. When the reaction was complete, the reaction mixture was cooled to room temperature, filtered and washed with CCl ₄ . The filtrate was concentrated and recrystallized to give 5-bromo-8-dibromomethylquinazoline (61 g, 67%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ , 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).

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) was added silver nitrate (110 g) in portions at 0°C . The reaction mixture was stirred at room temperature for 2 hours. The completion of the reaction was confirmed by TLC. The reaction mixture was filtered and the filtrate was washed with 10% NaHCO ₃ solution and extracted with ethyl acetate (3×500 ml). The combined organic layer was washed with water and brine. The solvent was dried over sodium sulfate and concentrated in vacuo to give 5-bromoquinazoline-8-carbaldehyde. This material was used in the next step without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 11.14 (s, 1H), 9.80 (s, 1H), 9.58 (s, 1H), 8.29 (d , J=12.3 Hz, 2H); MS: m/z=237/239 [M+H] ⁺ .

5-Bromoquinazoline-8-carbonitrile: To a stirred solution of 5-bromoquinazoline-8-carbaldehyde (25 g, 0.105 mol) in DMF (125 ml) were added hydroxylamine (7.3 g 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 using ¹ NMR. When the reaction was complete, the reaction mixture was cooled to room temperature and quenched with ice. The reaction mixture was filtered and the filtrate was made basic with sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give 5-bromoquinazolin-8-carbonitrile (8 g, 32%) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.80 (s, 1H), 9.58 (s, 1H), 8.55 (d, J=7.9 Hz, 2H ), 8.27(d, J=7.8 Hz, 2H); MS: m/z=232/234 [M+H] ⁺ .

Intermediate 8: 5-Bromo-quinoline-8-carbonitrile

5-Bromo-quinoline-8-carbaldehyde oxime: Sodium acetate (1.9 g; 23.3 mmol), 5-bromoquinoline-8-carbaldehyde (5.0 g; 21.2 mmol) and hydroxylamine hydrochloride (1.6 g; 23.3 mmol) was added to absolute ethanol (50 ml). Beige suspension was heated at 70°C for 3 hours and the reaction mixture was left to cool to room temperature. After water (25 ml) was added, the beige suspension was concentrated under reduced pressure to ~30 ml. To the beige suspension were added water (25 ml), tert-butyl methyl ether (12 ml) and heptane (12 ml), 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 1N aqueous sodium hydroxide solution (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 in vacuo to give 5-bromo-quinoline-8-carbaldehyde oxime (5.20 g; 94%) as a beige solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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); MS: m/z=251 [M+H] ⁺ .

5-Bromo-quinoline-8-carbonitrile: To a mixture of 5-bromo-quinoline-8-carbaldehyde oxime (5.1 g; 20.3 mmol) and copper(ii) acetate monohydrate (81.1 mg; 0.41 mmol ) in anhydrous acetonitrile (40 ml) was added acetic acid (1.4 ml; 24.4 mmol) and the reaction mixture was heated to 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 1N aqueous sodium hydroxide solution (25 ml) was added. The beige suspension was stirred at 0° C. for 10 minutes and filtered. The brown solid was purified by recrystallization in chloroform and hexane to give 5-bromo-quinoline-8-carbonitrile (1.22 g; 26%) as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) 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-trifluoromethylquinazoline

(650 мг). Реакционную смесь нагревали при кипячении с обратным холодильником в течение ночи. Полученную суспензию охлаждали, фильтровали на целите, твердые вещества промывали ацетонитрилом и фильтрат концентрировали при пониженном давлении. Остаток очищали хроматографией на колонке PuriFlash (40 г 15 мкм), элюируя гексаном и этилацетатом, с получением 5-бром-8-трифторметил-хиназолина (222 мг, 22%) в виде светло-желтого твердого вещества. МС: m/z=277 [M+H]⁺. ¹H ЯМР (400 МГц, DMSO-d₆, м.д.) δ 9,81 (с, 1H), 9,56 (с, 1H), 8,35 (д, J=8,0 Гц, 1H), 8,24 (д, J=8,0 Гц, 1H). 5-Bromo-8-trifluoromethyl-quinazoline: To a solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (1.0 g; 3.69 mmol) and formamidine hydrochloride (594 mg; 7.38 mmol) in anhydrous acetonitrile (30 ml) was added potassium carbonate (1.8 g; 12.9 mmol) and molecular sieves

(650 mg). The reaction mixture was heated at the boil under reflux overnight. The resulting suspension was cooled, filtered through 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 give 5-bromo-8-trifluoromethyl-quinazoline (222 mg, 22%) as a light yellow solid. MS: m/z=277 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , 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

5-bromo-8-methyl-[1,7]naphthyridine: To a mixture of 5-bromo-2-methyl-pyridin-3-ylamine (3.00 g; 16.0 mmol), glycerol (4.7 ml; 64 .1 mmol), iron(II) sulfate heptahydrate (892 mg; 3.2 mmol) sulfuric acid (5.6 ml; 96.2 mmol) was added dropwise. The resulting mixture was heated at 120° C. overnight (o/n). The reaction mixture was treated with ice, 2N sodium hydroxide solution, ethyl acetate and dichloromethane. After filtration to remove a dark brown solid, the organic layer was separated and washed with brine, dried and concentrated. The crude material was purified by silica gel chromatography eluting with ethyl acetate and hexane to give 5-bromo-8-methyl-[1,7]naphthyridine (470 mg, 13%). MS: m/z=224 [M+H] ⁺ . ¹ H 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

Ethyl 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate: in a 25 ml reaction tube, ethylpiperidine-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 ×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 1-(1,8-naphthyridin-4-yl)piperidine-4-carboxylate as a yellow solid (211 mg, 81%).

(Note: Method H can also use acetonitrile, DMSO, or NMP instead of EtOH as the solvent, and the reaction temperature can be between 95°C and 130°C)

Method I

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) sodium hydroxide (147 mg, 3.67 mmol) and water (3 ml) were added 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 of the resulting mixture was adjusted to 5 with HCl solution (3M). The mixture was extracted with DCM (50 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 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 with lithium hydroxide, methanol or a mixture of methanol and THF can also be used as a solvent instead of ethanol, and the reaction temperature can be in the range from room temperature to 50°C)

Way J

N-(2-(diethylamino)ethyl)-1-(1,8-naphthyridin-4-yl)piperidine-4-carboxamide. (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 complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with DCM (50 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge BEH130 Prep C18 OBD column, 19×150mm 5µm 13nm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 10% - 50% gradient over 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% pure, RT=0.80 min. MS: m/z=356.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CDCl ₃ , 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).

The following compounds were synthesized in a similar manner:

Compound 2 ((4-(diethylamino)piperidin-1-yl)(1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methanone): from 8-chloropyrido[2,3 -b]pyrazine, ethylpiperidine-4-carboxylate and N,N-diethylpiperidine-4-amine. HPLC: 96.5% purity, RT=1.18 min. MS: m/z=397.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , 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), 3.25-3.10 (m, 2 H), 3.06-2.93 (m, 2 H), 2.74 -2.65(m, 1H), 2.55-2.45(m, 5H), 1.85-1.60(m, 6H), 1.40-1.10(m, 2 H), 1.00-0.90 (m, 6H).

Compound 414from 5-bromo-quinoline-8-carbonitrile, ethylpiperidine-4-carboxylate and 2-(3,5-dimethyl-piperidin-1-yl)-ethylamine. HPLC: 95.7% purity, RT=2.60 min. MS: m/z=420 [M+H]⁺.^oneH 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= 8.0Hz, 1H), 6.23(s, 1H), 3.53(dt, J=12.9, 3.0Hz, 2H), 3.39(sq., J=5.6Hz , 2H), 2.90 (td, J=11.9, 2.8 Hz, 2H), 2.79 (d, J=10.2 Hz, 2H), 2.48 (t, J=6, 0 Hz, 2H), 2.35 (tt, J=11.1, 4.2 Hz, 1H), 2.13 (dsq, J=12.2, 11.2, 3.8 Hz, 2H) , 2.04 (dd, J=13.2, 3.7 Hz, 2H), 1.81-1.56 (m, 3H), 1.51 (t, J=10.8 Hz, 2H), 0.87 (d, J=6.5 Hz, 6H), 0.56 (sq., J=11.8 Hz, 1H).

Compound 415 ((2-dimethylamino-ethyl)-amide 1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid):from 5-bromo-quinoline-8-carbonitrile, ethylpiperidine-4-carboxylate and (2-aminoethyl)dimethylamine. HPLC: 97.8% purity, RT=1.84 min. MS: m/z=352 [M+H]⁺.^oneH 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, 2H), 3.37 (sq., J=6.1, 4.9 Hz, 2H), 2.89 (td, J=12.0, 2.7 Hz, 2H), 2.49-2.40 (m, 2H), 2.36 (tt, J=11 .2, 4.1 Hz, 1H), 2.25 (s, 6H), 2.14 (dsq, J=12.3, 11.4, 3.8 Hz, 2H), 2.08-1 .98 (m, 2H).

Compound 416 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid [2-(ethyl-methyl-amino)-ethyl]-amide): from 5-bromo-quinoline-8-carbonitrile , ethylpiperidine-4-carboxylate and (2-aminoethyl)(ethyl)methylamine. HPLC: >99% purity, RT=1.94 min. MS: m/z=366 [M+H] ⁺ . ¹ H 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 (sq., J=5.3 Hz, 2H), 2.89 (td, J=11.9, 2.7 Hz, 2H), 2.55-2.41 (m, 4H), 2.35 (tt, J=11.2, 4.2 Hz, 1H), 2.23 (s, 3H), 2.13 (dsq, J=12.2, 11.3, 3.8 Hz, 2H), 2.08-1.99 ( m, 2H), 1.07 (t, J=7.1 Hz, 3H).

Compound 419 ((2-morpholin-4-yl-ethyl)-amide 1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid): from 5-bromo-quinolin-8-carbonitrile, ethylpiperidine -4-carboxylate; and 4-(2-aminoethyl)morpholine. HPLC: >99% purity, RT=1.92 min. MS: m/z=394 [M+H] ⁺ . ¹ H 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(sq., J=5.6Hz, 2H), 2.91(td, J=11.9, 2.7Hz, 2H), 2.53(t, J=6.0Hz, 2H), 2.48 (t, J=4.7 Hz, 4H), 2.36 (tt, J=11.2, 4.2 Hz, 1H), 2.14 (dsq, J=12, 2, 11.4, 3.8 Hz, 2H), 2.08-1.98 (m, 2H).

Compound 420 ((2-dimethylamino-1-methyl-ethyl)-1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid amide): from 5-bromo-quinoline-8-carbonitrile, ethylpiperidine -4-carboxylate; and 1-dimethylamino-2-propylamine. HPLC: >99% purity, RT=2.06 min. MS: m/z=366 [M+H] ⁺ . ¹ H 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 (dsq, J=9.5, 5.9 Hz, 1H), 3.54 (d, J=12.2 Hz, 2H), 2.90 (td, J=11.9, 2.8 Hz, 2H), 2.44-2.29 (m, 2H), 2.25 (s, 6H), 2.23 -2.08 (m, 3H), 2.09-1.99 (m, 2H), 1.23 (d, J=6.4 Hz, 3H).

Compound 421 ([2-(4-methyl-piperazin-1-yl)-ethyl]-amide 1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid): from 5-bromo-quinoline -8-carbonitrile, ethylpiperidine-4-carboxylate and 2-(4-methyl-piperazin-1-yl)-ethylamine. HPLC: 89.1% purity, RT=1.83 min. MS: m/z=407 [M+H] ⁺ . ¹ H 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 =7.9Hz, 1H), 6.16(s, 1H), 3.54(d, J=12.3Hz, 2H), 3.40(square, J=5.5Hz, 2H) , 2.91 (td, J=11.9, 2.7 Hz, 2H), 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 (dsq, J=12.1, 11.3, 3.8 Hz , 2H), 2.07-2.01 (m, 2H).

Compound 422 ((2-pyrrolidin-1-yl-ethyl)-1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid amide): from 5-bromo-quinolin-8-carbonitrile, ethylpiperidine -4-carboxylate and n-(2-aminoethyl)pyrrolidine. HPLC: >99% purity, RT=2.05 min. MS: m/z=378 [M+H] ⁺ . ¹ H 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, 2H), 3.40 (sq., J=5.4 Hz, 2H), 2.89 (td, J=12.0, 2.6 Hz, 2H), 2.67-2.59 (m, 2H), 2.58-2.45 (m, 4H) , 2.36 (tt, J=11.3, 4.1 Hz, 1H), 2.14 (dsq, J=12.3, 11.5, 3.9 Hz, 2H), 2.03 ( dd, J=12.8, 3.1 Hz, 2H), 1.87-1.74 (m, 4H).

Compound 427from 5-bromo-quinoline-8-carbonitrile, ethylpiperidine-4-carboxylate and 2-(4,4-difluoropiperidin-1-yl)ethylamine. HPLC: >99% purity, RT=2.23 min. MS: m/z=428 [M+H]⁺.^oneH 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= 8.0Hz, 1H), 6.07-5.96(m, 1H), 3.54(ddt, J=11.9, 4.1, 2.0Hz, 2H), 3.41(kv ., J=5.6 Hz, 2H), 2.90 (td, J=12.0, 2.6 Hz, 2H), 2.67-2.48 (m, 6H), 2.35 (tt , J=11.2, 4.1 Hz, 1H), 2.14 (dsq., J=12.3, 11.4, 3.8 Hz, 2H), 2.07-1.91 (m, 6H).

Compound 433 (1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid ((1-methyl-pyrrolidin-2-ylmethyl)-amide): from 5-bromo-quinolin-8-carbonitrile, ethylpiperidine -4-carboxylate and (1-methylpyrrolidin-2-yl)methanamine. HPLC: 98.9% purity, RT=2.01 min. MS: m/z=378 [M+H] ⁺ . ¹ H 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, 3.6Hz, 2H), 2.42-2.35(m, 1H), 2.33(s, 3H), 2.25(square, J=8.9Hz , 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).

Compound 434from 5-bromo-quinoline-8-carbonitrile, ethylpiperidine-4-carboxylate and 1-(cyclopropylmethyl)pyrrolidin-3-amine. HPLC: 96.6% purity, RT=2.18 min. MS: m/z=404 [M+H]⁺.^oneH 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, 2H), 3.05 (td, J=8.8, 3.4 Hz, 1H), 2.88 (td, J=11.9, 2.7 Hz, 2H), 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 (dq, J=12.0, 11.5, 3.8 Hz, 2H), 2.06-1.97 (m, 2H), 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, 2H), 0.19-0.07 (m, 2H).

Compound 435 ([1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-amide (S)-1-ethyl-pyrrolidin-2-carboxylic acid): from 5-bromo-quinoline-8 -carbonitrile, ethylpiperidine-4-carboxylate and 1-ethyl-l-proline. HPLC: >99% purity, RT=2.21 min. MS: m/z=392 [M+H] ⁺ . ¹ H 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, 2H), 3.38-3.23 (m, 2H), 3.19 (td, J=6.9, 3.4Hz, 1H), 3.08 (dd, J=10.3, 4.4Hz, 1H), 2.86 (tt, J=11.9, 2 .9 Hz, 2H), 2.68 (dsq, J=12.1, 7.3 Hz, 1H), 2.52 (dsq, 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 (dq, J=12.2, 4.2 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H).

Compound 439 ((2-azetidin-1-yl-ethyl)-1-(8-cyano-quinolin-5-yl)-piperidine-4-carboxylic acid amide): from 5-bromo-quinoline-8-carbonitrile, ethylpiperidine -4-carboxylate and 2-(azetidin-1-yl)ethane-1-amine. HPLC: >99% purity, RT=1.89 min. MS: m/z=364 [M+H] ⁺ . ¹ H 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, 2H), 3.31-3.15 (m, 6H) , 2.88 (td, J=11.9, 2.7 Hz, 2H), 2.55 (dd, J=6.3, 5.3 Hz, 2H), 2.34 (tt, J=11 .2, 4.1 Hz, 1H), 2.22-1.98 (m, 6H).

Compound 440 ((2-piperidin-1-yl-ethyl)-1-(8-cyano-quinoxalin-5-yl)-piperidine-4-carboxylic acid amide): from 8-bromo-quinoxaline-5-carbonitrile, ethylpiperidine -4-carboxylate and 1-(2-aminoethyl)piperidine. HPLC: >99% purity, RT=1.96 min. MS: m/z=393 [M+H] ⁺ . ¹ H 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, 2.8Hz, 1H), 3.35(td, J=6.0, 4.8Hz, 2H), 3.12(ddd, J=12.4, 10.2, 3.9Hz , 2H), 2.50-2.30 (m, 7H), 2.16-1.99 (m, 3H), 1.58 (p, J=5.5 Hz, 4H), 1.46 ( sq., J=6.1 Hz, 2H).

Compound 454 (4-[4-(8-cyano-quinoxalin-5-yl)-piperazin-1-yl]-N,N-dimethyl-4-oxo-butyramide): from 8-bromo-quinoxalin-5-carbonitrile , 1-boc-piperazine and N,N-dimethylsuccinamic acid. HPLC: >99% purity, RT=2.13 min. MS: m/z=367 [M+H] ⁺ . ¹ H 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, 2H), 3.87 (t, J=5.1 Hz, 2H), 3.69 (t, J=5.1 Hz, 2H), 3.58 (t, J=5.2 Hz, 2H), 3.08 (s , 3H), 2.96 (s, 3H), 2.83-2.66 (m, 4H).

Compound 456 ((2-diethylamino-ethyl)-amide 1-(8-fluoro-pyrido[3,4-b]pyrazin-5-yl)-piperidine-4-carboxylic acid):from 5-chloro-8-fluoropyrido[3,4-b]pyrazine, ethylpiperidine-4-carboxylate and N,N-diethylethylenediamine. HPLC: >99% purity, RT=1.38 min. MS: m/z=376 [M+H]⁺.^oneH 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 )

Way K

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) was added MeI (53 mg, 0.37 mmol) and Cs₂CO₃ (100 mg, 0.31 mmol). The resulting solution was stirred for 1.5 hours at 0°C. When the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with DCM (30 ml×3) and the organic phases were combined, washed with brine and dried over Na₂SO_four. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep Column, 5 µm, 19 mm×250 mm; Mobile phase: acetonitrile in water (with 10 mmol/L NH_fourHCO₃), 10% - 23% gradient over 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 an off-white solid (7 mg, 10%).

Compound 3: HPLC: 99.1% pure, RT=0.81 min. MS: m/z=372.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CDCl ₃ , 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)

(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-yl)methanol was obtained as a yellow solid (275 mg, 89%).

Method L

(1-(Pyrido[2,3-b]pyrazin-8-yl)piperidin-4-yl)methyl methanesulfonate: To 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) methylsulfonyl chloride (152 mg, 1.33 mmol) was added in several batches at room temperature. The resulting solution was stirred for 2 hours at room temperature. When the reaction was complete, it was quenched by adding water (20 ml). The resulting mixture was extracted with dichloromethane (40 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give (1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-4-yl)methyl methanesulfonate as a brown solid (300 mg, 91%). MS: m/z=323.1 [M+H] ⁺ .

Method M

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 N,N-diethylpiperidin-4-amine (330 mg , 2.11 mmol) and DIEA (136 mg, 1.05 mmol, 2.00 eq.) 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 ×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge BEH130 Prep C18 OBD column, 19 x 150 mm 5 µm 13 nm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 10% - 23% gradient over 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 range from 80°C to 130°C)

Compound 4: HPLC: 97.6% pure, RT=0.73 min. MS: m/z=383.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , 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, 2H), 3, 11-3.00 (m, 2H), 2.85 (d, J=11.1 Hz, 2H), 2.49-2.31 (m, 5H), 2.13 (d, J=6, 7 Hz, 2H), 1.88-1.76 (m, 5H), 1.61 (d, J=12.0 Hz, 2H), 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-amine)

(1-(Quinolin-4-yl)piperidin-4-yl)methylmethanesulfonate: (1-(quinolin-4-yl)piperidin-4-yl)methylmethanesulfonate was prepared from 4-chloroquinoline, piperidin-4-ylmethanol and methanesulfonyl chloride using Methods H and L [1-(quinolin-4-yl)piperidin-4-yl]methylmethanesulfonate was obtained as a yellow solid (550 mg, crude). MS: m/z=321.0 [M+H] ⁺ .

Method N

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]methylmethanesulfonate (450 mg, crude) in acetoneitrile (8 mL) was added N,N-diethylpiperidin-4-amine (209 mg, 1.34 mmol) and Cs ₂ CO ₃ (651 mg, 2.00 mmol) 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 x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep Column, 5 μm, 19 mm × 250 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 15% - 60% gradient over 8 min; Detector UV 254 nm. N,N-diethyl-1-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]piperidin-4-amine was obtained as a light yellow solid (40 mg, 15% for 3 steps) .

(Note: Method N can also use DMF instead of acetonitrile as a solvent, and the reaction temperature can be in the range of 60°C to 130°C)

Compound 5: HPLC: 99.7% pure, RT=0.53 min. MS: m/z=381.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CDCl ₃ , ppm) δ 8.70 (d, J=5.0 Hz, 1H), 8.08-7.94 (m, 2H), 7.70-7 .55 (m, 1H), 7.50-7.40 (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, 2H), 2.81 (dd, J=12.8, 10.6 Hz, 2H), 2.78-2.48 (m, 5H ), 2.27 (d, J=7.0 Hz, 2H), 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

4-(4-((2-(Piperidin-1-yl)ethoxy)methyl)piperidin-1-yl): To 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 an additional 20 hours at room temperature. When the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with DCM (50 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Column: XBridge C18 OBD Prep Column, 5 µm, 19 mm×250 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 41% - 50% gradient over 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%).

Compound 6: HPLC: 98.9% pure, RT=1.17 min. MS: m/z=354.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CDCl ₃ , 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), 7.50-7.40 (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 (2-morpholino-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)ethanamine)

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

Method P

2-Morpholino-N-((1-(quinolin-4-yl)piperidin-4-yl)methyl)ethanamine: To 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 BH ₃ -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×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0%-25% gradient) to give 2- morpholino -N-((1-(quinolin-4-yl)piperidin-4- yl)methyl)ethanamine as a light yellow solid (50 mg, 10% for 4 steps).

Compound 7: HPLC: 98.9% pure, RT=0.82 min. MS: m/z=355.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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-butylpiperidine -4-ylmethylcarbamate using Method H. The crude product was purified by flash chromatography eluting with MeOH in DCM (0%-15% gradient) to give t-butyl N-[[1-(quinolin-4-yl)piperidine -4-yl]methyl]carbamate as a light yellow solid (600 mg, 94%). MS: m/z=342.1 [M+H] ⁺ .

Method Q

(1-(Quinolin-4-yl)piperidin-4-yl)methanamine: To 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 a concentrated solution of HCl (12 M, 1.5 ml) at room temperature. The resulting solution was stirred for 24 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure to give [1-(quinolin-4-yl)piperidin-4-yl]methanamine dihydrochloride as a yellow solid (380 mg, 84%). MS: m/z=242.1 [M+H] ⁺ .

(Note: Method Q can also use 1:1 dioxane / MeOH as solvent or dioxane instead of MeOH)

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)acetic acid using Method J. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep Column, 5 µm, 19 mm x 250 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 40% - 55% gradient over 10 min; Detector UV 254 nm. 2-(piperidin-1-yl)-N-[[1-(quinolin-4-yl)piperidin-4-yl]methyl]acetamide was obtained as a light yellow solid (152 mg, 72%).

Compound 8: HPLC: 98.1% pure, RT=1.46 min. MS: m/z=367.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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, 2 H), 3.19-3.09 (m, 2 H), 2.91 (s, 2 H), 2.86-2.70 (m, 2 H), 2 .50-2.30 (m, 4 H), 1.85-1.62 (m, 3 H), 1.62-1.31 (m, 8 H).

The following compounds were synthesized in a similar manner:

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, RT=1.16 min. MS: m/z=369 [M+H] ⁺ . ¹ H 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, 2H), 3.28 (t, J=6.3 Hz, 2H), 3.08 (td, J=12.4, 2.3 Hz, 2H), 2.97 (s, 2H) , 2.46 (s, 4H), 1.98-1.79 (m, 3H), 1.64-1.52 (m, 6H), 1.46 (dd, J=11.2.5, 5 Hz, 2H).

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, RT=0.92 min. MS: m/z=343 [M+H] ⁺ . ¹ H 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, 2H), 3.04 (s, 2H), 2.56 (sq., J=7.1 Hz, 4H), 2.13 (dd , J=13.1, 3.8 Hz, 2H), 1.77 (dsq., J=11.5, 3.8 Hz, 2H), 1.03 (t, J=7.1 Hz, 6H ).

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, RT=1.90 min. MS: m/z=408 [M+H] ⁺ . ¹ H 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, 2H), 6.25 (t, J=6.2 Hz, 1H), 4.45 (d, J=12.4 Hz, 2H), 3.94 ( s, 3H), 3.93 (s, 3H), 3.45 (t, J=6.3 Hz, 2H), 3.08 (td, J=12.4, 2.4 Hz, 2H), 2.08-1.97 (m, 1H), 1.96 (d, J=13.7 Hz, 2H), 1.65 (dsq, J=12.1, 3.9 Hz, 2H).

Compound 392 ((1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-pyridine-2-carboxylic acid amide): from 8-chloro-pyrido[2,3-b]pyrazine , 4-(boc-aminomethyl)piperidine and 2-picolinic acid. HPLC: 98.7% purity, RT=1.19 min. MS: m/z=349 [M+H] ⁺ . ¹ H 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, 2H), 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, 2H).

Compound 394 (2-Dimethylamino-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 N,N-dimethylglycine. HPLC: >99% purity, RT=0.89 min. MS: m/z=329 [M+H] ⁺ . ¹ H 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, 2H), 3.28 (t, J=6.3 Hz, 2H), 3.06 (td, J=12.4, 2.4 Hz, 2H), 2.97 ( s, 2H), 2.30 (s, 6H), 1.97-1.82 (m, 3H), 1.58 (dtd, J=13.3, 11.7, 3.8 Hz, 2H) .

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: purity 90.1% h, RT=1.02 min. MS: m/z=357 [M+H] ⁺ . ¹ H 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, 2H), 4.17-4.03 (m, 1H), 3.27 (ddd, J=13.0, 11.1, 2.7 Hz, 2H), 2.67 (t, J=5.9 Hz, 2H), 2.57 (q.v., J=7.1 Hz, 4H), 2.38 (t, J=5.8 Hz, 2H), 2.13 ( dd, J=12.8, 3.7 Hz, 2H), 1.73 (dq, J=11.0, 3.8 Hz, 2H), 1.06 (t, J=7.1 Hz, 6H).

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, RT=2.00 min. MS: m/z=342 [M+H] ⁺ . ¹ H 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, 2H), 3.24 (t, J=6.2 Hz, 2H), 3.07 (td, J=12.4, 2.3 Hz, 2H), 2.07 ( s, 2H), 1.93-1.79 (m, 3H), 1.56 (dq, J=13.5, 12.9, 3.7 Hz, 3H), 1.05 (s, 9H ).

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, RT=1.02 min. MS: m/z=369 [M+H] ⁺ . ¹ H 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 (n, J=7.3 Hz, 2H), 1.57 (n, J=5.6 Hz, 4H ), 1.50-1.37 (m, 2H).

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, RT=0.94 min. MS: m/z=341 [M+H] ⁺ . ¹ H 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, 2H), 3.32 (t, J=7.1 Hz, 4H), 3.26 (t, J=6.3 Hz, 2H), 3.12 (s, 2H), 3.06 (td, J=12.4, 2.3 Hz, 2H), 2.10 (p, J=7.1 Hz, 2H), 1.96-1.78 (m, 3H), 1.58 ( dkv., J=13.3, 3.7 Hz, 2H).

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, RT=1.07 min. MS: m/z=371 [M+H] ⁺ . ¹ H 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, 2H), 3.34 (d, J=7.3 Hz, 2H), 3.28 (s, 2H), 3.16 (s, 3H), 3.08 (td, J=12.3, 2.6 Hz, 2H) , 2.61 (sq., 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 (dq, J=13.0, 12.5, 3.9 Hz, 2H), 1.05 (t, J=6.9 Hz, 6H).

Compound 408 (2-(Ethyl-methyl-amino)-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 [ethyl(methyl)amino]acetic acid. HPLC: 98.9% purity, RT=1.35 min. MS: m/z=343 [M+H] ⁺ . ¹ H 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, 2H), 3.27 (t, J=6.3 Hz, 2H), 3.07 (td, J=12.5, 2.4 Hz, 2H), 3.01 ( s, 2H), 2.49 (sq., J=7.2 Hz, 2H), 2.28 (s, 3H), 1.96-1.81 (m, 3H), 1.58 (dq. , J=13.3, 3.7 Hz, 2H), 1.06 (t, J=7.1 Hz, 3H).

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, RT=2.25 min. MS: m/z=392 [M+H]⁺.^oneH 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, 2H), 7.04 (d, J= 8.0 Hz, 1H), 3.50 (d, J=12.5 Hz, 2H), 3.33 (t, J=6.5 Hz, 2H), 2.99 (s, 2H), 2 .86 (td, J=12.0, 2.3 Hz, 2H), 2.49 (s, 4H), 1.90 (d, J=12.7 Hz, 2H), 1.79 (dtt, J=14.0, 6.8, 3.9 Hz, 1H), 1.71-1.52 (m, 6H), 1.47 (s, 2H).

Compound 410 (N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-2-(ethyl-methyl-amino)-acetamide): from 5-bromo-quinolin-8-carbonitrile , 4-(boc-aminomethyl)piperidine and [ethyl(methyl)amino]acetic acid. HPLC: 95.9% purity, RT=2.09 min. MS: m/z=366 [M+H] ⁺ . ¹ H 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, 2H), 7.04 (d, J =8.0 Hz, 1H), 3.50 (d, J=12.3 Hz, 2H), 3.33 (t, J=6.5 Hz, 2H), 3.04 (s, 2H), 2.86 (td, J=12.0, 2.3 Hz, 2H), 2.52 (sq., J=6.7 Hz, 2H), 2.32 (s, 3H), 1.91 ( d, J=12.8 Hz, 2H), 1.79 (ddt, J=14.2, 6.9, 3.7 Hz, 1H), 1.62 (dsq, J=12.0, 3 .8 Hz, 2H), 1.09 (t, J=7.1 Hz, 3H).

Compound 411 ((1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-amide of 1-methyl-pyrrolidin-2-carboxylic acid): from 8-chloro-pyrido[2,3 -b]pyrazine, 4-(boc-aminomethyl)piperidine and 1-methylpyrrolidine-2-carboxylic acid. HPLC: 99.7% purity, RT=1.02 min. MS: m/z=355 [M+H] ⁺ . ¹ H 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, 2H), 3.25 (td, J=6.5, 2.3 Hz, 2H), 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).

Compound 412 (2-tert-Butoxy-N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide): from 5-bromo-quinolin-8-carbonitrile, 4-( boc-aminomethyl)piperidine and t-butoxyacetic acid. HPLC: >99% purity, RT=3.73 min. MS: m/z=381 [M+H] ⁺ . ¹ H 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, 2H), 3.34 (t, J =6.6Hz, 2H), 2.85(td, J=12.0, 2.3Hz, 2H), 1.92(d, J=13.4Hz, 2H), 1.80(dtt , J=14.3, 6.9, 3.8 Hz, 1H), 1.62 (dsq, J=12.0, 3.8 Hz, 2H), 1.25 (s, 9H).

Compound 417 (2-Azetidin-1-yl-N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide): from 5-bromo-quinolin-8-carbonitrile, 4 -(boc-aminomethyl)piperidine and 2-(azetidin-1-yl)acetic acid hydrochloride. HPLC: >99% purity, RT=2.05 min. MS: m/z=364 [M+H] ⁺ . ¹ H 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, 2H), 3.43-3.20 (m, 6H), 3.14 (s, 2H), 2.85 (td, J=12.1, 2.3 Hz, 2H), 2.11 (n, J=7.0 Hz, 2H), 1.91 (d, J= 12.9 Hz, 2H), 1.78 (dtt, J=14.3, 7.0, 3.8 Hz, 1H), 1.61 (dsq., J=12.0, 3.9 Hz, 2H).

Compound 418 ([1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-1-methyl-pyrrolidine-2-carboxylic acid amide): from 5-bromo-quinolin-8-carbonitrile, 4 -(boc-aminomethyl)piperidine and 1-methylpyrrolidine-2-carboxylic acid. HPLC: >99% purity, RT=2.11 min. MS: m/z=378 [M+H] ⁺ . ¹ H 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, 2H), 3.30 (td, J= 6.6, 2.0 Hz, 2H), 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, 2H), 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)

Method R

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), Pd ₂ (dba) ₃ .CHCl ₃ (115 mg, 0.11 mmol), DavePhos (87 mg, 0.22 mmol) and K ₃ PO ₄ (588 mg, 2.77 mmol) at room temperature. The resulting mixture was stirred for 2 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×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-2% gradient) to give t-butyl N-[(3R,5S)-1-[1,2-dimethyl -1H- pyrrolo [2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl]carbamate as a yellow solid (150 mg, 38%). MS: m/z=359.1 [M+H] ⁺ .

(Note: The catalyst in Method R may be Pd ₂ (dppf)Cl ₂ .CHCl ₃ ) instead of Pd ₂ (dba) ₃ .CHCl ₃

(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 obtained 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 Column, 5 µm, 19 mm × 250 mm; Mobile phase: methanol in water (with 10 mmol/l NH ₄ HCO ₃ ), 3% - 65% gradient over 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%).

Compound 9: HPLC: 97.8% pure, RT=0.91 min. MS: m/z=259.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 7.91 (d, J=5.7 Hz, 1H), 6.49 (d, J=5.7 Hz, 1H), 6 .30 (d, J=1.2 Hz, 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)

(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 Column, 5 µm, 19 mm × 250 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 3% - 22% gradient over 9 min; Detector UV 254 nm. (3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine was obtained as a yellow syrup (20 mg, 10% for 2 steps).

Compound 10: HPLC: 94.1% pure, RT=1.10 min. MS: m/z=244.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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), 2.08- 1.88 (m, 1H), 1.18-0.89 (m, 4H).

The following compounds were synthesized in a similar manner:

Compound 11 ((3R,5S)-5-methyl-1-(quinolin-4-yl)piperidin-3-amine): from tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate and 4-chloroquinoline . HPLC: 99.9% purity, RT=0.86 min. MS: m/z=242.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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=5.2Hz, 1H) , 3.83-3.74 (m, 1H), 3.64-3.55 (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).

Compound 12 (8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile): from 8-chloroquinoxaline-5-carbonitrile and tert-butyl (3R,5S)-5 -methylpiperidin-3-ylcarbamate. HPLC: 98.3% purity, RT=1.20 min. MS: m/z=268.0 [M+H] ⁺ . ¹ H NMR (300 MHz, CDCl ₃ , 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)

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 obtained from (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. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 3% - 75% gradient over 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%).

Compound 13: HPLC: 96.9% pure, RT=0.67 min. MS: m/z=317.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , 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), 3.88 -3.74 (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, 2H), 1.28-1.10 (m, 1H), 0.86 (d, J=6.5 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 14 (2-hydroxy-N-((3R,5S)-5-methyl-1-(quinolin-4-yl)piperidin-3-yl)acetamide):from (3R,5S)-5-methyl-1-(quinolin-4-yl)piperidin-3-amine and 2-hydroxyacetic acid. HPLC: 98.3% purity, RT=1.04 min. MS: m/z=300.2 [M+H]⁺.^oneH 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 ( e, J=6.4 Hz, 3H).

Compound 15 (2-hydroxy-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)piperidine-3-amine and 2-hydroxyacetic acid. HPLC: 95.3% purity, RT=0.73 min. MS: m/z=302.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

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)quinoxalin-5-carbonitrile and (S)-2-hydroxy-3-methylbutanoic acid. HPLC: 98.4% purity, RT=3.24 min. MS: m/z=368.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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), 4.05- 3.85 (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).

Compound 21 (((R)-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)quinoxalin-5-carbonitrile and (R)-2-hydroxy-3-methylbutanoic acid HPLC: 97.6% purity, RT=1, 31 min MS: m/z=368.3 [M+H] ^{+ .1} H NMR (300 MHz, DMSO-d ₆ , 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), 7.69 (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).

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-3-methylbutanoic acid . HPLC: 96.8% purity, RT=1.05 min. MS: m/z=344.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

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-3-methylbutanoic acid . HPLC: 96.9% purity, RT=1.02 min. MS: m/z=344.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

Compound 32 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(dimethylamino)acetamide): from 8-((3R,5S) -3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 2-(dimethylamino)acetic acid. HPLC: 96.9% purity, RT=1.25 min. MS: m/z=353.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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) .

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, RT=1.31 min. MS: m/z=329.0 [M+H]⁺.^oneH 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, 10-2.89 (m, 3H), 2.83-2.73 (m, 1H), 2.34 (s, 6H), 2.16-1.93 (m, 2H), 1.40- 1.28 (m, 1H), 1.04 (d, J=6.6 Hz, 3H).

Compound 36 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3-methyloxetan-3-carboxamide): from 8-chloroquinoxalin-5-carbonitrile , tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate and 3-methyloxetane-3-carboxylic acid. HPLC: 99.2% purity, RT=1.15 min. MS: m/z=366.0 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

Compound 37 from (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidine-3-amine and 3-methyloxetane-3-carboxylic acid. HPLC: 99.8% purity, RT=0.88 min. MS: m/z=342.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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, 2H), 4.39 (d, J=6.1 Hz, 2H), 4.15-4.03 (m, 1H), 2.91-2.71 (m, 2H), 2 .12-1.92 (m, 2H), 1.60 (s, 3H), 1.34-1.22 (m, 1H), 1.01 (d, J=6.6 Hz, 3H).

Compound 40 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-3,3-dimethylbutanamide): from 8-((3R,5S)- 3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 3,3-dimethylbutanoic acid. HPLC: 95.2% purity, RT=3.11 min. MS: m/z=366.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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).

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, RT=0.96 min. MS: m/z=342.2 [M+H]⁺.^oneH 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, 12 H).

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)quinoxalin-5-carbonitrile and 2-hydroxyacetic acid. HPLC: 97.5% purity, RT=1.35 min. MS: m/z=326.1 [M+H]⁺.^oneH NMR (400 MHz, CD₃OD, ppm) δ 9.05-8.83 (m, 2H), 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, 2H), 4.02 (s, 2H), 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).

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, RT=1.95 min. MS: m/z=395.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.83 (m, 2H), 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).

Compound 109 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide): from 8- ((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 2-(4-methylpiperazin-1-yl)acetic acid. HPLC: 99.8% purity, RT=1.47 min. MS: m/z=408.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 m, 2H), 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, 2H), 1.36-1.24 (m, 1H), 1.04 (d, J=6.4 Hz, 3H).

Compound 110 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(morpholin-4-yl)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, RT=1.31 min. MS: m/z=371.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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=6.5 Hz, 3H).

Compound 111 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3,3-trifluoropropanamide): from 8-((3R,5S )-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 3,3,3-trifluoropropanoic acid. HPLC: 91.5% purity, RT=1.38 min. MS: m/z=378.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.93-8.80 (m, 2H), 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 (square, J=10.7 Hz, 2H), 2.68 (dt, J=23.6, 11.6 Hz, 2H), 2.14-1.93 (m, 2H), 1.21-1.16 (m, 1H) , 0.98 (d, J=6.4 Hz, 3H).

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, RT=1.07 min. MS: m/z=354.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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=10.7Hz, 2H), 2.85-2.65(m, 2H), 2.15-1.85(m, 2H), 1.22 (td, J=12.0, 12.0 Hz, 1H), 0.99 (d, J=6.5 Hz, 3H).

Compound 130 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1H-imidazol-4-yl)acetamide hydrochloride): from 2 -(1H-imidazol-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity =, RT=1.05 min. MS: m/z=367.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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(brs, 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).

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)piperidin-3- amine. HPLC: 99.2% purity, RT=0.79 min. MS: m/z=352.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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, 2H), 4.12-4.00 (m, 1H), 3.52 (br s, 2H), 2.90-2.70 (m, 2H), 2.15-1.85 (m, 2H), 1.26 (td, J=12.0, 12.0 Hz, 1H), 1.00 (d, J=6.6 Hz, 3H).

Compound 132 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methyl-1H-imidazol-4-yl)acetamide) : from 2-(1-methyl-1H-imidazol-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile. HPLC: 96.2% purity, RT=1.39 min. MS: m/z=390.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.82 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.55 ( d, J=1.3 Hz, 1H), 7.29 (d, J=8.4 Hz, 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).

Compound 133 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(1-methyl-1H-imidazole -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)piperidine-3-amine. HPLC: 95.9% purity, RT=0.84 min. MS: m/z=366.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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, 13-3.99 (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).

Compound 134 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methoxyacetamide): from 2-methoxyacetic acid and 8-((3R, 5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.7% purity, RT=1.20 min. MS: m/z=340.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.82 (m, 2H), 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, 2H), 1.30 (td, J=12.5, 12.5 Hz, 1H), 0.99 (d, J=6.4 Hz, 3H).

Compound 140 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-methanesulfonamidoacetamide): from 2-(methylsulfonamido)acetic acid and 8-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 93.6% purity, RT=2.22 min. MS: m/z=403.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.81 (m, 2H), 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, 2H), 2.16-2.00 (m, 2H), 1.26 (td, J=11.8, 11.8 Hz, 1H), 0.99 (d, J=6.4 Hz, 3H).

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)piperidine-3-amine. HPLC: 98.5% purity, RT=0.82 min. MS: m/z=379.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 2.00-1.90 (m, 1H), 1.27 (td, J=12.0, 12.0 Hz, 1H), 0.99 (d, J=6.5 Hz, 3H).

Compound 142 (2-(tert-butylamino)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide): from 2-(tert-butylamino )acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity, RT=1.38 min. MS: m/z=381.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

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)piperidine-3-amine. HPLC: 97.7% purity, RT=1.04 min. MS: m/z=357.3 [M+H] ⁺ . ¹ H 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).

Compound 144 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-[(2-hydroxyethyl)(methyl)amino]acetamide): from 2-((2-hydroxyethyl)(methyl)amino)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 93.1% purity, RT=1.09 min. MS: m/z=383.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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=7.2 Hz, 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).

Compound 145 -yl]acetamide): from 2-((2-hydroxyethyl)(methyl)amino)acetic acid and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl) piperidine-3-amine. HPLC: 90.7% purity, RT=1.70 min. MS: m/z=359.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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).

Compound 163 (2-(tert-butoxy)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide): from 2-tert-butoxyacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.3% purity, RT=1.54 min. MS: m/z=382.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.97-8.85 (m, 2H), 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).

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)piperidine-3-amine. HPLC: 97.9% purity, RT=1.23 min. MS: m/z=358.3 [M+H] ⁺ . ¹ H 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, 2H), 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 ( e, J=6.5 Hz, 3H).

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, RT=1.39 min. MS: m/z=372.2 [M+H]⁺.^oneH 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), 4.47-4.27 (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).

Compound 166 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(oxolan-2-ylmethoxy)acetamide): from 2-(oxolane -2-ylmethoxy)acetic acid; and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile. HPLC: 99.0% purity, RT=2.78 min. MS: m/z=410.2 [M+H] ⁺ . ¹ H 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=8.4Hz, 1H), 7.29 (d, J=8.4Hz, 1H), 4.40 (d, J=11.9Hz, 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).

Compound 167 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2,3-dimethylbutanamide): from 2,3-dimethylbutanoic acid and 8- ((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 98.7% purity, RT=1.52 min. MS: m/z=366.3 [M+H] ⁺ . ¹ H 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), 2.94-2.79 (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).

Compound 168 (2,3-dimethyl-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]butanamide): from 2 ,3-dimethylbutanoic acid; and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidine-3-amine. HPLC: 98.7% purity, RT=1.21 min. MS: m/z=342.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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), 1.14-0.82 (m, 12H).

Compound 169 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1H-pyrazol-1-yl)acetamide): from 2- (1H-pyrazol-1-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.4% purity, RT=1.18 min. MS: m/z=376.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.93 (d, J=1.7 Hz, 1H), 8.89 (d, J=1.7 Hz, 1H), 8 .19-8.06 (m, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.56 (d, J=1.5 Hz, 1H), 7.28 (d, J=8.3Hz, 1H), 6.39-6.33(m, 1H), 4.42(d, J=11.7Hz, 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), 2.85-2.65 (m , 2H), 2.22-1.98 (m, 2H), 1.26 (td, J=12.0, 12.0 Hz, 1H), 1.03 (d, J=6.4 Hz, 3H).

Compound 170 (N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]-2-(1H-pyrazol-1-yl )acetamide): from 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, RT=1.73 min. MS: m/z=352.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

Compound 171 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-methylpyrrolidin-2-carboxamide): from 1-methylpyrrolidin-2-carboxylic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 98.5% purity, RT=1.85 min. MS: m/z=379.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 2.21- 1.97 (m, 3H), 1.85-1.71 (m, 3H), 1.33-1.19 (m, 1H), 0.99 (d, J=6.3 Hz, 3H) .

Compound 172 (Methyl-N-[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-yl]pyrrolidin-2-carboxamide): from 1 -methylpyrrolidin-2-carboxylic acid; and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidine-3-amine. HPLC: 97.5% purity, RT=2.22 min. MS: m/z=355.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

Compound 175 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]-3,3-dimethylbutanamide): from 3,3-dimethylbutanoic acid and cis-8-(3 -amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.1% purity, RT=2.95 min. MS: m/z=392.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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, 2H), 2.21-2.09 (m, 1H), 2.06 (s, 2H), 1.40-1.02 ( m, 2H), 1.01 (s, 9H), 0.63-0.38 (m, 3H), 0.18 (d, J=3.5 Hz, 2H).

Compound 179 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]-2-(dimethylamino)acetamide): from 2-(dimethylamino)acetic acid hydrochloride and cis-8 -(3-amino-5-cyclopropylpiperidin-1-yl)quinoxalin-5-carbonitrile. HPLC: 97.2% purity, RT=2.42 min. MS: m/z=379.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 4.16-3, 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).

Compound 230 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-hydroxycyclopropan-1-carboxamide): from 1-hydroxycyclopropan-1-carboxylic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: 98.8% purity, RT=3.40 min. MS: m/z=352.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.94-8.80 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 7.23 ( d, J=8.4 Hz, 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).

Compound 232 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-4-yl)acetamide: from 2-( 1-methylpiperidin-4-yl)acetic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile HPLC: 95.5% purity, RT=2, 03 min MS: m/z=407.3 [M+H] ^{+ .1} H NMR (300 MHz, Chloroform-d, ppm) δ 8.95 (d, J=1.7 Hz, 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, 6 Hz, 3H).

Compound 233 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1,4-dimethylpiperidin-4-yl)acetamide): from 2-(1,4-dimethylpiperidin-4-yl)acetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile. HPLC: 95.7% purity, RT=2.95 min. MS: m/z=421.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 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), 2.83-2.55 (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, 12.1 Hz, 1H), 1.08 (s, 3H), 1.01 (d, J=6, 3 Hz, 3H).

Compound 234 ]acetamide): from 2-(1-methylpiperidin-4-yl)acetic acid and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile. HPLC: 93.9% purity, RT=2.45 min. MS: m/z=457.3 [M+H] ⁺ . ¹ H 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=7.2 Hz, 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).

Compound 235 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-difluorocyclobutane-1-carboxamide): from 3,3-difluorocyclobutane -1-carboxylic acid; and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: 93.9% purity, RT=4.03 min. MS: m/z=386.0 [M+H] ⁺ . ¹ H 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).

Compound 236 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-methylpyrrolidin-3-carboxamide): from 3,3-difluorocyclobutan-1 -carboxylic acid; and 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoxaline-5-carbonitrile. HPLC: 97.5% purity, RT=2.06 min. MS: m/z=379.1 [M+H] ⁺ . ¹ H 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, 4.6 Hz, 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), 1.35-1.10 (m, 1H), 0.98 (d, J=6.6 Hz , 3H).

Compound 265 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-hydroxypropanamide): from 2-hydroxypropanoic acid and 8-((3R, 5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.3% purity, RT=1.16 min. MS: m/z=340.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.81 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 7.24 ( d, J=8.4 Hz, 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).

Compound 266: (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpiperidin-3-yl)acetamide hydrochloride): 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, RT=1.19 min. MS: m/z=407.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 9.01-8.89 (m, 2H), 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=6.4 Hz, 3H).

Compound 269 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(1-methylpyrrolidin-3-yl)acetamide): from 2- (tert-butoxycarbonylamino)-2-cyclopropylacetic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.1% purity, RT=2.41 min. MS: m/z=393.2 [M+H] ⁺ . ¹ H 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-1-yl)quinoxaline-5-carbonitrile hydrochloride)

Method S

tert-Butyl (3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl(methyl)carbamate: To 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 eq.) at room temperature. The mixture was stirred for 10 minutes at room temperature and then iodomethane (70 mg, 0.49 mmol) was added. The reaction mixture was stirred for 1 hour at room temperature. When the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give tert-butyl N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-N-methylcarbamate as a yellow solid (180 mg, crude product).

8-((3S,5R)-3-methyl-5-(methylamino)piperidin-1-yl)quinoxalin-5-carbonitrile hydrochloride: 8-((3S,5R)-3-methyl-5-(methylamino)piperidine -1-yl)quinoxalin-5-carbonitrile hydrochloride 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% - 40% gradient over 10 min; Detector UV 254 nm. 8-[(3S,5R)-3-methyl-5-(methylamino)piperidin-1-yl]quinoxalin-5-carbonitrile hydrochloride was obtained as a yellow solid (36 mg, 26% for 2 steps).

Compound 16: HPLC: 90.3% pure, RT=1.97 min. MS: m/z=282.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

The following compound was synthesized in a similar manner:

Compound 17 ((3R,5S)-N,5-dimethyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine):from tert-butyl (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-ylcarbamate and iodomethane. HPLC: 92.8% purity, RT=0.71 min. MS: m/z=258.2 [M+H]⁺.^oneH 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]pyrazin-8-yl)piperidine-3-amine)

(3R,5S)-N-(2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidine-3-amine: (3R,5S)-N-( 2-methoxyethyl)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidine-3-amine was obtained 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 Column, 5 µm, 19 mm × 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 3% - 80% gradient over 8 min; Detector UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-5-methyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine was obtained as a yellow oil (60 mg, 31 %).

Compound 18: HPLC: 96.8% pure, RT=1.88 min. MS: m/z=302.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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, 2H), 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).

The following compounds were synthesized in a similar manner:

Compound 19 (8-((3R,5S)-3-(2-methoxyethylamino)-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile):from 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 1-bromo-2-methoxyethane. HPLC: 97.8% purity, RT=1.22 min. MS: m/z=326.2 [M+H]⁺.^oneH 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), 4.59-4.47 (m, 1H), 4.14-4.03 (m, 1H), 3.55-3.45 (m, 2H), 3.34 (s, 3H), 3.06-2.78 (m, 3H), 2.66-2.51 (m, 2H), 2.20-1.85 (m, 2H), 1.10-0 .91 (m, 4H).

Compound 38 (8-((3R,5S)-3-(cyanomethylamino)-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile): from 8-((3R,5S)-3-amino-5-methylpiperidine -1-yl)quinoxalin-5-carbonitrile and 2-chloroacetonitrile. HPLC: 90.7% purity, RT=1.24 min. MS: m/z=307.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.93-8.86 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.18 ( d, J=8.4 Hz, 1H), 4.65-4.52 (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).

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, RT=0.97 min. MS: m/z=283.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 9.12-9.02 (m, 2H), 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).

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, RT=0.75 min. MS: m/z=301.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

Compound 122 (2-[[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]amino]acetamide): from 8-((3R,5S)-3- amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 2-chloroacetamide. HPLC: 99.5% purity, RT=1.03 min. MS: m/z=325.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

Compound 126 he): 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, RT=1.13 min. MS: m/z=341.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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), 3.76-3.62 (m, 1H), 3.48-3.35 (m, 2H), 3.21-3.04 (m, 1H), 2.87 ( s, 3H), 2.80-2.65 (m, 2H), 2.56-2.39 (m, 1H), 2.28-2.12 (m, 1H), 2.02-1, 76 (m, 2H), 1.18-0.99 (m, 4H).

Compound 176 (cis-8-[3-cyclopropyl-5-[(2-methoxyethyl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile): from 3,3-dimethylbutanoic acid and cis-8-(3- amino-5-cyclopropylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity, RT=1.42 min. MS: m/z=352.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 0.30-0, 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)

(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 obtained from 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl) quinoxaline-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)propanoic acid using Methods J and Q. The crude product was purified by preparative HPLC under the following conditions: Column, XBridge C18 OBD Prep Column, 5 µm, 19 mm x 250 mm; MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 80% gradient over 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 a yellow solid (25 mg, 26% for 2 stages).

Compound 24: HPLC: 94.4% pure, RT=1.39 min. MS: m/z=339.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 1.35- 1.17 (m, 4H), 1.04 (d, J=6.4 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 25 ((S)-2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)propanamide): from 8-((3R, 5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and (S)-2-(tert-butoxycarbonylamino)propanoic acid. HPLC: 91.3% purity, RT=1.40 min. MS: m/z=339.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

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)piperidine-3-amine and (R)-2-(tert-butoxycarbonylamino)propanoic acid. HPLC: 94.9% purity, RT=0.55 min. MS: m/z=315.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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).

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)piperidine-3-amine and (S)-2-(tert-butoxycarbonylamino)propanoic acid. HPLC: 94.0% purity, RT=0.93 min. MS: m/z=315.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 4.07-3, 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).

Compound 28 (N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(methylamino)acetamide hydrochloride): from 8-((3R,5S )-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 2-(tert-butoxycarbonyl(methyl)amino)acetic acid. HPLC: 98.3% purity, RT=1.21 min. MS: m/z=339.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

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, RT=0.83 min. MS: m/z=315.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , 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) .

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, RT=0.84 min. MS: m/z=327.1 [M+H]⁺.^oneH 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, 13-2.99 (m, 1H), 2.13-1.86 (m, 2H), 1.67-1.27 (m, 6H), 1.06 (d, J=6.4 Hz, 3H).

Compound 31 (1-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)cyclopropanecarboxamide hydrochloride): from 8-((3R,5S)- 3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid. HPLC: 97.5% purity, RT=1.22 min. MS: m/z=351.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 2.08-1.93 (m, 2H), 1.59-1.15 (m, 5H), 0.98 (d, J=6.3 Hz, 3H).

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, RT=0.83 min. MS: m/z=300.9 [M+H]⁺.^oneH 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).

Compound 35 (2-amino-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)acetamide hydrochloride): from 8-((3R,5S)- 3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 2-(tert-butoxycarbonylamino)acetic acid. HPLC: 96.6% purity, RT=1.19 min. MS: m/z=325.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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, 2H), 2.85-2.60 (m, 2H), 2.18-1.95 (m, 2H), 1.27-1.13 ( m, 1H), 0.99 (d, J=6.4 Hz, 3H).

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, RT=1.54 min. MS: m/z=367.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.10 (d, J=8.4 Hz, 1H), 7.28 ( d, J=8.5 Hz, 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).

Compound 103 ((2S)-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 (S)-2-(ethyl(methyl)amino)propanoic acid. HPLC: 97.8% purity, RT=2.07 min. MS: m/z=367.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94-8.90 (m, 2H), 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).

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-butoxycarbonylamino)- 3-methylbutanoic acid. HPLC: 94.0% purity, RT=0.90 min. MS: m/z=343.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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=11.5 Hz, 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).

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-butoxycarbonylamino)- 3-methylbutanoic acid. HPLC: 97.6% purity, RT=1.65 min. MS: m/z=343.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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=6.0 Hz , 1H), 2.95-2.84 (m, 1H), 2.79 (t, J=12.1 Hz, 1H), 2.17-1.85 (m, 3H), 1.30 ( e, J=12.0 Hz, 1H), 1.07-0.9 (m, 9H).

Compound 106 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-hydroxypropanamide): from 8-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid. HPLC: 92.4% purity, RT=0.93 min. MS: m/z=355.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89-9.11 (m, 2H), 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).

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-butoxycarbonylamino)- 3-hydroxypropanoic acid. HPLC: 95.0% purity, RT=0.96 min. MS: m/z=331.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

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)quinoxalin-5-carbonitrile and (S)-2-(tert-butoxycarbonylamino)-3-(pyridine-3- yl) propanoic acid. HPLC: 98.2% purity, RT=6.08 min. MS: m/z=416.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.82 (m, 2H), 8.38 (dt, J=3.0, 1.5 Hz, 2H), 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, 2H), 2.70-2.49 (m, 2H), 1.97 (br.s , 1H), 1.82-1.77 (m, 1H), 1.06-0.87 (m, 4H).

Compound 117 ((2S)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-phenylacetamide): from 8-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and (S)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid. HPLC: 99.9% purity, RT=1.66 min. MS: m/z=401.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , 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).

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 (S)-2- (tert-butoxycarbonylamino)-3-(pyridin-3-yl)propanoic acid. HPLC: 98.4% purity, RT=1.79 min. MS: m/z=392.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 7.72-7.68 (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, 2H), 2.80-2.58 (m, 2H), 2.00-1 .74 (m, 2H), 1.12-0.85 (m, 4H).

Compound 119 ((2R)-2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-phenylacetamide): from 8-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and (R)-2-(tert-butoxycarbonylamino)-2-phenylacetic acid. HPLC: 97.3% purity, RT=1.87 min. MS: m/z=401.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

Compound 128 (3-amino-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)piperidine-3-amine and 3-((tert-butoxycarbonyl)amino)oxetane-3-carboxylic acid . HPLC: 97.4% purity, RT=0.79 min. MS: m/z=343.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

Compound 129 (3-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]oxetan-3-carboxamide): from 3-(tert-butoxycarbonylamino )oxetan-3-carboxylic acid; and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.0% purity, RT=1.05 min. MS: m/z=367.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.97-8.86 (m, 2H), 8.10 (dt, J=8.6, 2.3 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 4.39-4.09 (m, 4H), 3.99-3.74 (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, 2.0 Hz, 3H).

Compound 268 (2-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-cyclopropylacetamide): from 2-(tert-butoxycarbonylamino) -2-cyclopropylacetic acid; and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: purity 47.7+47.3%, RT=2.04+2.17 min. MS: m/z=365.2 [M+H] ⁺ . ¹ H 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, 2H), 1.15-1.01 (m, 1H), 0.96 (d, J=6.6 Hz, 3H), 0.72-0.50 (m, 3H), 0.37 (s, 1H).

Compound 277 (4-amino-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): from 4-(tert- butoxycarbonylamino)-3,3-dimethylbutanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 93.8% purity, RT=2.08 min. MS: m/z=381.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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, 2H), 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)

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

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

((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 obtained 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 give N-[(1R)-3-(dimethylsulfanyl)-1-[[(3R,5S)-5-methyl-1-[pyrido[2,3-b]pyrazine- 8-yl]piperidin-3-yl]carbamoyl]propyl]carbamate as a brown solid (3.10 g, crude). The crude material was used directly in the next step without further purification.

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 obtained 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%-80% gradient over 45 min) to give 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 a yellow solid (270 mg, 5% for 3 stages).

(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-oxopyrrolidine -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) dropwise at room temperature. The resulting solution was stirred for 2 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated in vacuo. 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: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 80% gradient over 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 a brown solid (30 mg, 32%).

Compound 42: HPLC: 96.0% pure, RT=1.84 min. MS: m/z=327.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , 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)

(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 preparative HPLC under the following conditions: Column , XBridge C18 OBD Prep Column, 5 µm, 19 mm × 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 25% - 75% gradient over 10 min; Detector UV 254 nm. (2R,6S)-2,6-dimethyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine was obtained as a yellow solid (30 mg, 21%).

Compound 43: HPLC: 99.0% pure, RT=0.93 min. MS: m/z=245.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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, 2H), 3.97-3, 83 (m, 2H), 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)

8-((2R,6S)-2,6-dimethylmorpholino)quinoxaline-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 Column, 5 µm, 19 mm x 250 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 80% gradient over 10 min; Detector UV 254 nm. 8-[(2R,6S)-2,6-dimethylmorpholin-4-yl]quinoxalin-5-carbonitrile was obtained as a yellow solid (30 mg, 39%).

Compound 44: HPLC: 98.0% pure, RT=1.30 min. MS: m/z=269.2 [M+H] ⁺ . ¹ H 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, 2H), 3.91-3.79 ( m, 2H), 2.75-2.61 (m, 2H), 1.14 (d, J=6.2 Hz, 6H).

The following compound was synthesized in a similar manner:

Compound 45 ((2S,6R)-2,6-dimethyl-4-(quinolin-4-yl)morpholine): from 4-chloroquinoline and (2R,6S)-2,6-dimethylmorpholine. HPLC: 99.9% purity, RT=1.33 min. MS: m/z=243.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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, 2H), 3.47 (d, J=11.7 Hz, 2H), 2.64-2, 50 (m, 2H), 1.21 (dd, J=6.3, 1.1 Hz, 6H).

Example 17: Synthesis of compound 46 ((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: (2S,6R)-4-(1,2 -dimethyl-1H- pyrrolo [2,3-b]pyridin-4-yl)-2,6-dimethylmorpholine was obtained 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 × 250 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 25% - 70% gradient over 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 a white solid (32 mg, 12%) .

Compound 46: HPLC: 95.0% pure, RT=1.88 min. MS: m/z=260.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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 )

(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 mmol) in ethanol (25 ml) was added successively a solution of NH ₃ in MeOH (25 ml, 7M, 175 mmol) and NH _3. H ₂ O (28%, 14.8 mol/l, 53 ml, 0.78 mol). The resulting solution was stirred for 16 hours at room temperature. When the reaction was completed, the reaction mixture was concentrated under reduced pressure to obtain (2R)-1-amino-3-(benzyloxy)propan-2-ol as a colorless oil (6.2 g, crude product).

(R)-1-amino-3-(benzyloxy)propan-2-ol: To a solution of (2R)-1-amino-3-(benzyloxy)propan-2-ol (6.20 g, crude) in ethanol ( 50 ml) was added methyl (2S)-2-chloropropanoate (3.33 g, 54.42 mmol) 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%-50% gradient) to give (2S)-N-[(2R)-3-( benzyloxy)-2-hydroxypropyl]-2-chloropropanamide as a light yellow oil (5.65 g, 65% for 2 steps).

(2R,6R)-6-(benzyloxymethyl)-2-methylmorpholin-3-one: To a solution of (2S)-N-[(2R)-3-(benzyloxy)-2-hydroxypropyl]-2-chloropropanamide (4, 12 g, 15.18 mmol) in tetrahydrofuran (30 ml) was added sodium hydride (1.02 g, 42.50 mmol) in portions at room temperature. The resulting mixture was stirred for 2 hours at room temperature. When the reaction was complete, it was quenched by the slow addition of water (30 ml). The mixture was extracted with ethyl acetate (100 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in petroleum ether (0%-100% gradient) to give (2R,6R)-6-[(benzyloxy)methyl]-2-methylmorpholine-3 -one as a light yellow oil (2.68 g, 75%).

(2R,6R)-2-(benzyloxymethyl)-6-methylmorpholine: To a solution of (2R,6R)-6-[(benzyloxy)methyl]-2-methylmorpholin-3-one (5.40 g, 22.93 mmol ) in tetrahydrofuran (50 ml) was added LiAlH ₄ (2.00 g, 52.56 mmol) in portions at room temperature. The resulting mixture was stirred for 2 hours at room temperature. When the reaction was complete, it was quenched by adding water (40 ml). The resulting mixture was extracted with ethyl acetate (100 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give (2R,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine as a light yellow oil (5.40 g, crude).

((2R,6R)-6-methylmorpholin-2-yl)methanol:at -78°C to a solution of (2R,6R)-2-[(benzyloxy)methyl]-6-methylmorpholine (1.00 g, crude) in dichloromethane (20 ml) was added a solution of BBr₃ in dichloromethane (5 ml, 3 M, 15.00 mmol) dropwise over 10 minutes. The resulting solution was then stirred for 3 hours at -78°C. When the reaction was complete, it was quenched by the slow addition of NaOH solution (1M, 15 ml). The resulting mixture was extracted with dichloromethane (60 ml×3) and the organic phases were combined, washed with brine and dried over Na₂SO_four. The solvent was removed under reduced pressure to give [(2R,6R)-6-methylmorpholin-2-yl]methanol as a white solid (500 mg, crude).

((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 obtained 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%-50% gradient) to give [(2R,6R)-6-methyl-4-[pyrido[2,3 -b]pyrazin-8-yl]morpholin-2-yl]methanol as a yellow oil (2.00 g, 28% for 3 steps).

Method T

((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 mmol) in N,N-dimethylformamide (30 ml) was added sodium hydride (203 mg, 8.45 mmol) in portions. The resulting mixture was stirred for 10 minutes at 5°C and then a solution of 4-methylbenzene-1-sulfonyl chloride (926 mg, 4.86 mmol) in dichloromethane (3 ml) was added dropwise over 5 minutes. The reaction mixture was then stirred for 8 hours at room temperature. When the reaction was complete, it was quenched by adding water (50 ml). The mixture was extracted with ethyl acetate (100 mL×3) and the organic phases were combined, washed with brine and dried over Na₂SO_four. The solvent was removed under reduced pressure to give [(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]methyl 4-methylbenzene-1-sulfonate in as a yellow solid (600 mg, crude).

Way U

(2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine: To 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, crude) in N,N-dimethylformamide (5 ml) was added 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×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: SunFire Prep C18 OBD Column, 19x150mm 5µm 10nm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 25% - 75% gradient over 10 min; Detector UV 254nm. (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 2 stages).

Compound 47: HPLC: 94.7% pure, RT=1.41 min. MS: m/z=343.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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 ( e, 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-yl)morpholine)

(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 obtained from ((2R,6R)-6-methyl-4-(pyrido[2,3-b ]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and t-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 Column, 5 µm, 19 mm × 150 mm; Mobile phase: MeOH in water (with 0.02% v/v HCl), 3% - 8% gradient over 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 a light brown solid (15 mg, 22% for 2 stages).

Compound 48: HPLC: 99.5% pure, RT=0.92 min. MS: m/z=329.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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)

(2R,6S)-2-methyl-6-(piperazin-1-ylmethyl)-4-(quinolin-5-yl)morpholine: (2R,6S)-2-methyl-6-(piperazin-1-ylmethyl) -4-(quinolin-5-yl)morpholine was obtained 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 Column, 5 µm, 19 mm x 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 80% gradient over 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).

Compound 49: HPLC: 95.1% pure, RT=0.53 min. MS: m/z=327.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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)

8-((2R,6S)-2-methyl-6-((4-methylpiperazin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile hydrochloride: 8-((2R,6S)-2-methyl-6 -((4-methylpiperazin-1-yl)methyl) morpholino )quinoxalin-5-carbonitrile hydrochloride was obtained from ((2R,6R)-6-methylmorpholin-2-yl)methanol, 8-bromoquinoxalin-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 Column, 5 µm, 19 mm x 150 mm; Mobile phase: MeOH in water (with 0.02% v/v HCl), 15% - 40% gradient over 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 a black solid (50 mg, 20% for 3 steps ).

Compound 50: HPLC: 98.5% pure, RT=1.48 min. MS: m/z=367.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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)

(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 obtained 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 Column, 5 µm, 19 mm x 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 20% - 40% gradient over 8 min; Detector UV 254 nm. 4-[(2R,6S)-2-methyl-6-[(4-methylpiperazin-1-yl)methyl]morpholin-4-yl]quinoline was obtained as a light brown solid (45 mg, 55%).

Compound 51: HPLC: 99.9% pure, RT=1.10 min. MS: m/z=341.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

The following compounds were synthesized in a similar manner:

Compound 52 ((2R,6S)-2-methyl-6-((4-propylpiperazin-1-yl)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-propylpiperazine. HPLC: 96.3% purity, RT=0.99 min. MS: m/z=371.30 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 4.11-3.83 (m, 2H), 2.88-2.25 (m, 14H), 1.62-1.43 (m, 2H), 1.23 ( e, J=6.2 Hz, 3H), 0.90 (t, J=7.4 Hz, 3H).

Compound 53 ((2S,6R)-2-(((S)-3,4-dimethylpiperazin-1-yl)methyl)-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 (S)-1, 2-dimethylpiperazine hydrochloride. HPLC: 97.8% purity, RT=0.86 min. MS: m/z=357.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

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, RT=1.63 min. MS: m/z=371.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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=6.3Hz, 3H), 1 .08 (s, 6H).

Compound 55 4-amine): from ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl 4-methylbenzenesulfonate and N,N-dimethylpiperidine -4-amines. HPLC: 93.3% purity, RT=0.83 min. MS: m/z=371.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 4.64-4.52 (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), 2.35-1.99 (m, 9H), 1.92-1.78 (m, 2H) , 1.63-1.49 (m, 2H), 1.23 (d, J=6.2 Hz, 3H).

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, RT=0.90 min. MS: m/z=397.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 3.04-2.91 (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).

Compound 57 (8-((2R,6S)-2-methyl-6-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)morpholino)quinoxaline-5-carbonitrile): ,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate and 4-(pyrrolidin-1-yl)piperidine. HPLC: 97.4% purity, RT=2.24 min. MS: m/z=421.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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=6.2 Hz, 3H).

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, RT=1.11 min. MS: m/z=411.3 [M+H]⁺.^oneH 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, 2H), 3.25-2.97 (m, 2H), 2.86-2.72 (m, 2H), 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).

Compound 59 (8-((2S,6R)-2-(1,4'-bipiperidin-1'-ylmethyl)-6-methylmorpholino)quinoxaline-5-carbonitrile): 8-cyanoquinoxalin-5-yl)-6-methylmorpholin-2-yl)methyl 4-methylbenzenesulfonate and 1,4'-bipiperidine. HPLC: 98.8% purity, RT=0.72 min. MS: m/z=435.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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).

Compound 60 ((2R,6S)-2-methyl-6-((4-morpholinopiperidin-1-yl)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 4-(piperidin-4-yl)morpholine. HPLC: 96.3% purity, RT=1.85 min. MS: m/z=413.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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=6.2 Hz, 3H).

Compound 467 (8-[(2R,6S)-2-methyl-6-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}morpholin-4-yl]quinoxalin-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, RT=1.46 min. MS: m/z=437.3 [M+H]⁺.^oneH NMR (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 , 2H), 2.64-2.45 (m, 6H), 2.28-2.07 (m, 3H), 1.93 (d, J=9.9 Hz, 2H), 1.66- 1.54 (m, 2H), 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)piperidine -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: N-(1-(((2S,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl)piperidin-4-yl)isobutyramide was obtained from tert-butyl 4-aminopiperidin-1-carboxylate, isobutyric acid, and ((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methyl trifluoromethanesulfonate using Methods J, Q and U. 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: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 80% gradient over 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%).

Compound 61: HPLC: 96.6% pure, RT=1.21 min. MS: m/z=413.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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, 2H), 1.65-1.45 (m, 2H), 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)

1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid: To a solution of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (1.19 g, 4.87 mmol) in methanol (24 ml) and tetrahydrofuran ( 24 ml) was added a solution of LiOH (599 mg, 24.99 mmol) in water (8 ml) at room temperature. The resulting mixture was stirred for 15 hours at room temperature. When the reaction was complete, the pH of the reaction mixture was adjusted to 2 with a solution of hydrogen chloride (1 M). The resulting mixture was extracted with ethyl acetate (200 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid as a white solid (1.10 g, 84%). MS: m/z=128.0 [MH] ⁺ .

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-carboxamide was obtained 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 Methods J, Q and U. 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: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 80% gradient over 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 in as a yellow solid (20 mg, 10%).

Compound 62: HPLC: 90.4% pure, RT=1.11 min. MS: m/z=399.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 2.86- 2.72 (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)

(2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholine-2-carboxylic acid: at 10°C to 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 acetate (234 mg, 0.73 mmol) and TEMPO (11 mg, 0.07 mmol). The resulting solution was stirred for 30 minutes at 10°C and then warmed to room temperature and stirred for another 17 hours at room temperature. When the reaction was complete, it was quenched with a saturated solution of Na ₂ S ₂ O ₄ (2.5 ml). The pH of the mixture was adjusted to 9 with sodium hydroxide solution (1 M). The resulting mixture was washed with water (5 ml×3) and the combined aqueous phases were diluted with BuOH (10 ml). The pH of the aqueous solution was adjusted to 5 with H ₂ SO ₄ (5 M) and the resulting solution was extracted with BuOH (10 mL×3). The organic phases were combined and concentrated under reduced pressure to give (2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholine-2-carboxylic acid as a yellow solid (76 mg, crude product). MS: m/z=275.0 [MH] ⁺ . The crude product was used in the next step without further purification.

(3-aminoazetidin-1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanone: (3-aminoazetidine- 1-yl)((2R,6R)-6-methyl-4-(pyrido[2,3-b]pyrazin-8-yl)morpholin-2-yl)methanone was obtained from (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 Column, 5 µm, 19 mm × 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30%-70% gradient over 10 min; Detector UV 254 nm. 1-[[(2R,6R)-6-methyl-4-[pyrido[2,3-b]pyrazin-8-yl]morpholin-2-yl]carbonyl]azetidine-3-amine was obtained as light yellow solids (15 mg, 6%).

Compound 63: HPLC: 98.5% pure, RT=0.86 min. MS: m/z=329.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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).

The following compounds were synthesized in a similar manner:

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, RT=0.96 min. MS: m/z=357.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 3.06-2.79 (m, 3H), 2 .70-2.52 (m, 2H), 1.9-1.72 (m, 2H), 1.65-1.53 (m, 2H), 1.33 (d, J=6.2 Hz , 3H).

Compound 65 ((2R,6R)-6-methyl-N-(1-methylpiperidin-4-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 1-methylpiperidine-4-amine. HPLC: 95.8% purity, RT=1.00 min. MS: m/z=371.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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), 3.87-3.68 (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).

Compound 468 ((2R,6R)-4-(8-cyanoquinoxalin-5-yl)-6-methyl-N-(1-methylpiperidin-4-yl)morpholine-2-carboxamide): from (2R,6R)- 4-(8-cyanoquinoxalin-5-yl)-6-methylmorpholine-2-carboxylic acid and 1-methylpiperidin-4-amine. HPLC: 98.0% purity, RT=1.19 min. MS: m/z=395.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.96 (dd, J=17.8.1.7 Hz, 2H), 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, 2H), 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, 2H), 1.74-1.58 (m, 2H), 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)

tert-Butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate: At room temperature to 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 mol), K ₃ PO ₄ (2.19 g, 10.29 mmol), Pd ₂ (dba) ₃ CHCl ₃ (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×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-14% gradient) to give t-butyl N-[(3R,5S)-5-methyl-1-[8- (trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate as a yellow solid (1.10 g, 77%). MS: m/z=410.2 [M+H] ⁺ .

(3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine: At room temperature, to 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 solution of hydrogen chloride in 1,4-dioxane (5 ml, 4M). The resulting solution was stirred for 1 hour at room temperature. When the reaction was completed, 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 Column, 150 mm, 5 μm, 13 nm; mobile phase: acetonitrile in water (with 0.05% NH ₄ OH), 30% - 60% gradient over 10 min; detector UV 254 nm. (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine was obtained as a light yellow solid (500 mg, 83%).

Compound 66: HPLC: 99.7% pure, RT=3.18 min. MS: m/z=310.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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)

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

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

5-bromo-8-methoxyquinoxaline: To a solution of 5-methoxyquinoxaline (3.02 g, 18.86 mmol) in toluene (100 ml) and acetonitrile (100 ml) was added NBS (5.04 g, 28.29 mmol) 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 x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-100% gradient) to give 5-bromo-8-methoxyquinoxaline as a yellow solid (4.23 g, 94%) . MS: m/z=238.8 [M+H] ⁺ .

tert-Butyl N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamate: To a solution of 5-bromo-8-methoxyquinoxaline (1.92 g, 8 .04 mmol) in DMF (30 ml) was added tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (1.52 g, 7.09 mmol), K ₃ PO ₄ (5 .13 g, 24.17 mmol), Pd ₂ (dba) ₃ CHCl ₃ (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 x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-100% gradient) to give t-butyl N-[(3R,5S)-1-(8-methoxyquinoxaline-5- yl)-5-methylpiperidin-3-yl]carbamate as a dark red oil (1.11 g, 37%). MS: m/z=373.1 [M+H] ⁺ .

(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine: To 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 a solution of hydrogen chloride in dioxane (4 M, 30 ml) at room temperature. The resulting solution was then stirred for 1 hour at room temperature. When the reaction was complete, it was quenched by adding H ₂ O (50 ml). The resulting mixture was then adjusted to pH 8 with saturated sodium bicarbonate solution. The mixture was extracted with DCM (100 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine as a dark red oil (180 mg, 57%). MS: m/z=273.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , 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 , 2H), 0.91 (d, J=6.3 Hz, 3H), 0.79 (sq., J=12.0 Hz, 1H).

(3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine: To a solution of (3R,5S)-1-(8-methoxyquinoxalin-5 -yl)-5-methylpiperidin-3-amine (90 mg, 0.33 mmol) in acetoneitrile (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 quenched by adding water (50 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge BEH130 Prep C18 OBD Column, 150 mm, 5 µm, 13 nm; mobile phase: acetonitrile in water (with 0.05% NH ₄ OH), 35% - 65% gradient over 10 min; detector UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine was obtained as a yellow syrup (38 mg, 32%).

Compound 67: HPLC: 92.7% pure, RT=0.99 min. MS: m/z=331.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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, 2H), 2.41-2.29 (m, 2H), 2.20-2.04 (m, 2H), 1.04-0.87 (m, 4H).

The following compounds were synthesized in a similar manner:

Compound 201 ((2R)-2-hydroxy-N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3-methylbutanamide): from (S) -2-hydroxy-3-methylbutanoic acid; and (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: 97.9% purity, RT=1.12 min. MS: m/z=373.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.99-8.85 (m, 2H), 7.61 (d, J=8.3 Hz, 1H), 7.22 -7.12 (m, 2H), 5.29 (d, J=5.8 Hz, 1H), 4.04 (s, 1H), 3.93 (s, 3H), 3.69-3, 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).

Compound 202 (N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): from 3,3-dimethylbutanoic acid and (3R ,5S)-1-(8-Methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: 98.8% purity, RT=1.33 min. MS: m/z=371.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.98-8.82 (m, 2H), 7.70 (d, J=7.8 Hz, 1H), 7.22- 7.12 (m, 2H), 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).

Compound 203 (2-(dimethylamino)-N-[(3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide): from 2-(dimethylamino)acetic acid and (3R,5S)-1-(8-methoxyquinoxalin-5-yl)-5-methylpiperidin-3-amine. HPLC: 98.3% purity, RT=1.92 min. MS: m/z=371.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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)

tert-Butyl (3R,5S)-5-methyl-1-(quinolin-5-yl)piperidin-3-ylcarbamate: To a solution of tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl] carbamate (4.75 g, 22.16 mmol) in DMF (50 ml) was added 5-bromoquinoline (5.07 g, 24.38 mmol), K ₃ PO ₄ (14.16 g, 66.73 mmol), Davephos (1.75 g, 4.44 mmol) and Pd ₂ (dba) ₃ .CHCl ₃ (2.30 g, 2.22 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 (50 ml). The resulting mixture was extracted with ethyl acetate (100 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-20% gradient) to give t-butyl N-[(3R,5S)-5-methyl-1-(quinoline- 5-yl)piperidin-3-yl]carbamate as a yellow solid (4.00 g, 53%). MS: m/z=342.1 [M+H] ⁺ .

tert-Butyl N-[(3R,5S)-1-(8-iodoquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate: To 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) NIS (2.76 g, 12.25 mmol) was added at room temperature. The resulting solution was then stirred for 16 hours at room temperature. When the reaction was complete, it was quenched by adding water (30 ml). The resulting mixture was extracted with ethyl acetate (60 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-35% gradient) to give t-butyl N-[(3R,5S)-1-(8-iodoquinoline-5- yl)-5-methylpiperidin-3-yl]carbamate as a yellow solid (4.30 g, 83%). MS: m/z=468.1 [M+H] ⁺ .

tert-Butyl N-[(3R,5S)-1-(8-ethenylquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate: To 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) was added Pd(PPh ₃ ) 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 x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-17% gradient) to give t-butyl N-[(3R,5S)-1-(8-ethenylquinoline-5- yl)-5-methylpiperidin-3-yl]carbamate as a yellow solid (2.20 g, 68%). MS: m/z=368.2 [M+H] ⁺ .

tert-Butyl N-[(3R,5S)-1-(8-formylquinolin-5-yl)-5-methylpiperidin-3-yl]carbamate: To 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 OsO ₄ (145 mg, 0.57 mmol), NaIO ₄ (4.86 g, 22.74 mmol) and water (14 ml) at room temperature. The reaction mixture was stirred for 14 hours at room temperature. When the reaction was complete, it was quenched by adding a saturated solution of Na ₂ S ₂ O ₃ (20 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . 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] ⁺ .

tert-Butyl N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]carbamate: To 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) BAST (1.37 g, 6.18 mmol) was added at room temperature. The resulting solution was stirred for 3 hours at room temperature. When the reaction was complete, it was quenched by adding saturated sodium bicarbonate solution (30 ml). The resulting mixture was extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-17% gradient) to give t-butyl N-[(3R,5S)-1-[8-(difluoromethyl)quinoline -5-yl]-5-methylpiperidin-3-yl]carbamate as a yellow solid (400 mg, 50%). MS: m/z=392.2 [M+H] ⁺ .

(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine: To 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 2 hours at room temperature. When the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with DCM (20 ml×3) and the organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . 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 Column, 150 mm, 5 μm, 13 nm; mobile phase: acetonitrile in water (with 0.05% NH ₄ OH), 45% - 75% gradient over 10 min; detector UV 254 nm. (3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine was obtained as a yellow oil (20 mg, 57%).

Compound 68: HPLC: 97.3% pure, RT=1.34 min. MS: m/z=292.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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 .52-3.42 (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):

5-Cyclopropylpyridine-3-amine: To a solution of 5-bromopyridine-3-amine (4.75 g, 27.45 mmol) in dioxane (45 ml) was added cyclopropylboronic acid (4.75 g, 55.30 mmol), Cs ₂ CO ₃ (28 g, 85.67 mmol), tetrakis(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×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-100% gradient) to give 5-cyclopropylpyridine-3-amine as a light brown oil (2.08 g, 56% ). MS: m/z=135.0 [M+H] ⁺ .

tert-Butyl N-(5-cyclopropylpyridin-3-yl)carbamate: at 0°C to a solution of 5-cyclopropylpyridin-3-amine (2.08 g, 15.49 mmol) in tetrahydrofuran (30 ml) was added a solution of NaHMDS ( 6.84 g, 37.30 mmol) in tetrahydrofuran (20 ml) dropwise over 10 minutes. The resulting solution was stirred for 1 hour at 0°C and then a solution of di-tert-butyl dicarbonate (4.85 g, 22.20 mmol) in tetrahydrofuran (25 ml) was added dropwise. The resulting mixture was stirred for an additional 2 hours at room temperature. When the reaction was complete, it was quenched by adding a saturated solution of NH ₄ Cl (100 ml). The resulting mixture was extracted with ethyl acetate (100 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in EtOAc (0%-80% gradient) to give t-butyl N-(5-cyclopropylpyridin-3-yl)carbamate as a white solid ( 2.52 g, 69%). MS: m/z=235.0 [M+H] ⁺ .

tert-Butyl 5-cyclopropylpiperidin-3-ylcarbamate: To a sealed tube was added tert-butyl N-(5-cyclopropylpyridin-3-yl)carbamate (2.52 g, 10.74 mmol), PtO ₂ (520 mg, 2 .29 mmol), Rh/C (520 mg, 5%) and acetic acid (220 ml) at room temperature under nitrogen. The reaction tube was evacuated and purged with hydrogen. The reaction mixture was then hydrogenated for 24 hours at 70° C. under a hydrogen pressure of 15 atm. 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 H ₂ O (50 ml) and the pH of the mixture was adjusted to 9 with NaOH solution (0.5 mol/l). The resulting mixture was extracted with DCM (150 ml 3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give tert-butyl N-(5-cyclopropylpiperidin-3-yl)carbamate as a white solid (2.47 g, 57%). MS: m/z=241.1 [M+H] ⁺ .

tert-Butyl N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]carbamate: To a solution of 8-bromoquinoxaline-5-carbonitrile (2.47 g, 10.55 mmol) in N ,N-dimethylformamide (25 ml) was added tert-butyl N-(5-cyclopropylpiperidin-3-yl)carbamate (2.10 g, 8.74 mmol) and DIEA (3.14 g, 24.26 mmol) at room temperature. The resulting solution was then stirred for 15 hours at 130°C. After cooling to room temperature, the reaction mixture was quenched by adding water (80 ml). The resulting mixture was extracted with DCM (150 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0%-20% gradient) to give t-butyl N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidine -3-yl]carbamate as a yellow solid (2.80 g, 67%). MS: m/z=394.2 [M+H] ⁺ .

8-(3-amino-5-cyclopropylpiperidin-1-yl)quinoxalin-5-carbonitrile: To a solution of tert-butyl N-[1-(8-cyanoquinoxalin-5-yl)-5-cyclopropylpiperidin-3-yl]carbamate (850 mg, 2.16 mmol) in methanol (15 ml) was added a solution of hydrogen chloride in dioxane (4 M, 4 ml). The resulting solution was stirred for 1 hour at 40°C. When the reaction was complete, 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 Column, 150 mm, 5 μm, 13 nm; mobile phase: acetonitrile in water (with 0.05% NH ₄ OH), 30% - 60% gradient over 10 min; detector UV 254 nm. The two enantiomers were then obtained by chiral preparative HPLC separation under the following conditions: column, CHIRALPAK AD-3, 0.46×10 cm, 5 µm; mobile phase: hexane (0.1% DEA) in EtOH, 60% isocratic for 15 min; detector UV 254 nm. 8-[(3S,5S)-3-amino-5-cyclopropylpiperidin-1-yl]quinoxalin-5-carbonitrile was obtained as a yellow solid (78 mg, 12%).

Isomer 1 : HPLC: 99.3% pure, RT=1.44 min. MS: m/z=294.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.87 (dd, J=15.6, 1.8 Hz, 2H), 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, 2H), 2.23 (d, J=11.1 Hz, 1H), 1.28-1.06 (m, 2H), 0.65-0.38 (m, 3H), 0.23-0.11 (m, 2H).

Isomer 2 : HPLC: 99% pure, MS: m/z=294.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.87 (dd, J=15.6, 1.8 Hz, 2H), 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, 2H), 2.23 (d, J=11.1 Hz, 1H), 1.28-1.06 (m, 2H), 0.65-0.38 (m, 3H), 0.23-0.11 (m, 2H).

Example 30: Synthesis of compound 71 (cis-5-(3-Amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile)

Method V

cis-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-carbamic acid tert-butyl ester: 5-bromo-quinolin-8-carbonitrile mixture (500 mg; 2 .15 mmol), cis-3-(boc-amino)-5-(trifluoromethyl)piperidine (691 mg; 2.57 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1 adduct, 1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) with methyl tert-butyl ether (88 mg; 0.11 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1 '-biphenyl (50 mg; 0.11 mmol) and cesium carbonate (1.4 g; 4.3 mmol) in anhydrous tert-butanol (15 ml) were heated under microwave irradiation at 85° C. for 8 hours. The reaction mixture was concentrated under reduced pressure and purified by chromatography eluting with hexane and ethyl acetate to give [1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-carbamic acid tert-butyl ester ( 731 mg; 80%) as a light yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 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 (dtkv., 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: RuPhos Palladacycle 3rd generation palladium complex (Methanesulfonato(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl- 2-yl)palladium(II)) instead of 1st generation RuPhos Palladacycle (chlor(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(II )), THF or dioxane can also be used as a solvent instead of t-butanol, sodium t-butoxide can also be used as a base instead of cesium carbonate, and the reaction temperature can be in the range of 85°C to 100°C)

Cis-5-(3-Amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile: To a solution of tert-butyl ether [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 mmol) 4M in dioxane and the orange solution was stirred at room temperature temperature during the night. 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 in vacuo to give 5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride (571 mg; 94%) as yellow solid.

Compound 71: ¹ H NMR (400 MHz, D ₂ O) 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 ( e, J=12.3 Hz, 1H), 1.81 (sq., J=12.2 Hz, 1H); MS: m/z=321 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

Compound 423 (5-(5-Amino-3,3-difluoro-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride):from 5-bromo-quinoline-8-carbonitrile and (5,5-difluoro-piperidin-3-yl)-carbamic acid tert-butyl ester. HPLC: >99% purity, RT=1.88 min. MS: m/z=289 [M+H]⁺.^oneH 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).

Compound 510 (5,5-Difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine): from 5-bromo-8-trifluoromethyl-quinoline and tert-butyl ether (5,5- difluoro-piperidin-3-yl)-carbamic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). MS: m/z=332 [M+H] ⁺ .

Compound 524 (8-(3-Amino-4-fluoro-piperidin-1-yl)-quinoxalin-5-carbonitrile hydrochloride): from 8-bromo-quinoxaline-5-carbonitrile and tert-butyl 4-fluoro-piperidine-3 -yl)-carbamic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) 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] ⁺ .

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]⁺.^oneH 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 Compound 72 and Compound 73 -amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile):

The title compounds were isolated by chiral supercritical liquid chromatography (SLC) of compound 71. (Column: 2.1×25.0 cm Chiralpak AD-H from Chiral Technologies (West Chester, PA); CO ₂ Co-solvent (Solvent B): Methanol with 0.2% ammonium hydroxide Isocratic method: 20% co-solvent at 80 g/min System pressure: 100 bar Column temperature: 25°C

Isomer 1: ¹ H NMR (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(sq., J=12.1Hz, 1H ). MS: m/z=321 [M+H] ⁺ .

Isomer 2: ¹ H 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(sq., J=12.1Hz, 1H ). MS: m/z=321 [M+H] ⁺ .

Example 32 Synthesis of Compound 74 (5-((3R,5S)-3-Amino-5-methyl-piperidin-1-yl)-quinazolin-8-carbonitrile)

[(3R,5S)-1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-butyl ester: 5-bromo-quinazolin-8-carbonitrile solution ( 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 mmol) in anhydrous ethanol (3 ml) was heated under microwave irradiation at 100°C for 4 hours. The brown solution was concentrated under reduced pressure and purified by chromatography eluting with hexane and ethyl acetate to give [1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-butyl ester ( 270 mg; 86%) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) 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, 2H), 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); MS: m/z=368 [M+H] ⁺ .

5-((3R,5S)-3-Amino-5-methyl-piperidin-1-yl)-quinazolin-8-carbonitrile hydrochloride: To a solution of tert-butyl ether [(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) hydrochloric acid solution (4.6 ml; 18.4 mmol) was added 4M 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 in vacuo to give 5-(3-amino-5-methyl-1-piperidyl)quinazoline-8-carbonitrile hydrochloride (204 mg; 99%) as an orange solid.

Compound 74: ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 2H), 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=12.0Hz, 1H), 0.97(d, J=6.6Hz, 3H) ; MS: m/z=268 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

Compound 457 (5-((3R,5S)-3-Amino-5-methyl-piperidin-1-yl)-quinazolin-8-carbonitrile hydrochloride):from 5-bromo-quinazolin-8-carbonitrile and tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate. HPLC: >99% purity, RT=4.02 min. MS: m/z=368 [M+H]⁺.^oneH 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, 2H), 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).

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, RT=3.62 min. MS: m/z=362 [M+H] ⁺ . ¹ H 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 -3,3-difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile)

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

8-(5-Amino-3,3-difluoro-piperidin-1-yl)-quinoxalin-5-carbonitrile : To a solution of tert-butyl ether {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 (4.0M in dioxane) (3.1 ml; 12.58 mmol) 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 give a racemic mixture of 8-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoxalin-5-carbonitrile hydrochloride (200 mg, 97%) in form of a yellow solid. The 2 enantiomers were separated by chiral SLC (ASH column, methanol, carbon dioxide, 20 min cycle) to give the desired pure chiral compounds.

Isomer 1 : MS: m/z=290 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Isomer 2 : MS: m/z=290 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 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

N-(2-bromo-5-(trifluoromethyl)phenyl)acetamide:at 0°C triethylamine (798 mg, 7.89 mmol) was added to a solution of 2-bromo-5-(trifluoromethyl)aniline (950 mg, 3.96 mmol) in DCM (30 ml), then acetyl chloride (18 mg, 7 .87 mmol) drop by drop. The resulting solution was stirred for 16 hours at room temperature. When the reaction was complete, it was quenched by adding water (100 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na₂SO_four. The solvent was removed under reduced pressure to give N-[2-bromo-5-(trifluoromethyl)phenyl]acetamide as a light yellow solid (1.08 g, 98%). MS: m/z=281.9 [M+H]⁺.

Method 2

N-(6-bromo-2-nitro-3-(trifluoromethyl)phenyl)acetamide: at 0°C to a solution of HNO ₃ (7.5 ml, 68%) in sulfuric acid (12.5 ml, 98%) was added N-[2-bromo-5-(trifluoromethyl)phenyl]acetamide (1.08 g, 3.84 mmol) in portions over 20 minutes. The resulting solution was stirred for 2 hours at 0°C. When the reaction was complete, it was quenched by adding water (50 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by reverse phase flash chromatography eluting with acetonitrile in water (with 0.02% HCl), 0% - 80% gradient over 45 minutes, to give N-[6-bromo-2-nitro -3-(trifluoromethyl)phenyl]acetamide as a yellow solid (445 mg, 32%). MS: m/z=326.9 [M+H] ⁺ .

Method 3

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

Method 4

3-bromo-6-(trifluoromethyl)benzene-1,2-diamine: Fe powder (252 mg, 4.51 mmol) at room temperature. The resulting mixture was then stirred for 3 hours at 50°C. When the reaction was completed, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The pH of the residue was adjusted to 8 with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 3-bromo-6-(trifluoromethyl)benzene-1,2-diamine as a brown solid (143 mg, 84%). MS: m/z=326.9 [M+H] ⁺ .

Method 5

5-bromo-8-(trifluoromethyl)quinoxaline: To a solution of 3-bromo-6-(trifluoromethyl)benzene-1,2-diamine (143 mg, 0.56 mmol) in ethanol (5 ml) was added oxaldehyde (409 mg, 8.18 mmol) at room temperature. The resulting solution was heated to reflux and stirred for 1 hour. When the reaction was complete, 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%). MS: m/z=278.9 [M+H] ⁺ .

(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine: To a solution of 5-bromo-8-(trifluoromethyl)quinoxaline (157 mg, 0.57 mmol ) in DMF (5 ml) was added tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (118 mg, 0.55 mmol), Pd ₂ (dba) ₃ CHCl ₃ (57 mg , 0.06 mmol), K ₃ PO ₄ (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 quenched by adding water (10 ml). The resulting mixture was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-16% gradient) to give t-butyl N-[(3R,5S)-5-methyl-1-[8- (trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]carbamate as a yellow solid (107 mg, 46%). MS: m/z=411.2 [M+H] ⁺ .

Method 6

(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine: To 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 a solution of HCl in dioxane (5 M, 3.1 ml, 15.63 mmol) at room temperature. The resulting solution was stirred for 1 hour at room temperature. When the reaction was complete, the pH of the reaction mixture was adjusted to 7 with saturated sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD Column, 150 mm, 5 μm, 13 nm; mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 48% - 68% gradient over 8 min; detector UV 254 nm. (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine was obtained as a yellow solid (30 mg, 37%).

Compound 77: HPLC: 99.2% pure, RT=0.88 min. MS: m/z=311.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 9.01-8.87 (m, 2H), 8.05 (d, J=8.3 Hz, 1H), 7.26 ( d, J=8.3 Hz, 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)

2-bromo-5-chlorobenzenamine: To a solution of 4-bromo-1-chloro-2-nitrobenzene (2.94 g, 12.43 mmol) in AcOH (50 ml) was added Fe powder (5.67 g, 100.52 mmol) at room temperature. The resulting mixture was stirred for 1 hour at 80°C. When the reaction was completed, the solids present in the reaction mixture were filtered off and the filtrate was concentrated under reduced pressure. The pH of the residue was adjusted to 7-8 with sodium hydroxide solution (2N). The resulting mixture was extracted with ethyl acetate (100 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 5-bromo-2-chloroaniline as a yellow solid (2.06 g, 80%). MS: m/z=207.9 [M+H] ⁺ .

Method 7

5-bromo-8-chloroquinoline: To a solution of 5-bromo-2-chloroaniline (2.06 g, 9.88 mmol) in propane-1,2,3-triol (4.23 g, 45.90 mmol) was added FeSO ₄ .7H ₂ O (520 mg, 1.87 mmol) and sulfuric acid (3 g, 29.67 mmol) 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×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-94% gradient) to give 5-bromo-8-chloroquinoline as a yellow solid (760 mg, 32%). MS: m/z=243.8 [M+H] ⁺ .

(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine: (3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3- the 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 Column , 5 µm, 19 mm × 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 20% - 50% gradient over 10 min; detector UV 254 nm. (3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine was obtained as a light yellow solid (25 mg, 35%).

Compound 78: HPLC: 99.6% pure, RT=0.76 min. MS: m/z=276.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxypropanamide)

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% - 20% gradient) to give tert-butyl N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3 -yl]carbamate as a yellow solid (467 mg, 39%). MS: m/z=371.1 [M+H] ⁺ .

Method 8

tert-butyl (3R,5S)-1-(8-(difluoromethyl)quinoxalin-5-yl)-5-methylpiperidin-3-ylcarbamate: To 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) DAST (1.24 g, 7.66 mmol) was added at room temperature. The resulting solution was stirred for 16 hours at room temperature. When the reaction was complete, it was quenched by adding sodium bicarbonate solution (10%, 30 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-15% gradient) to give t-butyl N-[(3R,5S)-1-[8-(difluoromethyl)quinoxaline -5-yl]-5-methylpiperidin-3-yl]carbamate as a light brown solid (49 mg, 33%). MS: m/z=393.2 [M+H] ⁺ .

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 obtained 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 Column, 5 µm, 19 mm x 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 60% gradient over 10 min; detector UV 254 nm. N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxypropanamide was obtained as a yellow solid (21 mg, 18%).

Compound 79: HPLC: 95.6% pure, RT=1.58 min. MS: m/z=365.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, 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=8.2Hz, 1H), 4.26-3.89(m, 4H), 2.73(t, J=10.8Hz , 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)piperidine-3-amine)

Method 9

(R)-tert-butyl 5,5-dimethyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-ylcarbamate: To 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 quenched by adding water (20 ml). The resulting mixture was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-50% gradient) to give t-butyl N-[(3R)-1-(8-cyanoquinoxalin-5-yl) -5,5-dimethylpiperidin-3-yl]carbamate as a yellow solid (40 mg, 98%). MS: m/z=358.2 [M+H] ⁺ .

(3R)-5,5-dimethyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine: To 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 a solution of HCl in dioxane (4 M, 5 ml, 20 mmol) at room temperature. The resulting solution was stirred for 12 hours at room temperature. When the reaction was complete, 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 Column, 150 mm, 5 μm, 13 nm; mobile phase: acetonitrile in water (with 0.05% NH ₄ OH), 30% - 80% gradient over 10 min; detector UV 254 nm. (3R)-5,5-dimethyl-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine was obtained as a yellow oil (12 mg, 44%).

Compound 80: HPLC: 99.2% pure, RT=0.77 min. MS: m/z=258.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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)

8-[(3R,5S)-3-hydroxy-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile: at 0°C to a solution of 8-[(3R,5S)-3-amino-5-methylpiperidin- 1-yl]quinoxalin-5-carbonitrile (178 mg, 0.67 mmol) in AcOH (5 ml) was added dropwise to a solution of NaNO ₂ (229 mg, 3.33 mmol) in water (1 ml). The resulting solution was stirred for 10 hours at room temperature. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge BEH130 Prep C18 OBD Column, 19×150 mm, 5 µm, 13 nm; mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 80% gradient over 10 min; detector UV 254 nm. 8-[(3R,5S)-3-hydroxy-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile was obtained as a yellow solid (30 mg, 17%).

Compound 81: HPLC: 99.9% pure, RT=1.13 min. MS: m/z=269.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.88 (m, 2H), 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).

Example 39: Synthesis of Compound 82 and Compound 83 -amino-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5-carbonitrile)

Cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5-carbonitrile: cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5- carbonitrile was prepared from 8-bromoquinoxaline-5-carbonitrile and tert-butyl cis-5-(trifluoromethyl)piperidin-3-ylcarbamate using Methods 9 and 6. Cis-8-[3-amino-5-(trifluoromethyl)piperidine-1 -yl]quinoxaline-5-carbonitrile was obtained by preparative HPLC purification under the following conditions: XBridge C18 OBD Prep Column, 5 μm, 19 mm × 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 20% - 50% gradient over 10 min; detector UV 254 nm. HPLC: 99.0% purity, RT=1.21 min. MS: m/z=322.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 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).

8-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5-carbonitrile and 8-[(3S,5R)-3-amino-5-(trifluoromethyl)piperidine- 1-yl]quinoxalin-5-carbonitrile: The two enantiomers of cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5-carbonitrile were obtained by chiral preparative HPLC separation under the following conditions: column, Repaired ADH, 0.46 × 15cm, 5µm; mobile phase: EtOH in hexane (0.1% DEA), 30% isocratic for 20 min; detector UV 254 nm. Separated and received two products.

Isomer 1 : (60 mg, 13%, yellow solid) HPLC: 99.3% pure, RT=1.21 min. MS: m/z=322.0 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 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).

Isomer 2 : (56 mg, 12%, yellow solid) HPLC: 99.2% purity, RT=1.21 min. MS: m/z=322.0 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 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).

The following compounds were synthesized in a similar manner:

Compound 84 (cis-8-(3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile): from 8-chloropyrido[2,3-b]pyrazine and tert-butyl cis-5- (trifluoromethyl)piperidin-3-ylcarbamate. HPLC: 99.1% purity, RT=0.88 min. MS: m/z=298.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.96 (d, J=1.7 Hz, 1H), 8.83 (d, J=1.7 Hz, 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)

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 obtained from cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5-carbonitrile and 3,3 -dimethylbutanoic acid using Method J. The crude product was purified by preparative HPLC under the following conditions: XBridge C18 OBD Prep Column, 5 μm, 19 mm x 150 mm; Mobile phase: MeOH in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 80% gradient over 10 min; detector UV 254 nm. Cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-3,3-dimethylbutanamide was obtained as a yellow solid (50 mg, 45%).

Compound 85: HPLC: 99.3% pure, RT=2.12 min. MS: m/z=420.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 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, 2H), 1.59 (d, J=12.2 Hz, 1H), 1.01 (s , 9H).

The following compounds were synthesized in a similar manner:

Compound 86 (cis-3,3-dimethyl-N-[1-[pyrido[2,3-b]pyrazin-8-yl]-5-(trifluoromethyl)piperidin-3-yl]butanamide):from cis-1-(pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)piperidine-3-amine and 3,3-dimethylbutanoic acid. HPLC: 99.4% purity, RT=1.33 min. MS: m/z=396.2 [M+H]⁺.^oneH 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=12.5 Hz, 1H), 2.13 (s, 2H), 1.78-1.62 (m, 1H), 1.07 (s, 9H).

Compound 222 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-2-(dimethylamino)acetamide): from 2-(dimethylamino)acetic acid and 8 -(cis-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.1% purity, RT=2.57 min. MS: m/z=407.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.10 (d, J=8.3 Hz, 1H), 7.30 ( d, J=8.3 Hz, 1H), 4.58 (d, J=11.3 Hz, 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).

Compound 223 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-2-hydroxyacetamide): from 2-hydroxyacetic acid and cis-8-(3- amino-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile. HPLC: 95.3% purity, RT=1.16 min. MS: m/z=380.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.14 (d, J=8.4 Hz, 1H), 7.33 ( d, J=8.3 Hz, 1H), 4.65-4.54 (m, 1H), 4.36-4.14 (m, 2H), 4.02 (s, 2H), 3.15 -2.88 (m, 3H), 2.32 (d, J=12.9 Hz, 1H), 1.78 (td, J=12.1, 12.1 Hz, 1H).

Compound 228 (cis-N-[1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl]-2-(morpholin-4-yl)acetamide): from 2-(morpholin- 4-yl)acetic acid and 8-(cis-3-amino-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile. HPLC: 90.3% purity, RT=1.73 min. MS: m/z=449.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.09 (d, J=8.3 Hz, 1H), 7.29 ( d, J=8.3 Hz, 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, 12.1 Hz, 1H).

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)quinoxalin-5-carbonitrile. HPLC: 99.4% purity, RT=1.26 min. MS: m/z=462.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.13 (d, J=8.4 Hz, 1H), 7.33 ( d, J=8.4 Hz, 1H), 4.62 (apparent d, J=11.7 Hz, 1H), 4.34-4.16 (m, 2H), 3.17-2.87 ( m, 5H), 2.75-2.45 (m, 8H), 2.39-2.27 (m, 4H), 1.73 (td, J=12.1, 12.1 Hz, 1H) .

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, RT=2.66 min. MS: m/z=448 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J=4.2, 1.7 Hz, 1H), 8.47 (dd, J=8.6, 1, 7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.59 (dd, J=8.6, 4.2 Hz, 1H), 7.13 (dd, J= 8.1, 4.0 Hz, 2H), 4.41 (dtt, J=12.2, 8.4, 4.3 Hz, 1H), 3.84-3.71 (m, 1H), 3 .71 (t, J=4.6 Hz, 4H), 3.63 (ddd, J=11.4, 3.8, 1.9 Hz, 1H), 3.09-2.95 (m, 2H ), 2.94 (t, J=11.2 Hz, 1H), 2.84 (dtkv., J=15.5, 7.6, 4.1 Hz, 1H), 2.64-2.45 (m, 5H), 2.48-2.35 (m, 1H), 1.54 (sq., J=12.2 Hz, 1H).

Compound 426 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-dimethylaminoacetamide): from cis-5-(3-amino- 5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and N,N-dimethylglycine. HPLC: 98.8% purity, RT=2.61 min. MS: m/z=406 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J=4.2, 1.7 Hz, 1H), 8.48 (dd, J=8.6, 1 .7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.59 (dd, J=8.6, 4.2 Hz, 1H), 7.23 (s, 1H ), 7.12 (d, J=7.9 Hz, 1H), 4.41 (dtd, J=15.5, 8.4, 4.2 Hz, 1H), 3.81-3.73 ( m, 1H), 3.63 (d, J=11.1 Hz, 1H), 2.97-2.90 (m, 2H), 2.83 (ddp, J=11.4, 7.6, 3.7 Hz, 1H), 2.54 (t, J=11.1 Hz, 1H), 2.44 (d, J=12.2 Hz, 1H), 2.28 (s, 6H), 1 .55 (sq., J=12.3 Hz, 1H), 1.28-1.24 (m, 1H).

Compound 428 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3,3,3-trifluoropropionamide): from cis-5-( 3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and 3,3,3-trifluoropropionic acid. HPLC: >99% purity, RT=4.03 min. MS: m/z=431 [M+H] ⁺ . ¹ H 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=7.9 Hz, 1H), 7.59 (dd, J=8.6, 4.2 Hz, 1H), 7.11 (d, J =8.0 Hz, 1H), 5.93 (d, J=7.6 Hz, 1H), 4.42 (dtd, J=15.0, 8.6, 8.1, 4.1 Hz, 1H), 3.79 (ddt, J=11.6, 4.1, 1.7 Hz, 1H), 3.62 (ddt, J=11.3, 3.7, 1.5 Hz, 1H) , 3.11 (sq., J=10.5 Hz, 2H), 2.93 (t, J=11.2 Hz, 1H), 2.83 (dsq., J=15.4, 7.6 , 3.9 Hz, 1H), 2.56 (dd, J=11.6, 10.7 Hz, 1H), 2.47 (dt, J=12.6, 4.0 Hz, 1H), 1 .55 (sq., J=12.2 Hz, 1H).

Compound 431 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3,3-dimethylbutyramide):from cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride and 3,3-dimethylbutyric acid. HPLC: >99% purity, RT=4.37 min. MS: m/z=419 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.08 (dd, J=4.2, 1.7 Hz, 1H), 8.48 (dd, J=8.6, 1, 7 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.11 (d, J= 8.0 Hz, 1H), 5.28 (d, J=7.8 Hz, 1H), 4.41 (dddd, J=16.2, 12.4, 8.2, 4.3 Hz, 1H ), 3.79 (dq, J=10.0, 2.2 Hz, 1H), 3.66-3.57 (m, 1H), 2.92 (t, J=11.3 Hz, 1H ), 2.82 (ddq, J=15.5, 7.9, 3.8 Hz, 1H), 2.53-2.36 (m, 2H), 2.05 (d, J=1, 7 Hz, 2H), 1.48 (sq., J=12.2 Hz, 1H), 1.03 (s, 9H).

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.^oneH NMR (400 MHz, DMSO-d₆) δ 9.07 (d, J=4.0 Hz, 1H), 8.61 (d, J=8.7 Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 8.05-7.92 (m, 1H), 7.74 (dd, J=8.3, 3.8 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 4 .41 (s, 2H), 3.47 (dt, J=33.3, 11.5 Hz, 4H), 3.11 (s, 1H), 2.95 (t, J=3.6 Hz, 2H), 2.43 (s, 4H), 2.29 (s, 4H), 2.12 (d, J=2.8 Hz, 3H). MS: m/z=472 [M+H]⁺.

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.^oneH NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J=3.8 Hz, 1H), 8.59 (d, J=8.6 Hz, 1H), 8.12 (d, J=7.8 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.75 (dd, J=8.5, 3.9 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H ), 4.39 (s, 1H), 3.57 (d, J=5.5 Hz, 4H), 3.43 (d, J=13.6 Hz, 3H), 3.08 (d, J =9.7 Hz, 2H), 2.97 (s, 2H), 2.47-2.37 (m, 4H), 2.28 (d, J=15.5 Hz, 1H). MS: m/z=459 [M+H]⁺.

Compound 513 (2-Cyclopropyl-N-[5,5-difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-2-hydroxyacetamide):from cyclopropyl-hydroxyl-acetic acid; and 5,5-difluoro-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine.^oneH NMR (400 MHz, DMSO-d₆) δ 9.05 (dd, J=4.2, 1.6 Hz, 1H), 8.57 (dd, J=8.6, 4.7, 1.8 Hz, 1H), 8.12 ( dd, J=8.1, 2.0 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.73 (ddd, J=8.7, 4.2, 3, 1 Hz, 1H), 7.35 (dd, J=8.0, 4.6 Hz, 1H), 5.56 (d, J=4.4 Hz, 1H), 4.35 (dd, J= 8.8, 4.4 Hz, 1H), 3.65-3.49(m, 2H), 3.49-3.36(m, 2H), 3.01(q, J=9.8 , 8.9 Hz, 1H), 2.48-2.16 (m, 2H), 1.12-1.00 (m, 1H), 1.00-0.85 (m, 1H), 0, 54-0.19 (m, 4H). MS: m/z=430 [M+H]⁺.

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)-quinolin-8-carbonitrile hydrochloride and 2-methyl-2-piperidin-1-yl-propionic acid. HPLC: >99% purity, RT=2.92 min. MS: m/z=474.6 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1, 7 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.33 (d, J=8.1 Hz, 1H) , 4.23-4.11 (m, 1H), 3.59-3.43 (m, 2H), 3.20 (s, 1H), 2.94 (t, J=11.5 Hz, 1H ), 2.75 (t, J=11.1 Hz, 1H), 2.33 (t, J=5.4 Hz, 4H), 2.14-2.06 (m, 1H), 1.76 (q, J=12.2 Hz, 1H), 1.55 (q, J=5.0 Hz, 4H), 1.40 (d, J=6.9 Hz, 2H), 1.06 (d, J=13.1 Hz, 6H).

Compound 577 yl)-acetamide):from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (3,3-Dimethyl-pyrrolidin-1-yl)-acetic acid. HPLC: >99% purity, RT=2.98 min. MS: m/z=460.5 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1, 7 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 3.62-3.47 (m, 2H), 3.21 (s, 1H), 2.93 ( t, J=11.5 Hz, 1H), 2.75 (t, J=11.1 Hz, 1H), 2.66-2.58 (m, 2H), 2.37-2.28 (m , 2H), 2.15 (d, J=12.3 Hz, 1H), 1.71 (q., J=12.3 Hz, 1H), 1.53 (t, J=7.0 Hz, 2H), 1.05 (d, J=1.0 Hz, 6H).

Compound 578 ([(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-amide of 1-cyclopropyl-piperidine-4-carboxylic acid):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, RT=2.77 min. MS: m/z=472.30 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1.7 Hz, 1H) , 8.25 (d, J=8.0 Hz, 1H), 7.91 (d, J=7.3 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 3.62-3.50 (m, 2H), 3.19 (d, J=11.4 Hz, 1H), 2, 93 (td, J=9.6, 7.8, 4.0 Hz, 3H), 2.60 (t, J=11.2 Hz, 1H), 2.23-2.01 (m, 4H) , 1.71-1.37 (m, 6H), 0.38 (dt, J=6.5, 3.2 Hz, 2H), 0.30-0.20 (m, 2H).

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, RT=3.82 min. MS: m/z=476.5 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1, 7 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.4 Hz, 1H), 7.71 (dd, J=8.6, 4.2 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 4.13 (s, 1H), 3.61-3.51 (m, 2H), 3.30 ( d, J=7.0 Hz, 2H), 3.27-3.16 (m, 3H), 2.95 (t, J=11.6 Hz, 1H), 2.60 (t, J=11 .2 Hz, 1H), 2.42-2.27 (m, 3H), 2.18 (d, J=12.2 Hz, 1H), 1.51 (q., J=12.3 Hz, 1H), 1.11 (t, J=7.1 Hz, 3H), 0.96 (t, J=7.1 Hz, 3H).

Compound 584 ):from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (4,4-difluoro-cyclohexyl)-acetic acid. HPLC: >99% purity, RT=4.39 min. MS: m/z=481.5 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.07 (dd, J=4.2, 1.6 Hz, 1H), 8.59 (dd, J=8.6, 1, 7 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 4.15 (s, 1H), 3.62-3.52 (m, 2H), 3.21 ( d, J=11.6 Hz, 1H), 2.95 (t, J=11.6 Hz, 1H), 2.61 (t, J=11.2 Hz, 1H), 2.19 (d, J=12.4Hz, 1H), 2.07-2.02(m, 2H), 1.96(s, 2H), 1.82(s, 2H), 1.71(t, J=11 .1 Hz, 3H), 1.51 (Q, J=12.3 Hz, 1H), 1.19 (dQ, J=11.9, 6.1 Hz, 2H).

Compound 585 (N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethylpiperidin-3-yl]-2-(1-isopropylpiperidin-4-yl) -acetamide): from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile and (1-isopropyl-piperidin-4-yl)-acetic acid. HPLC: >99% purity, RT=2.85 min. MS: m/z=488.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1 .7 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.99 (d, J=7.3 Hz, 1H), 7.72 (dd, J=8.6 , 4.2 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 4.14 (s, 1H), 3.57 (d, J=8.9 Hz, 2H), 3.19 (s, 1H), 2.94 (t, J=11.6 Hz, 1H), 2.69 (s, 2H), 2.66-2.56 (m, 2H), 2.17 (d, J=12.1 Hz, 1H), 2.08-1.97 (m, 4H), 1.65-1.45 (m, 4H), 1.10 (d, J=12.6 Hz, 2H), 0.93 (d, J=6.6 Hz, 6H).

Example 41 Synthesis of Compound 87 and Compound 88 ((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: (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 was obtained 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: XBridge Shield RP18 OBD Column, 19×250 mm 10 µm; mobile phase: acetonitrile in water (0.05% NH ₃ H ₂ O), 30% - 40% gradient over 15 min; detector UV 254 nm. The two diastereomeric isomers of (S)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-(trifluoromethyl)piperidin-3-yl)-2-hydroxy-3-methylbutanamide were then prepared by separation by chiral preparative HPLC under the following conditions: CHIRALPAK AD-3 column, 0.46 x 5 cm, 3 µm; mobile phase: EtOH (0.1% DEA) in hexane, 40% isocratic for 20 min; detector UV 254 nm. Two diastereomeric products were separated and obtained.

Isomer 1 : (54 mg, 18%, yellow solid) HPLC: 98.5% purity, RT=2.58 min. MS: m/z=294.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.93 (d, J=1.8 Hz, 1H), 8.89 (d, J=1.8 Hz, 1H), 8 .11 (d, J=8.3 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.30 -4.09(m, 2H), 3.83(d, J=3.7Hz, 1H), 3.11-2.82(m, 3H), 2.29-2.25(m, 1H ), 2.09-2.03 (m, 1H), 1.81-1.69 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H).

Isomer 2 : (19 mg, 6%, yellow solid) HPLC: 95.7% purity, RT=3.03 min. MS: m/z=422.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.93 (d, J=1.8 Hz, 1H), 8.89 (d, J=1.8 Hz, 1H), 8 .11 (d, J=8.3 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 4.58 (d, J=12.0 Hz, 1H), 4.30 -4.09(m, 2H), 3.83(d, J=3.7Hz, 1H), 3.11-2.82(m, 3H), 2.29-2.25(m, 1H ), 2.09-2.03 (m, 1H), 1.81-1.69 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 89 and compound 90 ((2S)-2-hydroxy-3-methyl-N-[(3R,5S)-1-[pyrido[2,3-b]pyrazin-8-yl]-5-(trifluoromethyl) piperidin-3-yl]butanamide hydrochloride and ((2S)-2-hydroxy-3-methyl-N-[(3S,5R)-1-[pyrido[2,3-b]pyrazin-8-yl]-5 -(trifluoromethyl)piperidin-3-yl]butanamide hydrochloride): from 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, RT=1.42 min MS: m/z=398.1 [M+H] ^{+ 1} H NMR (300 MHz, CD ₃ OD, ppm) δ 9.10-8.95 (m, 2H), 8.63 (d, J=1.5 Hz, 1H), 7.41-7.32 (d, J =5.6 Hz, 1H), 6.12-5.31 (m, 1H), 5.21-4.82 (s, 1H), 4.29-4.19 (m, 1H), 3, 75 (d, J=10.5 Hz, 1H), 3.61-3.52 (m, 1H), 3.41-3.27 (m, 1H), 3.06-2.99 (m, 1H), 2.38-2.20 (m, 1H), 2.15-1.88 (m, 2H), 1.16-1.01 (m, 3H), 0.82-0.93 ( m, 3H) Isomer 2: HPLC: 95.8% purity, RT=0.89 min MS: m/z=398.1 [M+H] ^{+ .1} H NMR (300 MHz, CD ₃ OD, ppm) δ 910-8.95 (m, 2H), 8.63 (d, J=1.5 Hz, 1H), 7.41-7.32 (d, J=5.6 Hz, 1H), 6.12-5.31(m, 1H), 5.21-4.82(s, 1H), 4.29-4.19(m , 1H), 3.75 (d, J=10.5 Hz, 1H), 3.61-3.52 (m, 1H), 3.41-3.27 (m, 1H), 3.06- 2.99 (m, 1H), 2.38-2.20 (m, 1H), 2.15-1.88 (m, 2H), 1.16-1.01 (m, 3H), 0, 82-0.93 (m, 3H).

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)quinoxalin-5-carbonitrile and 3-hydroxy-4,4-dimethylpentanoic acid. Isomer 1: HPLC: 98.0% purity, RT=1.39 min. MS: m/z=396.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.82 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.28 ( d, J=8.5 Hz, 1H), 4.35 (dd, J=28.2, 11.8 Hz, 2H), 4.22-4.08 (m, 1H), 3.69 (dd , J=10.2, 2.6 Hz, 1H), 2.80-2.60 (m, 2H), 2.40 (dd, J=14.2, 2.6 Hz, 1H), 2, 28-2.06 (m, 3H), 1.23 (td, J=12.0, 12.0 Hz, 1H), 1.00 (d, J=6.5 Hz, 3H), 0.92 (s, 9H). Isomer 2: HPLC: 99.3% pure, RT=1.41 min. MS: m/z=396.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.82 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.31 ( d, J=8.4 Hz, 1H), 4.34 (t, J=11.4 Hz, 2H), 4.13 (d, J=12.1 Hz, 1H), 3.68 (dd, J=10.3, 2.6 Hz, 1H), 2.83-2.63 (m, 2H), 2.40 (dd, J=14.1, 2.6 Hz, 1H), 2.29 -2.04 (m, 3H), 1.22 (td, J=12.0, 12.0 Hz, 1H), 1.01 (d, J=6.4 Hz, 3H), 0.92 ( s, 9H).

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]pyrazine-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% pure, RT=1.09 min. MS: m/z=372.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8 .62 (d, J=5.7 Hz, 1H), 7.13 (d, J=5.7 Hz, 1H), 4.67 (t, J=11.0 Hz, 2H), 4.10 -3.98 (m, 1H), 3.66 (dd, J=10.2, 2.6 Hz, 1H), 2.88-2.65 (m, 2H), 2.38 (dd, J =14.2, 2.7 Hz, 1H), 2.26-2.07 (m, 2H), 1.99-1.89 (m, 1H), 1.23 (td, J=12.1 , 12.1 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.89 (s, 9H). Isomer 2: HPLC: 99.3% pure, RT=1.12 min. MS: m/z=372.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8 .62 (d, J=5.7 Hz, 1H), 7.13 (d, J=5.7 Hz, 1H), 4.67 (t, J=11.0 Hz, 2H), 4.10 -3.98 (m, 1H), 3.66 (dd, J=10.2, 2.6 Hz, 1H), 2.88-2.65 (m, 2H), 2.38 (dd, J =14.2, 2.7 Hz, 1H), 2.26-2.07 (m, 2H), 1.99-1.89 (m, 1H), 1.23 (td, J=12.1 , 12.1 Hz, 1H), 0.98 (d, J=6.6 Hz, 3H), 0.89 (s, 9H).

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-methylpiperidine -1-yl)quinoxalin-5-carbonitrile and 3-methylpentanoic acid. Isomer 1: HPLC: 92.2% purity, RT=2.86 min. MS: m/z=366.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.11 (d, J=8.4 Hz, 1H), 7.30 ( d, J=8.4 Hz, 1H), 4.40 (d, J=11.9 Hz, 1H), 4.32 (d, J=12.5 Hz, 1H), 4.22-4, 10 (m, 1H), 2.83-2.63 (m, 2H), 2.23 (dd, J=13.4, 6.1 Hz, 1H), 2.15-1.95 (m, 3H), 1.94-1.84 (m, 1H), 1.47-1.36 (m, 1H), 1.34-1.16 (m, 2H), 1.02 (d, J= 6.4 Hz, 3H), 0.95 (d, J=6.9 Hz, 6H). Isomer 2: HPLC: 90.4% purity, RT=1.54 min. MS: m/z=366.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.11 (d, J=8.4 Hz, 1H), 7.30 ( d, J=8.4 Hz, 1H), 4.40 (d, J=11.9 Hz, 1H), 4.32 (d, J=12.5 Hz, 1H), 4.22-4, 10 (m, 1H), 2.83-2.63 (m, 2H), 2.23 (dd, J=13.4, 6.1 Hz, 1H), 2.15-1.95 (m, 3H), 1.94-1.84 (m, 1H), 1.47-1.36 (m, 1H), 1.34-1.16 (m, 2H), 1.02 (d, J= 6.4 Hz, 3H), 0.95 (d, J=6.9 Hz, 6H).

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, RT=1.23 min. MS: m/z=342.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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), 7.17 (dd, J=5.8, 1.6 Hz, 1H), 4.77-4.65 (m, 2H), 4, 16-4.02 (m, 1H), 2.91-2.72 (m, 2H), 2.25 (dd, J=13.4, 6.1 Hz, 1H), 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, RT=1.23 min. MS: m/z=342.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, 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), 7.17 (dd, J=5.8, 1.6 Hz, 1H), 4.77-4.65 (m, 2H), 4, 16-4.02 (m, 1H), 2.91-2.72 (m, 2H), 2.25 (dd, J=13.4, 6.1 Hz, 1H), 2.16-1, 94 (m, 3H), 1.98-1.82 (m, 1H), 1.50-1.19 (m, 3H), 1.11-0.91 (m, 9H).

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-methylbutanamide): from 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 2-methylbutanoic acid. Isomer 1: HPLC: 92.2% purity, RT=2.41 min. MS: m/z=352.2 [M+H]⁺.^oneH NMR (400 MHz, CD₃OD, ppm) δ 8.95-8.82 (m, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.40-4.24 (m, 2H), 4.20-4.04 (m, 1H), 2.80-2.60 (m, 2H), 2.29-2.16 ( m, 1H), 2.13-1.96 (m, 3H), 1.68-1.32 (m, 2H), 1.35-1.07 (m, 5H), 1.03-0, 86 (m, 6H). Isomer 2: HPLC: 95.1% purity, RT=1.42 min. MS: m/z=342.3 [M+H]⁺.^oneH NMR (400 MHz, CD₃OD, ppm) δ 8.90 (dd, J=13.6, 1.8 Hz, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.40-4.24 (m, 2H), 4.20-4.04 (m, 1H), 2.80-2.60 (m, 2H), 2 .29-2.16 (m, 1H), 2.13-1.96 (m, 3H), 1.68-1.32 (m, 2H), 1.35-1.07 (m, 5H) , 1.03-0.86 (m, 6H).

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, RT=1.11 min. MS: m/z=328.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94 (d, J=1.8 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H), 8 .62 (d, J=6.0 Hz, 1H), 7.21 (d, J=6.0 Hz, 1H), 4.70-4.50 (m, 2H), 4.13-3, 99 (m, 1H), 2.97-2.77 (m, 2H), 2.32-2.15 (m, 1H), 2.14-1.91 (m, 2H), 1.70- 1.54 (m, 1H), 1.51-1.36 (m, 1H), 1.37-1.23 (m, 3H), 1.19-1.00 (m, 6H), 0, 92 (t, J=7.4 Hz, 3H). Isomer 2: HPLC: 91.8% purity, RT=1.11 min. MS: m/z=328.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94 (d, J=1.8 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H), 8 .62 (d, J=6.0 Hz, 1H), 7.21 (d, J=6.0 Hz, 1H), 4.70-4.50 (m, 2H), 4.13-3, 99 (m, 1H), 2.97-2.77 (m, 2H), 2.32-2.15 (m, 1H), 2.14-1.91 (m, 2H), 1.70- 1.54 (m, 1H), 1.51-1.36 (m, 1H), 1.37-1.23 (m, 3H), 1.19-1.00 (m, 6H), 0, 92 (t, J=7.4 Hz, 3H).

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-methylpiperidine -1-yl)quinoxalin-5-carbonitrile and 2-methoxypropanoic acid. Isomer 1: HPLC: 99.6% purity, RT=1.27 min. MS: m/z=354.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.98-8.84 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.28 ( d, J=8.4 Hz, 1H), 4.32-4.10 (m, 3H), 3.75 (sq., J=6.7 Hz, 1H), 3.37 (s, 3H) , 2.89 (dd, J=12.0, 10.4 Hz, 1H), 2.70 (dd, J=12.6, 10.6 Hz, 1H), 2.15-1.99 (m , 2H), 1.41-1.27 (m, 4H), 1.02 (d, J=6.4 Hz, 3H). Isomer 2: HPLC: 96.0% purity, RT=2.60 min. MS: m/z=354.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.96-8.82 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.28 ( d, J=8.4 Hz, 1H), 4.32-4.10 (m, 3H), 3.75 (sq., J=6.7 Hz, 1H), 3.37 (s, 3H) , 2.89 (dd, J=12.0, 10.4 Hz, 1H), 2.70 (dd, J=12.6, 10.6 Hz, 1H), 2.15-1.99 (m , 2H), 1.41-1.27 (m, 4H), 1.02 (d, J=6.4 Hz, 3H).

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, RT=1.27 min. MS: m/z=354.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (d, J=1.8 Hz, 1H), 8.81 (d, J=1.8 Hz, 1H), 8 .65 (d, J=5.6 Hz, 1H), 7.14 (d, J=5.6 Hz, 1H), 4.70-4.54 (m, 2H), 4.10 (tt, J=11.1, 4.2 Hz, 1H), 3.75 (sq., J=6.7 Hz, 1H), 3.37 (s, 3H), 2.96 (dd, J=12, 4, 10.8 Hz, 1H), 2.77 (dd, J=12.9, 11.1 Hz, 1H), 2.13-1.92 (m, 2H), 1.43-1.26 (m, 4H), 1.02 (d, J=6.5 Hz, 3H). Isomer 2: HPLC: 96.0% purity, RT=2.60 min. MS: m/z=354.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (d, J=1.8 Hz, 1H), 8.81 (d, J=1.8 Hz, 1H), 8 .65 (d, J=5.6 Hz, 1H), 7.14 (d, J=5.6 Hz, 1H), 4.70-4.54 (m, 2H), 4.10 (tt, J=11.1, 4.2 Hz, 1H), 3.75 (sq., J=6.7 Hz, 1H), 3.37 (s, 3H), 2.96 (dd, J=12, 4, 10.8 Hz, 1H), 2.77 (dd, J=12.9, 11.1 Hz, 1H), 2.13-1.92 (m, 2H), 1.43-1.26 (m, 4H), 1.02 (d, J=6.5 Hz, 3H).

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)quinoxalin-5-carbonitrile and (S)-2-hydroxy-3-methylbutanoic acid. Isomer 1: HPLC: 94.0% purity, RT=2.52 min. MS: m/z=394.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (d, J=1.8 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H), 8 .05 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 4.34-4.00 (m, 3H), 3.82 (d, J=3.7Hz, 1H), 3.03-2.85(m, 2H), 2.20-1.97(m, 2H), 1.54(square, J=11.6Hz, 1H), 1.22-1.04 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0, 72-0.56 (m, 1H), 0.52-0.38 (m, 2H), 0.18 (dd, J=4.8, 2.9 Hz, 2H). Isomer 2: HPLC: 93.8% purity, RT=2.57 min. MS: m/z=394.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (d, J=1.8 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H), 8 .05 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 4.34-4.00 (m, 3H), 3.82 (d, J=3.7Hz, 1H), 3.03-2.85(m, 2H), 2.20-1.97(m, 2H), 1.54(square, J=11.6Hz, 1H), 1.22-1.04 (m, 1H), 0.99 (d, J=6.9 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H), 0, 72-0.56 (m, 1H), 0.52-0.38 (m, 2H), 0.18 (dd, J=4.8, 2.9 Hz, 2H).

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)-quinolin-8-carbonitrile hydrochloride and (2S)-2-hydroxy-3-methylbutanoic acid. Isomer 1: HPLC: 98.8% purity, RT=3.80 min. MS: m/z=341 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.08 (dd, J=4.2, 1.7 Hz, 1H), 8.48 (dd, J=8.6, 1 .7 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.59 (dd, J=8.6, 4.2 Hz, 1H), 7.12 (d, J =8.0 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 4.41 (dtd, J=16.1, 8.2, 4.2 Hz, 1H), 4 .02 (d, J=3.1 Hz, 1H), 3.82-3.73 (m, 1H), 3.68-3.59 (m, 1H), 2.94 (t, J=11 .3 Hz, 1H), 2.83 (dtd, J=12.0, 8.0, 4.1 Hz, 1H), 2.54 (t, J=11.2 Hz, 1H), 2.44 (d, J=12.6 Hz, 1H), 2.24 (pd, J=6.9, 3.0 Hz, 1H), 1.54 (sq., J=12.3 Hz, 1H), 1.04 (d, J=7.0 Hz, 3H), 0.88 (d, J=6.9 Hz, 3H). Isomer 2: HPLC: >99% purity, RT=3.70 min. MS: m/z=341 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J=4.2, 1.7 Hz, 1H), 8.48 (dd, J=8.6, 1 .7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.13 (d, J =8.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 4.40 (dtt, J=16.3, 8.3, 4.2 Hz, 1H), 4 .03 (d, J=3.0 Hz, 1H), 3.81-3.72 (m, 1H), 3.68-3.60 (m, 1H), 2.93 (t, J=11 .2 Hz, 1H), 2.82 (ddt, J=15.0, 7.5, 3.9 Hz, 1H), 2.54 (t, J=11.1 Hz, 1H), 2.45 (d, J=12.5 Hz, 1H), 2.19 (pd, J=6.9, 3.0 Hz, 1H), 1.56 (sq., J=12.2 Hz, 1H), 1.02 (d, J=7.0 Hz, 3H), 0.80 (d, J=6.9 Hz, 3H).

Compound 437 and Compound 438 ]-amide and (S)-1-ethyl-pyrrolidin-2-carboxylic acid [(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]- amide):from cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and 1-ethyl-l-proline. Isomer 1: HPLC: >99% purity, RT=2.77 min. MS: m/z=446 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J=4.2, 1.7 Hz, 1H), 8.49 (dd, J=8.5, 1, 7 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.54 (d, J= 8.2 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 4.34 (dddd, J=16.3, 12.6, 8.4, 4.3 Hz, 1H ), 3.77-3.69 (m, 1H), 3.67-3.57 (m, 1H), 3.14 (dd, J=8.7, 6.8 Hz, 1H), 3, 05 (dd, J=10.5, 4.3 Hz, 1H), 2.93 (t, J=11.2 Hz, 1H), 2.83 (ddp, J=11.6, 7.8, 3.8 Hz, 1H), 2.71-2.46 (m, 3H), 2.41 (d, J=12.4 Hz, 1H), 2.33 (ddd, J=10.6, 9 .2, 6.0 Hz, 1H), 2.14 (dtd, J=13.0, 9.8, 7.5 Hz, 1H), 1.84-1.69 (m, 2H), 1, 68-1.57 (m, 1H), 1.54-1.46 (m, 1H), 1.10 (t, J=7.2 Hz, 3H). Isomer 2: HPLC: >99% purity, RT=2.79 min. MS: m/z=446 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.09 (dd, J=4.2, 1.7 Hz, 1H), 8.50 (dd, J=8.6, 1, 7 Hz, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.55 (d, J= 8.4 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 4.42-4.29 (m, 1H), 3.82-3.73 (m, 1H), 3.66-3.58 (m, 1H), 3.17 (t, J=7.6 Hz, 1H), 3.03 (dd, J=10.3, 4.4 Hz, 1H), 2 .95 (t, J=11.3 Hz, 1H), 2.82 (ddt, J=15.5, 7.9, 3.8 Hz, 1H), 2.60-2.38 (m, 4H ), 2.38-2.29 (m, 1H), 2.18 (dtd, J=13.0, 10.3, 7.8 Hz, 1H), 1.88 (ddd, J=12.6 , 8.2, 4.0 Hz, 1H), 1.84-1.76 (m, 1H), 1.71 (dd, J=12.7, 5.9 Hz, 1H), 1.54- 1.47 (m, 1H), 1.01 (t, J=7.2 Hz, 3H).

Example 42: Synthesis of Compound 91 and Compound 92 -(-3-((4-hydroxycyclohexyl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxaline-5-carbonitrile)

Method 10

Cis,cis-8-(3-((4-hydroxycyclohexyl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile and cis,trans-8-(3-((4-hydroxycyclohexyl) amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile): To a solution of cis-8-[3-amino-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5-carbonitrile (220 mg, 0.68 mmol) in methanol (5 ml) was added 4-hydroxycyclohexan-1-one (118 mg, 1.03 mmol), NaBH ₃ CN (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 complete, it was quenched by adding a saturated solution of NH ₄ Cl (10 ml). The resulting mixture was extracted with EtOAc (50 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . 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: XBridge Shield RP18 OBD Column, 19×150 mm 10 µm; mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 30% - 45% gradient over 11 min; detector UV 254 nm.

Isomer 1 : (25 mg, 23%, yellow solid) HPLC: 99.4% purity, RT=1.25 min. MS: m/z=420.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.84 (m, 2H), 8.10 (d, J=8.3 Hz, 1H), 7.24 ( d, J=8.3 Hz, 1H), 4.46-4.28 (m, 2H), 3.59-3.44 (m, 1H), 3.24-3.13 (m, 1H) , 3.01-2.93 (m, 1H), 3.01-2.80 (m, 2H), 2.70-2.57 (m, 2H), 2.33 (d, J=12, 5 Hz, 1H), 2.13 (dd, J=9.3, 6.1 Hz, 1H), 2.04-1.87 (m, 3H), 1.49-1.08 (m, 5H ).

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

The following compounds were synthesized in a similar manner:

Compound 93 and compound 94 (cis,cis-4-((1-(pyrido[2,3-b]pyrazin-8-yl)-5-(trifluoromethyl)piperidin-3-yl)amino)cyclohexanol 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, RT=0.98 min. MS: m/z=396.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.94 (d, J=1.7 Hz, 1H), 8.79 (d, J=1.7 Hz, 1H), 8 .69 (d, J=5.5 Hz, 1H), 7.09 (d, J=5.6 Hz, 1H), 4.83-4.63 (m, 2H), 3.59-3, 44 (m, 1H), 3.23-3.00 (m, 2H), 2.84 (dd, J=8.1, 3.9 Hz, 1H), 2.75-2.65 (m, 2H), 2.40-2.28 (m, 1H), 2.18-2.05 (m, 1H), 2.03-1.88 (m, 3H), 1.50-1.42 ( m, 1H), 1.35-1.15 (m, 4H). Isomer 2: NMR (300 MHz, CD ₃ OD, ppm) δ 8.93 (d, J=1.7 Hz, 1H), 8.79 (d, J=1.7 Hz, 1H), 8.69 (d, J=5.5 Hz, 1H), 7.09 (d, J=5.6 Hz, 1H), 4.78-4.69 (m, 2H), 3.88 (d , J=4.6 Hz, 1H), 3.23-2.99 (m, 2H), 2.94-2.67 (m, 3H), 2.36 (dd, J=12.2, 4 .2 Hz, 1H), 1.83-1.73 (m, 3H), 1.71-1.53 (m, 5H), 1.53-1.37 (m, 1H).

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

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, RT=1.33 min. MS: m/z=394.1 [M+H]⁺.^oneH NMR (300 MHz, CD₃OD, ppm) δ 8.94 (d, J=1.8 Hz, 1H), 8.80 (d, J=1.8 Hz, 1H), 8.70 (d, J=5, 6 Hz, 1H), 7.11 (d, J=5.6 Hz, 1H), 4.82-4.68 (m, 2H), 3.12-2.69 (m, 6H), 2, 49-2.31 (m, 3H), 1.50-1.38 (m, 1H).

Compound 135 and compound 136 (cis-8-((3R,5S)-3-((4-hydroxycyclohexyl)amino)-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and trans-8-((3R, 5S)-3-((4-hydroxycyclohexyl)amino)-5-methylpiperidin-1-yl)quinoxalin-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, RT=1.07 min. MS: m/z=366.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.7 Hz, 1H), 8 .07 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 4.63 (dd, J=13.4, 3.8 Hz, 1H) , 4.04-3.95 (m, 1H), 3.54 (tt, J=10.7, 4.0 Hz, 1H), 3.24-3.11 (m, 1H), 2.74 -2.49 (m, 3H), 2.22-2.08 (m, 2H), 2.06-1.89 (m, 4H), 1.41-1.11 (m, 4H), 1 .09-0.95 (m, 4H). Isomer 2: HPLC: 93.0% purity, RT=1.12 min. MS: m/z=366.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.8 Hz, 1H), 8 .08 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 4.69-4.55 (m, 1H), 4.06-3, 97 (m, 1H), 3.96-3.86 (m, 1H), 3.30-3.16 (m, 1H), 2.84-2.70 (m, 1H), 2.66- 2.52 (m, 2H), 2.19-1.94 (m, 2H), 1.92-1.74 (m, 3H), 1.73-1.51 (m, 5H), 1, 12-0.92 (m, 4H).

Compound 137 (8-[(3S,5R)-3-methyl-5-[(oxetan-3-yl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile): from oxetan-3-one and 8- ((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 95.1% purity, RT=1.12 min. MS: m/z=324.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.05 (d, J=8.3 Hz, 1H), 7.16 ( d, J=8.4 Hz, 1H), 4.88-4.76 (m, 2H), 4.59-4.40 (m, 3H), 4.26-4.12 (m, 1H) , 4.07-3.98 (m, 1H), 3.04-2.90 (m, 1H), 2.68-2.48 (m, 2H), 2.16-1.91 (m, 2H), 1.14-0.96 (m, 4H).

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

Compound 139 ((3R,5S)-5-methyl-N-(oxolan-3-yl)-1-[pyrido[2,3-b]pyrazin-8-yl]piperidin-3-amine): from dihydrofuran- 3(2H)-one and (3R,5S)-5-methyl-1-(pyrido[2,3-b]pyrazin-8-yl)piperidin-3-amine. HPLC: 97.1% purity, RT=0.89 min. MS: m/z=314.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (d, J=1.7 Hz, 1H), 8.80 (t, J=1.8 Hz, 1H), 8 .63 (d, J=5.6 Hz, 1H), 7.05 (d, J=5.7 Hz, 1H), 5.09-4.99 (m, 1H), 4.43-4, 28 (m, 1H), 4.00-3.84 (m, 2H), 3.87-3.49 (m, 3H), 3.06-2.94 (m, 1H), 2.76- 2.61 (m, 2H), 2.31-2.13 (m, 2H), 2.03-1.88 (m, 1H), 1.88-1.70 (m, 1H), 1, 16-1.00 (m, 4H).

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

(S)-2-((Benzyloxycarbonyl)(ethyl)amino)propanoic acid: At 0°C sodium hydride (324 mg, 13.50 mmol) was added to a solution of (2R)-2-[[(benzyloxy)carbonyl]amino ]propanoic acid (950 mg, 4.26 mmol) in tetrahydrofuran (50 ml). The mixture was stirred for 10 minutes at 0° C. and then iodoethane (5.32 g, 34.11 mmol) was added. The reaction mixture was heated to 60°C and stirred for 20 hours. When the reaction was complete, it was quenched by adding water (50 ml). The resulting mixture was extracted with ethyl acetate (60 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give (2R)-2-[[(benzyloxy)carbonyl](ethyl)amino]propanoic acid as a light yellow oil (900 mg, 32%). MS: m/z=252.2 [M+H] ⁺ .

Method 12

(S)-2-(ethyl(methyl)amino)propanoic acid: Under nitrogen, Pd/C (0.1g, 10%) was added to a solution of (2R)-2-[[(benzyloxy)carbonyl](ethyl) amino]propanoic acid (900 mg, 3.58 mmol, 1.00 eq.) and formalin (0.8 ml, 8.74 mmol, 40%) in ethanol (20 ml) and water (20 ml) at room temperature . The reaction flask was evacuated 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 complete, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give (2R)-2-[ethyl(methyl)amino]propanoic acid as a white solid (387 mg, 82%). MS: m/z=132.2 [M+H] ⁺ .

(R)-N-((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(ethyl(methyl)amino)propanamide: (R)-N -((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl)-2-(ethyl(methyl)amino)propanamide was obtained from 8-((3R,5S)- 3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and (S)-2-(ethyl(methyl)amino)propanoic acid using Method J. The crude product was purified by preparative HPLC under the following conditions: XBridge C18 column OBD Prep Column, 5 µm, 19 mm × 150 mm; Mobile phase: MeOH in water (with 0.05% NH ₃ ^. H ₂ O), 15% - 45% gradient over 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%).

Compound 98: HPLC: 90.0% pure, RT=1.95 min. MS: m/z=381.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89 (d, J=1.7 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H), 8 .05 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 4.33-4.22 (m, 2H), 4.16-4, 05 (m, 1H), 3.20-3.13 (m, 1H), 2.82-2.75 (m, 1H), 2.70-2.62 (m, 1H), 2.55- 2.42 (m, 2H), 2.25 (s, 3H), 2.08-1.95 (m, 2H), 1.25-1.16 (m, 4H), 1.08 (t , J=7.0 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H).

The following compounds were synthesized in a similar manner:

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)quinoxalin-5-carbonitrile and (R)-2-(ethyl(methyl)amino)propanoic acid. HPLC: 97.5% purity, RT=2.81 min. MS: m/z=381.2 [M+H]⁺.^oneH NMR (400 MHz, CD₃OD, ppm) δ 8.89 (d, J=1.8 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H), 8.06 (d, J=8, 4 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 4.34-4.23 (m, 2H), 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, 2H), 2.25 (s, 3H), 2.10-1.96 (m, 2H), 1.29-1.15 (m, 4H), 1.06 (t, J=7.2 Hz, 3H) , 0.98 (d, J=6.4 Hz, 3H).

Compound 100 ((2R)-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 (S)-2-(ethyl(methyl )amino)propanoic acid. HPLC: 95.7% purity, RT=1.11 min. MS: m/z=357.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (d, J=1.7 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H), 8 .63 (d, J=5.6 Hz, 1H), 7.12 (d, J=5.7 Hz, 1H), 4.63 (d, J=13.3 Hz, 2H), 4.12 -3.95(m, 1H), 3.18-3.12(m, 1H), 2.92-2.84(m, 1H), 2.79-2.71(m, 1H), 2 .55-2.46 (m, 2H), 2.26 (s, 3H), 2.10-1.92 (m, 2H), 1.34-1.24 (m, 1H), 1.20 (d, J=6.9 Hz, 3H), 1.09-1.04 (m, 3H), 0.99 (d, J=6.5 Hz, 3H).

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 (R)-2-(ethyl(methyl )amino)propanoic acid. HPLC: 95.7% purity, RT=1.11 min. MS: m/z=357.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (d, J=1.7 Hz, 1H), 8.77 (d, J=1.8 Hz, 1H), 8 .63 (d, J=5.6 Hz, 1H), 7.12 (d, J=5.7 Hz, 1H), 4.63 (d, J=13.3 Hz, 2H), 4.12 -3.95(m, 1H), 3.18-3.12(m, 1H), 2.92-2.84(m, 1H), 2.79-2.71(m, 1H), 2 .55-2.46 (m, 2H), 2.26 (s, 3H), 2.10-1.92 (m, 2H), 1.34-1.24 (m, 1H), 1.20 (d, J=6.9 Hz, 3H), 1.09-1.04 (m, 3H), 0.99 (d, J=6.5 Hz, 3H).

Example 44 Synthesis of compound 112 and compound 113 ((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)

Method 13

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 mmol) in dioxane (15 ml) and water (15 ml) sodium carbonate (1.90 g, 17.93 mmol) and Cbz-Cl (624 mg, 3.65 mmol) were added. The resulting mixture was stirred for 5 hours at room temperature. When the reaction was complete, the pH of the reaction mixture was adjusted to 2-3 with a solution of hydrogen chloride (4 M). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by reverse phase flash chromatography eluting with acetonitrile in water (15%-35% gradient over 30 min) to give 2-[[(benzyloxy)carbonyl]amino]-3,3,3 -trifluoropropanoic acid as a white solid (500 mg, 54%). MS: m/z=276 [MH] ⁺ .

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 obtained from 8-((3R, 5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile and 2-(benzyloxycarbonylamino)-3,3,3-trifluoropropanoic acid using Method J. The crude product was purified by flash chromatography eluting with EtOAc in hexane (0% - 50% gradient) to give benzyl N-(1-[[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamoyl] -2,2,2-trifluoroethyl)carbamate as a yellow solid (220 mg, 50%). MS: m/z=527 [MH] ⁺ .

Method 14

(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: To 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 a solution of HBr (40% in dioxane, 2 ml). The resulting solution was stirred for 2 hours at room temperature. When the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: MeOH in water (with 0.02% HCl), 10% - 27% gradient over 10 min; detector UV 254 nm. Two diastereomeric products were separated and obtained.

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

Isomer 2 : (60 mg, 40%, brown solid) HPLC: 99.1% pure, RT=1.05 min. MS: m/z=393.0 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 9.00-8.80 (m, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.26 ( d, J=8.4 Hz, 1H), 4.76-4.69 (square, J=7.4 Hz, 1H), 4.49-4.03 (m, 3H), 2.86- 2.60 (m, 2H), 2.20-1.96 (m, 2H), 1.33-1.15 (m, 1H), 1.03-0.95 (m, 3H).

The following compounds were synthesized in a similar manner:

Compound 114 and compound 115 ((S)-2-amino-3,3,3-trifluoro-N-((3R,5S)-5-methyl-1-(quinoxalin-5-yl)piperidin-3-yl) propanamide hydrochloride and (R)-2-amino-3,3,3-trifluoro-N-((3R,5S)-5-methyl-1-(quinoxalin-5-yl)piperidin-3-yl)propanamide hydrochloride) : 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, RT=0.97 min. MS: m/z=369.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 9.12 (d, J=1.8 Hz, 1H), 8.97 (d, J=1.9 Hz, 1H), 8 .61 (d, J=7.3 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 5.10-4.90 (m, 3H), 4.11-3, 91 (m, 1H), 3.37 (t, J=11.8 Hz, 1H), 3.16 (t, J=12.3 Hz, 1H), 2.12-1.92 (m, 2H ), 1.49-1.45 (m, 1H), 1.03 (d, J=6.4 Hz, 3H). Isomer 2: HPLC: 95.8% purity, RT=1.04 min. MS: m/z=369.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 9.02 (d, J=2.2 Hz, 1H), 8.68-8.58 (m, 1H), 7.33 ( d, J=7.4 Hz, 1H), 5.00-4.84 (m, 3H), 4.10-3.90 (m, 1H), 3.33 (t, J=11.9 Hz , 1H), 3.17 (t, J=12.4 Hz, 1H), 2.10-1.89 (m, 2H), 1.45-1.40 (m, 1H), 1.02 ( e, J=6.3 Hz, 3H).

Example 45 Synthesis of compound 123 (8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile)

Method 15

8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile: To a solution of 8-[(3R,5S)- 3-amino-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile (50 mg, 0.19 mmol) in acetoneitrile (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. When the reaction was completed, the reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 10% - 40% gradient over 10 min; detector UV 254 nm. 8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile was obtained as a yellow solid (15 mg, 23% ).

Compound 123: HPLC: 97.9% pure, RT=1.90 min. MS: m/z=351.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.96-8.87 (m, 2H), 8.08 (dd, J=9.5, 3.7 Hz, 1H), 7.23 (dt, J=8.2, 4.0 Hz, 1H), 4.71-4.52 (m, 1H), 4.12 (dt, J=10.7, 5.1 Hz, 1H), 3.67 (dd, J=10.1, 8.0 Hz, 1H), 3.47-3.12 (m, 3H), 2.73-2.45 (m, 3H), 2 .30-2.15 (m, 1H), 2.11-1.86 (m, 2H), 1.16-0.99 (m, 4H).

The following compounds were synthesized in a similar manner:

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, RT=1.70 min. MS: m/z=327.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.96 (d, J=1.7 Hz, 1H), 8.83-8.70 (m, 2H), 6.90 ( dd, J=5.5, 4.0 Hz, 1H), 4.84-4.65 (m, 1H), 4.30-4.19 (m, 1H), 3.62-3.51 ( m, 1H), 3.46-3.28 (m, 2H), 3.12-2.98 (m, 1H), 2.74-2.44 (m, 3H), 2.20 (dd, J=28.8, 12.5 Hz, 1H), 2.07-1.91 (m, 2H), 1.14-0.98 (m, 4H).

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 ]quinoxalin-5-carbonitrile and 8-[(3S,5R)-3-methyl-5-{[(3S)-1-methyl-2-oxopyrrolidin-3-yl]amino}piperidin-1-yl]quinoxalin- 5-carbonitrile)

8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile): 8-[(3S,5R)-3 -methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile was obtained 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: XBridge Prep C18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 10% - 40% gradient over 10 min; detector UV 254 nm. (19 mg, 28%, yellow solid). HPLC: 94.2% purity, RT=0.63 min. MS: m/z=365.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.88 (m, 2H), 8.13 (dd, J=8.4, 3.1 Hz, 1H), 7.27 (dd, J=8.4, 5.0 Hz, 1H), 4.75-4.55 (m, 1H), 4.17-4.04 (m, 1H), 3.93- 3.84 (m, 1H), 3.52-3.38 (m, 3H), 2.91 (s, 3H), 2.83-2.57 (m, 3H), 2.36-2, 20 (m, 1H), 2.13-1.86 (m, 2H), 1.27-1.04 (m, 4H). Then 2 isomers of 8-[(3S,5R)-3-methyl-5-[(2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile were obtained by chiral preparative HPLC separation under the following conditions: column EnantioPak A1-5, 2.12 x 25 cm, 5 µm; mobile phase: EtOH in hexane, 55% isocratic for 32 min; detector UV 254/220 nm.

Isomer 1 : HPLC: 98.8% purity, RT=1.15 min. MS: m/z=365.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.88 (m, 2H), 8.13 (dd, J=8.4, 3.1 Hz, 1H), 7.27 (dd, J=8.4, 5.0 Hz, 1H), 4.75-4.55 (m, 1H), 4.17-4.04 (m, 1H), 3.93- 3.84 (m, 1H), 3.52-3.38 (m, 3H), 2.91 (s, 3H), 2.83-2.57 (m, 3H), 2.36-2, 20 (m, 1H), 2.13-1.86 (m, 2H), 1.27-1.04 (m, 4H).

Isomer 2 : HPLC: 99.3% pure, RT=1.15 min. MS: m/z=365.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.88 (m, 2H), 8.13 (dd, J=8.4, 3.1 Hz, 1H), 7.27 (dd, J=8.4, 5.0 Hz, 1H), 4.75-4.55 (m, 1H), 4.17-4.04 (m, 1H), 3.93- 3.84 (m, 1H), 3.52-3.38 (m, 3H), 2.91 (s, 3H), 2.83-2.57 (m, 3H), 2.36-2, 20 (m, 1H), 2.13-1.86 (m, 2H), 1.27-1.04 (m, 4H).

Example 47 Synthesis of compound 162 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-1-(hydroxymethyl)cyclopropane-1-carboxamide)

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

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 obtained from 1-(hydroxymethyl)cyclopropanecarboxylic acid and 8-((3R,5S)- 3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile using Method J. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 25% - 45% gradient over 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%).

Compound 162: HPLC: 94.2% pure, RT=1.17 min. MS: m/z=366.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.92-8.82 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.25 ( d, J=8.4 Hz, 1H), 4.30 (t, J=13.8 Hz, 2H), 4.11 (d, J=11.5 Hz, 1H), 3.69-3, 52 (m, 2H), 2.84-2.64 (m, 2H), 2.12-1.96 (m, 2H), 1.24 (sq., J=11.7 Hz, 1H), 1.25-1.11 (m, 2H), 0.98 (d, J=6.5 Hz, 3H), 0.78-0.62 (m, 2H).

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)

(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 obtained 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: XBridge Shield RP18 OBD Column, 19×150 mm 10 µm; mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 35% - 65% gradient over 10 min; detector UV 254 nm.

Isomer 1 : (14 mg, 12%, yellow solid) HPLC: 95.0% purity, RT=2.76 min. MS: m/z=419.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.90 (d, J=1.8 Hz, 1H), 8.86 (d, J=1.8 Hz, 1H), 8 .07 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.41-4.24 (m, 2H), 4.20-4, 00 (m, 1H), 3.99-3.85 (m, 1H), 2.95-2.75 (m, 2H), 2.29-2.13 (m, 1H), 1.52- 1.05 (m, 2H), 0.70-0.37 (m, 3H), 0.22-0.12 (m, 2H).

Isomer 2 : (14 mg, 12%, yellow solid) HPLC: 94.4% purity, RT=3.14 min. MS: m/z=419.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.90 (d, J=1.8 Hz, 1H), 8.86 (d, J=1.8 Hz, 1H), 8 .07 (d, J=8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 4.41-4.24 (m, 2H), 4.20-4, 00 (m, 1H), 3.99-3.85 (m, 1H), 2.95-2.75 (m, 2H), 2.29-2.13 (m, 1H), 1.52- 1.05 (m, 2H), 0.70-0.37 (m, 3H), 0.22-0.12 (m, 2H).

Example 49: Synthesis of compound 180 (5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoline-8-carboxamide)

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-bromoquinolin-8-carbonitrile and tert-butyl (3R,5S)-5-methylpiperidin-3-ylcarbamate using Method 9. Crude product purified by flash chromatography eluting with DCM in petroleum ether (0%-100% gradient) to give tert-butyl N-[(3R,5S)-1-(8-cyanoquinolin-5-yl)-5-methylpiperidine -3-yl]carbamate as a yellow solid (128 mg, 29%). MS: m/z=367.0 [M+H] ⁺ .

5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoline-8-carboxamide: To a solution of tert-butyl N-[(3R,5S)-1-(8-cyanoquinoline-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 complete, it was quenched by adding ice water (30 ml) and the pH of the solution was adjusted to 10-12 with ammonia solution. The resulting solution was extracted with DCM (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 20% - 50% gradient over 10 min; detector UV 254 nm. 5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinoline-8-carboxamide was obtained as a light yellow solid (79 mg, 80%).

Compound 180: HPLC: 99.0% pure, RT=0.96 min. MS: m/z=285.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94 (dd, J=4.3, 1.8 Hz, 1H), 8.65-8.57 (m, 2H), 7.56 (dd, J=8.6, 4.2 Hz, 1H), 7.25 (d, J=8.2 Hz, 1H), 3.60-3.44 (m, 1H), 3 .39-3.31 (m, 1H), 3.24-3.12 (m, 1H), 2.55-2.35 (m, 2H), 2.19-2.01 (m, 2H) , 1.03-0.89 (m, 4H).

Example 50 Synthesis of Compound 181 (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: 5-[(3R,5S)-3- [(2S)-2-hydroxy-3-methylbutanamido]-5-methylpiperidin-1-yl]quinoline-8-carboxamide was obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 30% - 60% gradient over 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 a yellow solid (35 mg, 52% ).

Compound 181: HPLC: 97.4% pure, RT=1.21 min. MS: m/z=385.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.98-8.92 (m, 1H), 8.73-8.65 (m, 1H), 8.61 (d, J =8.1Hz, 1H), 7.59(dd, J=8.6, 4.3Hz, 1H), 7.30-7.23(m, 1H), 4.35-4.21( m, 1H), 3.83 (d, J=3.8 Hz, 1H), 3.61-3.52 (m, 1H), 3.38 (d, J=11.8 Hz, 1H), 2.64-2.44 (m, 2H), 2.23-1.98 (m, 3H), 1.34-1.19 (m, 1H), 1.08-0.92 (m, 6H ), 0.81 (d, J=6.8 Hz, 3H).

The following compounds were synthesized in a similar manner:

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, RT=1.45 min. MS: m/z=383.3 [M+H]⁺.^oneH NMR (400 MHz, CD₃OD, ppm) δ 8.95 (dd, J=4.2, 1.8 Hz, 1H), 8.69 (dd, J=8.6, 1.8 Hz, 1H), 8, 61 (d, J=8.2 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 4.29-4.17(m, 1H), 3.67-3.55(m, 1H), 3.42-3.32(m, 1H), 2.55-2.41(m, 2H ), 2.20-2.04 (m, 4H), 1.15 (td, J=12.0, 12.0 Hz, 1H), 1.06-0.93 (m, 12H).

Compound 186 (5-[(3R,5S)-3-[2-(dimethylamino)acetamido]-5-methylpiperidin-1-yl]quinoline-8-carboxamide): from 2-(dimethylamino)acetic acid and 5-( (3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoline-8-carboxamide. HPLC: 97.3% purity, RT=1.18 min. MS: m/z=370.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95 (dd, J=4.3, 1.8 Hz, 1H), 8.69 (dd, J=8.6, 1 .8 Hz, 1H), 8.61 (d, J=8.1 Hz, 1H), 7.59 (dd, J=8.6, 4.2 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 4.33-4.20 (m, 1H), 3.61-3.57 (m, 1H), 3.39-3.36 (m, 1H), 2, 99 (s, 2H), 2.62-2.42 (m, 2H), 2.29 (s, 6H), 2.16-2.09 (m, 2H), 1.20 (td, J= 12.0, 12.0 Hz, 1H), 1.03 (d, J=6.4 Hz, 3H).

Example 51: Synthesis of compound 183 (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: 5-[(3R,5S)-3-[(2-methoxyethyl )amino]-5-methylpiperidin-1-yl]quinolin-8-carboxamide was obtained from 1-bromo-2-methoxyethane and 5-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinolin- 8-carboxamide using Method M. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 35% - 65% gradient over 10 min; detector UV 254 nm. 5-[(3R,5S)-3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoline-8-carboxamide was obtained as a yellow solid (18 mg, 23%).

Compound 183: HPLC: 98.9% pure, RT=1.18 min. MS: m/z=343.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95 (dd, J=4.2, 1.8 Hz, 1H), 8.69 (dd, J=8.6, 1 .8 Hz, 1H), 8.61 (d, J=8.2 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 3.69-3.60 (m, 1H), 3.56-3.44 (m, 2H), 3.42-3.30 (m, 4H), 3, 18-3.06 (m, 1H), 2.97-2.80 (m, 2H), 2.58-2.38 (m, 2H), 2.28-2.05 (m, 2H), 1.06-0.92 (m, 4H).

Example 52: Synthesis of Compound 184 and Compound 185 -carboxamide and 5-((3R,5S)-3-((S)-2-amino-3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide)

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 obtained from 5-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinolin-8 α-carboxamide and 2-amino-3,3,3-trifluoropropanoic acid using Method J. The two diastereoisomers were separated by preparative HPLC under the following conditions: XBridge Shield RP18 OBD Column, 19×150 mm 10 µm; mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 30% - 60% gradient over 10 min; detector UV 254 nm.

Isomer 1 : (16 mg, 12%, off-white solid) HPLC: 98.3% purity, RT=1.18 min. MS: m/z=410.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.96 (dd, J=4.3, 1.8 Hz, 1H), 8.72-8.58 (m, 2H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 4.38-4.22 (m, 1H), 3 .91 (sq., J=7.7 Hz, 1H), 3.65-3.56 (m, 1H), 3.40 (dd, J=11.9, 2.9 Hz, 1H), 2 .60-2.42 (m, 2H), 2.23-2.10 (m, 2H), 1.19 (td, J=12.6, 12.6 Hz, 1H), 1.04 (d , J=6.3 Hz, 3H).

Isomer 2 : (16 mg, 12%, yellow solid) HPLC: 96.9 purity, RT=2.35 min. MS: m/z=410.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.96 (dd, J=4.3, 1.8 Hz, 1H), 8.72-8.58 (m, 2H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 4.38-4.22 (m, 1H), 3 .91 (sq., J=7.7 Hz, 1H), 3.65-3.56 (m, 1H), 3.40 (dd, J=11.9, 2.9 Hz, 1H), 2 .60-2.42 (m, 2H), 2.23-2.10 (m, 2H), 1.19 (td, J=12.6, 12.6 Hz, 1H), 1.04 (d , J=6.3 Hz, 3H).

Example 53: Synthesis of compound 187 ((3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine)

(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: XBridge Prep C18 OBD Column , 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 20% - 50% gradient over 10 min; detector UV 254 nm. (3R,5S)-1-(8-Methoxyquinolin-5-yl)-5-methylpiperidin-3-amine was obtained as a yellow solid (27 mg, 13% for 2 steps).

Compound 187: HPLC: 98.8% pure, RT=1.42 min. MS: m/z=272.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.83-8.77 (m, 1H), 8.66-8.59 (m, 1H), 7.58 (dd, J =8.5, 4.3 Hz, 1H), 7.23 (d, J=8.3 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 4.04 (s , 3H), 3.40-3.30 (m, 1H), 3.28-3.12 (m, 2H), 2.45 (t, J=10.5 Hz, 1H), 2.33 ( t, J=11.0 Hz, 1H), 2.18-2.03 (m, 2H), 1.05-0.91 (m, 4H).

Example 54: Synthesis of Compound 188

(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 obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 30% - 60% gradient over 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 a yellow solid (15 mg , 25%).

Compound 188: HPLC: 93.1% pure, RT=1.24 min. MS: m/z=372.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.83 (d, J=4.1 Hz, 1H), 8.46 (d, J=8.6 Hz, 1H), 7.62-7.53 (m, 2H), 7.15-7.05 (m, 2H), 5.30 (d, J=5.7 Hz, 1H), 4.06 (d, J= 10.8 Hz, 1H), 3.91 (s, 3H), 3.64 (t, J=4.8 Hz, 1H), 3.16 (d, J=10.0 Hz, 1H), 3 .12-3.03 (m, 1H), 2.49-2.41 (m, 1H), 2.27 (t, J=11.0 Hz, 1H), 2.07-1.98 (m , 1H), 1.97-1.87 (m, 2H), 1.18 (td, J=12.7, 12.7 Hz, 1H), 0.89 (dd, J=22.8, 6 .7 Hz, 6H), 0.72 (d, J=6.7 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 189(N-[(3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide):from 3,3-dimethylbutanoic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.1% purity, RT=1.45 min. MS: m/z=370.2 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.57 (dd, J=8.5, 1, 7 Hz, 1H), 7.50 (dd, J=8.5, 4.2 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.95 (d, J= 8.3 Hz, 1H), 5.22 (d, J=8.0 Hz, 1H), 4.35-4.33 (m, 1H), 4.07 (s, 3H), 3.55- 3.46 (m, 1H), 3.21-3.13 (m, 1H), 2.42-2.28 (m, 2H), 2.22-2.07 (m, 2H), 2. 04 (d, J=1.7 Hz, 2H), 1.08-0.92 (m, 13H).

Compound 193 (2-(dimethylamino)-N-[(3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-yl]acetamide): from 2-(dimethylamino)acetic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.2% purity, RT=1.74 min. MS: m/z=357.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.80 (dd, J=4.3, 1.7 Hz, 1H), 8.67 (dd, J=8.5, 1 .7 Hz, 1H), 7.59 (dd, J=8.5, 4.2 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 4.28-4.22 (m, 1H), 4.04 (s, 3H), 3.39-3.32 (m, 1H), 3.22-3, 13 (m, 1H), 2.99 (s, 2H), 2.51 (t, J=10.6 Hz, 1H), 2.39 (t, J=11.0 Hz, 1H), 2, 30 (s, 6H), 2.19-2.04 (m, 2H), 1.15 (td, J=12.0, 12.0 Hz, 1H), 1.03 (d, J=6, 4 Hz, 3H).

Example 55: Synthesis of compound 190 ((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: (3R,5S)-N-(2-methoxyethyl)-1- (8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine was obtained from (S)-2-hydroxy-3-methylbutanoic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)- 5-methylpiperidine-3-amine using Method J. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 35% - 65% gradient over 10 min; detector UV 254 nm. (3R,5S)-N-(2-methoxyethyl)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine was obtained as a yellow solid (24 mg, 35%).

Compound 190: HPLC: 99.2% pure, RT=1.89 min. MS: m/z=330.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.80 (dd, J=4.2, 1.7 Hz, 1H), 8.61 (dd, J=8.5, 1 .7 Hz, 1H), 7.58 (dd, J=8.5, 4.2 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 4.04 (s, 3H), 3.52 (t, J=5.3 Hz, 2H), 3.44-3.30 (m, 4H), 3.20 -2.95 (m, 2H), 2.94-2.77 (m, 2H), 2.48-2.28 (m, 2H), 2.23-2.00 (m, 2H), 1 .04-0.87 (m, 4H).

Example 56: Synthesis of Compound 191 and Compound 192 -carboxamide and 5-((3R,5S)-3-((S)-2-amino-3,3,3-trifluoropropanamido)-5-methylpiperidin-1-yl)quinoline-8-carboxamide)

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 obtained from (3R,5S)-1-(8-methoxyquinolin-5-yl)-5- methylpiperidine-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: XBridge Shield RP18 OBD Column, 19×150 mm 10 µm; mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 35% - 65% gradient over 10 min; detector UV 254 nm.

Isomer 1 : (7 mg, 6%, light yellow solid) HPLC: 97.3% purity, RT=1.94 min. MS: m/z=397.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.79 (dd, J=4.3, 1.7 Hz, 1H), 8.65 (dd, J=8.5, 1 .7 Hz, 1H), 7.58 (dd, J=8.5, 4.2 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.11 (d, J =8.3 Hz, 1H), 4.25-4.20 (m, 1H), 4.02 (s, 3H), 3.90 (sq., J=7.7 Hz, 1H), 3, 17 (d, J=11.3 Hz, 1H), 2.50-2.28 (m, 2H), 2.15-2.07 (m, 2H), 1.38-1.24 (m, 1H), 1.12 (td, J=12.7, 12.7 Hz, 1H), 1.01 (d, J=6.4 Hz, 3H).

Isomer 2 : (7 mg, 6%, light yellow solid) HPLC: 95.7% purity, RT=2.21 min. MS: m/z=397.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.79 (dd, J=4.3, 1.7 Hz, 1H), 8.65 (dd, J=8.5, 1 .7 Hz, 1H), 7.58 (dd, J=8.5, 4.2 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4.22 (t, J=11.3 Hz, 1H), 4.02 (s, 3H), 3.90 (sq., J=7.7 Hz, 1H) , 3.17 (d, J=11.3 Hz, 1H), 2.50-2.28 (m, 2H), 2.15-2.07 (m, 2H), 1.38-1.24 (m, 1H), 1.12 (td, J=12.7, 12.7 Hz, 1H), 1.01 (d, J=6.4 Hz, 3H).

Example 57: Synthesis of compound 194 ((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: (2S) -2-hydroxy-3-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]butanamide was obtained from 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 40% - 65% gradient over 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 white solids (19 mg, 16%).

Compound 194: HPLC: 93.9% pure, RT=3.58 min. MS: m/z=410.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95 (dd, J=4.0, 1.7 Hz, 1H), 8.67 (dd, J=8.7, 1 .7 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.6, 4.3 Hz, 1H), 7.24 (d, J =8.0 Hz, 1H), 4.32-4.27 (m, 1H), 3.85 (d, J=3.7 Hz, 1H), 3.69-3.54 (m, 1H) , 3.44-3.39 (m, 1H), 2.66-2.46 (m, 2H), 2.25-2.00 (m, 3H), 1.36-1.18 (m, 1H), 1.09-0.81 (m, 9H).

The following compounds were synthesized in a similar manner:

Compound 195 (3,3-dimethyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]butanamide): from 2-(dimethylamino )acetic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.9% purity, RT=2.91 min. MS: m/z=408.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94 (dd, J=4.3, 1.5 Hz, 1H), 8.66 (dd, J=8.6, 1 .6 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.63 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (d, J =8.1 Hz, 1H), 4.30-4.20 (m, 1H), 3.61 (dd, J=11.0, 4.2 Hz, 1H), 3.40-3.33 ( m, 1H), 2.60-2.40 (m, 2H), 2.21-2.06 (m, 4H), 1.16 (td, J=12.2, 12.2 Hz, 1H) , 1.05 (s, 3H), 1.03 (s, 9H).

Compound 199 ( 2-(dimethylamino)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide): from 2-(dimethylamino )acetic acid and (3R,5S)-1-(8-methoxyquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 96.2% purity, RT=2.68 min. MS: m/z=395.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.98-8.91 (m, 1H), 8.71-8.63 (m, 1H), 8.04 (d, J =8.0 Hz, 1H), 7.63 (dd, J=8.6, 4.2 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 4.32-4 .26 (m, 1H), 3.66-3.57 (m, 1H), 3.40 (d, J=12.1 Hz, 1H), 3.00 (s, 2H), 2.65- 2.45 (m, 2H), 2.31 (s, 6H), 2.25-2.07 (m, 2H), 1.22 (td, J=12.0, 12.0 Hz, 1H) , 1.05 (d, J=6.4 Hz, 3H).

Compound 239 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide): from 2-(morpholin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 99.7% purity, RT=1.85 min. MS: m/z=437.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.61 (dd, J=8.6, 1 .8 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.58 (dd, J=8.6, 4.2 Hz, 1H), 7.18 (d, J =8.0 Hz, 1H), 4.29-4.19 (m, 1H), 3.73-3.63 (m, 4H), 3.62-3.50 (m, 1H), 3, 38-3.30 (m, 1H), 2.99 (s, 2H), 2.60-2.38 (m, 6H), 2.17-2.04 (m, 2H), 1.19 ( td, J=12.3, 12.3 Hz, 1H), 1.00 (d, J=6.4 Hz, 3H).

Compound 240 (2-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide): from 2-hydroxyacetic acid and ( 3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 94.5% purity, RT=3.23 min. MS: m/z=368.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.3, 1.7 Hz, 1H), 8.65 (dd, J=8.6, 1 .8 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.61 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.34-4.26 (m, 1H), 3.98 (s, 2H), 3.60-3.56 (m, 1H), 3.42-3, 33 (m, 1H), 2.60 (t, J=11.0 Hz, 1H), 2.48 (t, J=11.2 Hz, 1H), 2.22-2.07 (m, 2H ), 1.25 (td, J=11.9, 11.9 Hz, 1H), 1.03 (d, J=6.4 Hz, 3H).

Compound 241 (1-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]cyclopropan-1-carboxamide): from 2- (morpholin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 95.9% purity, RT=3.12 min. MS: m/z=394.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.3, 1.7 Hz, 1H), 8.64 (dd, J=8.6, 1 .8 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.61 (dd, J=8.6, 4.2 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 4.33-4.21 (m, 1H), 3.62-3.53 (m, 1H), 3.38 (apparent d, J=11.5 Hz, 1H ), 2.63 (t, J=10.9 Hz, 1H), 2.50 (t, J=11.3 Hz, 1H), 2.18-2.11 (m, 2H), 1.30 (td, J=11.9, 11.9 Hz, 1H), 1.25-1.14 (m, 2H), 1.07-0.98 (m, 3H), 0.98-0.90 (m, 2H).

Compound 243 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide) : from 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, RT=2.66 min. MS: m/z=450.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.3, 1.7 Hz, 1H), 8.61 (dd, J=8.6, 1 .8 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.58 (dd, J=8.6, 4.2 Hz, 1H), 7.18 (d, J =8.0 Hz, 1H), 4.29-4.19 (m, 1H), 3.62-3.51 (m, 1H), 3.38-3.30 (m, 1H), 3, 04-2.97 (m, 2H), 2.59-2.38 (m, 10H), 2.26 (s, 3H), 2.20-2.02 (m, 2H), 1.17 ( td, J=12.2, 12.2 Hz, 1H), 1.00 (d, J=6.4 Hz, 3H).

Compound 244 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-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)quinolin-5-yl]piperidin-3-amine. HPLC: 99.2% purity, RT=0.99 min. MS: m/z=225.0 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.94-8.85 (m, 1H), 8.61 (dt, J=8.6, 2.0 Hz, 1H), 8.03-7.93 (m, 1H), 7.56-7.60 (m, 1H), 7.17 (dd, J=8.0, 2.6 Hz, 1H), 4.23- 4.13 (m, 1H), 3.58 (apparent d, J=9.9 Hz, 1H), 3.34 (apparent d, J=11.2 Hz, 1H), 2.92-2.76 (m, 2H), 2.47-2.38 (m, 2H), 2.24 (s, 3H), 2.20-1.90 (m, 6H), 1.80-1.58 (m , 3H), 1.36-1.19 (m, 2H), 1.09 (td, J=12.2, 12.2 Hz, 1H), 0.99 (d, J=6.5, 3H ).

Compound 245 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: 95.9% purity, RT=4.37 min. MS: m/z=463.5 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.83 (dd, J=4.2, 1.7 Hz, 1H), 8.55 (dd, J=8.6, 1 .8 Hz, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.52 (dd, J=8.6, 4.2 Hz, 1H), 7.11 (d, J =8.0 Hz, 1H), 4.17-4.08 (m, 1H), 3.57-3.46 (m, 1H), 3.28 (apparent d, J=11.6 Hz, 1H ), 2.50-2.20 (m, 6H), 2.19 (s, 3H), 2.15-1.95 (m, 4H), 1.65-1.49 (m, 2H), 1.45-1.32 (m, 2H), 1.15-0.89 (m, 7H).

Compound 246 -3-yl]acetamide): from 2-(1,4-dimethylpiperidin-4-yl)acetic acid and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidine -3-amines. HPLC: 97.6% purity, RT=3.21 min. MS: m/z=499.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.3, 1.7 Hz, 1H), 8.66-8.56 (m, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.58 (dd, J=8.6, 4.2 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H ), 5.90 (tt, J=48.6, 4.5 Hz, 1H), 4.27-4.10 (m, 1H), 3.59 (d, J=11.3 Hz, 1H) , 3.35 (d, J=11.9 Hz, 1H), 2.98-2.86 (m, 2H), 2.62-2.74 (m, 2H), 2.51-2.36 (m, 2H), 2.24-2.03 (m, 6H), 1.79-1.55 (m, 3H), 1.35-1.21 (m, 2H), 1.11 (td , J=12.4, 12.4 Hz, 1H), 1.03-0.96 (m, 3H).

Compound 247 (3,3-difluoro-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]cyclobutan-1-carboxamide): from 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, RT=1.55 min. MS: m/z=428.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.3, 1.7 Hz, 1H), 8.64 (dd, J=8.6, 1 .8 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.62 (dd, J=8.6, 4.2 Hz, 1H), 7.20 (d, J =8.0 Hz, 1H), 4.17-4.25 (m, 1H), 3.66-3.57 (m, 1H), 3.42-3.34 (m, 1H), 2, 91-2.84 (m, 1H), 2.83-2.59 (m, 4H), 2.50-2.43 (m, 2H), 2.19-2.09 (m, 2H), 1.13 (td, J=12.3, 12.3 Hz, 1H), 1.02 (d, J=6.4 Hz, 3H).

Compound 248 (1-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]pyrrolidin-3-carboxamide): from 1- methylpyrrolidin-3-carboxylic acid; and (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidine-3-amine. HPLC: 92.7% purity, RT=1.05 min. MS: m/z=421.3 [M+H] ⁺ . ¹ H NMR (300 MHz, Chloroform-d, ppm) δ 9.01 (dd, J=4.2, 1.8 Hz, 1H), 8.56-8.45 (m, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.49 (dd, J=8.6, 4.2 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H ), 6.83 (d, J=7.9 Hz, 1H), 4.29-4.16 (m, 1H), 3.64 (apparent d, J=10.9 Hz, 1H), 3, 35-3.24 (m, 1H), 2.89-2.82 (m, 3H), 2.52-2.31 (m, 7H), 2.27-1.88 (m, 4H), 1.11-0.92 (m, 4H).

Compound 278 (2-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]propanamide): from 2-hydroxypropanoic acid and ( 3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine. HPLC: 96.9% purity, RT=1.26 min. MS: m/z=382.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.51 (dd, J=8.6, 1 .8 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.51 (dd, J=8.6, 4.2 Hz, 1H), 7.04 (d, J =8.0Hz, 1H), 6.42(d, J=8.1Hz, 1H), 4.35-4.16(m, 2H), 3.70-3.60(m, 1H) , 3.31 (d, J=11.6 Hz, 1H), 2.52-2.32 (m, 2H), 2.25-2.190(m, 3H) 1.40 (d, J=6, 8 Hz, 3H), 1.14-0.95 (m, 4H).

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, RT=3.49 min. MS: m/z=449.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (dt, J=4.4, 1.3 Hz, 1H), 8.61 (dt, J=8.7, 2 .1 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.64-7.52 (m, 1H), 7.17 (dd, J=8.2, 2, 4 Hz, 1H), 4.27-4.10 (m, 1H), 3.58 (d, J=11.2 Hz, 1H), 3.34 (d, J=11.5 Hz, 1H) , 3.10-2.90 (m, 2H), 2.51-2.36 (m, 5H), 2.32-2.17 (m, 1H), 2.08 (d, J=9, 7 Hz, 6H), 1.85-1.55 (m, 3H), 1.21-0.95 (m, 5H).

Compound 283 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(1-methylpyrrolidin-3-yl)acetamide hydrochloride ): from 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, RT=2.71 min. MS: m/z=435.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 9.27 (d, J=8.6 Hz, 1H), 9.12 (d, J=5.2 Hz, 1H), 8 .31 (d, J=8.2 Hz, 1H), 8.07 (dd, J=8.6, 5.2 Hz, 1H), 7.52-7.42 (m, 1H), 4, 16 (d, J=12.3 Hz, 1H), 3.78-3.38 (m, 4H), 3.29-3.04 (m, 1H), 2.94-2.72 (m, 4H), 2.68-2.59 (m, 3H), 2.45-2.08 (m, 5H), 1.86-1.66 (m, 1H), 1.21 (td, J= 12.3, 12.3 Hz, 1H), 1.02 (d, J=6.4 Hz, 3H).

Compound 287 propanamide): from 2-(3,3-difluoroazetidin-1-yl)propanoic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidin-3-amine. HPLC: 98.4% purity, RT=1.81 min. MS: m/z=457.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.3, 1.7 Hz, 1H), 8.63 (dt, J=8.6, 1 .6 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (dd, J =8.0, 1.9 Hz, 1H), 4.27-4.18 (m, 1H), 3.70-3.61 (m, 4H), 3.56-3.53 (m, 1H ), 3.42-3.20 (m, 2H), 3.10-2.99 (m, 1H), 2.61-2.41 (m, 2H), 2.20-2.04 (m , 2H), 1.31-1.14 (m, 4H), 1.03 (d, J=6.5 Hz, 3H).

Compound 289 : 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, RT=1.75 min. MS: m/z=465.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.90 (dd, J=4.3, 1.7 Hz, 1H), 8.62 (dt, J=8.6, 1 .7 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.59 (dd, J=8.6, 4.3 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 4.24-4.16 (m, 1H), 3.58-3.55 (m, 2H), 3.37-3.32 (m, 1H), 3, 07-2.96 (m, 1H), 2.80-2.71 (m, 2H), 2.55-2.42 (m, 2H), 2.34-2.06 (m, 4H), 1.89-1.77 (m, 2H), 1.55-1.50 (m, 2H), 1.23-1.07 (m, 4H), 1.01 (d, J=6.4 Hz, 3H).

Compound 472 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]propionic acid amide): from (3R,5S)-1-[ 8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine and propionic acid. HPLC: >99% purity, RT=3.97 min. MS: m/z=362.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.01 (dd, J=4.2, 1.8 Hz, 1H), 8.84 (d, J=7.4 Hz , 1H), 8.50 (dd, J=8.6, 1.8 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8, 6, 4.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 4.15 (d, J=0.8 Hz, 1H), 4.08 (s, 1H) , 3.48 (d, J=11.0 Hz, 1H), 2.40 (t, J=11.3 Hz, 1H), 2.00 (d, J=14.0 Hz, 2H), 1 .13 (d, J=12.1 Hz, 1H), 0.94 (d, J=6.5 Hz, 3H).

Compound 473 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]but-3-ic acid amide): from (3R,5S) -1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine and 3-butyric acid. HPLC: >99% purity, RT=4.01 min. MS: m/z=376.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.52 (dd, J=8.6, 1.8 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.97 (d, J=7.4 Hz, 1H), 7.66 (dd, J=8, 6, 4.2 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 5.74 (t, J=6.6 Hz, 1H), 5.29 (d, J= 6.6 Hz, 2H), 4.08 (s, 1H), 3.54 (d, J=11.2 Hz, 1H), 3.39-3.32 (m, 1H), 2.48- 2.36(m, 2H), 2.15-1.96(m, 3H), 1.12(q, J=12.0Hz, 2H), 0.95(d, J=6.5 Hz, 3H).

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, RT=3.52 min. MS: m/z=445.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1.8 Hz, 1H), 8.02 (dd, J=24.1, 7.8 Hz, 2H), 7.66 (dd, J=8.6, 4.2 Hz, 1H), 7, 30 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.07 (d, J=6.6 Hz, 1H), 3.61 (d, J=4.1 Hz, 2H), 3.50 (d, J=10.2 Hz, 1H), 3.34 (d, J=11.0 Hz, 1H), 2.92 (s, 3H), 2.46- 2.37 (m, 1H), 2.04 (dd, J=29.3, 9.1 Hz, 2H), 1.14 (sq., J=12.0 Hz, 1H), 0.94 ( t, J=7.1 Hz, 3H).

Compound 475from (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid. HPLC: >99% purity, RT=4.83 min. MS: m/z=446.2 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d₆, ppm) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.51 (dd, J=8.6, 1.8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.67 (dd, J=8.5, 4.0 Hz, 2H), 7.20 (d, J=8.1 Hz, 1H), 4 .08 (s, 1H), 3.46-3.33 (m, 2H), 2.56 (d, J=10.9 Hz, 1H), 2.39 (t, J=11.4 Hz, 1H), 2.15-1.89 (m, 2H), 1.36-1.15 (m, 5H), 0.94 (d, J=6.6 Hz, 3H).

Compound 515 (2-Cyclopropyl-2-hydroxy-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide):from Cyclopropyl-hydroxyl-acetic acid and (3R,5S)-5-Methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride.^oneH NMR (400 MHz, DMSO-d₆) δ 9.02 (dt, J=4.1, 1.4 Hz, 1H), 8.54 (dt, J=8.6, 2.1 Hz, 1H), 8.07 (d, J= 8.1 Hz, 1H), 7.76-7.62 (m, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.21 (dd, J=8.1, 4 .3 Hz, 1H), 5.31 (dd, J=12.5, 5.4 Hz, 2H), 3.57-3.38 (m, 2H), 2.59 (t, J=10, 9 Hz, 1H), 2.43 (t, J=11.3 Hz, 1H), 1.98 (d, J=12.6 Hz, 2H), 1.24 (dsq, J=12.1 , 2.8 Hz, 1H), 1.12-1.01 (m, 1H), 0.96 (dt, J=6.5, 1.5 Hz, 3H), 0.43-0.21 ( m, 4H). MS: m/z=408 [M+H]⁺.

Compound 516 -propionamide:from 2-(4-Methyl-piperazin-1-yl)-propionic acid and (3R,5S)-5-Methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride.^oneH NMR (400 MHz, DMSO-d₆) δ 9.02 (dt, J=4.1, 1.5 Hz, 1H), 8.61-8.44 (m, 1H), 8.06 (dt, J=8.2, 2.7 Hz, 1H), 7.68 (dtd, J=9.2, 5.1, 4.6, 1.9 Hz, 2H), 7.20 (dd, J=12.5, 8.0 Hz, 1H), 4.20 (s, 1H), 3.55-3.39 (m, 1H), 3.34 (d, J=8.1 Hz, 3H), 3.33-3.25 (m , 2H), 3.08-2.90 (m, 1H), 2.44 (dt, J=11.1, 5.5 Hz, 7H), 2.14 (d, J=12.0 Hz, 3H), 2.12 (m, 2H), 1.99 (d, J=12.5 Hz, 2H), 1.18 (dsq, J=12.0, 2.5 Hz, 1H), 1 .08 (dd, J=6.9, 1.4Hz, 3H), 0.95 (dd, J=9.9, 6.4Hz, 3H). MS: m/z=464 [M+H]⁺.

Compound 517 (N-[(3R,5S)-5-Methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]acetamide): from acetic acid and (3R,5S)- 5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1.8 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.90 (d, J=7.4 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 3.52 (d, J=9.2 Hz, 1H), 2.43 (q, J=11.4 Hz , 2H), 2.03 (dd, J=26.1, 12.3 Hz, 2H), 1.82 (s, 3H), 1.08 (sq., J=12.1 Hz, 1H), 0.96 (d, J=6.5 Hz, 3H). MS: m/z=352 [M+H] ⁺ .

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.^oneH NMR (400 MHz, Methanol-d_four) δ 8.95 (dd, J=4.2, 1.7 Hz, 1H), 8.67 (dt, J=8.6, 1.8 Hz, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.63 (dd, J=8.6, 4.2 Hz, 1H), 7.23 (dd, J=8.0, 1.8 Hz, 1H), 4, 28 (dddd, J=14.9, 12.0, 5.8, 2.4 Hz, 1H), 3.60 (m, 1H), 3.40 (d, J=11.6 Hz, 1H) , 2.53 (dtd, J=25.3, 11.2, 2.9 Hz, 2H), 2.35 (d, J=7.9 Hz, 6H), 2.23-2.04 (m , 2H), 1.86 (dd, J=9.5, 3.3 Hz, 1H), 1.20 (q.v., J=12.1 Hz, 1H), 1.09-0.89 (m , 4H), 0.82-0.64 (m, 1H), 0.58-0.43 (m, 1H), 0.35 (tdd, J=12.5, 9.3, 4.8 Hz , 2H). MS: m/z=435 [M+H]⁺.

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.^oneH NMR (400 MHz, DMSO-d₆) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.54 (dd, J=8.6, 1.8 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.79-7.64 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 4.20-4.15 (m, 2H), 3.47(d, J=9.3Hz, 1H), 2.92(q, J=6.8Hz, 1H), 2.42(t, J=11.4Hz, 1H), 2 .15 (s, 6H), 2.13-1.88 (m, 2H), 1.20 (sq., J=12.0 Hz, 1H), 1.07 (d, J=6.9 Hz , 3H), 0.95 (d, J=6.6 Hz, 3H). MS: m/z=409 [M+H]⁺.

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.^oneH NMR (400 MHz, DMSO-d₆) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.54 (dd, J=8.6, 1.8 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.74 (d, J=7.4 Hz, 1H), 7.67 (dd, J=8.6, 4.1 Hz, 1H), 7.21 (d, J=8.1Hz, 1H), 4.06(s, 1H), 3.54(d, J=9.1Hz, 1H), 2.50-2.38(m, 2H), 2, 34 (s, 2H), 2.14-1.93 (m, 2H), 1.12 (sq., J=12.0 Hz, 1H), 0.96 (dd, J=6.5, 3 .6 Hz, 3H), 0.63-0.53 (m, 2H), 0.53-0.38 (m, 2H). MS: m/z=408 [M+H]⁺.

Compound 551 -yl)-piperidin-3-yl]-acetamide):from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 2-(8-methyl-8-azabicyclo[3.2.1]octane-3 hydrochloride -yl)acetic acid.^oneH NMR (400 MHz, DMSO-d₆) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1.8 Hz, 1H), 8.06 (d, J= 8.1 Hz, 1H), 7.92 (d, J=7.3 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.15 (m, 1H) 3.51 (d, J=9.9 Hz, 2H), 3.34 (d, J=11.6 Hz, 2H), 3.14 (s, 2H), 2.43 (dt, J=11.3, 5.9 Hz, 1H), 2.23 (d, J=5.7 Hz, 3H), 2.15 (dd , J=15.8, 7.9Hz, 2H), 2.02 (dd, J=16.8, 10.7Hz, 4H), 1.68 (d, J=8.2Hz, 2H) , 1.22(dd, J=13.8, 7.4Hz, 2H), 1.10(q, J=12.0Hz, 1H), 0.95(d, J=6.5Hz , 3H). MS: m/z=475 [M+H]⁺.

Compound 572 -acetamide):from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride; and 2-methyl-2-piperidin-1-yl-propionic acid. HPLC: >99% purity, RT=3.27 min. MS: m/z=463.6 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1, 8 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.68 (dd, J=8.6, 4.2 Hz, 1H), 7.49 (d, J= 8.2 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 4.11-3.97 (m, 1H), 3.45 (dd, J=11.6, 3 .9 Hz, 1H), 2.56 (t, J=10.9 Hz, 1H), 2.45 (t, J=11.4 Hz, 1H), 2.33 (s, 4H), 2, 09 (s, 1H), 1.97 (d, J=12.4 Hz, 1H), 1.54 (s, 4H), 1.41 (d, J=6.9 Hz, 2H), 1, 22 (q, J=12.0 Hz, 1H), 1.06 (d, J=9.0 Hz, 6H), 0.96 (d, J=6.6 Hz, 3H).

Compound 573 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, RT=3.32 min. MS: m/z=449.5 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1, 8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H), 7.57 (d, J= 8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 4.13-4.06 (m, 1H), 3.50-3.43 (m, 1H), 3.02 (d, J=3.0 Hz, 2H), 2.63 (m, 2H), 2.56 (t, J=10.9 Hz, 1H), 2.43 (t, J=11 .4 Hz, 1H), 2.38-2.29 (m, 2H), 2.08 (td, J=10.4, 9.1, 5.4 Hz, 1H), 1.99 (dd, J=12.4, 3.9Hz, 1H), 1.53(t, J=7.1Hz, 2H), 1.21(q, J=12.0Hz, 1H), 1.05 (d, J=1.3 Hz, 6H), 0.96 (d, J=6.6 Hz, 3H).

Compound 574from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and 1-cyclopropyl-piperidine-4-carboxylic acid. HPLC: 98% purity, RT=3.12 min. MS: m/z=461.5 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.7, 1, 8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.4 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 4.02 (s, 0H), 3.48 (d, J=10.9 Hz, 1H), 3 .36 (d, J=5.3 Hz, 0H), 2.92 (td, J=7.9, 3.9 Hz, 1H), 2.43 (sq., J=11.2 Hz, 1H ), 2.08 (ddt, J=11.5, 8.2, 3.7 Hz, 1H), 1.98 (d, J=13.0 Hz, 0H), 1.67-1.40 ( m, 2H), 1.10 (sq., J=12.1 Hz, 1H), 0.95 (d, J=6.6 Hz, 2H), 0.38 (dt, J=5.2, 2.6 Hz, 1H), 0.27 (sq., J=3.1, 2.5 Hz, 1H).

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, RT=3.98 min. MS: m/z=465.5 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1 .8 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.87 (d, J=7.4 Hz, 1H), 7.67 (dd, J=8.6 , 4.2 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.03 (s, 1H), 3.51 (d, J=10.2 Hz, 1H), 3.30 (d, J=6.8 Hz, 2H), 3.28-3.18 (m, 2H), 2.49 (d, J=6.9 Hz, 2H), 2.43 (td , J=11.1, 4.1 Hz, 2H), 2.34 (sq., J=7.6, 7.1 Hz, 2H), 2.06 (s, 1H), 1.99 (d , J=13.1 Hz, 1H), 1.15-1.03 (m, 4H), 0.97 (t, J=6.8 Hz, 6H).

Example 58: Synthesis of compound 196 ((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: (3R,5S)-N-(2-methoxyethyl )-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine was obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 30% - 60% gradient over 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 a yellow oil (14 mg, 15%).

Compound 196: HPLC: 94.9% pure, RT=2.77 min. MS: m/z=368.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.04-8.97 (m, 1H), 8.48 (dd, J=8.7, 1.7 Hz, 1H) , 8.05 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.6, 4.2 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 3.57-3.49 (m, 1H), 3.42-3.28 (m, 2H), 3.24 (s, 3H), 2.93 (t, J=10.8 Hz , 1H), 2.82-2.66 (m, 2H), 2.41-2.33 (m, 2H), 2.12-1.94 (m, 2H), 1.59 (br.s , 2H), 0.97-0.78 (m, 4H).

Example 59: Synthesis of compound 197 and compound 198 ((R)-2-amino-3,3,3-trifluoro-N-((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoline-5 -yl)piperidin-3-yl)propanamide and (S)-2-amino-3,3,3-trifluoro-N-((3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoline- 5-yl)piperidin-3-yl)propanamide)

(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 obtained 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 preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 19 × 150 mm 10 µm; mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 30% - 60% gradient over 10 min; detector UV 254 nm.

Isomer 1 : (14 mg, 21%, white solid) HPLC: 93.2% purity, RT=2.62 min. MS: m/z=434.9 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1.8 Hz, 1H), 8.37 (d, J=7.3 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.68 (dd, J=8, 6, 4.2 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.09-4.04 (m, 1H), 3.93-3.84 (m, 1H ), 3.49 (apparent d, J=11.6 Hz, 1H), 2.51-2.39 (m, 1H), 2.31 (apparent d, J=8.9 Hz, 2H), 2 .10-1.90 (m, 2H), 1.15 (td, J=12.0, 12.0 Hz, 1H), 0.96 (d, J=6.5 Hz, 3H).

Isomer 2 : (9 mg, 13%, white solid) HPLC: 90.5% purity, RT=2.71 min. MS: m/z=434.9 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1 .8 Hz, 1H), 8.37 (d, J=7.3 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.68 (dd, J=8.6 , 4.2 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.09-4.04 (m, 1H), 3.93-3.84 (m, 1H) , 3.49 (apparent d, J=11.6 Hz, 1H), 2.51-2.39 (m, 1H), 2.31 (apparent d, J=8.9 Hz, 2H), 2, 10-1.90 (m, 2H), 1.15 (td, J=12.0, 12.0 Hz, 1H), 0.96 (d, J=6.5 Hz, 3H).

Example 60: Synthesis of compound 200 (5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinolin-8-ol hydrochloride)

5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinolin-8-ol: at -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 BBr ₃ (553 mg, 2.19 mmol) in DCM (5 ml) dropwise. The resulting solution was stirred for 1 hour at -78°C, heated to -20°C and stirred for 2 hours at -20°C. When the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with DCM (20 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: Xbridge Shield RP18 OBD column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% HCl), 35% - 65% gradient over 10 min; detector UV 254 nm. 5-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]quinolin-8-ol hydrochloride was obtained as a brown solid (24 mg, 21%).

Compound 200: HPLC: 96.6% pure, RT=1.05 min. MS: m/z=258.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 9.38 (dd, J=8.5, 1.5 Hz, 1H), 9.09 (dd, J=5.2, 1 .3 Hz, 1H), 8.13 (dd, J=8.6, 5.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.47 (d, J =8.5 Hz, 1H), 3.73-3.67 (m, 1H), 3.53 (dd, J=10.8, 3.9 Hz, 1H), 3.24 (dd, J= 11.6, 3.6 Hz, 1H), 2.85 (t, J=10.7 Hz, 1H), 2.51 (t, J=11.2 Hz, 1H), 2.35-2, 17 (m, 2H), 1.27 (td, J=11.9, 11.9 Hz, 1H), 1.08 (d, J=6.5 Hz, 3H).

Example 61 Synthesis of compound 204 ((2S)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxy-3- methylbutanamide)

(2S)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-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 obtained from 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: XBridge Shield RP18 OBD Column, 5 µm , 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 25% - 50% gradient over 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%).

Compound 204: HPLC: 91.5% pure, RT=2.73 min. MS: m/z=392.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.91 (dd, J=4.2, 1.7 Hz, 1H), 8.65 (dd, J=8.6, 1 .8 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.88-7.54 (m, 2H), 7.27 (d, J=7.9 Hz, 1H ), 4.34-4.24 (m, 1H), 3.85 (d, J=3.8 Hz, 1H), 3.58-3.45 (m, 1H), 3.40-3, 28 (m, 1H), 2.59 (t, J=10.8 Hz, 1H), 2.48 (t, J=11.2 Hz, 1H), 2.24-2.00 (m, 4H ), 1.38-1.18 (m, 1H), 1.05 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.6 Hz, 3H), 0.84 (d, J=6.8 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 205 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): from 3,3-dimethylbutanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 98.9% purity, RT=1.59 min. MS: m/z=390.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.91 (dd, J=4.2, 1.7 Hz, 1H), 8.64 (dd, J=8.6, 1 .8 Hz, 1H), 7.95 (dt, J=7.9, 1.5 Hz, 1H), 7.85-7.65 (m, 2H), 7.26 (d, J=7, 9 Hz, 1H), 4.29-4.21 (m, 1H), 3.62-3.53 (m, 1H), 3.39-3.36 (m, 1H), 2.57-2 .37 (m, 2H), 2.23-2.06 (m, 4H), 1.15 (td, J=12.1, 12.1 Hz, 1H), 1.05 (s, 3H), 1.03 (s, 9H).

Compound 209 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(dimethylamino)acetamide): from 3,3-dimethylbutanoic acids and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 95.9% purity, RT=2.58 min. MS: m/z=377.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.91 (dd, J=4.2, 1.7 Hz, 1H), 8.64 (dd, J=8.6, 1 .8 Hz, 1H), 7.95 (dd, J=7.9, 1.3 Hz, 1H), 7.86-7.54 (m, 2H), 7.28 (d, J=7, 9 Hz, 1H), 4.33-4.24 (m, 1H), 3.61-3.54 (m, 1H), 3.40-3.28 (m, 1H), 3.10 (s , 2H), 2.60-2.40 (m, 2H), 2.37 (s, 6H), 2.24-2.09 (m, 2H), 1.20 (td, J=12.1 , 12.1 Hz, 1H), 1.05 (d, J=6.4 Hz, 3H).

Compound 302 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-hydroxypropanamide): from 2-hydroxypropanoic acid and (3R, 5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.0% purity, RT=2.13 min. MS: m/z=364.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.62 (dd, J=8.6, 1 .7 Hz, 1H), 7.93 (dd, J=7.9, 1.4 Hz, 1H), 7.86-7.50 (m, 2H), 7.26 (d, J=8, 0 Hz, 1H), 4.28-4.20 (m, 1H), 4.11 (td, J=6.8, 6.8 Hz, 1H), 3.54-3.49 (m, 1H ), 3.38-3.30 (m, 1H), 2.56 (t, J=10.9 Hz, 1H), 2.45 (t, J=11.2 Hz, 1H), 2.21 -2.05 (m, 2H), 1.32 (d, J=6.8 Hz, 3H), 1.22 (td, J=12.1, 12.1 Hz, 1H), 1.03 ( e, J=6.4 Hz, 3H).

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, RT=1.52 min. MS: m/z=431.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.62 (dd, J=8.6, 1 .8 Hz, 1H), 7.98-7.84 (m, 1H), 7.73-7.46 (m, 2H), 7.25 (d, J=7.8 Hz, 1H), 4 .22 (t, J=11.4 Hz, 1H), 3.57 (apparent d, J=11.6 Hz, 1H), 3.40-3.30 (m, 1H), 2.89-2 .72 (m, 2H), 2.50-2.41 (m, 2H), 2.25-2.23 (m, 3H), 2.19-1.82 (m, 6H), 1.81 -1.48 (m, 4H), 1.22-0.87 (m, 5H).

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, RT=2.82 min. MS: m/z=417.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.58 (dd, J=8.6, 1 .8 Hz, 1H), 7.96-7.41 (m, 3H), 7.21 (d, J=7.9 Hz, 1H), 4.26-4.09 (m, 1H), 3 .59-3.47 (m, 1H), 3.39-3.29 (m, 1H), 2.80-2.73 (m, 1H), 2.67-2.49 (m, 3H) , 2.46-2.37 (m, 2H), 2.33-2.30 (m, 3H), 2.28-2.17 (m, 3H), 2.12-1.95 (m, 3H), 1.54-1.40(m, 1H), 1.25(d, J=1.4Hz, 1H), 1.11(td, J=12.4, 12.4Hz, 1H ), 0.99 (d, J=6.4 Hz, 3H).

Compound 311 (2-(3,3-difluoroazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]propanamide ): from 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, RT=2.53 min. MS: m/z=439.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.61 (dt, J=8.6, 1 .7 Hz, 1H), 7.93 (dd, J=8.0, 1.5 Hz, 1H), 7.85-7.53 (m, 2H), 7.26 (dd, J=7, 9, 2.0 Hz, 1H), 4.27-4.18 (m, 1H), 3.75-3.56 (m, 4H), 3.53-3.49 (m, 1H), 3 .39-3.20 (m, 1H), 3.10-3.00 (m, 1H), 2.60-2.40 (m, 2H), 2.21-2.04 (m, 2H) , 1.31-1.13 (m, 4H), 1.03 (d, J=6.5 Hz, 3H).

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, RT=1.51 min. MS: m/z=447.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.86 (dd, J=4.2, 1.6 Hz, 1H), 8.59 (dt, J=8.6, 1 .8 Hz, 1H), 7.95-7.44 (m, 3H), 7.23 (d, J=7.9 Hz, 1H), 4.21 (d, J=11.8 Hz, 1H ), 3.69-3.50 (m, 2H), 3.40-3.20 (m, 1H), 3.01 (tt, J=3.6, 3.3 Hz, 1H), 2, 82-2.68 (m, 2H), 2.56-2.02 (m, 6H), 1.89-1.73 (m, 2H), 1.58-1.45 (m, 2H), 1.23-1.05 (m, 4H), 1.00 (d, J=6.4 Hz, 3H).

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, RT=1.02 min. MS: m/z=431.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.59 (dd, J=8.6, 1 .7 Hz, 1H), 7.94-7.43 (m, 3H), 7.21 (d, J=7.9 Hz, 1H), 4.24-4.13 (m, 1H), 3 .60-3.48 (m, 1H), 3.40-3.20 (m, 1H), 2.95-2.91 (m, 2H), 2.46-2.37 (m, 2H) , 2.29 (s, 3H), 2.18-2.02 (m, 6H), 1.83-1.60 (m, 3H), 1.37-1.20 (m, 2H), 1 .07-1.00 (m, 1H), 0.99 (d, J=6.3 Hz, 3H).

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. HPLC: 98.6% purity, RT=2.25 min. MS: m/z=410.2 [M+H] ⁺ . ¹ H NMR (300 MHz, Chloroform-d, ppm) δ 8.93 (dd, J=4.5, 1.8 Hz, 1H), 8.54 (d, J=8.5 Hz, 1H), 7.99-7.43 (m, 3H), 7.12 (d, J=7.9 Hz, 1H), 5.38-5.28 (m, 1H), 4.39-4 .23 (m, 1H), 3.68-3.64 (m, 1H), 3.31-3.27 (m, 1H), 2.94-2.62 (m, 5H), 2.49 -2.29 (m, 2H), 2.22-2.07 (m, 2H), 1.03-0.95 (m, 4H).

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, RT=2.22 min. MS: m/z=432.3 [M+H] ⁺ . ¹ H NMR (300 MHz, Chloroform-d, ppm) δ 9.07-8.87 (m, 2H), 7.94-7.54 (m, 3H), 7.30 (d, J = 8.3 Hz, 1H), 4.12-3.85 (m, 3H), 2.69-2.40 (m, 4H), 2.10 (s, 3H), 2.02-1, 70 (m, 4H), 1.65-1.35 (m, 3H), 1.16-0.98 (m, 1H), 0.95-0.75 (m, 4H).

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, RT=6.42 min. MS: m/z=418.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.85 (m, 2H), 7.93 (d, J=8.1 Hz, 1H), 7.63 ( t, J=55.8 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 4.23-3.92 (m, 3H), 3.04-2.89 (m , 1H), 2.85-2.40 (m, 9H), 2.29 (d, J=7.5 Hz, 2H), 2.20-2.00 (m, 3H), 1.63- 1.49 (m, 1H), 1.12-1.09 (m, 1H), 0.97 (d, J=6.4 Hz, 3H).

Compound 323 ): 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, RT=1.25 min. MS: m/z=440.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.85 (m, 2H), 7.97 (dd, J=8.2, 1.5 Hz, 1H), 7.63 (t, J=55.9 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 4.27-4.13 (m, 1H), 4.09-3 .95 (m, 2H), 3.77-3.58 (m, 4H), 3.11-3.01 (m, 1H), 2.75-2.68 (m, 1H), 2.57 -2.05(m, 1H), 2.14-2.03(m, 2H), 1.31-1.13(m, 4H), 1.01(d, J=6.5Hz, 3H ).

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, RT=1.50 min. MS: m/z=448.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.97-8.81 (m, 2H), 7.97 (d, J=8.2 Hz, 1H), 7.63 ( t, J=55.8 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 4.29-3.90 (m, 3H), 3.65-3.62 (m , 1H), 3.17-3.09 (m, 1H), 2.95-2.20 (m, 6H), 2.19-1.79 (m, 4H), 1.70-1.50 (m, 2H), 1.31-1.11 (m, 4H), 1.02 (d, J=6.3 Hz, 3H).

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, RT=1.31 min. MS: m/z=432.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.81 (m, 2H), 7.97 (d, J=8.3 Hz, 1H), 7.64 ( t, J=55.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 4.29-3.95 (m, 3H), 2.97-2.94 (m , 2H), 2.66-2.46 (m, 2H), 2.35 (s, 3H), 2.24-2.03 (m, 6H), 1.90-1.70 (m, 3H ), 1.40-1.36 (m, 2H), 1.14 (td, J=12.2, 12.2 Hz, 1H), 1.01 (dd, J=6.4, 2.3 Hz, 3H).

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

Example 62: Synthesis of compound 206 ((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): (3R,5S)-1-[8-( difluoromethyl)quinolin-5-yl]-N-(2-methoxyethyl)-5-methylpiperidin-3-amine was obtained from 1-bromo-2-methoxyethane and (3R,5S)-1-(8-(difluoromethyl)quinoline- 5-yl)-5-methylpiperidin-3-amine using Method N. The crude product was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD Column, 5 µm, 19 mm x 150 mm; mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 35% - 65% gradient over 8 min; detector UV 254 nm. (3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-N-(2-methoxyethyl)-5-methylpiperidin-3-amine was obtained as a yellow solid (11 mg, 24%).

Compound 206: HPLC: 96.4% pure, RT=1.41 min. MS: m/z=350.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.85 (dd, J=4.2, 1.8 Hz, 1H), 8.51 (dd, J=8.6, 1 .8 Hz, 1H), 7.95-7.85 (m, 1H), 7.82-7.43 (m, 2H), 7.22 (d, J=7.9 Hz, 1H), 3 .61-3.43 (m, 3H), 3.35-3.25 (m, 4H), 3.10-2.98 (m, 1H), 2.93-2.72 (m, 2H) , 2.50-2.30 (m, 2H), 2.23-1.96 (m, 2H), 1.02-0.83 (m, 4H).

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)

(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: 2- amino-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3,3-trifluoropropanamide was obtained 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 preparative HPLC under the following conditions: column XBridge Shield RP18 OBD Column, 19 × 150 mm 10 µm; mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 53% - 55% gradient over 12 min; detector UV 254 nm.

Isomer 1 : (11 mg, 16%, white solid) HPLC: 98.5% purity, RT=1.88 min. MS: m/z=417.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 8.87 (dd, J=4.2, 1.7 Hz, 1H), 8.58 (dd, J=8.6, 1.8 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.87-7.44 (m, 2H), 7.22 (d, J=7.9 Hz, 1H), 4.30-4.18 (m, 1H), 3.89 (dt, J=7.7, 7.7 Hz, 1H), 3.58-3.47 (m, 1H), 3 .39-3.28 (m, 1H), 2.55-2.35 (m, 2H), 2.3.9-2.08 (m, 2H), 1.29-1.05 (m, 1H), 1.00 (d, J=6.3 Hz, 3H).

Isomer 2 : (13 mg, 19%, yellow solid) HPLC: 93.8% purity, RT=3.84 min. MS: m/z=417.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.87 (dd, J=4.2, 1.7 Hz, 1H), 8.58 (dd, J=8.6, 1 .8 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.87-7.44 (m, 2H), 7.22 (d, J=7.9 Hz, 1H ), 4.30-4.18 (m, 1H), 3.89 (dt, J=7.7, 7.7 Hz, 1H), 3.58-3.47 (m, 1H), 3, 39-3.28(m, 1H), 2.55-2.35(m, 2H), 2.3.9-2.08(m, 2H), 1.29-1.05(m, 1H ), 1.00 (d, J=6.3 Hz, 3H).

Example 64: Synthesis of compound 210 (8-[(5R)-5-amino-3,3-dimethylpiperidin-1-yl]quinoxaline-5-carbonitrile hydrochloride)

1,5-dimethyl (2R)-2-aminopentanedioate: thionyl chloride (60.95 g, 512.33 mmol) dropwise over 20 minutes. The resulting solution was then stirred for 16 hours at room temperature. When the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (500 ml) and the mixture was adjusted to pH 8 with saturated sodium bicarbonate solution. The resulting mixture was extracted with DCM (300 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 1,5-dimethyl (2R)-2-aminopentanedioate as a yellow oil (19.80 g, 88%). MS: m/z=176.0 [M+H] ⁺ .

1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino]pentanedioate: To a solution of 1,5-dimethyl (2R)-2-aminopentanedioate (19.80 g, 119.30 mmol) in dioxane (200 ml) was added 4-dimethylaminopyridine (291 mg, 2.38 mmol), (Boc) ₂ O (29.93 g, 137.16 mmol) and water (200 ml) at room temperature. The resulting solution was stirred for 16 hours at room temperature. When the reaction was complete, it was quenched by adding water (100 ml). The resulting mixture was extracted with DCM (200 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with DCM in hexane (0%-30% gradient) to give 1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino ]pentanedioate as a colorless oil (23.75 g, 72%). MS: m/z=276.1 [M+H] ⁺ .

1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpentanedioate: at -78°C to a solution of 1,5-dimethyl (2R)-2-[[(tert- butoxy)carbonyl]amino]pentanedioate (3.80 g, 13.80 mmol) in THF (40 ml) was added a solution of LiHMDS (1 M in THF, 29 ml, 28.98 mmol) dropwise over 5 minutes. The resulting mixture was stirred at -78°C for 1 hour and then MeI (3.13 g, 22.13 mmol) was added slowly. The resulting solution was stirred for another 4.5 hours at -78°C. When the reaction was complete, it was quenched by adding a solution of hydrogen chloride (1 M, 40 ml). The resulting mixture was extracted with ethyl acetate (100 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-10% gradient) to give 1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino ]-4-methylpentanedioate as a white solid (3.33 g, 83%). MS: m/z=290.1 [M+H] ⁺ .

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 mmol) was added to THF (150 ml), then a solution of 1,5-dimethyl (2R)-2-[[(tert-butoxy)carbonyl]amino]-4-methylpentanedioate (3.52 g, 12.66 mmol) in tetrahydrofuran (50 ml) drop by drop over 5 minutes. The resulting solution was stirred for 0.5 hour at -78°C and then MeI (1079 g, 76 mmol) was added slowly. The resulting solution was then stirred for another 1 hour at -78°C. When the reaction was complete, it was quenched by adding a saturated solution of NH ₄ Cl (100 ml). The resulting mixture was extracted with ethyl acetate (200 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-5% gradient) to give 1,5-dimethyl (4R)-4-[[(tert-butoxy)carbonyl]amino ]-2,2-dimethylpentanedioate as a light yellow solid (2.00 g, 52%). MS: m/z=304.1 [M+H] ⁺ .

tert-Butyl N-[(2R)-1,5-dihydroxy-4,4-dimethylpentan-2-yl]carbamate: at 0°C to a solution of 1,5-dimethyl (4R)-4-[[(tert- butoxy)carbonyl]amino]-2,2-dimethylpentanedioate (1.44 g, 4.75 mmol) in EtOH (18 ml) was added THF (18 ml) and CaCl ₂ (2.19 g, 19.77 mmol). NaBH ₄ (1.56 g, 41.18 mmol) was then added portionwise over 20 minutes at 0°C. The resulting mixture was stirred for 16 hours at room temperature. When the reaction was complete, it was quenched by adding a solution of Na ₂ CO ₃ (10%, 50 ml). The resulting mixture was extracted with ethyl acetate (100 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give tert-butyl N-[(2R)-1,5-dihydroxy-4,4-dimethylpentan-2-yl]carbamate as a colorless oil (1.42 g, crude). MS: m/z=248.1 [M+H] ⁺ .

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, crude) in DCM (50 mL) TEA (2.32 g, 22.91 mmol) was added followed by MsCl (5.70 g , 49.76 mmol) drop by drop over 10 minutes. The resulting solution was then stirred for 2 hours at 0°C. When the reaction was complete, it was quenched by adding water (20 ml). The resulting mixture was extracted with ethyl acetate (60 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give tert-butyl N-[(2R)-1,5-bis(methanesulfonyloxy)-4,4-dimethylpentan-2-yl]carbamate as a colorless oil (2.60 g, crude product) . MS: m/z=426.1 [M+H] ⁺ .

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, crude) 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%-3% gradient) to give tert-butyl N-[(3R)-1-benzyl-5 ,5-dimethylpiperidin-3-yl]carbamate as a colorless oil (740 mg, 49% for 3 steps). MS: m/z=319.2 [M+H] ⁺ .

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

tert-Butyl N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]carbamate: To a solution of tert-butyl N-[(3R)-5,5- dimethylpiperidin-3-yl]carbamate (560 mg, crude) in DMF (5 ml) was added 8-bromoquinoxaline-5-carbonitrile (766 mg, 3.27 mmol) and DIEA (904 mg, 7.00 mmol) at room temperature . The resulting solution was then stirred for 16 hours at 130°C. After cooling to room temperature, the reaction mixture was quenched by adding water (30 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-14% gradient) to give t-butyl N-[(3R)-1-(8-cyanoquinoxalin-5-yl) -5,5-dimethylpiperidin-3-yl]carbamate as a yellow solid (477 mg, 60% for 2 steps). MS: m/z=382.0 [M+H] ⁺ .

8-[(5R)-5-amino-3,3-dimethylpiperidin-1-yl]quinoxalin-5-carbonitrile hydrochloride: To 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) at room temperature. The resulting solution was stirred for 3 hours at room temperature. When the reaction was complete, the resulting mixture was concentrated under reduced pressure to give 8-[(5R)-5-amino-3,3-dimethylpiperidin-1-yl]quinoxalin-5-carbonitrile hydrochloride as a yellow solid (450 mg, crude product). MS: m/z=282.2 [M+H] ⁺ .

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)

(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: 2-amino-N-((R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl)-3,3,3-trifluoropropanamide prepared from (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxalin-5-carbonitrile and 2-(tert-butoxycarbonylamino)-3,3,3-trifluoropropanoic acid using Method J and 6. The two diastereoisomers were separated by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 19×150 mm 10 µm; mobile phase: acetonitrile in water (with 0.05% NH₃ ^.H₂O), 40% - 70% gradient over 10 min; detector UV 254 nm.

Isomer 1 : (19 mg, 14% for 2 steps, yellow solid) HPLC: 93.0% purity=, RT=2.39 min. MS: m/z=407.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 9.01-8.91 (m, 2H), 8.13 (d, J=8.4 Hz, 1H), 7.31 ( d, J=8.4 Hz, 1H), 4.50-4.38 (m, 1H), 4.24 (dd, J=12.1, 4.1 Hz, 1H), 4.01-3 .90 (m, 2H), 3.00-2.84 (m, 2H), 1.86-1.70 (m, 1H), 1.58-1.48 (m, 1H), 1.12 (s, 3H), 1.08 (m, 3H).

Isomer 2 : (17 mg, 12% for 2 steps, yellow solid) HPLC: 93.7% purity, RT=2.46 min. MS: m/z=407.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ9.01-8.91 (m, 2H), 8.13 (d, J=8.4 Hz, 1H), 7.31 (d , J=8.4 Hz, 1H), 4.50-4.38 (m, 1H), 4.24 (dd, J=12.1, 4.1 Hz, 1H), 4.01-3, 90 (m, 2H), 3.00-2.84 (m, 2H), 1.86-1.70 (m, 1H), 1.58-1.48 (m, 1H), 1.12 ( s, 3H), 1.08 (m, 3H).

Example 66: Synthesis of compound 213 ((2R)-N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-hydroxy-3-methylbutanamide)

(2R)-N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-hydroxy-3-methylbutanamide: (2R)-N-[( 3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-hydroxy-3-methylbutanamide was obtained from (2R)-2-hydroxy-3-methylbutanoic acid and (R )-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxalin-5-carbonitrile using Method J. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 35% - 65% gradient over 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 a yellow solid (18 mg , 33%).

Compound 213: HPLC: 97.2% pure, RT=2.51 min. MS: m/z=382.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94 (dd, J=8.7, 1.8 Hz, 2H), 8.11 (d, J=8.3 Hz, 1H), 7.29 (d, J=8.4 Hz, 1H), 4.44-4.33 (m, 1H), 4.01 (dd, J=12.0, 4.0 Hz, 1H ), 3.91 (d, J=3.7 Hz, 1H), 3.79 (d, J=12.1 Hz, 1H), 3.22-3.15 (m, 1H), 3.03 (d, J=12.1 Hz, 1H), 2.22-2.10 (m, 1H), 1.82-1.61 (m, 2H), 1.16-1.00 (m, 9H ), 0.90 (d, J=6.8 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 214 (N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-2-(morpholin-4-yl)acetamide):from 8-[(5R)-5-amino-3,3-dimethylpiperidin-1-yl]quinoxalin-5-carbonitrile hydrochloride and 2-(morpholin-4-yl)acetic acid. HPLC: 97.0% purity, RT=1.87 min. MS: m/z=409.3 [M+H]⁺.^oneH NMR (400 MHz, CD₃OD, ppm) δ 8.92 (d, J=15.0 Hz, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.28 (d, J=6, 3 Hz, 1H), 4.49-4.35 (m, 1H), 4.16-4.07 (m, 1H), 3.90 (d, J=12.3 Hz, 1H), 3, 77-3.63 (m, 4H), 3.17-2.95 (m, 4H), 2.60-2.52 (m, 4H), 1.83-1.74 (m, 1H), 1.62-1.51 (m, 1H), 1.15-1.05 (m, 6H).

Compound 215 (N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-3,3-dimethylbutanamide): from 3,3-dimethylbutanoic acid and (R )-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 99.2% purity, RT=4.17 min. MS: m/z=380.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.85 (m, 2H), 8.10 (d, J=8.4 Hz, 1H), 7.30 ( d, J=8.4 Hz, 1H), 4.48-4.36 (m, 1H), 4.36-4.26 (m, 1H), 4.11 (d, J=12.6 Hz , 1H), 2.90 (d, J=12.4 Hz, 1H), 2.80-2.68 (m, 1H), 2.12 (s, 2H), 1.85-1.75 ( m, 1H), 1.44 (t, J=12.3 Hz, 1H), 1.13 (s, 3H), 1.04 (s, 9H), 1.02 (s, 3H).

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

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

Compound 220 (N-[(3R)-1-(8-cyanoquinoxalin-5-yl)-5,5-dimethylpiperidin-3-yl]-3,3,3-trifluoropropanamide): from 3,3,3-trifluoropropane acid and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.0% purity, RT=2.62 min. MS: m/z=392.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.11 (dd, J=8.4, 1.5 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 4.51-4.30 (m, 2H), 4.13-3.99 (m, 1H), 3.32-3.16 ( m, 2H), 2.94 (d, J=12.3 Hz, 1H), 2.82 (t, J=11.9 Hz, 1H), 1.90-1.81 (m, 1H), 1.47 (t, J=12.2 Hz, 1H), 1.15 (s, 3H), 1.08 (s, 3H).

Example 67: Synthesis of compound 216 (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]quinoxalin-5-carbonitrile: 8-[(5R)-5-[(2-methoxyethyl)amino ]-3,3-dimethylpiperidin-1-yl]quinoxalin-5-carbonitrile was obtained from 3,3-dimethylbutanoic acid and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxalin-5 α-carbonitrile using Method N. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 35% - 65% gradient over 8 min; detector UV 254 nm. 8-[(5R)-5-[(2-methoxyethyl)amino]-3,3-dimethylpiperidin-1-yl]quinoxalin-5-carbonitrile was obtained as a yellow oil (13 mg, 11%).

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

The following compounds were synthesized in a similar manner:

Compound 219 (8-[(5R)-3,3-dimethyl-5-[(1-methyl-2-oxopyrrolidin-3-yl)amino]piperidin-1-yl]quinoxalin-5-carbonitrile): from 2- hydroxyacetamide; and (R)-8-(5-amino-3,3-dimethylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.3% purity, RT=2.46 min. MS: m/z=379.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.05 (dd, J=8.3, 0.9 Hz, 1H), 7.20 (dd, J=8.5, 2.1 Hz, 1H), 4.59 (br.s, 1H), 3.95-3.81 (m, 1H), 3.70 (t, J=8.7 Hz, 1H), 3.48-3.35 (m, 3H), 2.89-2.80 (m, 4H), 2.67-2.48 (m, 2H), 1 .97-1.76 (m, 2H), 1.31-1.18 (m, 1H), 1.11 and 1.06 (s, 6H).

Example 68: Synthesis of compound 221 (cis-8-[3-[(2-methoxyethyl)amino]-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5-carbonitrile)

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

Compound 221: HPLC: 99.2% pure, RT=1.37 min. MS: m/z=380.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.13 (d, J=8.3 Hz, 1H), 7.28 ( d, J=8.4 Hz, 1H), 4.50-4.33 (m, 2H), 3.59-3.47 (m, 2H), 3.36 (s, 3H), 3.13 -2.79 (m, 5H), 2.76-2.66 (m, 1H), 2.45-2.37 (m, 1H), 1.43 (td, J=12.1, 12, 1 Hz, 1H).

Example 69: Synthesis of Compound 224, Compound 225, Compound 226 and Compound 227 (trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile, 8-((3R,5S)-3-(((S)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-( trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile, 8-((3S,5R)-3-(((R)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl )piperidin-1-yl)quinoxalin-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

8-((3R,5S)-3-(((R)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile, 8 -((3R,5S)-3-(((S)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile, 8- ((3S,5R)-3-(((R)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile and 8-( (3S,5R)-3-(((S)-1-methyl-2-oxopyrrolidin-3-yl)amino)-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile: To a solution of cis- 8-[3-Amino-5-(trifluoromethyl)piperidin-1-yl]quinoxalin-5-carbonitrile (228mg, 0.71mmol) in tetrahydrofuran (2mL) TEA (359.03mg, 3.55mmol) was added ), KI (353.39 mg, 2.13 mmol), 3-bromo-1-methylpyrrolidin-2-one (377.73 mg, 2.12 mmol) at room temperature. The resulting solution was stirred for 2 days at 100°C. When the reaction was complete, it was quenched by adding water (15 ml). The resulting mixture was extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 35% - 65% gradient over 10 min; detector UV 254 nm. The four enantiomers of cis-8-(3-(1-methyl-2-oxopyrrolidin-3-ylamino)-5-(trifluoromethyl)piperidin-1-yl)quinoxalin-5-carbonitrile were then prepared by chiral preparative HPLC separation under the following conditions : CHIRAL ADH column, 0.46 x 15 cm, 5 µm; mobile phase: EtOH (0.1% DEA) in hexane, 50% isocratic for 20 min; detector UV 254 nm. Four products were divided and received.

Isomer 1 : (25 mg, 8%, yellow solid) HPLC: 98.4% purity, RT=0.90 min. MS: m/z=419.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.15 (d, J=8.3 Hz, 1H), 7.31 ( d, J=8.4 Hz, 1H), 4.56-4.46 (m, 1H), 4.43-4.33 (m, 1H), 3.71 (t, J=8.7 Hz , 1H), 3.48-3.34 (m, 2H), 3.32-3.25 (m, 1H), 3.09-2.82 (m, 5H), 2.77 (dd, J =11.9, 10.6 Hz, 1H), 2.55-2.39 (m, 2H), 1.93-1.78 (m, 1H), 1.47 (sq., J=12, 1 Hz, 1H).

Isomer 2 : (25 mg, 8%, yellow solid) HPLC: 97.4% purity, RT=1.17 min. MS: m/z=407.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.99 (d, J=1.7 Hz, 1H), 8.85 (d, J=1.8 Hz, 1H), 8 .03 (d, J=8.1 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 4.56-4.42 (m, 1H), 4.38-4, 30 (m, 1H), 4.22-4.06 (m, 1H), 3.82-3.68 (m, 1H), 3.60-3.20 (m, 3H), 3.10- 2.40 (m, 8H), 2.15-1.82 (m, 1H), 1.30-1.20 (s, 1H).

Isomer 3 : (25 mg, 8%, yellow solid) HPLC: 97.1% purity, RT=0.90 min. MS: m/z=419.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.82 (m, 2H), 8.13 (d, J=8.3 Hz, 1H), 7.30 ( d, J=8.4 Hz, 1H), 4.49-4.43(m, 2H), 3.77-3.63(m 1H), 3.49-3.34(m, 2H), 3.29-3.01 (m, 1H), 3.07-2.80 (m, 5H), 2.79-2.67 (m, 1H), 2.56-2.36 (m, 2H ), 1.93-1.81 (m, 1H), 1.55-1.41 (m, 1H).

Isomer 4 : (25 mg, 8%, yellow solid) HPLC: 93.9% purity, RT=0.90 min. MS: m/z=419.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.15 (d, J=8.3 Hz, 1H), 7.31 ( d, J=8.4 Hz, 1H), 4.56-4.46 (m, 1H), 4.43-4.33 (m, 1H), 3.71 (t, J=8.7 Hz , 1H), 3.48-3.34 (m, 2H), 3.32-3.25 (m, 1H), 3.09-2.82 (m, 5H), 2.77 (dd, J =11.9, 10.6 Hz, 1H), 2.55-2.39 (m, 2H), 1.93-1.78 (m, 1H), 1.47 (sq., J=12, 1 Hz, 1H).

The following compounds were synthesized in a similar manner:

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): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine and 3-bromo-1-methylpyrrolidin-2-one. Isomer 1: 14 mg, 11%, yellow solid) HPLC: 97.0% purity, RT=1.69 min. MS: m/z=407.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.2, 1.7 Hz, 1H), 8.59 (dd, J=8.6, 1 .8 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 3.73-3.59 (m, 2H), 3.43-3.24 (m, 4H), 2.85 (s, 3H), 2.54-2, 36 (m, 3H), 2.28-2.18 (m, 1H), 2.15-2.07 (m, 1H), 1.89-1.79 (m, 1H), 1.07- 0.92 (m, 4H). Isomer 2: (11 mg, 9%, yellow solid) HPLC: 98.7% purity, RT=1.46 min. MS: m/z=407.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.2, 1.7 Hz, 1H), 8.59 (dd, J=8.6, 1 .8 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 3.73-3.59 (m, 2H), 3.43-3.24 (m, 4H), 2.85 (s, 3H), 2.54-2, 36 (m, 3H), 2.28-2.18 (m, 1H), 2.15-2.07 (m, 1H), 1.89-1.79 (m, 1H), 1.07- 0.92 (m, 4H).

Example 70: Synthesis of compound 231

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 obtained from methyl 2-bromo-2-methylpropanoic acid and 8-[(3R,5S)-3-amino-5-methylpiperidine-1- yl]quinoxaline-5-carbonitrile using Method N. The crude product was purified by flash chromatography eluting with MeOH in DCM (0%-5% gradient) to give methyl 2-[[(3R,5S)-1-( 8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]amino]-2-methylpropanoate as a yellow solid (190 mg, 61%). MS: m/z=368.2 [M+H] ⁺ .

Method 17

8-[(3R,5S)-3-[(1-hydroxy-2-methylpropan-2-yl)amino]-5-methylpiperidin-1-yl]quinoxalin-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) LiAlH ₄ ( 14 mg, 0.37 mmol). The resulting mixture was stirred for 0.5 hour at 0°C. When the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with DCM (20 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 32% - 35% gradient over 10 min; detector UV 254 nm. 8-[(3R,5S)-3-[(1-hydroxy-2-methylpropan-2-yl)amino]-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile was obtained as a yellow solid (15 mg , eleven%).

Compound 231: HPLC: 98.9% pure, RT=0.56 min. MS: m/z=340.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94 (d, J=1.7 Hz, 1H), 8.87 (d, J=1.7 Hz, 1H), 8 .10 (d, J=8.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 4.60-4.50 (m, 1H), 3.99-3, 90 (m, 1H), 3.48 (d, J=10.8 Hz, 1H), 3.40 (d, J=10.8 Hz, 1H), 3.23-3.11 (m, 1H ), 2.64-2.52 (m, 2H), 2.14-1.97 (m, 2H), 1.21-1.01 (m, 10H).

The following compounds were synthesized in a similar manner:

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, RT=1.54 min. MS: m/z=382.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.57 (dd, J=8.6, 1 .7 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.55 (dd, J=8.6, 4.2 Hz, 1H), 7.17 (d, J =8.0 Hz, 1H), 3.50-3.21 (m, 4H), 3.20-3.10 (m, 1H), 2.47-2.32 (m, 2H), 2, 17-2.01 (m, 2H), 1.07 (d, J=9.0 Hz, 6H), 0.99-0.95 (m, 4H).

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, RT=1.27 min. MS: m/z=383.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.16-8.86 (m, 2H), 8.05 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 4.70-4.47 (m, 1H), 4.23 (d, J=11.8 Hz, 1H), 3.88 (dd, J= 11.6, 3.8 Hz, 1H), 3.49-3.10 (m, 5H), 3.09-2.89 (m, 1H), 2.50-2.35 (m, 3H) , 2.03-1.87 (m, 2H), 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)

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 obtained from 1-methylpyrrolidin-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: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 44% - 46% gradient over 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%).

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

The following compounds were synthesized in a similar manner:

Compound 250 (2-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide): from 2-hydroxyacetic acid and ( 3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 99.0% purity, RT=2.60 min. MS: m/z=369.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.88 (m, 2H), 8.05 (d, J=8.3 Hz, 1H), 7.29 ( d, J=8.3 Hz, 1H), 4.31-4.23 (m, 1H), 4.18 (dd, J=11.6, 4.3 Hz, 1H), 4.10-4 .03 (m, 1H), 3.30-3.20 (m, 2H), 2.84 (dd, J=11.5, 10.4 Hz, 1H), 2.63 (dd, J=12 .1, 10.4 Hz, 1H), 2.16-2.10 (m, 2H), 1.33 (td, J=12.1, 12.1 Hz, 1H), 1.05 (d, J=6.4 Hz, 3H).

Compound 251 (1-hydroxy-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]cyclopropan-1-carboxamide): from 1- hydroxycyclopropanecarboxylic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 99.8% purity, RT=1.46 min. MS: m/z=395.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.96-8.85 (q, J=1.7 Hz, 2H), 8.05 (d, J=8.3 Hz , 1H), 7.29 (d, J=8.3 Hz, 1H), 4.28-4.00 (m, 3H), 2.88 (t, J=10.9 Hz, 1H), 2 .65 (t, J=12.0 Hz, 1H), 2.18-2.06 (m, 2H), 1.37 (td, J=12.3, 12.3 Hz, 1H), 1, 31-1.15 (m, 2H), 1.09-0.96 (m, 5H).

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, RT=2.27 min. MS: m/z=450.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.02 (d, J=1.7 Hz, 1H), 8.95 (d, J=1.7 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 4, 21-4.07 (m, 2H), 3.99-3.94 (m, 1H), 2.75-2.50 (m, 4H), 2.12 (s, 3H), 2.03- 1.87 (m, 4H), 1.80 (t, J=11.5 Hz, 2H), 1.67-1.50 (m, 3H), 1.23-1.04 (m, 3H) , 0.92 (d, J=6.3 Hz, 3H).

Compound 254 (2-(dimethylamino)-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: 97.4% purity, RT=0.98 min. MS: m/z=396.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.88 (m, 2H), 8.04 (d, J=8.3 Hz, 1H), 7.29 ( d, J=8.4 Hz, 1H), 4.30-4.16 (m, 2H), 4.11-4.07 (m, 1H), 3.01 (d, J=1.6 Hz , 2H), 2.82-2.71 (m, 1H), 2.60 (dd, J=12.2, 10.6 Hz, 1H), 2.33 (s, 6H), 2.18- 2.05 (m, 2H), 1.26 (td, J=12.4, 12.4 Hz, 1H), 1.03 (d, J=6.4 Hz, 3H).

Compound 255 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, RT=5.03 min. MS: m/z=464.5 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.86 (m, 2H), 8.08-7.99 (m, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.28-4.08 (m, 3H), 2.70-2.25 (m, 9H), 2.20-2.04 (m, 4H), 1, 80-1.62 (m, 2H), 1.58-1.40 (m, 2H), 1.25-0.90 (m, 7H).

Compound 256 -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, RT=2.62 min. MS: m/z=500.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.88 (m, 2H), 8.04 (d, J=8.4 Hz, 1H), 7.29 ( d, J=8.3 Hz, 1H), 6.15-5.85 (m, 1H), 4.27-4.08 (m, 3H), 3.02-2.94 (m, 2H) , 2.82-2.51 (m, 4H), 2.27-2.21 (m, 2H), 2.19-2.05 (m, 4H), 1.85-1.67 (m, 3H), 1.43-1.27 (m, 2H), 1.18 (td, J=12.5, 12.5 Hz, 1H), 1.02 (d, J=6.3 Hz, 3H ).

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

Compound 258 (1-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]pyrrolidin-3-carboxamide): from 3, 3-difluorocyclobutanecarboxylic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 90.4% purity, RT=1.28 min. MS: m/z=422.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.93-8.86 (m, 2H), 8.02 (d, J=8.3 Hz, 1H), 7.27 ( d, J=8.3 Hz, 1H), 4.25-4.06 (m, 3H), 3.04-2.89 (m, 2H), 2.82-2.77 (m, 1H) , 2.70-2.42 (m, 4H), 2.37 (s, 3H), 2.17-1.96 (m, 4H), 1.16 (td, J=12.4, 12, 4 Hz, 1H), 1.00 (d, J=6.4 Hz, 3H).

Compound 259 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide) : from 3,3-difluorocyclobutanecarboxylic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidine-3-amine. HPLC: 97.1% purity, RT=1.38 min. MS: m/z=451.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.10-8.95 (m, 2H), 8.07 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 4.17-3.93 (m, 3H), 3.40-3.30 ( m, 1H), 3.00-2.85 (m, 2H), 2.78 (t, J=11.1 Hz, 1H), 2.62-2.22 (m, 8H), 2.16 (s, 3H), 1.95 (d, J=11.5 Hz, 2H), 1.26 (td, J=12.3, 12.3 Hz, 1H), 0.94 (d, J= 6.3 Hz, 3H).

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

Compound 293 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(1-methylpiperidin-3-yl)acetamide) : from 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, RT=1.03 min. MS: m/z=450.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.05-8.95 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 4.25-4.07 (m, 2H), 3.99-3.87 ( m, 1H), 2.59-2.40 (m, 4H), 2.10 (s, 3H), 2.02-1.72 (m, 6H), 1.65-1.35 (m, 4H), 1.10 (td, J=12.0, 12.0 Hz, 1H), 0.95-0.78 (m, 4H).

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, RT=4.92 min. MS: m/z=436.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.03 (d, J=1.7 Hz, 1H), 8.97 (d, J=1.7 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 4, 22-4.07 (m, 2H), 3.99-3.85 (m, 1H), 2.70-2.30 (m, 9H), 2.18-2.02 (m, 3H), 2.00-1.80 (m, 3H), 1.42-1.29 (m, 1H), 1.20-1.04 (m, 1H), 0.93 (d, J=6.3 Hz, 3H).

Compound 299 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, RT=2.63 min. MS: m/z=458.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92-8.88 (m, 2H), 8.02 (d, J=8.3 Hz, 1H), 7.27 ( d, J=8.3 Hz, 1H), 4.20-4.06 (m, 3H), 3.76-3.59 (m, 4H), 3.14-3.02 (m, 1H) , 2.81-2.70 (m, 1H), 2.61-2.55 (m, 1H), 2.14-1.99 (m, 2H), 1.32-1.18 (m, 4H), 1.01 (d, J=6.4 Hz, 3H).

Example 72: Synthesis of Compound 260 and Compound 261 -2-one and (S)-3-[[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]amino]-1-methylpyrrolidin-2-one)

(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 obtained 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: XBridge Prep C18 OBD Column, 19×150 mm 10 µm; mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 20% - 55% gradient over 8 min; detector UV 254 nm. The two diastereoisomers of 3-[[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]amino]-1-methylpyrrolidin-2-one were then prepared by chiral preparative HPLC separation. under the following conditions: Chiral PAK ID-3 column, 0.46 x 10 cm, 3 µm; mobile phase: EtOH in hexane, 50% isocratic for 12 min; detector UV 254/220 nm.

Isomer 1 : (30 mg, 15%, light yellow solid) HPLC: 99.4% purity, RT=1.26 min. MS: m/z=373.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.96 (d, J=4.3 Hz, 1H), 8.72-8.65 (m, 1H), 7.86 ( d, J=8.1 Hz, 1H), 7.67 (dd, J=8.5, 4.3 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 4, 09 (t, J=9.1 Hz, 1H), 3.83-3.64 (m, 2H), 3.54-3.40 (m, 2H), 3.40-3.25 (m, 1H), 2.92 (s, 3H), 2.71 (t, J=10.5 Hz, 1H), 2.56 (dt, J=12.7, 6.9 Hz, 1H), 2, 46 (t, J=11.3 Hz, 1H), 2.34 (d, J=12.4 Hz, 1H), 2.26-2.14 (m, 1H), 2.13-1.97 (m, 1H), 1.21 (td, J=12.0, 12.0 Hz, 1H), 1.07 (d, J=6.5 Hz, 3H).

Isomer 2 : (30 mg, 15%, light yellow solid) HPLC: 99.1% purity, RT=0.98 min. MS: m/z=373.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ8.96 (d, J=4.3 Hz, 1H), 8.72-8.65 (m, 1H), 7.86 (d , J=8.1 Hz, 1H), 7.67 (dd, J=8.5, 4.3 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 4.09 (t, J=9.1 Hz, 1H), 3.83-3.64 (m, 2H), 3.54-3.40 (m, 2H), 3.40-3.25 (m, 1H ), 2.92 (s, 3H), 2.71 (t, J=10.5 Hz, 1H), 2.56 (dt, J=12.7, 6.9 Hz, 1H), 2.46 (t, J=11.3 Hz, 1H), 2.34 (d, J=12.4 Hz, 1H), 2.26-2.14 (m, 1H), 2.13-1.97 ( m, 1H), 1.21 (td, J=12.0, 12.0 Hz, 1H), 1.07 (d, J=6.5 Hz, 3H).

Example 73: Synthesis of compound 262 (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: N-[(3R,5S)- 1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-(morpholin-4-yl)acetamide was obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 20% - 39% (39.0% hold for 7 min) gradient over 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%).

Compound 262: HPLC: 99.8% pure, RT=1.43 min. MS: m/z=403.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.93 (dd, J=4.2, 1.7 Hz, 1H), 8.71 (dd, J=8.5, 1 .7 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.65 (dd, J=8.5, 4.2 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 4.31-4.24 (m, 1H), 3.73 (t, J=4.6 Hz, 4H), 3.54-3.44 (m, 1H) , 3.32-3.23 (m, 1H), 3.04 (s, 2H), 2.59-2.40 (m, 6H), 2.23-2.03 (m, 2H), 1 .21 (td, J=12.0, 12.0 Hz, 1H), 1.04 (d, J=6.5 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 263 (N-[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-hydroxyacetamide): from 2-hydroxyacetic acid and (3R,5S)- 1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.9% purity, RT=1.25 min. MS: m/z=334.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.93 (dd, J=4.2, 1.6 Hz, 1H), 8.71 (dd, J=8.5, 1 .6 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.65 (dd, J=8.5, 4.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 4.35-4.27 (m, 1H), 3.99 (s, 2H), 3.52-3.43 (m, 1H), 3.31-3, 25 (m, 1H), 2.58 (t, J=10.8 Hz, 1H), 2.45 (t, J=11.1 Hz, 1H), 2.24-2.07 (m, 2H ), 1.24 (td, J=12.0, 12.0 Hz, 1H), 1.04 (d, J=6.5 Hz, 3H).

Compound 264 (N-[(3R,5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-yl]-2-(dimethylamino)acetamide): from 2-hydroxyacetic acid and (3R, 5S)-1-(8-chloroquinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.4% purity, RT=1.50 min. MS: m/z=361.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.91 (dd, J=4.3, 1.7 Hz, 1H), 8.74-8.64 (m, 1H), 7.79 (dd, J=8.3, 0.8 Hz, 1H), 7.62 (dd, J=8.5, 4.2 Hz, 1H), 7.23-7.13 (m, 1H), 4.29-4.20(m, 1H), 3.48-3.43(m, 1H), 3.27-3.22(m, 1H), 2.97(s, 2H) , 2.51 (t, J=10.8 Hz, 1H), 2.42 (t, J=11.2 Hz, 1H), 2.28 (s, 6H), 2.17-2.06 ( m, 2H), 1.17 (td, J=12.2, 12.2 Hz, 1H), 1.02 (d, J=6.4 Hz, 3H).

Example 74: Synthesis of Compound 267

Method 18

Ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin-1-yl)propanoate: To a solution of tert-butyl N-(azetidin-3-yl)carbamate (475 mg, 2.76 mmol) in DCM (40 m) was added triethylamine (418 mg, 4.14 mmol) and ethyl 2-bromopropanoate (749 mg, 4.14 mmol) at room temperature. The resulting solution was stirred for 13 hours at room temperature. When the reaction was complete, it was quenched by adding water (10 ml). The resulting solution was extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-50% gradient) to give ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidine-1- yl) propanoate as a yellow oil (330 mg, 44%). MS: m/z=259.3 [M+H] ⁺ .

Method 19

Ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin-1-yl): To a solution of ethyl 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin-1-yl)propanoate (475 mg, 1.74 mmol) in THF (5 ml) was added 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 complete, the pH of the reaction mixture was adjusted to 5 with a solution of hydrogen chloride (2 M). The resulting mixture was extracted with DCM (50 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 2-(3-[[(tert-butoxy)carbonyl]amino]azetidin-1-yl)propanoic acid as a white solid (300 mg, 70%). MS: m/z=245.1 [M+H] ⁺

2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]propanamide: 2-(3-aminoazetidine- 1-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]propanamide was obtained from 2-(3-(tert-butoxycarbonylamino)azetidine-1 -yl)propanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile using Methods J and 6. The crude product was purified by preparative HPLC under the following conditions: XBridge column Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 24% - 31% gradient over 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 2 stages).

Compound 267: HPLC: 95.6% pure, RT=1.27 min. MS: m/z=394.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.85 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.28 ( d, J=8.5 Hz, 1H), 4.35-4.05 (m, 3H), 3.66-3.50 (m, 3H), 2.96-2.65 (m, 5H) , 2.07 (d, J=11.9 Hz, 2H), 1.33-1.22 (m, 1H), 1.16 (d, J=6.7 Hz, 3H), 1.02 ( e, J=6.3 Hz, 3H).

Example 75: Synthesis of compound 270 ((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: (3R,5S)-1-(8-cyanoquinoxaline) -5-yl)-5-methylpiperidin-3-yl 2-(3-hydroxyazetidin-1-yl)acetate was obtained from 3-(tert-butyldimethylsilyloxy)azetidine, methyl 2-bromoacetate and 8-((3R,5S)- 3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile using Method 18, 19 and J. The crude product was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD Column, 5 µm, 19 mm x 150 mm ; Mobile phase: acetonitrile in water (with 0.05% NH ₃ ^. H ₂ O), 28% - 32% gradient over 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 a yellow solid (22 mg, 10% for 3 stages).

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

The following compounds were synthesized in a similar manner:

Compound 271 ((3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl 2-(3-hydroxyazetidin-1-yl)propanoate):from 3-(tert-butyldimethylsilyloxy)azetidine, ethyl 2-bromopropanoate and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 96.9% purity, RT=1.06 min. MS: m/z=395.2 [M+H]⁺.^oneH NMR (400 MHz, CD₃OD, ppm) δ 8.95-8.85 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.27 (dd, J=8.4, 1 .1 Hz, 1H), 4.39-4.23 (m, 3H), 4.18-4.07 (m, 1H), 3.66-3.60 (m, 2H), 3.01- 2.76 (m, 4H), 2.73-2.62 (m, 1H), 2.08-2.03 (m, 2H), 1.36-1.20 (m, 1H), 1, 16 (d, J=6.8 Hz, 3H), 1.01 (d, J=6.4 Hz, 3H).

Compound 273 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(3,3-difluoroazetidin-1-yl)propanamide): from 3,3-difluoroazetidine, ethyl 2-bromopropanoate and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)quinoxaline-5-carbonitrile. HPLC: 97.0% purity, RT=1.50 min. MS: m/z=415.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.27 ( d, J=8.4 Hz, 1H), 4.34-4.21 (m, 2H), 4.20-4.06 (m, 1H), 3.77-3.58 (m, 4H) , 3.12-3.02 (m, 1H), 2.90-2.78 (m, 1H), 2.74-2.62 (m, 1H), 2.11-1.98 (m, 2H), 1.37-1.18 (m, 4H), 1.01 (d, J=6.4 Hz, 3H).

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

Compound 284 ((3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl 2-(3-hydroxyazetidin-1-yl)acetate): from 2-( 3-(tert-butyldimethylsilyloxy)azetidin-1-yl)acetic acid. HPLC: 99.9% purity, RT=1.32 min. MS: m/z=423.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.91 (dd, J=4.2, 1.7 Hz, 1H), 8.63 (dd, J=8.6, 1 .8 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 4.40-4.16 (m, 2H), 3.74-3.65 (m, 2H), 3.61-3.52 (m, 1H), 3, 41-3.32 (m, 1H), 3.15 (s, 2H), 3.01 (dd, J=8.2, 6.0 Hz, 2H), 2.60-2.40 (m, 2H), 2.20-2.05 (m, 2H), 1.19 (td, J=12.0, 12.0 Hz, 1H), 1.02 (d, J=6.4 Hz, 3H ).

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, RT=3.41 min. MS: m/z=437.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94 (dd, J=4.3, 1.7 Hz, 1H), 8.69-8.62 (m, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.63 (dd, J=8.6, 4.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H ), 4.38-4.31 (m, 1H), 4.25 (dd, J=11.7, 4.7 Hz, 1H), 3.62 (d, J=6.4 Hz, 3H) , 3.39 (d, J=12.0 Hz, 1H), 2.95 (dt, J=23.0, 6.3 Hz, 3H), 2.62-2.42 (m, 2H), 2.11-2.16 (m, 2H), 1.28-1.12 (m, 4H), 1.08-1.01 (m, 3H).

Compound 296 : from 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, RT=1.26 min. MS: m/z=424.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92-8.85 (m, 2H), 8.02 (d, J=8.4 Hz, 1H), 7.29- 7.22 (m, 1H), 4.34 (tt, J=6.1, 6.1 Hz, 1H), 4.21-416 (m, 2H), 4.08-4.05 (m, 1H), 3.71 (dd, J=8.4, 6.2 Hz, 2H), 3.17 (s, 2H), 3.05-3.01 (m, 2H), 2.78-2 .67 (m, 1H), 2.57 (t, J=11.4 Hz, 1H), 2.09-2.05 (m, 2H), 1.22 (td, J=12.7, 11 .8 Hz, 1H), 1.01 (d, J=6.4 Hz, 3H).

Compound 297 ((3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl 2-(3-hydroxyazetidin-1-yl)propanoate): from 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, RT=3.18 min. MS: m/z=438.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.88 (m, 2H), 8.04 (d, J=8.3 Hz, 1H), 7.29 ( d, J=8.3 Hz, 1H), 4.38-4.34 (m, 1H), 4.20-4.06 (m, 3H), 3.69-3.60 (m, 2H) , 3.00-2.82 (m, 3H), 2.76-2.74 (m, 1H), 2.59 (t, J=11.7 Hz, 1H), 2.18-2.04 (m, 2H), 1.33-1.14 (m, 4H), 1.03 (d, J=6.5 Hz, 3H).

Compound 308 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(3-hydroxyazetidin-1-yl)acetamide): from 2-(3-(t-butyldimethylsilyloxy)azetidin-1-yl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 97.9% purity, RT=2.52 min. MS: m/z=405.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.61 (dd, J=8.6, 1 .8 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.83-7.55 (m, 2H), 7.25 (d, J=7.9 Hz, 1H ), 4.40-4.30 (m, 1H), 4.27-4.18 (m, 1H), 3.74-3.65 (m, 2H), 3.58-3.49 (m , 1H), 3.35-3.20 (m, 1H), 3.15 (s, 2H), 3.05-2.96 (m, 2H), 2.58-2.38 (m, 2H ), 2.18-2.02 (m, 2H), 1.17 (td, J=12.0, 12.0 Hz, 1H), 1.03 (d, J=6.5 Hz, 3H) .

Compound 309 (N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-2-(3-hydroxyazetidin-1-yl)propanamide): from 2-(3-(t-butyldimethylsilyloxy)azetidin-1-yl)propanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 95.7% purity, RT=2.47 min. MS: m/z=419.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.61 (dt, J=8.6, 1 .7 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.85-7.55 (m, 2H), 7.26 (d, J=7.9 Hz, 1H ), 4.36-4.28 (m, 1H), 4.26-4.17 (m, 1H), 3.62-3.55 (m, 2H), 3.55-3.48 (m , 1H), 3.39-3.20 (m, 1H), 2.94-2.85 (m, 3H), 2.56-2.41 (m, 2H), 2.20-2.04 (m, 2H), 1.23-1.13 (m, 4H), 1.03 (d, J=6.5 Hz, 3H).

Compound 320 (N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(3-hydroxyazetidin-1-yl)acetamide): from 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, RT=2.97 min. MS: m/z=406.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.90-8.82 (m, 2H), 7.96 (d, J=8.2 Hz, 1H), 7.63 ( t, J=55.6 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 4.40-4.30 (m, 1H), 4.25-4.15 (m , 1H), 4.09 (dd, J=11.4, 4.1 Hz, 1H), 3.98 (d, J=12.0 Hz, 1H), 3.74-3.70 (m, 2H), 3.17 (s, 2H), 3.05-3.01 (m, 2H), 2.69 (t, J=11.0 Hz, 1H), 2.53 (t, J=11 .4 Hz, 1H), 2.18-2.04 (m, 2H), 1.22-1.18 (m, 1H), 1.01 (d, J=6.4 Hz, 3H).

Compound 321 (N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-2-(3-hydroxyazetidin-1-yl)propanamide): from 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, RT=1.24 min. MS: m/z=420.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.91-8.80 (m, 2H), 8.00-7.92 (m, 1H), 7.63 (t, J =55.9Hz, 1H), 7.33(d, J=8.2Hz, 1H), 4.36-4.30(m, 1H), 4.22-4.16(m, 1H) , 4.11-3.95 (m, 2H), 3.66-3.60 (m, 2H), 3.00-2.85 (m, 3H), 2.72-2.65 (m, 1H), 2.52 (t, J=11.5 Hz, 1H), 2.09 (m, 2H), 1.31-1.13 (m, 4H), 1.01 (d, J=6 .4 Hz, 3H).

Example 76: Synthesis of compound 272 (N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(2,2-difluorocyclopropyl)acetamide)

2-(2,2-difluorocyclopropyl)ethyl benzoate: But-3-en-1-ylbenzoate (2.85 g, 16.17 mmol) and trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl) acetate (7.98 g , 31.89 mmol) was mixed neat, then 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 quenched by adding water (20 ml). The resulting mixture was extracted with ethyl acetate (80 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-6% gradient) to give 2-(2,2-difluorocyclopropyl)ethyl benzoate as a yellow oil (1.84 g, 50 %). MS: m/z=227.1 [M+H] ⁺ .

2-(2,2-difluorocyclopropyl)ethan-1-ol: To a solution of 2-(2,2-difluorocyclopropyl)ethylbenzoate (900 mg, 3.98 mmol) in water (20 ml) was added sodium hydroxide (1.60 g , 40.00 mmol) 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×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 2-(2,2-difluorocyclopropyl)ethan-1-ol as a colorless liquid (210 mg, 43%). GCMS: m/z=122 [M] ⁺ .

2-(2,2-difluorocyclopropyl)acetic acid: at 0°C, water (92 ml) was added to a solution of CrO ₃ (5.70 g, 57.00 mmol) in sulfuric acid (8.3 ml). A solution of 2-(2,2-difluorocyclopropyl)ethan-1-ol (180 mg, 1.47 mmol) in acetone (30 ml) was then added dropwise over 20 minutes. The resulting mixture was stirred for 4 hours at room temperature. When the reaction was complete, the reaction mixture was extracted with ether (50 ml x 4). The organic layers were combined, washed with 2 M sodium hydroxide solution (50 ml ×4) and the aqueous layers were combined. The resulting aqueous solution was adjusted to pH 1 with sulfuric acid and extracted with ether (50 mL×4). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 2-(2,2-difluorocyclopropyl)acetic acid as a colorless oil (117 mg, 58%). GCMS: m/z=136 [M] ⁺ .

(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 obtained from 3-(tert-butyldimethylsilyloxy)azetidine, ethyl 2-bromopropanoate and 8-((3R, 5S)-3-amino-5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile using Method J. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.1% NH ₃ ^. H ₂ O), 30% - 60% gradient over 7 min; 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%).

Compound 272: HPLC: 98.5% pure, RT=1.45 min. MS: m/z=386.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.10 (d, J=8.4 Hz, 1H), 7.30 ( d, J=8.4 Hz, 1H), 4.45-4.36 (m, 1H), 4.32 (d, J=12.7 Hz, 1H), 4.21-4.09 (m , 1H), 2.82-2.62 (m, 2H), 2.51-2.30 (m, 2H), 2.16-1.83 (m, 3H), 1.62-1.48 (m, 1H), 1.33-1.07 (m, 2H), 1.02 (d, J=6.4 Hz, 3H).

The following compounds were synthesized in a similar manner:

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, RT=1.77 min. MS: m/z=428.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.97-8.91 (m, 1H), 8.74-8.62 (m, 1H), 8.03 (d, J =8.0 Hz, 1H), 7.64 (dd, J=8.6, 4.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 4.24 (m , 1H), 3.69-3.60 (m, 1H), 3.44-3.35 (m, 1H), 2.56-2.39 (m, 3H), 2.33 (dd, J =15.4, 7.4 Hz, 1H), 2.24-2.09 (m, 2H), 2.00-1.80 (m, 1H), 1.61-1.45 (m, 1H ), 1.23-0.97 (m, 5H).

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, RT=1.73 min. MS: m/z=429.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-.88 (m, 2H), 8.10 (d, J=8.3 Hz, 1H), 7.35 (d , J=8.4 Hz, 1H), 4.34-4.14 (m, 3H), 2.78-2.28 (m, 4H), 2.22-2.11 (m, 2H), 2.05-1.86 (m, 1H), 1.66-1.52 (m, 1H), 1.31-1.13 (m, 2H), 1.08 (d, J=6.4 Hz, 3H).

Compound 310 (2-(2,2-difluorocyclopropyl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide): from 2 -(2,2-difluorocyclopropyl)acetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 99.3% purity, RT=1.46 min. MS: m/z=410.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.91 (dd, J=4.1, 1.7 Hz, 1H), 8.67-8.60 (m, 1H), 7.95 (d, J=7.9 Hz, 1H), 7.85-7.54 (m, 2H), 7.26 (d, J=7.9 Hz, 1H), 4.28-4 .20 (m, 1H), 3.65-3.56 (m, 1H), 3.40-3.34 (m, 1H), 2.52-2.41 (m, 3H), 2.32 (dd, J=15.6, 7.8 Hz, 1H), 2.24-2.08 (m, 2H), 1.96-1.84 (m, 1H), 1.58-1.49 (m, 1H), 1.22-1.01 (m, 5H).

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

Example 77: Synthesis of compound 274

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

2-(azetidin-3-yl)-N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide: at 0°C to tert-butyl 3 -([[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]carbamoyl]methyl)azetidine-1-carboxylate (85 mg, 0.18 mmol) solution was added HF-Pyridine (7 ml) drop by drop. The resulting solution was stirred for an additional 2 hours at room temperature. When the reaction was complete, it was quenched by adding water (15 ml). The resulting mixture was extracted with DCM (30 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0%-10% gradient) to give 2-(azetidin-3-yl)-N-[(3R,5S)-1- (8-cyanoquinoxalin-5-yl)-5-methylpiperidin-3-yl]acetamide as a yellow solid (14 mg 21%).

Compound 274: HPLC: 91.4% pure, RT=2.80 min. MS: m/z=365.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.80 (m, 2H), 8.10-7.98 (m, 1H), 7.22 (d, J =8.4Hz, 1H), 4.28(t, J=14.1Hz, 2H), 4.13-3.85(m, 3H), 3.65(t, J=8.4Hz , 2H), 3.13 (dt, J=15.7, 7.8 Hz, 1H), 2.77-2.42 (m, 4H), 2.12-1.92 (m, 2H), 1.25-0.92 (m, 4H).

Example 78: Synthesis of compound 276 )acetamide)

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 obtained 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. Crude the product was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), 27% - 28% gradient over 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 in as a yellow solid (12 mg, 5% for 3 steps).

Compound 276: HPLC: 96.6% pure, RT=1.08 min. MS: m/z=422.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 7.24 ( d, J=8.5 Hz, 1H), 4.38-4.12 (m, 3H), 3.15 (s, 2H), 2.90-2.60 (m, 10H), 2.37 (s, 3H), 2.14-1.94 (m, 2H), 1.90-1.74 (m, 2H), 1.29 (d, J=12.4 Hz, 1H), 1, 00 (d, J=6.4 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 290 3-yl]acetamide): from 2-(4-methyl-1,4-diazepan-1-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoline-5- yl) piperidine-3-amine. HPLC: 96.5% purity, RT=1.47 min. MS: m/z=464.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.2, 1.8 Hz, 1H), 8.65 (dd, J=8.6, 1 .8 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.61 (dd, J=8.6, 4.2 Hz, 1H), 7.22 (d, J =8.0 Hz, 1H), 4.28 (t, J=11.4 Hz, 1H), 3.58 (d, J=11.0 Hz, 1H), 3.38 (d, J=11 .7 Hz, 1H), 3.18-3.14 (m, 2H), 2.81-2.30 (m, 13H), 2.23-2.03 (m, 2H), 1.83 ( sq., J=5.7 Hz, 2H), 1.25 (td, J=11.9, 11.9 Hz, 1H), 1.04 (d, J=6.4 Hz, 3H).

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- methylpiperidine-3-amine. HPLC: 95.3% purity, RT=2.46 min. MS: m/z=446.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.91 (dd, J=4.3, 1.8 Hz, 1H), 8.65 (dd, J=8.5, 1 .8 Hz, 1H), 8.00-7.54 (m, 3H), 7.29 (d, J=7.9 Hz, 1H), 4.36-4.24 (m, 1H), 3 .61-3.52 (m, 1H), 3.44-3.30 (m, 1H), 3.18 (s, 2H), 2.84-2.67 (m, 8H), 2.64 -2.44(m, 2H), 2.41(s, 3H), 2.27-2.08(m, 2H), 1.87-1.81(m, 2H), 1.26(td , J=12.1, 12.0 Hz, 1H), 1.06 (d, J=6.4 Hz, 3H).

Compound 326 -yl)acetamide): from 2-(4-methyl-1,4-diazepan-1-yl)acetic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5- methylpiperidine-3-amine. HPLC: 87.1% purity, RT=1.29 min. MS: m/z=447.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.85 (m, 2H), 7.97 (d, J=8.2 Hz, 1H), 7.63 ( t, J=56.0 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H), 4.32-4.18 (m, 1H), 4.13-4.09 (m , 1H), 4.00-3.98 (m, 1H), 3.20-2.95 (m, 2H), 2.83-2.64 (m, 9H), 2.55 (t, J =11.3 Hz, 1H), 2.39 (s, 3H), 2.13-2.07 (m, 2H), 1.90-1.76 (m, 2H), 1.30-1, 24 (m, 1H), 1.12-0.99 (m, 3H).

Compound 362 3-yl]acetamide): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine and 2-(4-methyl-1,4-diazepane -1-yl)acetic acid. HPLC: 93.7% purity, RT=2.36 min. MS: m/z=465.1 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.86 (m, 2H), 8.04 (d, J=8.3 Hz, 1H), 7.28 ( d, J=8.3 Hz, 1H), 4.23-4.09 (m, 3H), 3.21 (s, 2H), 2.86-2.60 (m, 10H), 2.49 (s, 3H), 2.12-2.08 (m, 2H), 1.89-1.85 (m, 2H), 1.36-1.20 (m, 1H), 1.04 (d , J=6.3 Hz, 3H).

Example 79: Synthesis of compound 280 )

Method 20

2-bromo-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide: To (3R,5S)-5-methyl solution -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, 42 mmol), T ₃ P (817 mg, 2.57 mmol), DIEA (551 mg, 4.26 mmol) at room temperature. The resulting solution was stirred for 14 hours at room temperature. When the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with DCM (50 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give 2-bromo-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide as a yellow solid (400 mg, crude product).

(Note: Method 20 can also use dichloromethane instead of N,N-dimethylformamide as a solvent)

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)azetidine- 3-yl]carbamate was obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), 30% - 45% gradient over 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 2 steps). MS: m/z=522.3 [M+H] ⁺ .

Method 21

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) trifluoroacetic acid (0.5 ml) was added at room temperature. The resulting solution was stirred for 12 hours at room temperature. When the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O), 30% - 45% gradient over 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 white solids (7 mg, 44%).

Compound 280: HPLC: 92.4% pure, RT=2.48 min. MS: m/z=422.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.3, 1.7 Hz, 1H), 8.64 (dd, J=8.6, 1 .8 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (d, J =8.0 Hz, 1H), 4.30-4.16 (m, 1H), 3.70-3.53 (m, 4H), 3.38 (d, J=11.5 Hz, 1H) , 3.14 (s, 2H), 2.98-2.90 (m, 2H), 2.60-2.40 (m, 2H), 2.22-2.08 (m, 2H), 1 .20 (td, J=12.0, 12.0 Hz, 1H), 1.03 (d, J=6.5 Hz, 3H).

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: 2-( 3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]propanamide was obtained from 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 37% gradient over 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 white solids (17 mg, 17% for 2 steps).

Compound 281: HPLC: 99.2% pure, RT=2.51 min. MS: m/z=436.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.2, 1.7 Hz, 1H), 8.63 (dt, J=8.6, 1 .8 Hz, 1H), 8.02 (d, J=8.1 Hz, 1H), 7.61 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (d, J =8.0 Hz, 1H), 4.29-4.15 (m, 1H), 3.61-3.47 (m, 4H), 3.41-3.33 (m, 1H), 2, 91-2.75 (m, 3H), 2.59-2.41 (m, 2H), 2.21-2.05 (m, 2H), 1.31-1.09 (m, 4H), 1.03 (d, J=6.4 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 282 (2-amino-2-cyclopropyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide): from 2- (tert-butoxycarbonylamino)-2-cyclopropylacetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinolin-5-yl)piperidine-3-amine. HPLC: 96.3% purity, RT=1.76 min. MS: m/z=407.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 9.19-9.04 (m, 2H), 8.26 (d, J=6.2 Hz, 1H), 7.98- 7.95 (m, 1H), 7.42 (t, J=7.8 Hz, 1H), 4.26-4.25 (m, 1H), 3.69 (d, J=11.4 Hz , 1H), 3.48 (d, J=11.3 Hz, 1H), 3.15 (dd, J=9.7, 4.8 Hz, 1H), 2.77-2.53 (m, 2H), 2.25-2.05 (m, 2H), 1.28-1.23 (m, 2H), 1.03 (d, J=6.3 Hz, 3H), 0.84-0 .58 (m, 3H), 0.56-0.45 (m, 1H).

Compound 288 (2-(azetidin-3-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]acetamide): from 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, RT=4.98 min. MS: m/z=407.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.13-9.00 (m, 2H), 8.23 (d, J=8.2 Hz, 1H), 7.92 ( dd, J=8.6, 4.8 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 4.28-4.08 (m, 3H), 3.93 (t , J=8.9 Hz, 2H), 3.70 (d, J=11.1 Hz, 1H), 3.48 (d, J=11.7 Hz, 1H), 3.30-3.16 (m, 1H), 2.69-2.52 (m, 4H), 2.25-2.09 (m, 2H), 1.21 (td, J=14.0, 11.9 Hz, 1H ), 1.04 (d, J=6.3 Hz, 3H).

Compound 291 (4-amino-3,3-dimethyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]butanamide): from 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, RT=1.09 min. MS: m/z=423.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.3, 1.7 Hz, 1H), 8.61 (dd, J=8.6, 1 .8 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.58 (dd, J=8.6, 4.2 Hz, 1H), 7.17 (d, J =8.0 Hz, 1H), 4.23-4.16 (m, 1H), 3.63-3.52 (m, 1H), 3.35 (apparent d, J=12.0 Hz, 1H ), 2.64 (s, 2H), 2.52-2.38 (m, 2H), 2.18 (s, 2H), 2.13-2.04 (m, 2H), 1.29- 0.96 (m, 10H).

Compound 476 ):from (3R,5S)-1-[8-(trifluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-amine; and (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid. HPLC: >99% purity, RT=2.69 min. MS: m/z=397.2 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d₆, ppm) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1.8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.7 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H), 7 .19 (d, J=8.1 Hz, 1H), 4.67 (t, J=5.6 Hz, 1H), 3.48 (dt, J=10.2, 5.0 Hz, 2H) , 3.42-3.33 (m, 2H), 3.17 (dd, J=6.2, 4.9 Hz, 1H), 2.42 (t, J=11.4 Hz, 1H), 2.14-1.93(m, 2H), 1.78(s, 2H), 1.16(q, J=12.1Hz, 1H), 0.95(d, J=6.5 Hz, 3H).

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-methylbutyric acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.54 (dd, J=8.6, 1.8 Hz, 1H), 8.21 (d, J=7.5 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.68 (dd, J=8.6, 4.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 3.61-3.46 (m, 1H), 2.47-2.34 (m, 2H), 2.10 (s, 4H), 1.68 (s, 2H), 1.06 (s, 6H), 0.96 (d, J=6.5 Hz, 3H). 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)

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 obtained from 2-(1-methylpiperidin-3-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine using Methods J and 6. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 column OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), 30% - 55% gradient over 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 a yellow solid (30 mg, 38% for 2 stages).

Compound 294: HPLC: 99.3% pure, RT=1.46 min. MS: m/z=408.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.88 (m, 2H), 8.05 (d, J=8.3 Hz, 1H), 7.29 ( d, J=8.3 Hz, 1H), 4.26-4.20 (m, 2H), 4.11 (dd, J=12.3, 3.3 Hz, 1H), 2.77-2 .53 (m, 3H), 2.18-2.05 (m, 2H), 1.31-1.17 (m, 1H), 1.11-0.96 (m, 4H), 0.64 -0.44 (m, 3H), 0.40-0.31 (m, 1H).

The following compounds were synthesized in a similar manner:

Compound 300 (2-(azetidin-3-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]acetamide): from 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid and (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine. HPLC: 91.9% purity, RT=5.29 min. MS: m/z=408.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.02 (d, J=1.8 Hz, 1H), 8.96 (d, J=1.8 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.27 (d, J=8.4 Hz, 1H), 4.21-4.05 (m , 2H), 4.00-3.84 (m, 1H), 3.63-3.40 (m, 4H), 2.81-2.48 (m, 3H), 2.39 (d, J =7.7 Hz, 2H), 1.99-1.94 (m, 2H), 1.12 (td, J=12.0, 12.0 Hz, 1H), 0.92 (d, J= 6.3 Hz, 3H).

Compound 301 (4-amino-3,3-dimethyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]butanamide): from 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, RT=1.06 min. MS: m/z=424.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (d, J=7.3 Hz, 2H), 8.05 (d, J=8.3 Hz, 1H), 7 .29 (d, J=8.3 Hz, 1H), 4.31-4.05 (m, 3H), 2.78-2.46 (m, 4H), 2.19 (s, 2H), 2.13-2.10 (m, 2H), 1.19 (td, J=12.2, 12.2 Hz, 1H), 1.03 (d, J=5.1 Hz, 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: 2-(3 -aminoazetidin-1-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide was obtained from 2-bromoacetic acid, tert- butyl azetidin-3-ylcarbamate and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine using Methods 20, 18 and 6. The crude product was purified by preparative HPLC at following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 30% - 60% gradient over 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 a white solid substances (20 mg, 12% for 3 stages).

Compound 304: HPLC: 92.6% pure, RT=2.72 min. MS: m/z=404.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.88 (dd, J=4.3, 1.7 Hz, 1H), 8.66-8.57 (m, 1H), 8.00-7.86 (m, 1H), 7.85-7.51 (m, 2H), 7.25 (d, J=7.9 Hz, 1H), 4.27-4.19 ( m, 1H), 3.68-3.61 (m, 2H), 3.62-3.49 (m, 2H), 3.42-3.32 (m, 1H), 3.14 (s, 2H), 2.98-2.90 (m, 2H), 2.58-2.38 (m, 2H), 2.21-2.00 (m, 2H), 1.18 (td, J= 12.0, 12.0 Hz, 1H), 1.02 (d, J=6.4 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 361 : from (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine, 2-bromoacetic acid and tert-butyl azetidin-3-ylcarbamate. HPLC: 99.1% purity, RT=2.27 min. MS: m/z=423.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.02 (d, J=1.7 Hz, 1H), 8.97 (d, J=1.6 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 4, 12-3.92 (m, 3H), 3.5-3.53 (m, 2H), 3.41-3.39 (m, 1H), 3.06-2.90 (m, 2H), 2.84-2.64 (m, 3H), 2.58-2.55 (m, 1H), 1.92-1.88 (m, 2H), 1.26-1.16 (m, 1H ), 0.93 (d, J=6.3 Hz, 3H).

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, RT=1.21 min. MS: m/z=405.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92-8.82 (m, 2H), 7.96 (d, J=8.2 Hz, 1H), 7.80- 7.51 (m, 1H), 7.33 (d, J=8.1 Hz, 1H), 4.28-4.05 (m, 2H), 4.04-3.94 (m, 1H) , 3.82-3.68 (m, 3H), 3.25-3.12 (m, 4H), 2.69-2.64 (m, 1H), 2.53-2.49 (m, 1H), 2.09-2.05 (m, 2H), 1.31-1.12 (m, 1H), 1.01 (d, J=6.4 Hz, 3H).

Example 83: Synthesis of compound 305

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 obtained from 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 preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ ), 37% - 39% gradient over 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 a white solid substances (29 mg, 23% for 2 stages).

Compound 305: HPLC: 94.5% pure, RT=1.37 min. MS: m/z=418.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.58 (d, J=8.6 Hz, 1H), 7.95-7.43 (m, 3H), 7.22 (d, J=7.9 Hz, 1H), 4.26-4.12 (m, 1H), 3.61-3 .42 (m, 4H), 3.40-3.20 (m, 1H), 2.91-2.74 (m, 3H), 2.56-2.35 (m, 2H), 2.16 -1.96 (m, 2H), 1.25-1.05 (m, 4H), 1.00 (d, J=6.4 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 306 (2-amino-2-cyclopropyl-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide): from 2-( tert-butoxycarbonylamino)-2-cyclopropylacetic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 84.9% purity, RT=2.57+2.60 min. MS: m/z=389.2 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.92 (d, J=3.7 Hz, 1H), 8.54-8.50(m, 1H), 7.99- 7.56 (m, 2H), 7.50-7.47 (m, 1H), 7.19-6.98 (m, 2H), 4.34-4.26 (m, 1H), 3. 71-3.59 (m, 1H), 3.32-3.28 (m, 1H), 2.85-2.70 (m, 1H), 2.42 (apparent square, J=11.3 Hz, 2H), 2.22-1.75 (m, 4H), 1.13-0.92 (m, 5H), 0.68-0.47 (m, 3H), 0.32-0, 23 (m, 1H).

Compound 312 (2-(azetidin-3-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]acetamide): from 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, RT=6.65 min. MS: m/z=389.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.90 (dd, J=4.3, 1.8 Hz, 1H), 8.62 (dd, J=8.7, 1 .8 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.85-7.50 (m, 2H), 7.26 (d, J=7.9 Hz, 1H ), 4.22 (d, J=12.4 Hz, 1H), 3.96-3.75 (m, 2H), 3.65-3.45 (m, 3H), 3.24-3, 05 (m, 2H), 2.63-2.36 (m, 4H), 2.20-2.08 (m, 2H), 1.22-0.94 (m, 4H).

Compound 315 (4-amino-N-[(3R,5S)-1-[8-(difluoromethyl)quinolin-5-yl]-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): from 4- [[(t-butoxy)carbonyl]amino]-3,3-dimethylbutanoic acid and (3R,5S)-1-(8-(difluoromethyl)quinolin-5-yl)-5-methylpiperidin-3-amine. HPLC: 95.7% purity, RT=5.17 min. MS: m/z=405.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.59 (dd, J=8.6, 1 .7 Hz, 1H), 7.94-7.45 (m, 3H), 7.22 (d, J=7.9 Hz, 1H), 4.28-4.11 (m, 1H), 3 .55-3.50 (m, 1H), 3.40-3.20 (m, 1H), 2.56 (s, 2H), 2.53-2.33 (m, 2H), 2.19 -2.02 (m, 4H), 1.18-1.07 (m, 1H), 0.98-0.88 (m, 9H).

Compound 324 (2-(azetidin-3-yl)-N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]acetamide): from 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, RT=1.15 min. MS: m/z=390.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.85 (m, 2H), 7.96 (d, J=8.1 Hz, 1H), 7.63 ( t, J=55.9 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 4.22-4.01 (m, 2H), 3.94-3.90 (m , 2H), 3.66-3.62 (m, 2H), 3.23-3.09 (m, 1H), 2.65-2.44 (m, 4H), 2.10-2.03 (m, 2H), 1.13 (td, J=12.4, 12.4 Hz, 1H), 1.00 (d, J=6.4 Hz, 3H).

Compound 327 (4-amino-N-[(3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide): from 4- [[(t-butoxy)carbonyl]amino]-3,3-dimethylbutanoic acid and (3R,5S)-1-[8-(difluoromethyl)quinoxalin-5-yl]-5-methylpiperidin-3-amine. HPLC: 90.8% purity, RT=1.29 min. MS: m/z=406.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.93-8.82 (m, 2H), 7.96 (d, J=8.1 Hz, 1H), 7.63 ( t, J=56.0 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 4.23-3.95 (m, 3H), 2.67-2.56 (m , 3H), 2.50 (t, J=11.4 Hz, 1H), 2.19 (s, 2H), 2.11-2.08 (m, 2H), 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)

cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine: cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3- the 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), hold at 36%, 10 min gradient; detector UV 254 nm. cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine was obtained as a yellow solid (20 mg, 6.5% for 2 steps).

Compound 330: HPLC: 96.7% pure, RT=1.62 min. MS: m/z=337.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.01 (d, J=1.8 Hz, 1H), 8.96 (d, J=1.7 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.28-7.16 (m, 1H), 4.18-4.07 (m, 2H), 2.97-2.81 ( m, 1H), 2.77-2.61 (m, 1H), 2.60-2.57 (m, 2H), 2.50-2.20 (m, 1H), 2.10-2, 03 (m, 1H), 1.15-0.99 (m, 2H), 0.63-0.51 (m, 1H), 0.48-0.34 (m, 2H), 0.24- 0.11 (m, 2H).

The following compounds were synthesized in a similar manner:

Compound 331 (cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine): from 5-bromo-8-(trifluoromethyl)quinoline and tert-butyl cis-5-cyclopropylpiperidine -3-ylcarbamate. HPLC: 93.2% purity, RT=2.71 min. MS: m/z=336.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.8 Hz, 1H), 8.50 (dd, J=8.7, 1 .8 Hz, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.55 (dd, J=8.6, 4.2 Hz, 1H), 7.20 (d, J =8.0 Hz, 1H), 3.55-3.38 (m, 2H), 3.20-3.03 (m, 1H), 2.63-2.44 (m, 2H), 2, 25 (d, J=10.9 Hz, 1H), 1.28-1.03 (m, 2H), 0.66-0.34 (m, 3H), 0.28-0.09 (m, 2H).

Compound 333 (cis-5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-amine): from 5-bromo-8-fluoroquinoline and t-butyl cis-5-cyclopropylpiperidin-3-ylcarbamate. HPLC: 99.3% purity, RT=1.20 min. MS: m/z=286.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.86 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dt, J=8.6, 1 .6 Hz, 1H), 7.61 (dd, J=8.6, 4.3 Hz, 1H), 7.42 (dd, J=10.7, 8.4 Hz, 1H), 7.22 (dd, J=8.4, 4.2 Hz, 1H), 3.40-3.25 (m, 2H), 3.22-3.08 (m, 1H), 2.62-2.42 (m, 2H), 2.26 (d, J=10.7 Hz, 1H), 1.31-1.07 (m, 2H), 0.67-0.37 (m, 3H), 0, 29-0.10 (m, 2H).

Compound 334 (cis-5-cyclopropyl-1-(8-methoxyquinolin-5-yl)piperidin-3-amine): from 5-bromo-8-fluoroquinoline and t-butyl cis-5-cyclopropylpiperidin-3-ylcarbamate. HPLC: 98.0% purity, RT=1.11 min. MS: m/z=298.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.80 (dd, J=4.3, 1.7 Hz, 1H), 8.57 (dd, J=8.6, 1 .7 Hz, 1H), 7.57 (dd, J=8.5, 4.3 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 4.05 (s, 3H), 3.40-3.10 (m, 3H), 2.60-2.40 (m, 2H), 2.27 (d, J=10.8Hz, 1H), 1.28-1.07(m, 2H), 0.71-0.56(m, 1H), 0.44-0.48(m, 2H), 0 .18-0.23(m, 2H).

Example 85: Synthesis of compound 332 (cis-5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin-3-amine)

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- bromquinoline and t-butyl cis-5-cyclopropylpiperidin-3-ylcarbamate using Method R. The crude product was purified by flash chromatography eluting with EtOAc in hexane to give t-butyl cis-N-[5-methyl-1-[ 8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate as a yellow solid (400 mg, 48%).

Method 22

tert-Butyl cis-N-[5-cyclopropyl-1-(8-iodoquinolin-5-yl)piperidin-3-yl]carbamate: To a solution of tert-butyl cis-N-[5-cyclopropyl-1-(quinoline- 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 complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane to give t-butyl cis-N-[5-cyclopropyl-1-(8-iodoquinolin-5-yl)piperidin-3-yl]carbamate as a yellow solid (350 mg, 69%). MS: m/z=494.2 [M+H] ⁺ .

Method 23

tert-butyl cis-N-[5-cyclopropyl-1-(8-ethenylquinolin-5-yl)piperidin-3-yl]carbamate: To a solution of cis-N-[5-cyclopropyl-1-(8-iodoquinoline-5 -yl)piperidin-3-yl]carbamate (350 mg, 0.67 mmol) in toluene (40 ml) was added Pd(PPh ₃ ) 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 x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . 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%). MS: m/z=394.2 [M+H] ⁺ .

Method 24

tert-butyl cis-N-[5-cyclopropyl-1-(8-formylquinolin-5-yl)piperidin-3-yl]carbamate: To 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) was added OsO ₄ (13 mg, 0.05 mmol), NaIO ₄ (435 mg, 1.93 mmol) and water (2.3 ml) at room temperature. The reaction mixture was stirred for 2 hours at room temperature. When the reaction was complete, it was quenched by adding a saturated solution of Na ₂ S ₂ O ₃ (10 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure. This gave t-butyl cis-N-[5-cyclopropyl-1-(8-formylquinolin-5-yl)piperidin-3-yl]carbamate as a yellow solid (150 mg, 79%). MS: m/z=396.2 [M+H] ⁺ .

tert-butyl cis-N-[5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin-3-yl]carbamate: To a solution of tert-butyl cis-N-[5-cyclopropyl-1- (8-Formylquinolin-5-yl)piperidin-3-yl]carbamate (150mg, 0.36mmol) in DCM (8mL) BAST (252mg, 1.08mmol) was added at room temperature. The resulting solution was stirred for 2 hours at room temperature. When the reaction was complete, it was quenched by adding saturated sodium bicarbonate solution (30 ml). The resulting mixture was extracted with ethyl acetate (30 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane to give t-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] ⁺ .

cis-5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin-3-amine: cis-5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin-3- the amine was prepared from t-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 at aid MeOH in DCM (0% - 10% gradient). cis-5-cyclopropyl-1-[8-(difluoromethyl)quinolin-5-yl]piperidin-3-amine was obtained as a light yellow solid (14 mg, 40%).

Compound 332: HPLC: 99.3% pure, RT=1.29 min. MS: m/z=318.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.51 (dd, J=8.6, 1 .8 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.88-7.48 (m, 2H), 7.28 (d, J=7.9 Hz, 1H ), 3.67-3.38 (m, 2H), 3.28-3.07 (m, 1H), 2.61 (t, J=10.9 Hz, 1H), 2.52 (t, J=10.8 Hz, 1H), 2.37-2.20 (m, 1H), 1.29-1.10 (m, 2H), 0.47-0.60 (m, 1H), 0 .55-0.36 (m, 2H), 0.23-0.18 (m, 2H).

Example 86: Synthesis of compound 335 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: cis-N-[5-cyclopropyl- 1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide was obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm×150 mm; Mobile phase: acetonitrile in water (with 0.0.5% NH ₃ .H ₂ O), 46% - 52% gradient over 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 a light yellow solid (11 mg, 13%).

Compound 335: HPLC: 97.2% pure, RT=0.90 min. MS: m/z=464.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.95-8.85 (m, 2H), 8.05 (d, J=8.3 Hz, 1H), 7.29 ( d, J=8.3 Hz, 1H), 4.19-4.11 (m, 3H), 3.88-3.62 (m, 4H), 3.22-2.98 (m, 2H) , 2.94-2.74 (m, 2H), 2.69-2.42 (m, 4H), 2.22 (d, J=12.5 Hz, 1H), 1.48 (d, J =11.7 Hz, 1H), 1.40-1.13 (m, 1H), 0.67-0.64 (m, 1H), 0.52-0.49 (m, 2H), 0, 24 (dt, J=6.7, 2.6 Hz, 2H).

The following compounds were synthesized in a similar manner:

Compound 336 (cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(morpholin-4-yl)acetamide): from 2-(morpholine -4-yl)acetic acid; and cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine. HPLC: 99.3% purity, RT=1.91 min. MS: m/z=463.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.3, 1.7 Hz, 1H), 8.60 (dt, J=8.6, 1 .6 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.26-7.19 (m, 1H), 4.25-4.17 (m, 1H), 3.71 (t, J=4.7 Hz, 4H), 3.62-3.53 (m, 1H), 3, 52-3.43 (m, 1H), 3.02 (d, J=1.3 Hz, 2H), 2.70 (t, J=11.3 Hz, 1H), 2.65-2.47 (m, 5H), 2.22 (d, J=12.3 Hz, 1H), 1.41 (q, J=12.0 Hz, 1H), 1.26 (q, J=10, 5 Hz, 1H), 0.67-0.60 (m, 1H), 0.51-0.48 (m, 2H), 0.30-0.15 (m, 2H).

Compound 338 (cis-N-[5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(4-methylpiperazin-1-yl)acetamide): from 2- (4-methylpiperazin-1-yl)acetic acid and cis-5-cyclopropyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine. HPLC: 96.7% purity, RT=3.28 min. MS: m/z=476.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.92 (dd, J=4.3, 1.7 Hz, 1H), 8.61 (dd, J=8.6, 1 .7 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.23 (d, J =8.0 Hz, 1H), 4.27-4.14 (m, 1H), 3.63-3.54 (m, 1H), 3.47 (d, J=11.2 Hz, 1H) , 3.04 (d, J=1.6 Hz, 2H), 2.75-2.40 (m, 10H), 2.32-2.20 (m, 4H), 1.40 (sq., J=11.9Hz, 1H), 1.27(t, J=10.5Hz, 1H), 0.71-0.58(m, 1H), 0.55-0.41(m, 2H ), 0.30-0.16 (m, 2H).

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)

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 obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 52% - 59% gradient over 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 solids (20 mg, 23%).

Compound 337: HPLC: 93.0% pure, RT=2.58 min. MS: m/z=477.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.94-8.90 (m, 1H), 8.61-8.55 (m, 1H), 8.03 (dd, J =10.8, 8.0 Hz, 1H), 7.62-7.57 (m, 1H), 7.27 (dd, J=16.4, 8.1 Hz, 1H), 4.81 ( d, J=12.2 Hz, 1H), 3.69 (t, J=4.7 Hz, 2H), 3.52-3.45 (m, 3H), 3.40-3.10 (m , 3H), 3.05 (s, 2H), 2.90-2.80 (m, 2H), 2.70-2.40 (m, 5H), 2.20-2.00 (m, 1H ), 1.70 (dt, J=24.3, 12.0 Hz, 1H), 1.42-1.22 (m, 1H), 0.73-0.59 (m, 1H), 0. 57-0.38 (m, 2H), 0.33-0.09 (m, 2H).

Example 88: Synthesis of Compound 339 and Compound 340 -yl)-5-methylpiperidin-3-amine)

(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-fluorobenzamine, 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: XBridge Shield RP18 OBD Column, 19×150 mm 10 µm; mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O), 5% - 47% gradient over 10 min; detector UV 254 nm. The two enantiomeric isomers were then obtained by chiral preparative HPLC separation under the following conditions: CHIRALPAK IE column, 2×25 cm, 5 µm; mobile phase: EtOH in hexane, 30% isocratic for 25 min; detector UV 254/220 nm.

Isomer 1 : (35 mg, 0.13%, yellow solid, for 7 steps) HPLC: 95.2% purity, RT=2.57 min. MS: m/z=261.0 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.05-8.93 (m, 2H), 7.57 (dd, J=10.2, 8.7 Hz, 1H) , 7.15 (dd, J=8.7, 4.9 Hz, 1H), 3.83-3.64 (m, 2H), 3.40-3.20 (m, 2H), 3.03 -2.87(m, 1H), 2.31-2.21(m, 2H), 1.97-1.87(m, 2H), 0.98-0.72(m, 4H).

Isomer 2 : (33 mg, 0.12%, yellow solid, for 7 steps) HPLC: 97.3% purity, RT=2.58 min. MS: m/z=261.0 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.05-8.93 (m, 2H), 7.57 (dd, J=10.2, 8.7 Hz, 1H) , 7.15 (dd, J=8.7, 4.9 Hz, 1H), 3.83-3.64 (m, 2H), 3.40-3.20 (m, 2H), 3.03 -2.87(m, 1H), 2.31-2.21(m, 2H), 1.97-1.87(m, 2H), 0.98-0.72(m, 4H).

Example 89: Synthesis of compound 341 ((3R,5S)-1-(8-fluoroquinolin-5-yl)-5-methylpiperidin-3-amine)

(3R,5S)-1-(8-fluoroquinolin-5-yl)-5-methylpiperidin-3-amine: (3R,5S)-1-(8-fluoroquinolin-5-yl)-5-methylpiperidin-3- the amine was prepared in 35% yield for 2 steps from 5-bromo-8-fluoroquinoline and tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate using Method V and 6.

Compound 341: HPLC: 97.7% pure, RT=1.45 min. MS: m/z=260 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 8.97 (dd, J=4.2, 1.6 Hz, 1H), 8.53 (d, J=8.5 Hz , 1H), 8.19 (s, 3H), 7.66 (dd, J=8.6, 4.2 Hz, 1H), 7.52 (dd, J=10.8, 8.3 Hz, 1H), 7.19 (dd, J=8.4, 4.2 Hz, 1H), 3.61-3.39 (m, 2H), 3.16 (d, J=10.0 Hz, 1H ), 2.62 (t, J=10.7 Hz, 1H), 2.36 (t, J=11.2 Hz, 1H), 2.16 (d, J=12.3 Hz, 1H), 2.05 (ddd, J=16.8, 8.9, 5.2 Hz, 1H), 1.15 (sq., J=11.7 Hz, 1H), 0.96 (d, J=6 .6 Hz, 3H).

The following compounds were synthesized in a similar manner:

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, RT=1.37 min. MS: m/z=256 [M+H] ⁺ . ¹ H NMR (400 MHz, deuterium oxide, ppm) δ 9.35 (d, J=8.9 Hz, 1H), 9.09 (dt, J=5.4, 1.4 Hz, 1H ), 8.08 (ddd, J=8.6, 5.5, 1.1 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.55 (d, J= 7.9 Hz, 1H), 3.89-3.74 (m, 1H), 3.66 (d, J=11.3 Hz, 1H), 3.39 (d, J=11.0 Hz, 1H), 2.98 (t, J=10.8 Hz, 1H), 2.80 (s, 3H), 2.54 (t, J=11.5 Hz, 1H), 2.37 (d, J=12.7 Hz, 1H), 2.33-2.17(m, 1H), 1.33(q, J=12.0 Hz, 1H), 1.05(d, J=6, 7 Hz, 3H).

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, RT=1.60 min. MS: m/z=310.30 [M+H]⁺.^oneH NMR (400 MHz, Deuterium Oxide, ppm) δ 9.34-9.29 (m, 1H), 9.03 (dd, J=5.5, 1.6 Hz, 1H), 8, 04 (ddt, J=8.6, 5.5, 1.4Hz, 1H), 7.91 (dd, J=7.9, 1.1Hz, 1H), 7.56 (d, J= 7.9 Hz, 1H), 3.82 (td, J=11.3, 5.7 Hz, 1H), 3.71 (s, 1H), 3.63-3.56 (m, 1H), 3.56-3.48 (m, 1H), 3.10 (ddp, J=11.9, 7.7, 3.9 Hz, 1H), 2.97 (dt, J=17.3, 11 .2 Hz, 2H), 2.73 (d, J=1.0 Hz, 3H), 2.54 (d, J=12.2 Hz, 1H), 1.71 (q., J=12, 2 Hz, 1H).

Example 90 Synthesis of compound 342 (8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-7-fluoroquinoxalin-5-carbonitrile)

N-(4-fluoro-2-methylphenyl)acetamide: 4-fluoro-2-methylaniline (3.80 g, 30.37 mmol) was added to 100 ml of acetic anhydride at room temperature. The resulting solution was stirred for 3 hours at room temperature. When the reaction was complete, it was quenched by adding water (100 ml) and the resulting mixture was extracted with dichloromethane (300 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure to give N-(4-fluoro-2-methylphenyl)acetamide as a white solid (2.70 g, 50%). MS: m/z=168.2 [M+H] ⁺ .

Method 25

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 mmol) in acetic anhydride ( 60 ml) was added dropwise with HNO ₃ (65% in water, 3.2 ml, 46.22 mmol) over 20 minutes. The resulting mixture was then stirred for 15 hours at room temperature. When the reaction was complete, it was quenched by adding ice water (100 ml) and the pH of the resulting mixture was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (300 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-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] ⁺ .

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. The crude product was purified by flash -chromatography eluting with EtOAc in hexane (0%-17% gradient) to give 4-fluoro-2-methyl-6-nitroaniline as a yellow solid (730 mg, 64%). MS: m/z=171.1 [M+H] ⁺ .

Method 26

5-fluoro-3-methylbenzene-1,2-diamine: To a solution of 4-fluoro-2-methyl-6-nitroaniline (730 mg, 4.29 mmol) in methanol (10 ml) was added Raney Ni (95 mg, 11 .09 mmol) at room temperature under a nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen. The reaction mixture was then stirred for 30 minutes at room temperature under a hydrogen atmosphere under a hydrogen balloon. When the reaction was complete, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-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] ⁺ .

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% - 25% gradient) to give 7-fluoro-5-methylquinoxaline as a yellow solid (540 mg, 62%). MS: m/z=163.1 [M+H] ⁺ .

Method 27

5-bromo-6-fluoro-8-methylquinoxaline: To a solution of 7-fluoro-5-methylquinoxaline (540 mg, 3.33 mmol) in acetoneitrile (10 mL) was slowly added NBS (1425 mg, 8.01 mmol) at room temperature. The resulting solution was stirred for 15 hours at 80°C. When the reaction was complete, it was quenched by adding water (20 ml). The resulting mixture was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-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

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 CCl ₄ was slowly added NBS (4275 mg, 24.02 mmol) and AIBN (67 mg, 0.40 mmol) in order. The resulting solution was stirred for 15 hours at 80°C. When the reaction was complete, it was quenched by adding water (20 ml). The resulting mixture was extracted with ethyl acetate (60 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-15% gradient) to give 5-bromo-8-(dibromomethyl)-6-fluoroquinoxaline as a yellow solid (450 mg, 62%). MS: m/z=400.5 [M+H] ⁺ .

Method 29

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) was added sodium formate (404 mg, 5 .94 mmol), NH ₂ OH.HCl (165 mg, 2.38 mmol) and water (3 ml) at room temperature. The resulting mixture was stirred for 15 hours at 85°C. When the reaction was complete, it was quenched by adding water (50 ml). The resulting mixture was extracted with ethyl acetate (100 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-17% gradient) to give 8-bromo-7-fluoroquinoxaline-5-carbonitrile as a white solid (240 mg, 84%). MS: m/z=253.8 [M+H] ⁺ .

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 obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/L NH_fourHCO₃and 0.1% NH₃.H₂O), 5% - 65% gradient over 8 min; detector UV 254 nm. 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-7-fluoroquinoxaline-5-carbonitrile was obtained as a yellow solid (55 mg, 48% for 2 steps).

Compound 342: HPLC: 99.2% pure, RT=1.08 min. MS: m/z=286.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J=1.7 Hz, 1H), 8.88 (d, J=1.7 Hz, 1H), 7 .88 (d, J=12.2 Hz, 1H), 4.05 (d, J=12.0 Hz, 1H), 3.76 (d, J=12.6 Hz, 1H), 3.49 -3.32(m, 1H), 3.1-3.04(m, 1H), 3.02-2.90(m, 1H), 2.28-1.92(m, 2H), 1 .21-1.16 (m, 1H), 1.00 (d, J=6.6 Hz, 3H).

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

N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-3,3-dimethylbutanamide: To 8-[(3R,5S) solution -3-amino-5-methylpiperidin-1-yl]-7-fluoroquinoxalin-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 2 hours at room temperature. When the reaction was complete, it was quenched by adding water (5 ml). The resulting mixture was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 45% - 67% gradient over 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 %).

Compound 343: HPLC: 99.5% pure, RT=1.85 min. MS: m/z=384.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.09-8.95 (m, 2H), 8.43 (d, J=12.9 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 3.72-3.93(m, 3H), 3.03-2.96(m, 1H), 2.87-2.78(m 1H) , 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]quinoxalin-5-carbonitrile: 7-fluoro-8-[(3R,5S) -3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile was obtained from 8-[(3R,5S)-3-amino-5-methylpiperidin-1-yl]-7 α-fluoroquinoxaline-5-carbonitrile and 1-bromo-2-methoxyethane using Method M. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 42% - 43% gradient over 7 min; detector UV 254 nm. 7-fluoro-8-[(3R,5S)-3-[(2-methoxyethyl)amino]-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile was obtained as a yellow oil (13 mg, 22%).

Compound 344: HPLC: 98.6% pure, RT=1.39 min. MS: m/z=344.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.85 (m, 2H), 8.10 (d, J=12.7 Hz, 1H), 4.16- 4.11(m, 1H), 3.86-3.76(m, 1H), 3.61-3.49(m, 2H), 3.38(s, 3H), 3.14-2, 83 (m, 5H), 2.18 (d, J=12.4 Hz, 1H), 2.01-1.88 (m, 1H), 1.13-0.96 (m, 4H).

Example 93: Synthesis of Compound 345 and Compound 346 ]-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)

(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 obtained from 2 -amino-3,3,3-trifluoropropanoic acid and 8-((3R,5S)-3-amino-5-methylpiperidin-1-yl)-7-fluoroquinoxalin-5-carbonitrile using Method 30. The crude product was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD Column, 19 × 150 mm 10 µm; mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 40% - 45% gradient over 10 min; detector UV 254 nm. Two diastereoisomers were separated and obtained.

Isomer 1 : (34 mg, 16%, yellow solid) HPLC: 97.1% purity, RT=1.04 min. MS: m/z=411.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.05-8.95 (m, 2H), 8.42 (d, J=12.8 Hz, 1H), 8.30 (d, J=7.7 Hz, 1H), 4.10-3.70 (m, 4H), 3.11-2.95 (m, 1H), 2.94-2.78 (m, 1H ), 2.38-2.22 (m, 2H), 2.07-1.91 (m, 2H), 1.26-1.10 (m, 1H), 0.92 (d, J=6 .2 Hz, 3H).

Isomer 2 : (34 mg, 16%, yellow solid) HPLC: 96.4% purity, RT=2.16 min. MS: m/z=411.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.07-8.97 (m, 2H), 8.43 (d, J=12.8 Hz, 1H), 8.32 (d, J=7.8 Hz, 1H), 4.05-3.80 (m, 3H), 3.74 (d, J=12.8 Hz, 1H), 3.12-2.96 ( m, 1H), 2.94-2.78 (m, 1H), 2.38-2.20 (m, 2H), 2.06-1.92 (m, 2H), 1.22-1, 08 (m, 1H), 0.92 (d, J=6.3 Hz, 3H).

Example 94 : Synthesis of Compound 347

N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(dimethylamino)acetamide:N-[(3R,5S)-1-(8-cyano-6-fluoroquinoxalin-5-yl)-5-methylpiperidin-3-yl]-2-(dimethylamino)acetamide was obtained from 8-[(3R,5S) -3-amino-5-methylpiperidin-1-yl]-7-fluoroquinoxalin-5-carbonitrile and 2-(dimethylamino)acetic acid using Method J. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/L NH_fourHCO₃and 0.1% NH₃.H₂O), 42% - 43% gradient over 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%).

Compound 347: HPLC: 97.5% pure, RT=0.91 min. MS: m/z=371.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.11-8.95 (m, 2H), 8.41 (d, J=12.9 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 4.06-3.92 (m, 1H), 3.83-3.67 (m, 2H), 3.20-3.04 (m, 1H ), 2.95-2.76 (m, 3H), 2.19 (s, 6H), 2.00-1.84 (m, 2H), 1.32-1.16 (m, 1H), 0.91 (d, J=6.3 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 587 -acetamide): from (3R,5S)-1-(8-methyl-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-ylamine hydrochloride and (1-methyl-piperidin-4-yl)-acetic acid . HPLC: 99% purity, RT=1.90 min. MS: m/z=449.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 8.93 (dd, J=4.1, 1.7 Hz, 1H), 8.53 (dd, J=8.5, 1 .8 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.57 (dd, J=8.5, 4.1 Hz, 1H), 7.54 (dd, J =7.6, 1.1 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 4.13 (s, 1H), 3.13 (d, J=11.6 Hz , 2H), 2.76 (t, J=11.4 Hz, 2H), 2.69 (dd, J=7.4, 3.6 Hz, 2H), 2.46 (d, J=10, 9 Hz, 1H), 2.16 (d, J=12.0 Hz, 1H), 2.12 (s, 3H), 1.99 (d, J=6.9 Hz, 2H), 1.85 -1.77(m, 2H), 1.63-1.49(m, 3H), 1.44(q, J=12.2Hz, 1H), 1.15(dq, J=9 .1, 5.9, 4.7 Hz, 2H).

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-methylbutyric acid. HPLC: 98% purity, RT=2.06 min. MS: m/z=356.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (dd, J=4.1, 1.8 Hz, 1H), 8.47 (dd, J=8.5, 1 .8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.55 (dd, J=8.5, 4.1 Hz, 1H), 7.51 (dd, J =7.6, 1.1 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 4.77 (s, 1H), 3.16 (dd, J=10.9, 2.9 Hz, 1H), 2.65 (d, J=0.9 Hz, 3H), 2.38 (t, J=10.7 Hz, 1H), 2.30 (t, J=11, 1 Hz, 1H), 2.20 (s, 2H), 2.04 (s, 1H), 1.99 (d, J=13.3 Hz, 1H), 1.13 (d, J=1, 2 Hz, 6H), 1.04 (q, J=11.9 Hz, 1H), 0.94 (d, J=6.4 Hz, 3H).

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 cyclopropyl-hydroxy-acetic acid. HPLC: >99% purity, RT=2.09 min. MS: m/z=354.30 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (ddd, J=4.2, 1.8, 0.8 Hz, 1H), 8.48 (ddd, J=8 .5, 2.7, 1.8 Hz, 1H), 7.59-7.48 (m, 2H), 7.08 (dd, J=7.6, 4.1 Hz, 1H), 5, 28 (s, 1H), 4.07 (s, 0H), 3.55-3.48 (m, 1H), 3.28 (d, J=11.0 Hz, 1H), 3.16 (d , J=10.0 Hz, 1H), 2.65 (t, J=0.9 Hz, 2H), 2.47 (dd, J=10.7, 2.1 Hz, 1H), 2.31 (t, J=11.1 Hz, 1H), 1.95 (d, J=12.6 Hz, 1H), 1.24-1.10 (m, 1H), 1.11-0.91 ( m, 3H), 0.43-0.23 (m, 3H).

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 acid . HPLC: >99% purity, RT=1.71 min. MS: m/z=395.40 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (dd, J=4.1, 1.8 Hz, 1H), 8.47 (dd, J=8.5, 1 .8 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.54 (dd, J=8.5, 4.1 Hz, 1H), 7.51 (dd, J =7.5, 1.1 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H), 3.15 (d, J=10.6 Hz, 1H), 2.68 (d , J=3.3 Hz, 2H), 2.64 (d, J=1.0 Hz, 3H), 2.32 (dt, J=18.2, 10.9 Hz, 2H), 2.10 (s, 3H), 1.97 (d, J=6.8 Hz, 2H), 1.94 (s, 1H), 1.82-1.72 (m, 2H), 1.62-1, 48 (m, 3H), 1.13 (dd, J=10.2, 6.1 Hz, 2H), 1.03 (sq., J=12.1 Hz, 1H), 0.93 (d, J=6.5 Hz, 3H).

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 acid . HPLC: >99% purity, RT=1.65 min. MS: m/z=381.40 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (dd, J=4.1, 1.8 Hz, 1H), 8.47 (dd, J=8.5, 1 .8 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.55 (dd, J=8.5, 4.1 Hz, 1H), 7.51 (dd, J =7.6, 1.2 Hz, 1H), 7.07 (dd, J=7.7, 1.4 Hz, 1H), 4.02 (s, 1H), 3.16 (d, J= 11.4 Hz, 2H), 2.64 (d, J=0.9 Hz, 3H), 2.40 (ddd, J=9.1, 6.3, 2.7 Hz, 4H), 2, 36-2.25 (m, 3H), 2.20 (d, J=3.6 Hz, 3H), 2.12 (dt, J=7.7, 1.5 Hz, 2H), 2.10 -2.04 (m, 2H), 2.03 (s, 1H), 1.96 (d, J=13.2 Hz, 2H), 1.34 (tdd, J=13.0, 7.3 , 5.8 Hz, 1H), 1.03 (q, J=12.0 Hz, 1H), 0.93 (d, J=6.5 Hz, 3H).

Example 95: Synthesis of Compound 348 acetamide)

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 obtained from 8-[(3R,5S)- 3-amino-5-methylpiperidin-1-yl]quinoxalin-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: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), 42% - 55% gradient over 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 stages).

Compound 348: HPLC: 99.4% pure, RT=1.51 min. MS: m/z=429.3 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.97 (d, J=1.7 Hz, 1H), 8.86 (d, J=1.7 Hz, 1H), 8 .02 (d, J=8.3 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.18-6.98 (m, 1H), 4.46-4, 37 (m, 1H), 4.36-4.21 (m, 2H), 3.14 (s, 2H), 2.85-2.68 (m, 6H), 2.23-2.00 ( m, 6H), 1.30-1.14 (m, 1H), 1.03 (d, J=6.6 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 350 acetamide): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-amine and 2-(4,4-difluoropiperidin-1-yl)acetic acid. HPLC: 99.1% purity, RT=2.83 min. MS: m/z=471.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.02 (dd, J=4.1, 1.6 Hz, 1H), 8.53 (dd, J=8.6, 1.7 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.68 (dd, J=8, 6, 4.2 Hz, 1H), 7.22 (d, J=8.1 Hz, 1H), 4.15-4.05 (m, 1H), 3.51-3.30 (m, 2H ), 3.02 (s, 2H), 2.57-2.35 (m, 6H), 2.12-1.93 (m, 6H), 1.25-1.21 (m, 1H), 0.96 (d, J=6.5 Hz, 3H).

Compound 354 acetamide): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine and 2-(4,4-difluoropiperidin-1-yl)acetic acid. HPLC: 99.0% purity, RT=2.00 min. MS: m/z=472.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.03 (d, J=1.7 Hz, 1H), 8.97 (d, J=1.7 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 4, 19-3.95 (m, 3H), 3.06-2.97 (m, 2H), 2.87-2.81 (m, 1H), 2.58-2.49 (m, 5H), 2.07-1.58 (m, 6H), 1.35-1.20 (m, 1H), 0.94 (d, J=6.3 Hz, 3H).

Example 96 Synthesis of Compound 349 yl) propanamide)

Method 31

Ethyl 2-methyl-2-(pyridin-4-yl)propanoate: To a solution of ethyl 2-(pyridin-4-yl)acetate (1.90 g, 11.50 mmol) in N,N-dimethylformamide (30 ml) a solution of LiHMDS (1 M in THF, 14.4 ml, 14.4 mmol) was added slowly at 0°C. The resulting solution was stirred at room temperature for 0.5 hour and then CH ₃ I (2.61 g, 18.4 mmol) was added slowly. The reaction mixture was stirred at room temperature for 1 hour. Then a solution of LiHMDS (1 M in THF, 14.4 ml, 14.4 mmol) was again added to the reaction mixture at 0°C. The resulting mixture was stirred at room temperature for 0.5 hour and then CH ₃ I (2.61 g, 18.4 mmol) was added slowly. The reaction mixture was stirred at room temperature for an additional 2 hours. When the reaction was complete, it was quenched by adding ice water (50 ml). The resulting mixture was extracted with DCM (150 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-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] ⁺ .

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 mmol) in EtOH (20 ml) Rh/Al ₂ O ₃ (285 mg, 2.77 mmol) was added in a pressure vessel. The resulting mixture was hydrogenated at room temperature under a hydrogen pressure of 4 bar for 12 hours. When the reaction was complete, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0%-50% gradient) to give ethyl 2-methyl-2-(piperidin-4-yl)propanoate as a yellow oil (300 mg, 25%). MS: m/z=200.1 [M+H] ⁺ .

Method 32

Ethyl 2-methyl-2-(1-methylpiperidin-4-yl)propanoate: To a solution of ethyl 2-methyl-2-(piperidin-4-yl)propanoate (180 mg, 0.90 mmol) in methanol (10 ml) added polyformaldehyde (836 mg, 9.28 mmol), NaOAc (1.56 g, 18.99 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours and then NaBH ₄ (541 mg, 14.31 mmol) was added at room temperature. The resulting mixture was stirred for an additional 12 hours at room temperature. When the reaction was complete, it was quenched by adding water (20 ml). The resulting solution was extracted with ethyl acetate (50 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-25% gradient) to give ethyl 2-methyl-2-(1-methylpiperidin-4-yl)propanoate as a colorless oils (160 mg, 83%). MS: m/z=214.1 [M+H] ⁺ .

Method 33

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), then a solution of sodium hydroxide (355 mg, 8.86 mmol) 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: XBridge BEH130 Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% TFA), 0% - 15% gradient over 9 min; detector UV 254 nm. 2-methyl-2-(1-methylpiperidin-4-yl)propanoic acid was obtained as a colorless oil (100 mg, 58%). MS: m/z=186.0 [M+H] ⁺ .

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 obtained from 8-[(3R ,5S)-3-amino-5-methylpiperidin-1-yl]quinoxalin-5-carbonitrile and 2-methyl-2-(1-methylpiperidin-4-yl)propanoic acid using Method 30. The crude product was purified by preparative HPLC at following conditions: XBridge BEH130 Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), 26% - 45% gradient over 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 yellow solids (28 mg, 39%).

Compound 349: HPLC: 99.9% pure, RT=0.67 min. MS: m/z=379.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.82 (m, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.29 ( d, J=8.4 Hz, 1H), 4.37-4.10 (m, 3H), 3.00-2.78 (m, 3H), 2.72-2.65 (m, 1H) , 2.26 (s, 3H), 2.04-1.96 (m, 4H), 1.69-1.25 (m, 6H), 1.13 (s, 6H), 1.00 (d , J=6.3 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 351 yl)propanamide): from 2-methyl-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinolin-5-yl]piperidin-3-yl]-2-(1-methylpiperidine -4-yl)propanamide; and 2-methyl-2-(1-methylpiperidin-4-yl)propanoic acid. HPLC: 96.3% purity, RT=3.56 min. MS: m/z=477.2 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.54 (dd, J=8.6, 1.7 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.69 (dd, J=8.6, 4.2 Hz, 1H), 7.32-7, 16 (m, 2H), 4.20-4.05 (m, 1H), 3.50-3.30 (m, 2H), 2.84-2.70 (m, 2H), 2.50- 2.35 (m, 1H), 2.15-1.85 (m, 5H), 1.80-1.65 (m, 2H), 1.50-1.10 (m, 7H), 1, 05-0.90 (m, 9H).

Compound 355 yl)propanamide): from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-amine and 2-methyl-2-(1-methylpiperidin-4-yl ) propanoic acid. HPLC: 97.7% purity, RT=2.35 min. MS: m/z=478.3 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.95-8.86 (m, 2H), 8.04 (d, J=8.4 Hz, 1H), 7.30 ( d, J=8.3 Hz, 1H), 4.30-4.05 (m, 3H), 3.09 (d, J=11.2 Hz, 2H), 2.90-2.72 (m , 1H), 2.66-2.50 (m, 1H), 2.40 (s, 3H), 2.30-1.96 (m, 4H), 1.75-1.60 (m, 3H ), 1.51-1.26 (m, 4H), 1.15 (s, 6H), 1.02 (d, J=6.4 Hz, 3H).

Example 97: Synthesis of Compound 352 and Compound 353 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)

(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 obtained 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: XBridge Shield RP18 OBD Column, 19 × 150 mm 10 µm; mobile phase: acetonitrile in water (0.05% NH ₃ .H ₂ O), 36% - 43% gradient over 7 min; detector UV 254 nm. The two diastereomeric isomers were then obtained by chiral preparative HPLC separation under the following conditions: Packed column Lux 5 μ Cellulose-4, AXIA, 2.12 x 25 cm, 5 μm; mobile phase: EtOH in hexane, 50% isocratic for 12 min; detector UV 254/220 nm.

Isomer 1 : (25 mg, 19%, yellow solid) HPLC: 95.4% purity, RT=2.06 min. MS: m/z=430.3 [M+Na] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.08-8.95 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 4.29 (d, J=11.5Hz, 1H), 4.03 (d, J=11.6Hz, 1H), 3.47-3 .21 (m, 4H), 3.05-2.98 (m, 1H), 2.74 (s, 3H), 2.60-2.45 (m, 1H), 2.38-2.22 (m, 1H), 2.18-2.08 (m, 1H), 1.99-1.85 (m, 2H), 1.73-1.58 (m, 1H), 0.95-0 .92 (m, 4H).

Isomer 2 : (24 mg, 18%, yellow solid) HPLC: 94.7% purity, RT=2.22 min. MS: m/z=430.3 [M+Na] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.08-8.95 (m, 2H), 8.05 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 4.29 (d, J=11.5Hz, 1H), 4.03 (d, J=11.6Hz, 1H), 3.47-3 .21 (m, 5H), 3.05-2.98 (m, 1H), 2.74 (s, 3H), 2.60-2.45 (m, 1H), 2.38-2.22 (m, 1H), 2.10-2.00 (m, 1H), 1.99-1.85 (m, 1H), 1.73-1.58 (m, 1H), 0.95-0 .92 (m, 4H).

Example 98: Synthesis of Compound 356

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 obtained from 8-((3R,5S)-3-amino- 5-methylpiperidin-1-yl)quinoxalin-5-carbonitrile, 2-bromoacetic acid and t-butyl azetidin-3-ylcarbamate using Methods 30, 18 and 6. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD column Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), 2% - 33% gradient over 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%).

Compound 356: HPLC: 97.8% pure, RT=0.96 min. MS: m/z=380.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 9.10-8.90 (m, 2H), 8.21 (d, J=8.4 Hz, 1H), 7.66 ( d, J=8.1 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H), 4.39-3.85 (m, 3H), 3.70-3.37 (m , 4H), 3.07-2.60 (m, 7H), 1.98-1.82 (m, 2H), 1.33-1.24 (m, 1H), 0.93-0.76 (m, 3H).

Example 99 : Synthesis of compound 357 and 358 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)

Benzylbis(methoxymethyl)amine: To a solution of phenylmethanamine (95 g, 886.58 mmol) in MeOH (1 L) was added polyformaldehyde (78.4 g, 870.08 mmol) at room temperature. The resulting solution was then stirred overnight at 70°C. When the reaction was complete, it was quenched by adding water (ml). The solvent was removed under reduced pressure, and the residue was purified by distillation under reduced pressure (10 mmHg), and a fraction was collected at 70~72°C to obtain benzylbis(methoxymethyl)amine as a colorless liquid (104.0 g, 75%).

Benzylbis(methoxymethyl)amine: To a solution of benzylbis(methoxymethyl)amine (16.0 g, 81.94 mmol) in DCM (200 ml) was added cyclobutanone (6.8 g, 96.62 mmol), chlorotrimethylsilane (22.8 g , 210.74 mmol) and ZnBr ₂ (21.7 g, 96.17 mmol) at room temperature. The resulting mixture was stirred for 16 hours at room temperature. After cooling to room temperature, the reaction mixture was quenched by adding water (500 ml). The resulting mixture was extracted with ethyl acetate (200 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0% - 90% gradient) to give 3-benzyl-6,6-dimethoxy-3-azabicyclo[3.1.1]heptane in as a light yellow oil (6.4 g, 32%). MS: m/z=248.3 [M+H] ⁺ .

Benzylbis(methoxymethyl)amine: 3-benzyl-6,6-dimethoxy-3-azabicyclo[3.1.1]heptane (3.6 g, 14.56 mmol) was slowly added to trifluoroacetic acid (100 ml) at room temperature. The resulting solution was then stirred for 13 hours at 50°C. When the reaction was complete, the reaction mixture was concentrated under reduced pressure and diluted with H ₂ O (50 ml). The pH of the resulting mixture was adjusted to 9 with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate (100 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0%-10% gradient) to give 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one as a brown oil (2.5 g, 84%). MS: m/z=202.0 [M+H] ⁺ .

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 mmol) in ethylene glycol dimethyl ether (100 mL) sodium hydride (294 mg, 12.25 mmol) was added slowly. The resulting mixture was stirred at 0° C. for 10 minutes and then ethyl 2-(diethoxyphosphoryl)acetate (3.9 g, 17.29 mmol) was added. The reaction mixture was then stirred for an additional 1.5 hours at 0°C. When the reaction was complete, it was quenched by adding a saturated solution of NH ₄ Cl. The resulting mixture was extracted with ethyl acetate (100 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in DCM (0%-10% gradient) to give ethyl 2-[3-benzyl-3-azabicyclo[3.1.1]heptan-6-ylidene ]acetate as a light yellow oil (1.4 g, 53%). MS: m/z=272.1 [M+H] ⁺ .

Ethyl 2-[3-benzyl-3-azabicyclo[3.1.1]heptan-6-ylidene]acetate: To a solution of ethyl 2-[3-benzyl-3-azabicyclo[3.1.1]heptan-6-ylidene]acetate ( 1.4 g, 5.16 mmol) in MeOH (100 ml) was added Pd/C (10%, 400 mg) at room temperature under nitrogen atmosphere. The reaction flask was evacuated and purged with hydrogen. The reaction mixture was then hydrogenated at 55° C. for 16 hours under a hydrogen atmosphere under a hydrogen balloon. When the reaction was complete, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give ethyl 2-[3-azabicyclo[3.1.1]heptan-6-yl]acetate as a light yellow oil (800 mg, 85% ). MS: m/z=184.2 [M+H] ⁺ .

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-methylpiperidine -3-yl)-2-(3-methyl-3-aza-bicyclo[3.1.1]heptan-6-yl)acetamide was obtained from 8-((3R,5S)-3-amino-5-methylpiperidine-1 -yl)quinoxalin-5-carbonitrile, ethyl 2-(3-aza-bicyclo[3.1.1]heptan-6-yl)acetate and polyformaldehyde using Methods 32, 19 and 30. The crude product was purified by preparative HPLC under the following conditions: column XBridge Prep C18 OBD Column, 19 × 150 mm 10 µm; mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 29% - 33% gradient over 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, RT=2.90 min. MS: m/z=419.1 [M+Na] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.89 (m, 2H), 8.10 (d, J=8.3 Hz, 1H), 7.30 ( d, J=8.4 Hz, 1H), 4.43-4.28 (m, 2H), 4.17-4.10 (m, 1H), 3.16-3.07 (m, 2H) , 2.85-2.63 (m, 4H), 2.54 (d, J=8.0 Hz, 2H), 2.41 (s, 3H), 2.33-2.31 (m, 1H ), 2.18-1.99 (m, 5H), 1.69-1.66 (m, 1H), 1.30-1.14 (m, 1H), 1.02 (d, J=6 .5 Hz, 3H).

Isomer 2 : (6 mg, 4.4% for 3 steps, light yellow solid) HPLC: 97.7% purity, RT=1.16 min. MS: m/z=419.5 [M+Na] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.99-8.89 (m, 2H), 8.10 (d, J=8.4 Hz, 1H), 7.29 ( d, J=8.3 Hz, 1H), 4.38-4.31(m, 2H), 4.15-4.09(m, 1H), 3.17-3.04(m, 2H) , 2.92-2.80 (m, 2H), 2.79-2.51 (m, 3H), 2.41 (s, 3H), 2.37-2.30 (m, 4H), 2 .11-2.03 (m, 2H), 1.92-1.75 (m, 2H), 1.23-1.15 (m, 1H), 1.02 (d, J=6.4 Hz , 3H).

Example 100 : Synthesis of Compound 359

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 obtained 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 25% - 31% gradient over 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% pure, RT=0.84 min. MS: m/z=379.2 [M+H] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD, ppm) δ 8.99-8.88 (m, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.26 ( d, J=8.4 Hz, 1H), 4.36-4.31(m, 2H), 4.12-4.04(m, 1H), 3.55-3.50(m, 2H) , 3.03-2.98 (m, 2H), 2.90-2.60 (m, 3H), 2.45 (d, J=7.7 Hz, 2H), 2.33 (s, 3H ), 2.15-1.94 (m, 2H), 1.26-1.10 (m, 1H), 0.99 (d, J=6.3 Hz, 3H).

The following compounds were synthesized in a similar manner:

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, RT=2.27 min. MS: m/z=421.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.02 (dd, J=4.2, 1.6 Hz, 1H), 8.52 (dd, J=8.6, 1.8 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.92 (d, J=7.4 Hz, 1H), 7.68 (dd, J=8, 6, 4.2 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 4.01-3.99 (m, 1H), 3.48-3.21 (m, 3H ), 2.81-2.70 (m, 2H), 2.51-2.28 (m, 4H), 2.16 (s, 3H), 2.09-1.95 (m, 3H), 1.18-0.91 (m, 4H).

Compound 363 (N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxalin-5-yl]piperidin-3-yl]-2-(1-methylazetidin-3-yl)acetamide) : from 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, RT=5.81 min. MS: m/z=422.3 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.08-8.95 (m, 2H), 8.07 (d, J=8.2 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 4.23-4.04 (m, 2H), 3.92-3.81 ( m, 1H), 3.43-3.26 (m, 2H), 2.80-2.65 (m, 5H), 2.34-2.31 (m, 2H), 2.16 (s, 3H), 1.95-1.83 (m, 2H), 1.21-1.02 (m, 1H), 0.93 (d, J=6.2 Hz, 3H).

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, RT=1.24 min. MS: m/z=403.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.89 (dd, J=4.2, 1.7 Hz, 1H), 8.60 (dd, J=8.6, 1 .8 Hz, 1H), 7.93 (dd, J=7.8, 1.6 Hz, 1H), 7.83-7.55 (m, 2H), 7.24 (d, J=7, 9 Hz, 1H), 4.25-4.12 (m, 1H), 3.59-3.43 (m, 3H), 2.98-2.93 (m, 2H), 2.79-2 .75 (m, 1H), 2.51-2.36 (m, 4H), 2.30 (s, 3H), 2.13-2.07 (m, 2H), 1.19-0.97 (m, 5H).

Example 101 : Synthesis of compound 366 (cis-5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-amine)

5-bromo-8-fluoroquinoxaline: 5-bromo-8-fluoroquinoxaline was prepared from 2-bromo-5-fluorobenzenamine, acetyl chloride and oxalaldehyde using Method 1-5. The crude product was purified by flash chromatography eluting with EtOAc in hexane (0%-10% gradient) to give 5-bromo-8-fluoroquinoxaline as a white solid (637 mg, 71%, for 5 steps). MS: m/z=226.8 [M+H] ⁺ .

Method 34

tert-butyl cis-N-[5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-yl]carbamate: To a solution of 5-bromo-8-fluoroquinoxaline (66 mg, 0.29 mmol) in tert-butanol (10 ml) was added tert-butyl N-(5-cyclopropylpiperidin-3-yl)carbamate (62 mg, 0.26 mmol), RuPhos (29 mg, 0.06 mmol), Cs ₂ CO ₃ (151 .6 mg, 0.44 mmol) and 2nd 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 quenched by adding water (20 ml). The resulting mixture was extracted with ethyl acetate (20 ml×3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue loaded onto a C18 gel column and purified by reverse phase flash chromatography eluting with acetonitrile in water (with 10 mmol/L NH ₄ HCO ₃ ) (0%-60% gradient over 30 min) to give tert-Butyl N-[5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-yl]carbamate as a yellow solid (32 mg, 29%). MS: m/z=387.2 [M+H] ⁺ .

cis-5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-amine: cis-5-cyclopropyl-1-(8-fluoroquinoxalin-5-yl)piperidin-3-amine was obtained from 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm × 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 35% - 65% gradient over 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%).

Compound 366: HPLC: 99.0% pure, RT=1.78 min. MS: m/z=278.1 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.02-8.92 (m, 2H), 7.57 (dd, J=10.2, 8.6 Hz, 1H) , 7.16 (dd, J=8.7, 4.9 Hz, 1H), 3.86-3.72 (m, 2H), 2.93-2.88 (m, 1H), 2.50 -2.40 (m, 2H), 2.33-2.29 (m, 1H), 2.15-1.90 (m, 2H), 1.02-1.1 (m, 2H), 0 .65-0.32 (m, 3H), 0.16-0.14 (m, 2H).

Example 102 : Synthesis of compound 367 (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: 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: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 36% - 47% gradient over 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 a yellow solid (50 mg, 62%) .

Compound 367: HPLC: 99.9% pure, RT=1.09 min. MS: m/z=413.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.86 (dd, J=4.3, 1.6 Hz, 1H), 8.65 (dt, J=8.7, 1 .6 Hz, 1H), 7.63 (dd, J=8.6, 4.3 Hz, 1H), 7.42 (dd, J=10.7, 8.4 Hz, 1H), 7.22 (dd, J=8.4, 4.2 Hz, 1H), 4.19-4.12 (m, 1H), 3.74-3.67 (m, 4H), 3.45-3.26 (m, 2H), 3.02 (s, 2H), 2.70-2.47 (m, 6H), 2.26-2.14 (m, 1H), 1.43-1.20 (m , 2H), 0.63-0.45 (m, 3H), 0.29-0.12 (m, 2H).

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

Method 35

Cis-N-[5-cyclopropyl-1-(8-fluoroquinolin-5-yl)piperidin-3-yl]-N-methyl-2-(morpholin-4-yl)acetamide: To 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 tetrahydrofuran (15 ml) was added sodium hydride ( 17 mg, 0.73 mmol) at room temperature. The mixture was stirred for 10 minutes at room temperature and then MeI (294 mg, 2.07 mmol) was added. The resulting mixture was stirred for an additional 14 hours at room temperature. When the reaction was complete, it was quenched by adding water (20 ml). The resulting mixture was extracted with DCM (50 ml x3). The organic phases were combined, washed with brine and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the residue was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), 32% - 40% gradient over 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 a light brown solid ( 10 mg, 9%).

Compound 368: HPLC: 95.5% pure, RT=0.91 min. MS: m/z=427.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CD ₃ OD, ppm) δ 8.87 (dd, J=4.2, 1.6 Hz, 1H), 8.64 (dt, J=8.7, 1 .8 Hz, 1H), 7.63 (dd, J=8.7, 4.3 Hz, 1H), 7.43 (dd, J=10.6, 8.4 Hz, 1H), 7.23 (dd, J=8.4, 4.2 Hz, 1H), 4.27-4.14 (m, 3H), 4.03-3.98 (m, 4H), 3.75-3.66 (m, 4H), 3.48-3.47 (m, 1H), 3.42 (s, 3H), 2.71-2.51 (m, 2H), 2.27-2.21 (m , 1H), 1.36-1.25 (m, 3H), 0.63-0.59 (m, 1H), 0.53-0.43 (m, 2H), 0.21-0.18 (m, 2H).

Example 104 : Synthesis of Compound 369 and Compound 370 -yl]piperidin-3-yl]propanamide and (2S)-2-(3-aminoazetidin-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline- 5-yl]piperidin-3-yl]propanamide)

(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 obtained from (3R,5S)-5-methyl-1-(8-(trifluoromethyl)quinoxalin-5-yl)piperidin-3-amine and 2-(3-(tert-butoxycarbonylamino)azetidin-1-yl)propanoic acid using Methods J and 6. The crude product was first purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 μm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ HCO ₃ and 0.1% NH ₃ .H ₂ O), 30% - 50% gradient over 7 min; detector UV 254 nm. The two enantiomeric isomers were then obtained by chiral preparative HPLC separation under the following conditions: CHIRALPAK IC column, 2×25 cm, 5 µm; mobile phase: EtOH in hexane (0.1% DEA), 30% isocratic for 18 min; detector UV 254/220 nm.

Isomer 1 : (18 mg, 26%, yellow solid) HPLC: 98.1% purity, RT=1.31 min. MS: m/z=437.5 [M+Na] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.06-8.94 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.3 Hz, 1H), 4.20-3.85 (m, 3H), 3.54-3.35 ( m, 3H), 2.86-2.51 (m, 6H), 2.02-1.85 (m, 2H), 1.35-0.85 (m, 8H).

Isomer 2 : (28 mg, 26%, yellow solid) HPLC: 91.6% purity, RT=1.28 min. MS: m/z=437.4 [M+Na] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.06-8.94 (m, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 4.14-3.97 (m, 3H), 3.49-3.32 ( m, 3H), 2.87-2.52 (m, 4H), 2.20-1.85 (m, 4H), 1.31-0.89 (m, 8H).

The following compounds were synthesized in a similar manner:

Compound 371 and Compound 372 -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 2-(4-hydroxypiperidin-1-yl ) propanoic acid. Isomer 1: HPLC: 91.9% purity, RT=1.44 min. MS: m/z=466.5 [M+Na] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.06-8.94 (m, 2H), 8.07 (d, J=8.4 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 4.62-4.46 (m, 1H), 4.20-3.90 ( m, 3H), 3.50-3.34 (m, 1H), 3.14-3.00 (m, 1H), 2.85-2.50 (m, 4H), 2.30-2, 05 (m, 2H), 2.03-1.87 (m, 2H), 1.79-1.63 (m, 2H), 1.46-1.17 (m, 3H), 1.07 ( d, J=6.8 Hz, 3H), 0.93 (d, J=6.2 Hz, 3H). Isomer 2: HPLC: 97.0% pure, RT=5.48 min. MS: m/z=466.5 [M+Na] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ , ppm) δ 9.09-8.95 (m, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.77 -7.63(m, 1H), 7.28(d, J=8.4Hz, 1H), 4.62-4.48(m, 1H), 4.24-3.90(m, 3H ), 3.49-3.30 (m, 1H), 3.03-3.01 (m, 1H), 2.83-2.53 (m, 4H), 2.21-2.12 (m , 2H), 1.95-1.92 (m, 2H), 1.79-1.68 (m, 2H), 1.42-1.38 (m, 2H), 1.24-1.20 (m, 1H), 1.09 (d, J=6.8 Hz, 3H), 0.94 (d, J=6.2 Hz, 3H).

Example 105 Synthesis of compound 373 (1-pyrido[2,3-b]pyrazin-8-yl-piperidine-4-carboxylic acid (2-piperidin-1-yl-ethyl)-amide

1-Pyrido[2,3-b]pyrazin-8-yl-piperidine-4-carboxylic acid (2-piperidin-1-yl-ethyl)-amide: (2-piperidin-1-yl-ethyl)-amide 1 -pyrido[2,3-b]pyrazin-8-yl-piperidine-4-carboxylic acid was obtained from 8-chloro-pyrido[2,3-b]pyrazine, 1-(2-aminoethyl)piperidine and 1-tert- butoxycarbonylpiperidine-4-carboxylic acid in 11% yield for 3 steps using Method 20, Q and V.

Compound 373: HPLC: 97.0% pure, RT=1.13 min. MS: m/z=369 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.97 (d, J=1.7 Hz, 1H), 8.83 (d, J=5.4 Hz, 1H), 8 .75 (d, J=1.7 Hz, 1H), 6.91 (d, J=5.4 Hz, 1H), 6.36 (s, 1H), 4.47 (dt, J=12, 7, 2.9 Hz, 2H), 3.38 (sq., J=5.7 Hz, 2H), 3.30-3.12 (m, 2H), 2.51-2.38 (m, 6H), 2.10-2.01 (m, 4H), 2.00-1.84 (m, 1H), 1.60 (n, J=5.6 Hz, 4H), 1.53 -1 .39 (m, 2H).

The following compounds were synthesized in a similar manner:

Compound 379 ((2-piperidin-1-yl-ethyl)-amide 1-pyrido[2,3-b]pyrazin-8-yl-piperidine-4-carboxylic acid): from 8-chloro-pyrido[2,3 -b]pyrazine, N,N-diethylethylenediamine and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid. HPLC: 93.2% purity, RT=1.06 min. MS: m/z=357 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.96 (d, J=1.7 Hz, 1H), 8.81 (d, J=5.3 Hz, 1H), 8 .74 (d, J=1.7 Hz, 1H), 6.89 (d, J=5.4 Hz, 1H), 6.26 (s, 1H), 4.45 (dt, J=11, 4, 2.9Hz, 2H), 3.32(Q, J=5.5Hz, 2H), 3.17(ddd, J=12.7, 8.3, 6.1Hz, 2H) , 2.70-2.49 (m, 6H), 2.51-2.38 (m, 1H), 2.17-1.95 (m, 4H), 1.03 (t, J=7, 1 Hz, 6H).

Compound 380 (4-[(2-diethylamino-acetylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester): from 8-chloro-pyrido[2,3-b]pyrazine, 2-(diethylamino) hydrochloride acetic acid and 1-boc-4-(aminomethyl)piperidine. HPLC: >99% purity, RT=1.11 min. MS: m/z=357 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.92 (s, 1H), 8.77 (dd, J=5.8, 2.5 Hz, 1H), 8.70 ( s, 1H), 7.57 (t, J=6.3 Hz, 1H), 6.85 (dd, J=5.8, 2.5 Hz, 1H), 4.43 (d, J=12 .2 Hz, 3H), 3.23 (d, J=6.6 Hz, 4H), 3.14-2.96 (m, 5H), 2.54 (sq., J=6.5 Hz, 7H), 1.85(d, J=11.3Hz, 5H), 1.55(q, J=12.2Hz, 4H), 1.01(t, J=6.9Hz, 10H ).

Compound 432 ((2-diethylamino-ethyl)-amide 1-(8-cyano-quinoxalin-5-yl)-piperidine-4-carboxylic acid): from 8-bromo-quinoxaline-5-carbonitrile, 1-tert-butoxycarbonylpiperidine -4-carboxylic acid and N,N-diethylethylenediamine. HPLC: 91.4% purity, RT=1.95 min. MS: m/z=381 [M+H] ⁺ . ¹ H 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), 7.06 (d, J=8.4 Hz, 1H), 4.24 (dt, J=12.3, 2.6 Hz, 2H) , 3.44-3.29 (m, 2H), 3.19-3.07 (m, 2H), 2.58 (s, 5H), 2.44 (s, 2H), 2.21-1 .95 (m, 4H), 1.20-0.83 (m, 6H).

Example 106: Synthesis of Compound 374

4-[(2-Diethylamino-ethylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester: 4-Formyl-n-cbz-piperidine solution (2.0 g; 8.09 mmol), N,N-diethylethylenediamine (1.4 ml; 9.71 mmol) and sodium triacetoxyborohydride (1.9 g; 8.90 mmol) in anhydrous 1,2-dichloroethane (80 ml) were heated at 65°C for 3 hours. The colorless cloudy solution was cooled, diluted with dichloromethane (250 ml) and washed with saturated aqueous sodium carbonate solution (2×250 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 PuriFlash 40g 30µm eluting with a gradient of methanol in DCM to give 4-[(2-diethylamino-ethylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester (1.5 g, 43% ). MS: m/z=348 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 7.52-7.17 (m, 5H), 5.06 (s, 2H), 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, 1H), 1.01 (td, J=12.2, 4.2 Hz, 2H), 0.93 (t, J=7.1 Hz, 6H).

4-{[tert-Butoxycarbonyl-(2-diethylamino-ethyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester: 4-[(2-Diethylamino-ethylamino)-methyl]-piperidine-benzyl ester solution 1-carboxylic acid (1.5 g; 4.32 mmol), triethylamine (1.2 ml; 8.63 mmol) 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 PuriFlash 40 g 15 μm column eluting with a gradient of methanol in DCM to give the benzyl ester 4-{[tert-butoxycarbonyl-(2-diethylamino-ethyl)-amino]- methyl}-piperidine-1-carboxylic acid (1.57 g; 68%). MS: m/z=448 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 7.46-7.21 (m, 5H), 5.06 (s, 2H), 3.99 (d, J=13, 1 Hz, 2H), 3.17 (d, J=4.7 Hz, 2H), 3.05 (d, J=7.2 Hz, 2H), 2.77 (s, 2H), 2.45 (sq., J=7.0 Hz, 4H), 1.86-1.69 (m, 1H), 1.56 (d, J=13.3 Hz, 2H), 1.38 (s, 9H ), 1.03 (td, J=12.3, 4.0 Hz, 2H), 0.94 (t, J=7.2 Hz, 6H).

4-[(2-Diethylamino-ethylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester: Solution of 4-{[tert-butoxycarbonyl-(2-diethylamino-ethyl)-amino]-methyl}-piperidine- 1-carboxylic acid (1.6 g; 3.46 mmol) in methanol (70 ml) was pumped through an H-Cube flow hydrogenator equipped with a 20 mol% Pd(OH) ₂ /C catalyst cartridge and heated to 50°C (all hydrogen mode, flow rate 1 ml/min). The resulting colorless solution was concentrated under reduced pressure, and the colorless oil was dried in vacuo to give (2-diethylamino-ethyl)-piperidin-4-ylmethyl-carbamic acid tert-butyl ester (1.06 g; 98%). MS: m/z=314 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 3.34 (s, 1H), 3.12 (t, J=7.4 Hz, 2H), 3.02 (d, J =7.2Hz, 2H), 2.92(d, J=12.1Hz, 2H), 2.48-2.35(m, 8H), 1.69-1.55(m, 1H) , 1.48 (d, J=12.4 Hz, 2H), 1.38 (s, 9H), 1.01 (td, J=12.0, 3.7 Hz, 2H), 0.94 ( t, J=7.1 Hz, 6H).

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]-ethan-1,2-diamine was obtained in 43% yield for 2 steps from 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, RT=1.33 min. MS: m/z=373 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 7.96 (dt, J=8.3, 3.2 Hz, 1H), 7.56 (d, J=10.4 Hz, 1H), 7.38 (t, J=8.8 Hz, 1H), 6.77 (s, 1H), 3.57 (d, J=11.8 Hz, 2H), 2.80 (t, J=11.7 Hz, 2H), 2.76-2.69 (m, 2H), 2.70-2.63 (m, 4H), 2.64-2.51 (m, 5H), 1 .96 (d, J=12.8 Hz, 2H), 1.80-1.69 (m, 1H), 1.59 (sq., J=11.9 Hz, 2H), 1.05 (t , J=6.8 Hz, 5H).

The following compounds were synthesized in a similar manner:

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, RT=1.23 min. MS: m/z=359 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.69 (t, J=3.8 Hz, 1H), 8.12-7.98 (m, 1H), 7.61 ( dd, J=10.0, 3.3 Hz, 1H), 7.42 (td, J=8.0, 6.8, 3.9 Hz, 1H), 6.87 (t, J=3, 8 Hz, 1H), 3.59 (d, J=11.7 Hz, 2H), 2.83 (t, J=12.0 Hz, 2H), 2.72 (sq., J=6.2 , 5.7 Hz, 2H), 2.65 (d, J=6.1 Hz, 2H), 2.64-2.47 (m, 6H), 1.96 (d, J=12.8 Hz , 2H), 1.79-1.68 (m, 3H), 1.60 (sq., J=12.2 Hz, 2H), 1.05 (t, J=7.0 Hz, 6H).

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, RT=1.65 min. MS: m/z=409 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.79 (d, J=5.0 Hz, 1H), 8.35 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.64 (dd, J=8.8, 1.9 Hz, 1H), 6.93 (d, J=5.0 Hz, 1H), 3.64 (d, J=12.1Hz, 2H), 2.88(td, J=12.1, 2.3Hz, 2H), 2.73(t, J=6.2Hz, 2H), 2.66( d, J=6.6 Hz, 2H), 2.63-2.40 (m, 6H), 2.05-1.92 (m, 2H), 1.77 (ddt, J=13.9, 6.6, 3.7 Hz, 1H), 1.61 (dsq, J=12.1, 3.8 Hz, 2H), 1.05 (t, J=7.1 Hz, 6H).

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, RT=1.59 min. MS: m/z=409 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.80 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 8.14 (d, J=8 .8 Hz, 1H), 7.82 (dd, J=8.9, 2.1 Hz, 1H), 6.92 (d, J=5.1 Hz, 1H), 3.64 (d, J =12.3 Hz, 2H), 2.90 (td, J=11.9, 2.0 Hz, 2H), 2.73 (t, J=6.2 Hz, 2H), 2.67 (d , J=6.6 Hz, 2H), 2.60 (t, J=6.0 Hz, 2H), 2.56 (sq., J=7.1 Hz, 4H), 1.99 (d, J=10.6Hz, 2H), 1.77(ddd, J=12.9, 8.9, 5.3Hz, 1H), 1.64(td, J=12.7, 4.0Hz , 2H), 1.28 (s, 2H), 1.05 (t, J=7.1 Hz, 6H).

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, RT=1.59 min. MS: m/z=409 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.69 (d, J=5.0 Hz, 1H), 8.05 (dd, J=9.2, 5.6 Hz, 1H ), 7.61 (dd, J=10.2, 2.9 Hz, 1H), 7.43 (dd, J=9.2, 8.0, 2.9 Hz, 1H), 6.88 ( d, J=4.9 Hz, 1H), 3.59 (d, J=12.4 Hz, 1H), 2.83 (td, J=12.0, 2.3 Hz, 2H), 2, 78 (t, J=6.3 Hz, 2H), 2.66 (d, J=6.6 Hz, 2H), 2.51 (t, J=6.3 Hz, 2H), 2.44 ( t, J=5.3 Hz, 4H), 2.05 (s, 0H), 1.97 (dd, J=12.3, 2.8 Hz, 2H), 1.77 (ddtd, J=14 .1, 10.3, 6.8, 3.6 Hz, 1H), 1.70-1.52 (m, 6H), 1.47 (p, J=5.6, 5.1 Hz, 2H ).

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, RT=1.34 min. MS: m/z=385 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 7.94 (dd, J=9.2, 5.5 Hz, 1H), 7.54 (dd, J=10.2, 2, 9 Hz, 1H), 7.36 (ddd, J=9.2, 8.0, 2.9 Hz, 1H), 6.75 (s, 1H), 3.55 (d, J=12.3 Hz, 2H), 2.80 (dd, J=12.0, 2.4 Hz, 2H), 2.74 (t, J=6.3 Hz, 2H), 2.65 (s, 3H), 2.63 (d, J=6.7 Hz, 2H), 2.47 (t, J=6.3 Hz, 2H), 2.40 (s, 4H), 1.94 (dd, J=13 .2, 3.5 Hz, 2H), 1.79-1.67 (m, 1H), 1.64-1.49 (m, 6H), 1.49-1.34 (m, 2H).

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, RT=1.31 min. MS: m/z=371 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.60 (d, J=4.9 Hz, 1H), 7.95 (d, J=9.1 Hz, 1H), 7, 31 (dd, J=9.1, 2.9 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 6.83 (d, J=5.0 Hz, 1H), 3.94 (s, 3H), 3.58 (d, J=11.7 Hz, 2H), 3.29 (s, 2H), 3.25 (d, J=6.8 Hz, 2H), 2.77 (t, J=11.8 Hz, 2H), 2.57 (q, J=7.1 Hz, 6H), 1.86 (d, J=10.9 Hz, 3H), 1 .68-1.53 (m, 2H), 1.48 (s, 9H), 1.06 (t, J=7.1 Hz, 6H).

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, RT=1.20 min. MS: m/z=359 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.68 (d, J=5.0 Hz, 1H), 7.99 (dd, J=9.3, 6.2 Hz, 1H ), 7.64 (dd, J=10.2, 2.6 Hz, 1H), 7.23 (dd, J=9.3, 8.0, 2.6 Hz, 1H), 6.80 ( d, J=5.1 Hz, 1H), 3.59 (d, J=12.4 Hz, 2H), 2.84 (td, J=12.1, 2.1 Hz, 2H), 2, 70 (t, J=6.1 Hz, 2H), 2.63 (d, J=6.6 Hz, 2H), 2.58 (t, J=6.1 Hz, 2H), 2.54 ( square, J=7.1 Hz, 4H), 1.94 (dd, J=12.4, 3.2 Hz, 2H), 1.73 (dtt, J=14.1, 6.8, 3 .9 Hz, 1H), 1.57 (dq, J=12.2, 3.8 Hz, 2H), 1.03 (t, J=7.1 Hz, 6H).

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, RT=1.36 min. MS: m/z=355 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.64 (d, J=4.9 Hz, 1H), 7.92 (d, J=8.6 Hz, 1H), 7, 75 (s, 1H), 7.46 (dd, J=8.6, 2.0 Hz, 1H), 6.80 (d, J=5.0 Hz, 1H), 3.61 (d, J =12.3Hz, 2H), 2.80(td, J=12.0, 2.3Hz, 2H), 2.71(t, J=6.1Hz, 2H), 2.64(d , J=6.6 Hz, 2H), 2.58 (t, J=5.8 Hz, 2H), 2.57-2.49 (m, 7H), 1.94 (dd, J=12, 6, 3.3 Hz, 2H), 1.73 (dfp, J=9.8, 6.4, 3.8, 3.3 Hz, 1H), 1.60 (dsq, J=12.0 , 3.8 Hz, 2H), 1.03 (t, J=7.1 Hz, 6H).

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, RT=1.33 min. MS: m/z=387 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 7.93 (dd, J=9.1, 5.5 Hz, 1H), 7.74 (s, 1H), 7.33 (dd , J=9.1, 8.0, 2.9 Hz, 1H), 3.33 (s, 2H), 3.17 (d, J=11.8 Hz, 2H), 2.72 (t, J=6.2Hz, 2H), 2.68-2.61(m, 5H), 2.60(d, J=5.8Hz, 2H), 2.55(square, J=7, 1 Hz, 4H), 2.37 (s, 3H), 1.86 (d, J=12.1 Hz, 2H), 1.73 (s, 1H), 1.51 (q, J=11 .7 Hz, 2H), 1.03 (t, J=7.1 Hz, 6H).

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, RT=1.13 min. MS: m/z=373 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 7.92 (dd, J=9.2, 6.2 Hz, 1H), 7.56 (dd, J=10.4, 2, 6 Hz, 1H), 7.17 (ddd, J=9.2, 8.0, 2.6 Hz, 1H), 6.69 (s, 1H), 3.57 (d, J=12.3 Hz, 2H), 2.81 (td, J=12.1, 2.3 Hz, 2H), 2.70 (t, J=6.1 Hz, 2H), 2.64 (s, 3H), 2.63 (d, J=6.6 Hz, 2H), 2.58 (t, J=6.0 Hz, 2H), 2.53 (sq., J=7.1 Hz, 4H), 1 .93 (dd, J=12.6, 2.4 Hz, 2H), 1.73 (dd, J=13.9, 7.5, 6.7, 3.6 Hz, 1H), 1.56 (dsq, J=12.1, 3.8 Hz, 2H), 1.03 (t, J=7.1 Hz, 6H).

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, RT=1.57 min. MS: m/z =421 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.78 (d, J=5.1 Hz, 1H), 8.29 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.80 (dd, J=8.8, 2.1 Hz, 1H), 6.90 (d, J=5.1 Hz, 1H), 3.62 (d, J=12.6Hz, 2H), 2.88(td, J=12.2, 2.4Hz, 2H), 2.74(t, J=6.3Hz, 2H), 2.65( d, J=6.7 Hz, 2H), 2.47 (t, J=6.3 Hz, 2H), 2.39 (s, 4H), 1.97 (dd, J=12.7, 3 .2 Hz, 2H), 1.76 (dt, J=11.4, 3.0 Hz, 1H), 1.67-1.50 (m, 6H), 1.44 (td, J=6, 2, 3.3 Hz, 2H).

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, RT=1.29 min. MS: m/z=355 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.65 (d, J=5.0 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7, 80 (s, 1H), 7.29 (dd, J=8.6, 1.8 Hz, 1H), 6.77 (d, J=5.0 Hz, 1H), 3.62 (d, J =12.4Hz, 2H), 2.81(td, J=12.1, 2.3Hz, 2H), 2.70(t, J=6.1Hz, 2H), 2.63(d , J=6.6 Hz, 2H), 2.62-2.44 (m, 9H), 1.93 (dd, J=12.6, 2.3 Hz, 2H), 1.73 (ddq. , J=13.9, 6.7, 3.6 Hz, 1H), 1.58 (dsq., J=12.0, 3.8 Hz, 2H), 1.03 (t, J=7, 1 Hz, 6H).

Compound 401 (5-{4-[(2-diethylamino-ethylamino)-methyl]-piperidin-1-yl}-quinolin-8-carbonitrile):from 5-bromo-quinoline-8-carbonitrile, 4-formyl-n-cbz-piperidine and N,N-diethylethylenediamine. HPLC: >99% purity, RT=1.67 min. MS: m/z=366 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J=4.2, 1.7 Hz, 1H), 8.43 (dd, J=8.6, 1, 7 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.6, 4.2 Hz, 1H), 7.05 (d, J= 8.0 Hz, 1H), 3.50 (d, J=11.9 Hz, 2H), 2.87 (td, J=12.0, 2.3 Hz, 2H), 2.71 (t, J=6.1Hz, 2H), 2.64(d, J=6.6Hz, 2H), 2.62-2.46(m, 6H), 1.96(tt, J=12.4 , 2.1 Hz, 3H), 1.73 (dtt, J=14.0, 6.7, 3.7 Hz, 1H), 1.58 (dsq., J=12.0, 3.8 Hz , 2H), 1.03 (t, J=7.1 Hz, 5H).

Example 107: Synthesis of compound 393 (cis-5-(2,6-dimethyl-morpholin-4-yl)-quinazolin-8-carbonitrile)

Cis-5-(2,6-dimethyl-morpholin-4-yl)-quinazolin-8-carbonitrile: cis-5-(2,6-dimethyl-morpholin-4-yl)-quinazolin-8-carbonitrile was obtained from 5 -bromo-quinazoline-8-carbonitrile and cis-2,6-dimethylmorpholine in 79% yield using Method H.

Compound 393: HPLC: >99% purity, RT=2.70 min. MS: m/z=269 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.61 (s, 1H), 9.43 (s, 1H), 8.16 (d, J=8.2 Hz, 1H) , 7.07 (d, J=8.2 Hz, 1H), 4.03 (dq.d, J=10.2, 6.3, 2.1 Hz, 2H), 3.41 (dt, J =11.8, 1.8 Hz, 2H), 2.77 (dd, J=12.2, 10.3 Hz, 2H), 1.28 (d, J=6.3 Hz, 6H).

The following compounds were synthesized in a similar manner:

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, RT=2.38 min. MS: m/z=263 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.96 (d, J=1.9 Hz, 1H), 8.80 (d, J=1.8 Hz, 1H), 8, 23 (d, J=1.3 Hz, 1H), 4.72-4.56 (m, 2H), 3.91 (dqd, J=10.4, 6.2, 2.2 Hz, 2H), 2.81 (dd, J=12.9, 10.4 Hz, 2H), 1.27 (d, J=6.3 Hz, 6H).

Example 108: Synthesis of compound 395 (N-[1-(8-cyano-quinazolin-5-yl)-piperidin-4-ylmethyl]-2-diethylaminoacetamide)

N-[1-(8-cyano-quinazolin-5-yl)-piperidin-4-ylmethyl]-2-diethylaminoacetamide): N-[1-(8-cyano-quinazolin-5-yl)-piperidin- 4-ylmethyl]-2-diethylaminoacetamide) was obtained from 5-bromo-quinazolin-8-carbonitrile, 2-(diethylamino)acetic acid hydrochloride and 1-boc-4-(aminomethyl)piperidine in 40% yield for 3 steps, using Method 20, Q and H.

Compound 395: HPLC: >99% purity, RT=1.88 min. MS: m/z=381 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.54 (s, 1H), 9.39 (s, 1H), 8.12 (d, J=8.2 Hz, 1H) , 7.62 (t, J=5.9 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 3.65 (dt, J=13.0, 2.8 Hz, 2H), 3.31 (t, J=6.5 Hz, 2H), 3.06 (s, 2H), 3.01 (td, J=12.2, 2.4 Hz, 2H), 2, 58 (sq., J=7.1 Hz, 4H), 1.93 (dd, J=13.3, 3.1 Hz, 2H), 1.84 (dtt, J=14.4, 6.9 , 4.0 Hz, 1H), 1.62 (dsq, J=12.4, 3.9 Hz, 2H), 1.05 (t, J=7.1 Hz, 6H).

The following compounds were synthesized in a similar manner:

Compound 397 (1-(8-cyano-quinazolin-5-yl)-piperidine-4-carboxylic acid (2-diethylamino-ethyl)-amide):from 5-bromo-quinazoline-8-carbonitrile, 1-tert-butoxycarbonylpiperidine-4-carboxylic acid and N,N-diethylethylenediamine. HPLC: >99% purity, RT=1.75 min. MS: m/z=381 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.58 (s, 1H), 9.41 (s, 1H), 8.13 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.2 Hz, 1H), 6.28 (s, 1H), 3.69 (dt, J=12.1, 2.4 Hz, 2H), 3.34 (kv ., J=5.1 Hz, 2H), 3.06 (ddd, J=12.3, 10.3, 3.8 Hz, 2H), 2.63-2.47 (m, 6H), 2 .39 (tt, J=10.2, 5.1 Hz, 1H), 2.19-2.03 (m, 4H), 1.03 (t, J=7.1 Hz, 6H).

Compound 398 (N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-2-diethylamino-acetamide): from 5-bromo-quinolin-8-carbonitrile, 2-(diethylamino) hydrochloride )acetic acid; and 2-(diethylamino)acetic acid hydrochloride. HPLC: 98.8% purity, RT=2.13 min. MS: m/z=380 [M+H] ⁺ . ¹ H 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), 7.60 (s, 1H), 7.47 (dd, J=8.5, 4.2 Hz, 1H ), 7.04 (d, J=8.0 Hz, 1H), 3.50 (d, J=11.9 Hz, 2H), 3.32 (t, J=6.5 Hz, 2H), 3.07 (s, 2H), 2.86 (td, J=12.0, 2.2 Hz, 2H), 2.59 (sq., J=7.1 Hz, 4H), 1.90 ( d, J=12.6 Hz, 2H), 1.78 (dtt, J=14.4, 6.8, 3.6 Hz, 1H), 1.62 (dsq, J=12.1, 3 .8 Hz, 2H), 1.06 (t, J=7.1 Hz, 6H).

Compound 403 ((2-piperidin-1-yl-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 1-(2-aminoethyl)piperidine. HPLC: 96.7% purity, RT=2.07 min. MS: m/z=392 [M+H]⁺.^oneH 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), 6.22 (s, 1H), 3.54 (d, J=12.3 Hz, 2H), 3.37 (sq., J=5.6 Hz, 2H), 2.91 (td, J=11.9, 2.8 Hz, 2H), 2.76-2.23 (m, 7H), 2.13 (dq, J=12.2, 11.3, 3.8 Hz, 2H), 2.08-1.94 (m, 2H), 1.73-1.52 (m, 4H), 1.53-1.36 (m, 2H).

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, RT=2.01 min. MS: m/z=380 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.05 (dd, J=4.2, 1.7 Hz, 1H), 8.44 (dd, J=8.5, 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), 6.25 (s, 1H), 3.53 (d, J=12.6 Hz, 2H), 3.34 (sq., J=5.5 Hz, 2H), 2.90 (td, J=11.8, 2.8 Hz, 2H), 2.69-2.44 (m, 6H), 2.35 (tt, J=11.1, 4.3 Hz, 1H), 2.22-1.92 (m, 4H), 1.03 (t, J=7.1 Hz, 6H).

Example 109: Synthesis of compound 404 (2-(3-methoxyphenylamino)-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide)

Method 36

2-(3-Methoxy-phenylamino)-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide: 2-[(3-Methoxyphenyl)amino]acetic solution acids (77.7 mg; 0.429 mmol) and 1,1'-carbonyldiimidazole (69.6 mg; 0.429 mmol) in anhydrous THF (2.0 ml) were stirred at room temperature for 15 minutes, then C-(1 -pyrido[2,3-b]pyrazin-8-yl-piperidin-4-yl)-methylamine hydrochloride (80.0 mg; 0.286 mmol). 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 PuriFlash NH2 35 g 30 µm column eluting with a gradient of methanol in DCM to give 2-(3-methoxy-phenylamino)-N-(1-pyrido[2,3-b]pyrazine- 8-yl-piperidin-4-ylmethyl)-acetamide (63 mg; 54.2%).

(Note: Method 36 can also use DMF instead of THF as a solvent)

Compound 404: HPLC: >99% purity, RT=1.93 min. MS: m/z=407 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (d, J=1.7 Hz, 1H), 8.79 (d, J=5.4 Hz, 1H), 8 .71 (d, J=1.7 Hz, 1H), 7.11 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 6.85 (d, J=5, 5Hz, 1H), 6.37(ddd, J=8.2, 2.3, 0.8Hz, 1H), 6.24(ddd, J=8.1, 2.3, 0.9Hz , 1H), 6.18 (t, J=2.3 Hz, 1H), 4.40 (d, J=12.4 Hz, 2H), 3.82 (s, 2H), 3.76 (s , 3H), 3.27 (t, J=6.4 Hz, 2H), 3.02 (td, J=12.4, 2.4 Hz, 2H), 1.95-1.73 (m, 3H), 1.51 (dsq, J=12.0, 3.9 Hz, 2H).

The following compounds were synthesized in a similar manner:

Compound 406 (2-tert-Butylamino-N-(1-pyrido[2,3-b]pyrazin-8-yl-piperidin-4-ylmethyl)-acetamide):from C-(1-Pyrido[2,3-b]pyrazin-8-yl-piperidin-4-yl)-methylamine hydrochloride; and 2-(tert-butylamino)acetic acid hydrochloride. HPLC: 98.1% purity, RT=1.11 min. MS: m/z=357 [M+H]⁺.^oneH 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), 7.67 (s, 1H), 6.87 (d, J=5.4 Hz, 1H), 4.44 (d, J=12.1 Hz, 2H), 3.33-3.19 (m, 4H), 3.07 (td, J=12.5, 2.3 Hz, 2H), 1.90-1.84 (m, 2H) , 1.73-1.64 (m, 1H), 1.57 (dq, J=12.3, 11.8, 3.8 Hz, 2H), 1.09 (s, 8H).

Compound 413 (2-tert-Butylamino-N-[1-(8-cyano-quinolin-5-yl)-piperidin-4-ylmethyl]-acetamide): from 5-bromo-quinolin-8-carbonitrile, 4-( boc-aminomethyl)piperidine; and 2-(tert-butylamino)acetic acid hydrochloride. HPLC: 97.7% purity, RT=2.19 min. MS: m/z=380 [M+H] ⁺ . ¹ H 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), 8.00 (d, J=8.0 Hz, 1H), 7.73 (s, 1H), 7.47 (dd, J=8.5, 4.2 Hz, 1H ), 7.04 (d, J=8.0 Hz, 1H), 3.50 (d, J=12.3 Hz, 3H), 3.32 (t, J=6.5 Hz, 2H), 3.29 (s, 2H), 2.85 (td, J=12.0, 2.3 Hz, 2H), 1.91 (d, J=12.0 Hz, 2H), 1.78 (dddd , J=17.6, 10.3, 6.8, 3.1 Hz, 1H), 1.62 (dsq., J=12.0, 3.8 Hz, 2H), 1.12 (s, 9H).

Example 110: Synthesis of compound 425 (N-[1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylaminoacetamide)

N-[1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylaminoacetamide: N-[1-(8-cyano-quinolin-5- yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylaminoacetamide was obtained from 5-(5-amino-3,3-difluoro-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride and N,N-dimethylglycine in 39% yield using Method 20.

Compound 425: HPLC: 96.6% pure, RT=2.16 min. MS: m/z=374 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.11 (dd, J=4.2, 1.7 Hz, 1H), 8.65 (dd, J=8.6, 1 .7 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.87 (s, 1H), 7.57 (dd, J=8.6, 4.2 Hz, 1H ), 7.14 (d, J=8.0 Hz, 1H), 4.63 (s, 1H), 3.51 (sq., J=10.7, 10.3 Hz, 1H), 3, 41 (sq., J=12.4 Hz, 1H), 3.37-3.16 (m, 2H), 3.06-2.84 (m, 2H), 2.45-2.31 (m , 1H), 2.28 (s, 6H), 1.56 (s, 1H).

Example 111: Synthesis of compound 436

[2-(ethyl-methyl-amino)-ethyl]-amide 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid: [2-(ethyl-methyl-amino)-ethyl]- 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid amide was obtained from 5-bromo-8-(trifluoromethyl)quinolone, ethylpiperidine-4-carboxylate and (2-aminoethyl)(ethyl)methylamine with 48% yield for 3 steps using Method V, I and 20.

Compound 436: HPLC: 98.3% pure, RT=2.55 min. MS: m/z=409 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J=4.2, 1.8 Hz, 1H), 8.50 (dd, J=8.6, 1 .8 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.6, 4.2 Hz, 1H), 7.06 (d, J =8.0Hz, 1H), 6.25(s, 1H), 3.47(dt, J=12.6, 3.5Hz, 2H), 3.40(d, J=6.2Hz , 2H), 2.86 (td, J=11.9, 2.7 Hz, 2H), 2.53 (s, 4H), 2.42-2.20 (m, 4H), 2.13 ( dq, J=12.1, 11.3, 3.8 Hz, 2H), 2.04 (dd, J=12.8, 3.6 Hz, 2H), 1.10 (t, J=5 .9 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 441 ((2-piperidin-1-yl-ethyl)-amide 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid): from 5-bromo-8-(trifluoromethyl)quinolone, ethylpiperidine-4-carboxylate; and 1-(2-aminoethyl)piperidine. HPLC: 98.0% purity, RT=2.63 min. MS: m/z=435 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.03 (dd, J=4.2, 1.8 Hz, 1H), 8.50 (dd, J=8.6, 1 .8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.6, 4.2 Hz, 1H), 7.06 (d, J =8.0 Hz, 1H), 6.24 (s, 1H), 3.47 (dt, J=11.9, 2.6 Hz, 2H), 3.37 (td, J=6.1, 4.8 Hz, 2H), 2.86 (td, J=11.8, 2.7 Hz, 2H), 2.47 (t, J=6.0 Hz, 2H), 2.44-2, 27 (m, 5H), 2.13 (dq, J=12.1, 11.3, 3.8 Hz, 2H), 2.08-1.96 (m, 2H), 1.59 (p , J=5.6 Hz, 4H), 1.52-1.38 (m, 2H).

Compound 442from 5-bromo-8-(trifluoromethyl)quinolone, ethylpiperidine-4-carboxylate and (1-methylpyrrolidin-2-yl)methanamine. HPLC: 98.7% purity, RT=2.55 min. MS: m/z=421 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J=4.2, 1.8 Hz, 1H), 8.50 (dd, J=8.6, 1, 8 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.6, 4.2 Hz, 1H), 7.06 (d, J= 7.9 Hz, 1H), 6.12 (d, J=7.8 Hz, 1H), 3.66 (ddd, J=13.7, 7.9, 2.5 Hz, 1H), 3, 47 (dt, J=12.1, 3.3 Hz, 2H), 3.13 (ddd, J=13.7, 4.1, 2.4 Hz, 1H), 3.07 (ddd, J= 9.3, 6.8, 2.5 Hz, 1H), 2.86 (tt, J=11.8, 3.2 Hz, 2H), 2.46-2.38 (m, 1H), 2 .33 (s, 3H), 2.24 (td, J=9.4, 7.5 Hz, 1H), 2.14 (kw, J=11.3, 3.3 Hz, 2H), 2.03 (dd, J=13.5, 3.6 Hz, 2H), 1.96-1.83 (m, 1H), 1.80-1.65 (m, 2H), 1.60- 1.47 (m, 2H).

Compound 446 ((2-diethylamino-ethyl)-amide 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid):from 5-bromo-8-(trifluoromethyl)quinolone, ethylpiperidine-4-carboxylate and N,N-diethylethylenediamine. HPLC: >99% purity, RT=2.63 min. MS: m/z=423 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J=4.2, 1.8 Hz, 1H), 8.49 (dd, J=8.6, 1, 8 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 7.47 (dd, J=8.6, 4.2 Hz, 1H), 7.06 (d, J= 8.0Hz, 1H), 6.25(s, 1H), 3.47(dt, J=11.8, 2.8Hz, 2H), 3.34(sq., J=5.3Hz , 2H), 2.86 (td, J=11.8, 2.8 Hz, 2H), 2.63-2.49 (m, 6H), 2.34 (tt, J=11.2, 4 .3 Hz, 1H), 2.12 (dq, J=12.2, 11.2, 3.8 Hz, 2H), 2.07-1.97 (m, 2H), 1.04 (t , J=7.1 Hz, 6H).

Example 112: Synthesis of compound 443 (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: 2-diethylamino-N-[1-(8-trifluoromethyl-quinolin-5-yl) -piperidin-4-ylmethyl]-acetamide was prepared from 5-bromo-8-trifluoromethyl-quinoline, 4-(boc-aminomethyl)piperidine and 2-(diethylamino)acetic acid hydrochloride in 55% yield for 3 steps using Method V, Q and 20.

Compound 443: HPLC: >99% purity, RT=2.76 min. MS: m/z=423 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.02 (dd, J=4.2, 1.8 Hz, 1H), 8.45 (dd, J=8.6, 1 .8 Hz, 1H), 7.95 (d, J=8.1 Hz, 1H), 7.60 (s, 1H), 7.44 (dd, J=8.6, 4.2 Hz, 1H ), 7.04 (d, J=8.0 Hz, 1H), 3.43 (dt, J=12.7, 2.9 Hz, 2H), 3.32 (t, J=6.5 Hz , 2H), 3.06 (s, 2H), 2.81 (td, J=11.9, 2.3 Hz, 2H), 2.58 (sq., J=7.2 Hz, 4H), 1.89 (dd, J=12.8, 3.0 Hz, 2H), 1.77 (ddtd, J=13.6, 10.0, 6.6, 3.6 Hz, 1H), 1, 62 (dsq, J=11.9, 3.8 Hz, 2H), 1.05 (t, J=7.2 Hz, 6H).

The following compounds were synthesized in a similar manner:

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, RT=2.79 min. MS: m/z=435 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 9.03 (dd, J=4.2, 1.8 Hz, 1H), 8.46 (dd, J=8.6, 1, 8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.6, 4.2 Hz, 2H), 7.05 (d, J= 8.0 Hz, 1H), 3.44 (dt, J=11.7, 2.4 Hz, 2H), 3.33 (t, J=6.5 Hz, 2H), 2.99 (s, 2H), 2.82 (td, J=11.9, 2.3 Hz, 2H), 2.49 (t, J=5.3 Hz, 4H), 1.89 (dd, J=12.3 , 2.6 Hz, 2H), 1.77 (tdd, J=10.0, 8.6, 5.0 Hz, 1H), 1.70-1.54 (m, 6H), 1.54- 1.42 (m, 2H).

Example 113: Synthesis of compound 444 and compound 445 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid 1-cyclopropylmethyl-pyrrolidin-3-yl)-amide)

1-(8-Trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid ((R)-1-cyclopropylmethyl-pyrrolidin-3-yl)-amide and ((S)-1-cyclopropylmethyl-pyrrolidine-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)-piperidin-4-carboxylic acid and ((S)-1-cyclopropylmethyl-pyrrolidin-3-yl)-amide 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acids were prepared from 1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid and 1-(cyclopropylmethyl)pyrrolidin-3-amine in 62% yield using Method 20. The enantiomers were isolated by chiral SLC chromatography. (Column: 1.0 × 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, RT=2.84 min. MS: m/z=447 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J=4.2, 1.8 Hz, 1H), 8.49 (dd, J=8.6, 1 .8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.6, 4.2 Hz, 1H), 7.06 (d, J =7.9 Hz, 1H), 5.95 (s, 1H), 4.50 (dddd, J=10.6, 8.5, 4.5, 2.8 Hz, 1H), 3.47 ( d, J=12.5 Hz, 2H), 3.02 (td, J=8.7, 3.5 Hz, 1H), 2.84 (td, J=11.8, 2.6 Hz, 2H ), 2.77 (dd, J=10.1, 2.4 Hz, 1H), 2.53 (dd, J=10.0, 6.5 Hz, 1H), 2.41-2.19 ( m, 5H), 2.12 (dq, J=12.0, 11.5, 3.7 Hz, 2H), 2.06-1.96 (m, 2H), 1.63 (dtd, J =11.9, 7.9, 3.7 Hz, 1H), 0.89 (dddd, J=11.5, 8.1, 4.8, 2.4 Hz, 1H), 0.58-0 .45 (m, 2H), 0.13 (ddd, J=6.7, 4.9, 3.7 Hz, 2H).

Isomer 2: HPLC: >99% purity, RT=2.84 min. MS: m/z=447 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J=4.2, 1.8 Hz, 1H), 8.49 (dd, J=8.6, 1 .8 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.47 (dd, J=8.6, 4.2 Hz, 1H), 7.06 (d, J =8.0 Hz, 1H), 5.96 (s, 1H), 4.52 (s, 1H), 3.47 (d, J=11.9 Hz, 2H), 3.04 (s, 1H ), 2.84 (td, J=11.9, 2.7 Hz, 2H), 2.78 (d, J=8.2 Hz, 1H), 2.54 (dd, J=10.1, 6.5 Hz, 1H), 2.47-2.19 (m, 4H), 2.12 (dq, J=11.9, 11.4, 3.7 Hz, 2H), 2.02 ( d, J=12.8 Hz, 2H), 1.62 (s, 2H), 0.98-0.82 (m, 1H), 0.65-0.41 (m, 2H), 0.14 (sq., J=5.0 Hz, 2H).

Example 114: Synthesis of compound 447 (N-[(3R,5S)-1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-2-dimethylaminoacetamide)

N-[(3R,5S)-1-(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-2-dimethylaminoacetamide: N-[(3R,5S)-1 -(8-cyano-quinazolin-5-yl)-5-methyl-piperidin-3-yl]-2-dimethylaminoacetamide was obtained from 5-[(3R,5S)-3-amino-5-methyl-1- piperidyl]quinazoline-8-carbonitrile hydrochloride and N,N-dimethylglycine in 77% yield using Method 20.

Compound 447: HPLC: 97.2% pure, RT=2.01 min. MS: m/z=353 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.61 (s, 1H), 9.41 (s, 1H), 8.11 (d, J=8.2 Hz, 1H) , 7.14 (d, J=8.9 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H), 4.34-4.20 (m, 1H), 3.92 ( ddt, J=11.7, 4.0, 1.9 Hz, 1H), 3.61 (ddd, J=12.3, 4.0, 2.0 Hz, 1H), 2.96 (s, 2H), 2.76-2.59(m, 2H), 2.30(s, 6H), 2.26-2.05(m, 2H), 1.18(q, J=11.9 Hz, 1H), 1.01 (d, J=6.5 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 460 ):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, RT=1.65 min. MS: m/z=347 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.94 (d, J=1.8 Hz, 1H), 8.82 (d, J=1.8 Hz, 1H), 8, 21 (d, J=1.4 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 4.90 (ddt, J=12.3, 4.1, 1.8 Hz , 1H), 4.66 (ddt, J=12.7, 3.8, 1.8 Hz, 1H), 4.25-4.13 (m, 1H), 3.01-2.89 (m , 2H), 2.79 (dd, J=12.3, 10.7 Hz, 1H), 2.61 (dd, J=12.7, 11.0 Hz, 1H), 2.30 (s, 6H), 2.22-2.14(m, 1H), 2.08(dddt, J=14.9, 10.8, 7.8, 3.6 Hz, 1H), 1.13(q. , J=11.8 Hz, 1H), 1.00 (d, J=6.7 Hz, 3H).

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, RT=1.62 min. MS: m/z=383 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.93 (dd, J=4.2, 1.8 Hz, 1H), 8.54 (dd, J=8.5, 1, 8 Hz, 1H), 7.48-7.38 (m, 2H), 7.02 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 4.42-4, 26 (m, 1H), 3.71 (t, J=4.6 Hz, 4H), 3.52 (ddt, J=10.8, 4.1, 1.7 Hz, 1H), 3.22 (ddt, J=11.4, 3.7, 1.7 Hz, 1H), 3.08-2.93 (m, 2H), 2.74 (d, J=0.9 Hz, 3H), 2.60-2.44 (m, 4H), 2.39 (td, J=10.8, 2.1 Hz, 2H), 2.24-2.07 (m, 2H), 1.11- 0.93 (m, 4H).

Compound 469 (2-dimethylamino-N-[(3R,5S)-1-(8-fluoro-quinolin-5-yl)-5-methyl-piperidin-3-yl]-acetamide):from (3R,5S)-1-(8-Fluoro-quinolin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride and N,N-dimethylglycine. HPLC: 94.0% purity, RT=1.70 min. MS: m/z=345 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (dd, J=4.2, 1.7 Hz, 1H), 8.55 (dt, J=8.6, 1, 7 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.29 (dd, J=10.4, 8.3 Hz, 1H), 7.07 ( d, J=8.5 Hz, 1H), 7.02 (dd, J=8.3, 4.2 Hz, 1H), 4.32 (dddd, J=14.6, 10.5, 8, 4, 4.1 Hz, 1H), 3.52 (ddt, J=10.9, 4.1, 1.8 Hz, 1H), 3.20 (ddt, J=11.3, 3.7, 1.8 Hz, 1H), 2.93 (d, J=2.2 Hz, 2H), 2.39 (sq., J=10.9 Hz, 2H), 2.28 (s, 6H), 2.21-2.04 (m, 2H), 1.11-0.92 (m, 4H).

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, RT=1.73 min. MS: m/z=387 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (dd, J=4.1, 1.7 Hz, 1H), 8.55 (dt, J=8.6, 1, 7 Hz, 1H), 7.50 (dd, J=8.6, 4.2 Hz, 1H), 7.29 (dd, J=10.4, 8.3 Hz, 1H), 7.03 ( dd, J=8.3, 4.2 Hz, 1H), 6.99 (s, 1H), 4.41-4.23 (m, 1H), 3.71 (s, 4H), 3.55 -3.46(m, 1H), 3.25-3.16(m, 1H), 3.00(s, 2H), 2.51(s, 4H), 2.44-2.27(m , 2H), 2.22-2.05 (m, 2H), 1.11-0.90 (m, 4H).

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, RT=1.84 min. MS: m/z=399 [M+H]⁺.^oneH NMR (400 MHz, Chloroform-d, ppm) δ 8.95 (dd, J=4.2, 1.7 Hz, 1H), 8.55 (dt, J=8.6, 1, 7 Hz, 1H), 7.51 (dd, J=8.6, 4.2 Hz, 1H), 7.29 (dd, J=10.4, 8.3 Hz, 1H), 7.01 ( dd, J=8.3, 4.2 Hz, 1H), 5.25 (d, J=8.0 Hz, 1H), 4.31 (ddq, J=16.1, 8.3, 4 .1 Hz, 1H), 3.63-3.48 (m, 1H), 3.26-3.08 (m, 1H), 2.81 (t, J=10.3 Hz, 2H), 2 .35 (dt, J=17.8, 10.8 Hz, 2H), 2.25 (s, 3H), 2.21-2.07 (m, 2H), 1.93 (tdd, J=11 .7, 5.4, 2.6 Hz, 2H), 1.80 (dp, J=11.2, 3.5 Hz, 1H), 1.74-1.64 (m, 2H), 1, 34-1.21 (m, 2H), 1.04-0.91 (m, 4H).

Example 115: Synthesis of compound 449 and compound 450 (N-[(R)-1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylaminoacetamide and N-[ (S)-1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylaminoacetamide)

N-[(R)-1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylaminoacetamide and N-[(S)-1-( 8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-dimethylaminoacetamide : N-[(R)-1-(8-cyano-quinolin-5-yl) -5,5-difluoro-piperidin-3-yl]-2-dimethylaminoacetamide and N-[(S)-1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3 -yl]-2-dimethylaminoacetamide was prepared from 5-(5-Amino-3,3-difluoro-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride and N,N-dimethylglycine in 25% yield using Method 20. Enantiomers were isolated by chiral SLC 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 pressure: 100 bar Column temperature: 30°C).

Isomer 1: HPLC: >99% purity, RT=2.06 min. MS: m/z=374 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.11 (dd, J=4.2, 1.7 Hz, 1H), 8.65 (dd, J=8.6, 1 .7 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.87 (s, 1H), 7.57 (dd, J=8.6, 4.2 Hz, 1H ), 7.14 (d, J=7.9 Hz, 1H), 4.63 (s, 1H), 3.51 (dd, J=21.5, 10.2 Hz, 1H), 3.43 (d, J=11.9 Hz, 1H), 3.35-3.18 (m, 2H), 3.04-2.90 (m, 2H), 2.46-2.30 (m, 2H ), 2.28 (s, 6H).

Isomer 2: HPLC: >99% purity, RT=2.08 min. MS: m/z=374 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.11 (dd, J=4.2, 1.7 Hz, 1H), 8.65 (dd, J=8.6, 1 .7 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.86 (s, 1H), 7.57 (dd, J=8.6, 4.2 Hz, 1H ), 7.14 (d, J=7.9 Hz, 1H), 4.63 (s, 1H), 3.51 (sq., J=10.4 Hz, 1H), 3.43 (d, J=11.9 Hz, 1H), 3.37-3.17 (m, 2H), 3.04-2.90 (m, 2H), 2.46-2.29 (m, 2H), 2 .28 (s, 6H).

Example 116: Synthesis of compound 451 (Methyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine hydrochloride)

Methyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine hydrochloride : Methyl-[(3R,5S)-5-methyl- 1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine hydrochloride was obtained from tert-butyl ether [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5 -yl)-piperidin-3-yl]-carbamic acid and iodomethane in 68% yield for 2 steps using Method 35 and Q.

Compound 451: HPLC: 98.8% pure, RT=2.74 min. MS: m/z=324 [M+H] ⁺ . ¹ H NMR (400 MHz, deuterium oxide, ppm) δ 9.21 (dt, J=8.7, 1.3 Hz, 1H), 9.13 (dt, J=5.2, 1, 4 Hz, 1H), 8.41 (d, J=8.3 Hz, 1H), 8.08 (ddd, J=8.5, 5.2, 1.1 Hz, 1H), 7.55 ( d, J=8.3 Hz, 1H), 3.86 (d, J=11.2 Hz, 1H), 3.72 (tt, J=7.7, 3.8 Hz, 1H), 3, 51 (d, J=12.1 Hz, 1H), 3.07 (t, J=11.0 Hz, 1H), 2.85 (s, 3H), 2.62 (t, J=11.8 Hz, 1H), 2.47 (d, J=12.5 Hz, 1H), 2.36-2.21 (m, 1H), 1.34 (sq., J=12.0 Hz, 1H) , 1.07 (d, J=6.6 Hz, 3H).

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: 2-dimethylamino-N- methyl-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-acetamide was obtained from Methyl-[(3R,5S)-5- methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine hydrochloride and N,N-dimethylglycine in 56% yield using Method 20.

Compound 452: HPLC: 95.0% pure, RT=3.11 min. MS: m/z=409 [M+H] ⁺ .

Example 118: Synthesis of compound 453

(2-diethylamino-ethyl)-amide 4-(8-cyano-quinoxalin-5-yl)-piperazine-1-carboxylic acid: (2-diethylamino-ethyl)-amide 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 in 11% yield over 3 steps using Method H, Q and 36.

Compound 453: HPLC: 96.4% pure, RT=1.85 min. MS: m/z=382 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.98 (d, J=1.8 Hz, 1H), 8.84 (d, J=1.8 Hz, 1H), 8 .03 (d, J=8.3 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 5.36 (s, 1H), 3.77-3.59 (m, 8H), 3.37-3.25(m, 2H), 2.56(s, 6H), 1.03(s, 6H).

The following compound was was synthesized in a similar manner:

Compound 463 (4-(8-cyano-quinoxalin-5-yl)-piperazine-1-carboxylic acid ((2-dimethylamino-ethyl)-amide): HPLC: >99% purity, RT=1.62 min. MS: m/z=354 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.98 (d, J=1.8 Hz, 1H), 8.83 (d, J=1.8 Hz, 1H), 8 .03 (d, J=8.3 Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 5.28 (s, 1H), 3.79-3.67 (m, 4H), 3.67-3.57 (m, 4H), 3.35 (dt, J=5.9, 4.8 Hz, 2H), 2.47 (t, J=5.8 Hz, 2H ), 2.26 (s, 6H).

Example 119: Synthesis of compound 458 (5-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-pyrido[4,3-d]pyrimidine-8-carbonitrile hydrochloride)

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 mmol) and iodine ( 863 mg; 3.40 mmol) in 0.4 N sodium hydroxide solution (15 ml) was heated to 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 minutes. The suspension was filtered, the solid was washed with water and dried in vacuo to give 8-iodo-6H-pyrido[4,3-d]pyrimidin-5-one (727 mg; 76%) as a light yellow solid. MS: m/z=274 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 12.15 (s, 1H), 9.42 (s, 1H), 9.33 (s, 1H), 8.13 (s , 1H).

[(3R,5S)-1-(8-iodo-pyrido[4,3-d]pyrimidin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-butyl ester: Solution 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 mmol) in anhydrous DMSO (9 ml) were placed in a sealed tube and heated at 40°C overnight . The light yellow solution was cooled to room temperature, poured into saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (3×50 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 hexane and ethyl acetate, to give tert-butyl ester [(3R,5S)-1-(8-iodo-pyrido[4,3-d]pyrimidin-5-yl) -5-methyl-piperidin-3-yl]-carbamic acid (212 mg; 41%) as a yellow solid. MS: m/z=470 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.41 (s, 1H), 9.38 (s, 1H), 8.77 (s, 1H), 4.45 (s, 1H), 4.33 (ddt, J=12.4, 4.2, 1.9 Hz, 1H), 4.02 (ddt, J=12.9, 4.0, 1.8 Hz, 1H) , 3.87 (s, 1H), 2.74 (dd, J=12.3, 10.8 Hz, 1H), 2.66 (t, J=12.1 Hz, 1H), 2.19 ( e, J=12.6 Hz, 1H), 2.06 (s, 1H), 1.45 (s, 9H), 1.13-0.95 (m, 4H).

[(3R,5S)-1-(8-cyano-pyrido[4,3-d]pyrimidin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-butyl ester: A mixture of tert- [(3R,5S)-1-(8-iodo-pyrido[4,3-d]pyrimidin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid butyl ester (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(diphenylphosphino)ferrocene (5.9 mg; 0.011 mmol ) in anhydrous DMF (3 ml) was heated under microwave irradiation at 120°C for 2 hours. The black suspension was filtered on celite, washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by chromatography on a PuriFlash column (12 g 30 μm), eluting with hexane and ethyl acetate, to give tert-butyl ester [(3R,5S)-1-(8-cyano-pyrido[4,3-d]pyrimidin-5-yl) -5-methyl-piperidin-3-yl]-carbamic acid (50 mg; 64%) as a yellow solid. MS: m/z=369 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.54 (s, 1H), 9.40 (s, 1H), 8.66 (s, 1H), 4.70 (d, J=12.7Hz, 1H), 4.48(d, J=12.0Hz, 2H), 3.81(s, 1H), 2.89(dd, J=12.6, 11.0 Hz, 1H), 2.75 (t, J=12.4 Hz, 1H), 2.21 (d, J=12.5 Hz, 1H), 1.99 (s, 1H), 1.45 ( s, 9H), 1.15 (q, J=12.0 Hz, 1H), 1.05 (d, J=6.6 Hz, 3H).

5-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-pyrido[4,3-d]pyrimidine-8-carbonitrile hydrochloride: Hydrochloric acid solution (692 µl; 2.77 mmol ) 4M in dioxane was added to a solution of tert-butyl ether [(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 (10 ml) was added. The yellow suspension was filtered, the yellow solid was washed with ethyl acetate and dried in vacuo to give 5-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-pyrido[4,3-d]pyrimidin-8 -carbonitrile hydrochloride (18 mg; 64%) as a yellow solid.

Compound 453: HPLC: >99% purity, RT=1.42 min. MS: m/z=269 [M+H] ⁺ . ¹ H NMR (400 MHz, deuterium oxide, ppm) δ 9.58 (s, 1H), 9.32 (s, 1H), 8.79 (s, 1H), 4.85 (d, J =12.5Hz, 1H), 4.38(d, J=13.7Hz, 1H), 3.73-3.62(m, 1H), 3.42-3.33(m, 1H) , 3.22 (t, J=12.5 Hz, 1H), 2.37 (d, J=12.8 Hz, 1H), 2.08 (s, 1H), 1.51 (q., J =12.2 Hz, 1H), 1.06 (d, J=6.7 Hz, 3H).

Example 119: Synthesis of compound 461 (cis-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ol)

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 prepared from 5-bromo-8-(trifluoromethyl)quinolone and cis-5-methyl-piperidin-3-ol in 7% yield using Method V.

Compound 461: HPLC: 95.7% pure, RT=3.67 min. MS: m/z=311 [M+H] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.04 (dd, J=4.2, 1.8 Hz, 1H), 8.44 (dd, J=8.6, 1 .8 Hz, 1H), 7.98 (dd, J=8.0, 0.9 Hz, 1H), 7.47 (dd, J=8.5, 4.2 Hz, 1H), 7.08 (d, J=8.0 Hz, 1H), 4.18-4.03 (m, 1H), 3.57 (ddt, J=11.0, 4.4, 1.9 Hz, 1H), 3.30 (ddt, J=11.7, 3.7, 1.7 Hz, 1H), 2.59 (dd, J=11.0, 10.0 Hz, 1H), 2.38 (t, J=11.3 Hz, 1H), 2.26 (ddd, J=11.8, 3.9, 1.8 Hz, 1H), 2.10 (dddt, J=11.9, 10.6, 6.6, 4.0 Hz, 1H), 1.12 (td, J=12.1, 10.8 Hz, 1H), 1.02 (d, J=6.7 Hz, 3H).

Example 120: Synthesis of compound 464

1-(8-trifluoromethyl-quinolin-5-yl)-piperidine-4-carboxylic acid ((3R,4S)-4-fluoro-pyrrolidin-3-yl)-amide hydrochloride: 1-(8-trifluoromethyl-quinolin- 5-yl)-piperidine-4-carboxylic acid ((3R,4S)-4-fluoro-pyrrolidin-3-yl)-amide hydrochloride was obtained from 5-bromo-8-(trifluoromethyl)quinolone, ethylpiperidine-4-carboxylate and (3R,4S)-3-amino-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester in 45% yield for 4 steps using Method V, I, 20 and Q.

Compound 464: HPLC: >99% purity, RT=2.45 min. MS: m/z=411 [M+H] ⁺ . ¹ H NMR (400 MHz, Deuterium oxide, ppm) δ 8.97 (dd, J=4.7, 1.6 Hz, 1H), 8.79 (dd, J=8.6, 1, 7 Hz, 1H), 8.19 (d, J=8.2 Hz, 1H), 7.79 (dd, J=8.6, 4.7 Hz, 1H), 7.32 (d, J= 8.2Hz, 1H), 5.42(dt, J=52.4, 3.3Hz, 1H), 4.92-4.81(m, 1H), 3.95-3.76(m , 3H), 3.52 (d, J=12.2 Hz, 2H), 3.35 (t, J=11.4 Hz, 1H), 3.02-2.87 (m, 2H), 2 .73-2.59 (m, 1H), 2.17-1.92 (m, 4H).

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: 3-amino- 3,N-dimethyl-N-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-butyramide was obtained from methyl-[(3R,5S )-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amine hydrochloride and 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid in 13% yield for 2 steps with using Method 20 and Q.

Compound 465: HPLC: 93.2% pure, RT=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: To solution (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 (2-isocyanatoethyl)dimethylamine was charged into the flask. The reaction mixture was stirred for 16 hours. The reaction mixture was filtered and concentrated. The crude product was purified by preparative HPLC under the following conditions: XBridge Prep C18 OBD Column, 5 µm, 19 mm x 150 mm; Mobile phase: acetonitrile in water (with 0.05% NH ₃ .H ₂ O), 30% - 65% gradient over 7 min; detector UV 254 nm.

Compound 477: HPLC: >99% purity, RT=2.86 min. MS: m/z=424.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.00 (dd, J=4.2, 1.7 Hz, 1H), 8.52 (dd, J=8.6, 1.8 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.65 (dd, J=8.6, 4.2 Hz, 1H), 7.19 (d, J=8.1Hz, 1H), 6.09(d, J=7.4Hz, 1H), 5.71(t, J=5.4Hz, 1H), 3.56(d, J= 9.2 Hz, 1H), 3.14-2.98 (m, 2H), 2.46-2.33 (m, 2H), 2.23 (t, J=6.3 Hz, 2H), 2.12 (s, 6H), 1.98 (d, J=20.5 Hz, 2H), 1.03-0.88 (m, 4H).

Example 122: Synthesis of compound 478

Method 37

cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(1-methyl-piperidin-4-yl)-acetamide: cis-5 solution -(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride (100 mg; 0.28 mmol), (1-methyl-piperidin-4-yl)-acetic acid (53 mg ; 0.34 mmol) and DIPEA (0.2 ml; 0.84 mmol) in DMSO (2 ml) were stirred at room temperature for 5 minutes and then bop (149 mg; 0.34 mmol) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (XBridge column), eluting with acetonitrile in water (0.1%NH _3. H ₂ O), 30% - 70% gradient, to give [00984] cis-N-[1-(8- cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-2-(1-methyl-piperidin-4-yl)-acetamide as a white solid (70 mg, 54%).

Compound 478: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 9.01 (dd, J=4.3, 1.6 Hz, 1H), 8.67 (dd, J=8 .6, 1.7 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.70 (dd, J=8.6, 4.3 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.32 (tt, J=11.3, 4.3 Hz, 1H), 3.76-3.62 (m, 2H), 3.16- 2.94 (m, 2H), 2.87 (t, J=10.8 Hz, 2H), 2.60 (t, J=11.2 Hz, 1H), 2.35 (d, J=12 .5 Hz, 1H), 2.27 (s, 3H), 2.21-2.11 (m, 2H), 2.02 (ddt, J=14.5, 9.0, 2.9 Hz, 2H), 1.90-1.46 (m, 4H), 1.32 (dt, J=11.9, 5.4 Hz, 2H). MS: m/z=460 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

Compound 481 (cis-N-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3-hydroxy-3-methylbutyramide): from cis-5-(3 -amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride and 3-hydroxy-3-methyl-butyric acid. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.07 (dd, J=4.2, 1.6 Hz, 1H), 8.59 (dd, J=8.6, 1.7 Hz, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 7.73 (dd, J=8, 6, 4.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 4.70 (s, 1H), 4.19 (s, 1H), 3.57 (d, J=9.3Hz, 2H), 3.21(s, 1H), 2.95(t, J=11.6Hz, 1H), 2.65(t, J=11.3Hz, 1H) , 2.22 (s, 2H), 1.53 (sq, J=12.2 Hz, 1H), 1.16 (s, 6H). MS: m/z=421 [M+H] ⁺ .

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-tert-butoxycarbonylamino-cyclohexyl)-acetic acid.^oneH NMR (400 MHz, Methanol-d_four, ppm) δ 8.95 (d, J=4.2 Hz, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.7, 4.1 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 4.25 (s, 1H), 3.63 (d, J=11.4 Hz, 1H), 3.40 (d, J=11.6 Hz, 1H), 2.50 (sq., J=11.4 Hz, 2H), 2 .31 (s, 2H), 2.14 (d, J=12.6 Hz, 2H), 1.67-1.35 (m, 11H), 1.16 (sq., J=12.4 Hz , 1H), 1.05 (d, J=6.2 Hz, 3H). MS: m/z=449 [M+H]⁺.

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 hydrochloride and 3-hydroxy-3-methylbutyric acid,^oneH NMR (400 MHz, Methanol-d_four, ppm) δ 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.67 (dd, J=8.6, 1.8 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.63 (dd, J=8.6, 4.2 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 4 .26 (ddt, J=17.3, 13.6, 6.9 Hz, 1H), 3.68-3.59 (m, 1H), 3.47-3.36 (m, 2H), 2 .55-2.37 (m, 2H), 2.36 (s, 2H), 2.17 (s, 2H), 1.27 (d, J=0.9 Hz, 6H), 1.17 ( sq., J=12.6 Hz, 1H), 1.05 (d, J=6.4 Hz, 3H). MS: m/z=410 [M+H]⁺.

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)-acetic acid hydrochloride.^oneH NMR (400 MHz, DMSO-d₆) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.57 (dd, J=8.6, 1.7 Hz, 1H), 8.25 (d, J= 8.0 Hz, 1H), 8.02 (d, J=7.4 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 4.12(s, 2H), 3.56(t, J=8.9Hz, 2H), 3.24(tdd, J=7.2, 4.0 , 2.1 Hz, 2H), 2.93 (t, J=11.6 Hz, 1H), 2.82-2.68 (m, 2H), 2.64-2.53 (m, 2H) , 2.43-2.28 (m, 2H), 2.15 (s, 3H), 1.50 (sq., J=12.3 Hz, 1H). MS: m/z=432 [M+H]⁺.

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.^oneH NMR (400 MHz, DMSO-d₆) δ 9.07 (dd, J=4.2, 1.6 Hz, 1H), 8.59 (dd, J=8.6, 1.7 Hz, 1H), 8.26 (d, J= 8.0 Hz, 1H), 8.06 (d, J=7.4 Hz, 1H), 7.73 (dd, J=8.6, 4.2 Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 4.25(m, 1H), 4.57(s, 1H), 3.70-3.48(m, 2H), 3.21(d, J=11 .2 Hz, 1H), 2.95 (t, J=11.6 Hz, 1H), 2.64 (t, J=11.2 Hz, 1H), 2.21 (s, 3H), 1, 65-1.28 (m, 9H), 1.19 (sq., J=10.7, 10.1 Hz, 1H). MS: m/z=461 [M+H]⁺.

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 methyl ester of cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid and 1-methyl-piperazine.^oneH NMR (400 MHz, DMSO-d₆) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1.7 Hz, 1H), 8.25 (d, J= 8.0 Hz, 1H), 8.02 (d, J=7.3 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 4.13(d, J=8.2Hz, 1H), 3.57(d, J=11.7Hz, 1H), 3.41(d, J= 5.0 Hz, 3H), 3.19 (s, 1H), 2.95 (t, J=11.6 Hz, 1H), 2.70-2.54 (m, 2H), 2.41- 2.24 (m, 3H), 2.15 (s, 3H), 1.51 (sq., J=12.3 Hz, 1H). MS: m/z=503 [M+H]⁺.

Compound 554 -4-yl)-acetamide): from 3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and 1-methyl-4 -piperidineacetic acid. MS: m/z=396 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (dd, J=4.1, 1.7 Hz, 1H), 8.44 (dd, J=8.5, 1.7 Hz, 1H ), 8.10 (s, 1H), 7.87-7.76 (m, 2H), 4.06-3.97 (m, 1H), 3.45-3.36 (m, 1H), 3.26-3.19 (m, 1H), 2.88 (s, 3H), 2.74-2.63 (m, 2H), 2.42 (sq., J=11.0 Hz, 2H ), 2.11 (s, 3H), 2.08-1.91 (m, 4H), 1.85-1.72 (m, 2H), 1.65-1.48 (m, 3H), 1.22-1.06(m, 2H), 1.05(q, J=11.8Hz, 1H), 0.95(d, J=6.5Hz, 3H).

Compound 555 butyramide): from (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and beta-hydroxyisovaleric acid. MS: m/z=357 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.03 (dd, J=4.1, 1.7 Hz, 1H), 8.45 (dd, J=8.5, 1.7 Hz, 1H), 8.11 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.80 (dd, J=8.5, 4.1 Hz, 1H), 4.77 (s, 1H), 4.13-3.95 (m, 1H), 3.47-3.37 (m, 1H), 3.28-3.18 (m, 1H) , 2.88 (s, 3H), 2.43 (dd, J=23.0, 11.1 Hz, 2H), 2.21 (s, 2H), 2.12-1.91 (m, 2H ), 1.14 (s, 3H), 1.13 (s, 3H), 1.12-1.00 (m, 1H), 0.95 (d, J=6.4 Hz, 3H).

Compound 556 -3-yl]-acetamide): from (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and hydrochloride (1- methyl-azetidin-3-yl)-acetic acid. MS: m/z=357 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ , ppm) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.43 (dd, J=8.5, 1.7 Hz, 1H), 8.10 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.79 (dd, J=8.5, 4.1 Hz, 1H), 4.03-3.95 (m, 1H), 3.44-3.35 (m, 1H), 3.23 (ddt, J=8.4, 4.6, 2.4 Hz, 3H), 2.88 (s, 3H), 2.73 (td, J=6.3, 2.2 Hz, 2H), 2.61-2.52 (m, 1H), 2.41 (dt , J=15.1, 11.0 Hz, 2H), 2.32 (dd, J=7.7, 1.6 Hz, 2H), 2.14 (s, 3H), 2.05-1, 93 (m, 2H), 1.05 (q, J=12.0 Hz, 1H), 0.94 (d, J=6.5 Hz, 3H).

Compound 557 (tert-butyl ester 3-{[(3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylcarbamoyl]-methyl}- azetidin-1-carboxylic acid): from (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and tert-butyl ether 3 -carboxymethyl-azetidine-1-carboxylic acid. MS: m/z=454 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4, ppm) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.60 (dd, J=8.6, 1 .7 Hz, 1H), 8.05 (s, 1H), 7.79 (dd, J=8.6, 4.2 Hz, 1H), 4.25-4.13 (m, 1H), 4 .05 (sq., J=8.0 Hz, 2H), 3.69-3.58 (m, 2H), 3.56-3.52 (m, 1H), 2.96 (s, 3H) , 2.96-2.82 (m, 1H), 2.55-2.43 (m, 4H), 2.18-2.07 (m, 2H), 1.42 (s, 9H), 1 .41-1.35(m, 1H), 1.14(q, J=12.6Hz, 1H), 1.04(d, J=6.4Hz, 3H).

Compound 558 -yl]-acetamide): from (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and cyclopropyl-hydroxy-acetic acid . MS: m/z=355 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J=4.1, 1.7 Hz, 1H), 8.46 (dd, J=8.5, 1 .7 Hz, 1H), 8.11 (s, 1H), 7.80 (dd, J=8.5, 4.1 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H ), 5.28 (s, 1H), 4.13-4.00 (m, 1H), 3.51 (d, J=6.2 Hz, 1H), 3.37-3.33 (m, 1H), 3.26-3.22 (m, 1H), 2.88 (s, 3H), 2.57 (t, J=10.8 Hz, 1H), 2.41 (t, J=11 .2 Hz, 1H), 2.09-2.01 (m, 1H), 1.99-1.90 (m, 1H), 1.19 (sq., J=12.1 Hz, 1H), 1.09-0.98 (m, 1H), 0.95 (d, J=6.6 Hz, 3H), 0.42-0.23 (m, 4H).

Compound 559 -yl]-acetamide): from (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and cyclopropyl-hydroxy-acetic acid . MS: m/z=355 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J=4.1, 1.7 Hz, 1H), 8.45 (dd, J=8.5, 1 .8 Hz, 1H), 8.10 (s, 1H), 7.80 (dd, J=8.5, 4.1 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H ), 5.32 (s, 1H), 4.11-4.03 (m, 1H), 3.53 (d, J=6.0 Hz, 1H), 3.40-3.34 (m, 1H), 3.27-3.20 (m, 1H), 2.88 (s, 3H), 2.57 (t, J=10.8 Hz, 1H), 2.41 (t, J=11 .2 Hz, 1H), 2.08-2.03 (m, 1H), 1.99-1.94 (m, 1H), 1.20 (sq., J=12.0 Hz, 1H), 1.10-0.98 (m, 1H), 0.95 (d, J=6.5 Hz, 3H), 0.42-0.25 (m, 4H).

Compound 560 -3-yl)-acetamide): from (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and (1- methyl-pyrrolidin-3-yl)-acetic acid. MS: m/z=382 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4, ppm) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.60 (dd, J=8.6, 1 .7 Hz, 1H), 8.05 (s, 1H), 7.79 (dd, J=8.5, 4.2 Hz, 1H), 4.24-4.17 (m, 1H), 3 .60-3.50 (m, 1H), 2.96 (s, 3H), 2.85 (dt, J=9.8, 7.4 Hz, 1H), 2.75-2.56 (m , 3H), 2.49 (td, J=10.9, 6.8 Hz, 2H), 2.40 (d, J=4.0 Hz, 3H), 2.35-2.25 (m, 3H), 2.22-1.99 (m, J=5.1 Hz, 4H), 1.53 (dp, J=14.3, 7.0 Hz, 1H), 1.14 (sq., J=12.5 Hz, 1H), 1.04 (d, J=6.4 Hz, 3H).

Example 123: Synthesis of compound 479 (cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride)

Cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride: Cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8 -carbonitrile hydrochloride was prepared from cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride and (1-t-butoxycarbonylamino-cyclohexyl)-acetic acid using Method 37 and Q .

Compound 479: ¹ H NMR (400 MHz, Methanol-d ₄ , ppm) δ 9.01 (dd, J=4.3, 1.6 Hz, 1H), 8.68 (dd, J=8 .6, 1.7 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.70 (dd, J=8.6, 4.3 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 4.42-4.22 (m, 1H), 3.78-3.57 (m, 2H), 3.15-2.86 (m, 2H ), 2.62 (t, J=11.2 Hz, 1H), 2.42-2.24 (m, 3H), 1.70-1.21 (m, 11H). MS: m/z=460 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

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 acids.^oneH NMR (400 MHz, Methanol-d_four, ppm) δ 8.95 (d, J=4.2 Hz, 1H), 8.66 (d, J=8.6 Hz, 1H), 8.04 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.7, 4.1 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 4.25 (s, 1H), 3.63 (d, J=11.4 Hz, 1H), 3.40 (d, J=11.6 Hz, 1H), 2.50 (sq., J=11.4 Hz, 2H), 2 .31 (s, 2H), 2.14 (d, J=12.6 Hz, 2H), 1.67-1.35 (m, 11H), 1.16 (sq., J=12.4 Hz , 1H), 1.05 (d, J=6.2 Hz, 3H). MS: m/z=449 [M+H]⁺.

Compound 486 and compound 487 (rac-(R)-2-amino-N-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]- 2-cyclopropylacetamide 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. Isomer 1:^oneH NMR (400 MHz, Methanol-d4, ppm) δ 9.02 (dd, J=4.2, 1.6 Hz, 1H), 8.69 (dd, J=8.6, 1, 7 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.71 (dd, J=8.6, 4.3 Hz, 1H), 7.34 (d, J= 8.0 Hz, 1H), 4.34 (dm, J=11.3, 5.2, 4.3 Hz, 1H), 3.68 (d, J=10.5 Hz, 2H), 3 .12-2.84 (m, 2H), 2.73-2.50 (m, 2H), 1.65 (sq., J=12.2 Hz, 1H), 0.99 (dtd, J= 13.2, 8.3, 4.9 Hz, 1H), 0.68-0.23 (m, 3H). MS: m/z=418 [M+H]⁺. Isomer 2:^oneH NMR (400 MHz, Methanol-d4, ppm) δ 9.01 (dd, J=4.3, 1.6 Hz, 1H), 8.69 (dd, J=8.6, 1, 7 Hz, 1H), 8.17 (d, J=8.0 Hz, 1H), 7.70 (dd, J=8.6, 4.3 Hz, 1H), 7.33 (d, J= 8.0 Hz, 1H), 4.34 (ddd, J=15.4, 11.1, 4.2 Hz, 1H), 3.82-3.60 (m, 2H), 3.18-2 .87 (m, 2H), 2.69-2.52 (m, 2H), 2.38 (d, J=12.5 Hz, 1H), 1.63 (sq., J=12.2 Hz , 1H), 1.03 (q.t., J=8.3, 4.9 Hz, 1H), 0.72-0.51 (m, 2H), 0.41 (ddq., J=45, 4, 9.3, 5.0 Hz, 2H). MS: m/z=418 [M+H]⁺.

Compound 493 :from cis-5-(3-amino-5-trifluoromethyl-piperidin-1-yl)-quinolin-8-carbonitrile hydrochloride and (4-t-butoxycarbonylamino-tetrahydro-pyran-4-yl)-acetic acid.^oneH NMR (400 MHz, DMSO-d₆) δ 9.08 (dd, J=4.2, 1.6 Hz, 1H), 8.78 (d, J=7.1 Hz, 1H), 8.59 (dd, J=8.6, 1.7 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.16 (s, 3H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 3.91-3.66 (m, 3H), 3.67-3.42 (m, 4H), 3.33-3 .11 (m, 1H), 2.98 (t, J=11.5 Hz, 1H), 2.78-2.56 (m, 3H), 2.25 (d, J=12.3 Hz, 1H), 1.88-1.41 (m, 5H). MS: m/z=462 [M+H]⁺.

Compound 561 -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] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.51 (dd, J=8.5, 1 .8 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.67 (dd, J=8.5, 4.1 Hz, 1H), 7.14 (d , J=8.1 Hz, 1H), 4.35-4.27 (m, 1H), 3.66-3.61 (m, 2H), 3.35-3.23 (m, 1H), 3.04 (s, 3H), 2.88 (d, J=8.9 Hz, 1H), 2.50 (td, J=10.9, 6.6 Hz, 2H), 2.20-2 .09 (m, 2H), 1.16-1.06 (m, 1H), 1.03 (d, J=6.5 Hz, 3H), 0.72-0.53 (m, 3H), 0.37-0.33 (m, 1H).

Compound 562 -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] ⁺ . ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.99 (dd, J=4.2, 1.7 Hz, 1H), 8.41 (dd, J=8.5, 1 .8Hz, 1H), 8.10(s, 1H), 7.68-7.48(m, 2H), 4.96(brs, 3H), 4.25(brs, 1H) , 3.62-3.45(m, 1H), 3.28-3.22(m, 1H), 3.01(s, 3H), 2.61-2.43(m, 1H), 2 .39 (t, J=11.1 Hz, 1H), 2.19-2.04 (m, 2H), 1.18-1.05 (m, 2H), 0.99 (d, J=6 .3 Hz, 3H), 0.57 (br.s, 3H), 0.38 (br.s, 1H).

Compound 563 ]-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 Boc deprotection using Method Q. MS: m/z=396 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4, ppm) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.59 (dd, J=8.5, 1 .8 Hz, 1H), 8.55 (br s, 1H), 8.06 (s, 1H), 7.78 (dd, J=8.6, 4.2 Hz, 1H), 4.28 -4.21 (m, 1H), 3.61-3.53 (m, 1H), 3.37-3.35 (m, 1H), 2.97 (s, 3H), 2.70- 2.41 (m, 4H), 2.20-2.08 (m, 2H), 1.88-1.47 (m, 9H), 1.45-1.35 (m, 1H), 1. 16 (q, J=12.6 Hz, 1H), 1.04 (d, J=6.4 Hz, 3H).

Example 124: Synthesis of compound 480 (cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamide)

Cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid methyl ester: cis-N-[(3R,5S)-1- methyl ester (8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid was obtained from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl) -quinoline-8-carbonitrile hydrochloride and succinic acid monomethyl ester using Method 37.

Method 38

cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamide: Solution of cis-N-[1-(8-cyano-quinoline-5) methyl ester -yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid (55 mg; 0.13 mmol) in a solution of ammonia 7.0 M in methanol (2.00 ml; 14.00 mmol) was stirred at 60°C in within 1 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%NH _3. H ₂ O), 20% - 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: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1, 7 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.02 (d, J=7.3 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.25 (s, 1H), 6.70 (s, 1H), 4.23 (d, J= 10.5 Hz, 1H), 3.57 (d, J=11.5 Hz, 2H), 2.94 (t, J=11.6 Hz, 1H), 2.60 (t, J=11, 2 Hz, 1H), 2.35-2.25 (m, 3H), 2.18 (d, J=12.3 Hz, 1H), 1.50 (sq., J=12.3 Hz, 1H ). MS: m/z=420 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

Compound 482 (cis-4-Azetidin-1-yl-N-[(1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-4-oxo-butyramide): from methyl ester of cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid and azetidine ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1.7 Hz, 1H), 8.25 (d, J=8, 0 Hz, 1H), 8.04 (d, J=7.3 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.32 (d, J= 8.1 Hz, 1H), 4.10 (t, J=7.6 Hz, 3H), 3.79 (td, J=7.8, 2.8 Hz, 2H), 3.56 (d, J=11.7Hz, 2H), 3.20(d, J=10.9Hz, 1H), 2.95(t, J=11.6Hz, 1H), 2.60(t, J= 11.2Hz, 1H), 2.38-1.99(m, 7H), 1.50(q, J=12.3Hz, 1H) MS: m/z=460 [M+H] ⁺ .

Compound 492 cis-(N--1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-N'-methyl-succinamide):from cis-N-[1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-succinamic acid methyl ester and methylamine.^oneH NMR (400 MHz, DMSO-d₆) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1.7 Hz, 1H), 8.25 (d, J= 8.0 Hz, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 2H), 7.32 (d, J=8.1Hz, 1H), 4.15(m, 1H), 3.68-3.50(m, 2H), 3.20(d, J=10.0Hz, 1H), 2, 94 (t, J=11.6 Hz, 1H), 2.54 (d, J=4.6 Hz, 3H), 2.30 (dsq, J=6.7, 6.0, 4.2 Hz, 4H), 2.18 (d, J=12.1 Hz, 1H), 1.50 (sq., J=12.3 Hz, 1H). MS: m/z=434 [M+H]⁺.

Compound 564 (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-methylsuccinate, followed by reaction with ammonia in methanol at 50°C overnight . MS: m/z=356 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.44 (dd, J=8.5, 1 .7 Hz, 1H), 8.10 (s, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.79 (dd, J=8.5, 4.1 Hz, 1H ), 7.24 (s, 1H), 6.69 (s, 1H), 4.05-3.95 (m, 1H), 3.48-3.36 (m, 1H), 3.24 ( d, J=10.5 Hz, 1H), 2.88 (s, 3H), 2.41 (sq., J=11.3 Hz, 2H), 2.36-2.21 (m, 4H) , 2.10-1.92(m, 2H), 1.05(q, J=12.0Hz, 1H), 0.95(d, J=6.5Hz, 3H).

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-methylsuccinate, followed by reaction with methylamine in ethanol at room temperature temperature during the night. MS: m/z=370 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.44 (dd, J=8.5, 1 .7 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.79 (dd, J=8.5, 4.1 Hz, 1H ), 7.71 (d, J=5.4 Hz, 1H), 4.05-3.94 (m, 1H), 3.43-3.37 (m, 1H), 3.24 (d, J=10.1Hz, 1H), 2.88(s, 3H), 2.54(d, J=4.6Hz, 3H), 2.41(q, J=11.2Hz, 2H ), 2.35-2.24 (m, 4H), 2.07-1.93 (m, 2H), 1.05 (sq., J=12.0 Hz, 1H), 0.95 (d , J=6.4 Hz, 3H).

Compound 566 4-oxo-butyramide): from (3R,5S)-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and mono-methylsuccinate, followed by interaction with azetidine in ethanol at room temperature overnight. MS: m/z=396 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J=4.1, 1.7 Hz, 1H), 8.44 (dd, J=8.5, 1 .7 Hz, 1H), 8.41 (s, 1H), 8.10 (s, 1H), 7.88 (d, J=7.4 Hz, 1H), 7.80 (dd, J=8 .5, 4.1 Hz, 1H), 4.09 (t, J=7.7 Hz, 2H), 4.04-3.96 (m, 1H), 3.78 (td, J=7, 8, 2.2 Hz, 2H), 3.42-3.38 (m, 1H), 3.25-3.22 (m, 1H), 2.88 (s, 3H), 2.41 (td , J=10.9, 7.6 Hz, 2H), 2.35-2.26 (m, 2H), 2.26-2.18 (m, 2H), 2.18-2.08 (m , 2H), 2.08-1.90 (m, 2H), 1.05 (q., J=12.0 Hz, 1H), 0.95 (d, J=6.5 Hz, 3H).

Example 125: Synthesis of compound 488 ((3R,5S)-1-(7-Fluoro-8-methyl-quinolin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride)

5-bromo-7-fluoro-8-methylquinoline: A mixture of 5-bromo-3-fluoro-2-methyl-phenylamine (2.91 g; 14.3 mmol), glycerol (4.20 ml; 57.1 mmol) , iron(II) sulfate heptahydrate (793 mg; 2.85 mmol) and sulfuric acid (4.66 ml; 85.6 mmol) were stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, then added ice (50 g) and solid sodium hydroxide (4.5 g), the mixture was stirred for 30 minutes and was extracted with dichloromethane (70 ml ×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 silica gel column chromatography eluting with ethyl acetate and hexane to give 5-bromo-7-fluoro-8-methyl-quinoline (1.10 g, 32%). ¹ H NMR (400 MHz, Chloroform-d, ppm) δ 8.99 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.5, 1 .7 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.50 (dd, J=8.5, 4.2 Hz, 1H), 2.70 (d, J =2.5 Hz, 3H). MS: m/z=239 [M+H] ⁺ .

[(3R,5S)-1-(7-fluoro-8-methyl-quinolin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid tert-butyl ester: [(3R ,5S)-1-(7-Fluoro-8-methyl-quinolin-5-yl)-5-methyl-piperidin-3-yl]-carbamic acid was obtained from 5-bromo-7-fluoro-8-methyl-quinoline and ((3R,5S)-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester in 56% yield using Method V. ¹ H NMR (400 MHz, DMSO-d ₆ , ppm). ) δ 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.43 (dd, J=8.5, 1.7 Hz, 1H), 7.53 (s, 1H) , 7.04 (d, J=11.5 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 3.73 (s, 1H), 3.36 (s, 1H) , 3.18 (d, J=11.5 Hz, 1H), 2.54 (d, J=2.3 Hz, 3H), 2.34 (dt, J=27.7, 10.9 Hz, 2H), 2.08-1.80(m, 2H), 1.39(s, 8H), 1.03(q, J=12.2Hz, 1H), 0.93(d, J= 6.4 Hz, 3H). MS: m/z=374 [M+H] ⁺ .

(3R,5S)-1-(7-Fluoro-8-methyl-quinolin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride: (3R,5S)-1-(7-Fluoro-8- methyl-quinolin-5-yl)-5-methyl-piperidin-3-ylamine hydrochloride was obtained from tert-butyl ether [(3R,5S)-1-(7-Fluoro-8-methyl-quinolin-5-yl)- 5-methyl-piperidin-3-yl]-carbamic acid in 88% yield using Method Q.

Compound 388: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (dd, J=4.4, 1.7 Hz, 1H), 8.56 (d, J=8.3 Hz, 1H ), 8.29 (s, 3H), 7.61 (dd, J=8.5, 4.4 Hz, 1H), 16 (d, J=11.4 Hz, 1H), 3.27- 3.11 (m, 1H), 2.71-2.59 (m, 1H), 2.57 (d, J=2.3 Hz, 3H), 2.43 (t, J=11.3 Hz , 1H), 2.18 (d, J=12.4 Hz, 1H), 2.06 (s, 1H), 1.18 (sq., J=11.9 Hz, 1H), 0.98 ( e, J=6.6 Hz, 3H). MS: m/z=274 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

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 ((3R,5S)-5-methyl-piperidin-3-yl)-carbamic acid tert-butyl ester.^oneH NMR (400 MHz, DMSO-d₆) δ 8.89 (dd, J=4.1, 1.8 Hz, 1H), 8.58 (dd, J=8.5, 1.8 Hz, 1H), 7.65-7.54 ( m, 1H), 7.51 (dd, J=13.1, 1.2 Hz, 1H), 3.06 (d, J=11.1 Hz, 1H), 2.95 (d, J=11 .3 Hz, 2H), 2.78-2.58 (m, 5H), 2.02-1.83 (m, 2H), 1.60 (s, 2H), 0.97-0.84 ( m, 3H). MS: m/z=274 [M+H]⁺.

Example 126: Separation of Compound 494 and Compound 495 -oxo-butyramide and 4-azetidin-1-yl-N-[(3S,5R)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-4-oxo -butyramide)

The title compounds were isolated by chiral SLC chromatography of compound 482. (Column: Phenomenex 250×21.20 mm Lux Cellulose-2; CO ₂ co-solvent (Solvent B): Methanol; Isocratic method: 40% co-solvent at 70 ml/ min; System pressure: 100 bar; Column temperature: 40°C).

Isomer 1: MS: m/z=460 [M+H] ⁺ .

Isomer 2: MS: m/z=460 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

Compound 497 and Compound 498 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 10×250 mm IC; CO ₂ co-solvent (Solvent B): Ethanol with 0.5% dimethylethylamine; Isocratic method: 55% co-solvent at 9 ml/min; System pressure: 100 bar ; Column temperature: 30°C). Isomer 1: MS: m/z=460 [M+H] ⁺ . Isomer 2: MS: m/z=460 [M+H] ⁺ .

Compound 520 and Compound 521 ]-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 10×250 mm ADH; CO2 co-solvent (Solvent B): Methanol with 0.5% dimethylethylamine; Isocratic method: 40% co-solvent at 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]⁺.

Compound 522 and Compound 523 -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 compounds 504 (Column: CHIRALPAK 10×250 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: MS: m/z=429 [M+H]⁺. Isomer 2: MS: m/z=429 [M+H]⁺.

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 10×250 mm IF; CO ₂ co-solvent (Solvent B): ethanol with 0.5% dimethylethylamine; Isocratic method : 55% co-solvent at 4 ml/min; System pressure: 100 bar; Column temperature: 40°C). 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)-quinoxalin-5-carbonitrile hydrochloride)

[(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-carbamic acid tert-butyl ester: 8-bromo-quinoxaline-5-carbonitrile mixture ( 84 mg; 0.36 mmol), tert-butyl ester ((S)-5-Fluoro-piperidin-3-yl)-carbamic acid tert-butyl ester (94 mg; 0.43 mmol) potassium dicarbonate (64 mg; 0.47 mmol) and DMSO (2 ml) were heated under microwave irradiation at 120° C. for 1 hour. The reaction mixture was purified by reverse phase chromatography (XBridge column) eluting with acetonitrile in water (0.1%NH ₃ .H ₂ O) to give the tert-butyl ester [(3R,5S)-1-(8-cyano-quinoxaline -5-yl)-5-fluoro-piperidin-3-yl]-carbamic acid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (d, J=1.8 Hz, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.25 (d , J=8.4 Hz, 1H), 7.33 (d, J=8.4 Hz, 1H), 7.02 (d, J=7.6 Hz, 1H), 4.85 (dt, J =9.2, 4.7 Hz, 1H), 4.49 (s, 1H), 3.93 (d, J=12.1 Hz, 1H), 3.73 (s, 1H), 3.17 (ddd, J=13.2, 9.1, 4.9 Hz, 1H), 3.04 (t, J=10.9 Hz, 1H), 1.76 (sq., J=11.1 Hz , 1H), 1.40 (s, 9H). MS: m/z=373 [M+H] ⁺ .

8-((3R,5S)-3-amino-5-fluoro-piperidin-1-yl)-quinoxalin-5-carbonitrile hydrochloride: 8-((3R,5S)-3-amino-5-fluoro-piperidine- 1-yl)-quinoxalin-5-carbonitrile hydrochloride was obtained from [(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-carbamic tert-butyl ester acids using Method Q.

Compound 499: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.20-9.07 (m, 1H), 9.03 (d, J=1.8 Hz, 1H), 8.42-8 .12 (m, 4H), 7.38 (d, J=8.4 Hz, 1H), 5.19-4.93 (m, 1H), 3.93 (ddd, J=33.2, 13 .0, 8.3 Hz, 2H), 3.78 (dd, J=12.6, 3.0 Hz, 1H), 2.46-2.29 (m, 1H), 2.22-2, 07 (m, 1H). MS: m/z=273 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

Compound 500 ([(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-fluoro-piperidin-3-yl]-carbamic acid tert-butyl ester): from 5-bromo-quinolin- 8-carbonitrile and ((3R,5S)-5-Fluoro-piperidin-3-yl)-carbamic acid tert-butyl ester. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.55 (d, J=8.6 Hz, 1H), 8 .25 (d, J=8.1 Hz, 1H), 7.71 (dd, J=8.7, 4.2 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H) , 6.97 (d, J=7.4 Hz, 1H), 4.99 (s, 1H), 3.85 (s, 1H), 3.63 (s, 1H), 3.44 (d, J=11.8Hz, 1H), 3.00(s, 1H), 2.71(t, J=10.9Hz, 1H), 2.37(t, J=11.9Hz, 1H) , 1.70 (t, J=11.1 Hz, 1H), 1.39 (s, 5H). MS: m/z=372 [M+H] ⁺ .

Compound 501 (8-((3S,5R)-3-amino-5-fluoro-piperidin-1-yl)-quinoxalin-5-carbonitrile hydrochloride): from tert-butyl ether [(3S,5R)-1-( 8-cyano-quinoxalin-5-yl)-5-fluoro-piperidin-3-yl]-carbamic acid. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 9.06 (d, J=1.8 Hz, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.23 (d , J=8.2 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 5.16 (dt, J=46.0, 2.7 Hz, 1H), 4.55 -4.38 (m, 1H), 4.05-3.89 (m, 1H), 3.81 (s, 1H), 3.59 (ddd, J=36.7, 13.4, 1, 8 Hz, 1H), 3.38 (dd, J=13.5, 1.9 Hz, 1H), 2.58-2.43 (m, 1H), 2.39 (ddd, J=15.8 , 4.4, 3.1 Hz, 1H), 2.28 (ddd, J=15.8, 4.5, 3.1 Hz, 1H). MS: m/z=273 [M+H] ⁺ .

Example 128: Synthesis of Compound 502 1-yl)-acetamide):

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 obtained from (4-methyl-piperazin-1-yl)-acetic acid and 8-((3R,5S)-3-amino-5-fluoro-piperidin-1-yl)-quinoxalin-5-carbonitrile hydrochloride using Method J ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (d, J=1.8 Hz, 1H), 8.96 (d, J=1.8 Hz, 1H), 8.24 ( d, J=8.4 Hz, 1H), 8.12 (d, J=7.4 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 5.00 (s, 1H), 4.20-4.01 (m, 2H), 3.98 (d, J=14.5 Hz, 1H), 3.82 (dd, J=29.6, 12.7 Hz, 1H ), 3.52 (d, J=11.8 Hz, 1H), 2.97-2.75 (m, 2H), 2.33 (d, J=24.5 Hz, 4H), 2.11 (d, J=4.5 Hz, 3H), 2.01 (s, 3H). 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: N-[1 -(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-2-(4-methyl-piperazin-1-yl)-acetamide was obtained from (4-methyl-piperazin- 1-yl)-acetic acid and 8-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoxalin-5-carbonitrile hydrochloride using Method J.

Compound 503: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (d, J=1.8 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 8, 30 (d, J=8.4 Hz, 1H), 8.21 (d, J=7.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.32- 4.11 (m, 2H), 3.98 (s, 1H), 3.87-3.62 (m, 2H), 2.39 (d, J=13.8 Hz, 5H), 2.14 (s, 3H), 2.02 (s, 3H). MS: m/z=430 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

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)-quinoxalin-5-carbonitrile hydrochloride.^oneH NMR (400 MHz, DMSO-d₆) δ 9.09 (d, J=1.8 Hz, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.12 (d, J=6.9 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 4.80 (s, 1H), 4.20 (s, 1H), 4.07 (d, J=13.4 Hz, 1H), 3.79 (dd, J=29.1, 13.5 Hz, 2H), 3.16 (dd, J=13.0, 10, 2 Hz, 2H), 2.71 (d, J=11.4 Hz, 2H), 2.41 (m, 2H), 2.13 (s, 3H), 2.06 (d, J=6, 8Hz, 1H), 1.82(t, J=11.2Hz, 2H), 1.60(d, J=12.9Hz, 2H), 1.18(q, J=11.9 , 11.3 Hz, 2H). MS: m/z=429 [M+H]⁺.

Compound 506 (2-chloro-N-[1-(8-cyano-quinoxalin-5-yl)-5, 5-difluoro-piperidin-3-yl]-propionamide):from 2-chloro-propionic acid; and 8-(5-amino-3,3-difluoro-piperidin-1-yl)-quinoxaline-5-carbonitrile hydrochloride.^oneH NMR (400 MHz, DMSO-d₆) δ 9.10 (d, J=1.8 Hz, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.56 (d, J=6.9 Hz, 1H), 8.31 (d, J=8.3 Hz, 1H), 7.44 (dd, J=8.4, 3.6 Hz, 1H), 4.75-4.45 (m, 2H), 4 .21 (s, 1H), 3.97 (t, J=11.3 Hz, 1H), 3.82 (dd, J=25.6, 13.4 Hz, 1H), 3.41-3, 32 (m, 1H), 2.44 (d, J=13.2 Hz, 1H), 2.26 (s, 1H), 1.59 (dd, J=6.8, 2.4 Hz, 3H ). MS: 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)

3-amino-N-[1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-3-methyl-butyramide hydrochloride: 3-amino-N-[1- (8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-3-methyl-butyramide hydrochloride was obtained from 3-tert-butoxycarbonylamino-3-methyl-butyric acid and 8-(5 -amino-3,3-difluoro-piperidin-1-yl)-quinoxalin-5-carbonitrile hydrochloride using Method J and Q.

Compound 505: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (d, J=1.8 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 8, 64 (d, J=7.0 Hz, 1H), 8.29 (d, J=8.4 Hz, 1H), 8.00 (s, 2H), 7.42 (d, J=8.5 Hz, 1H), 4.72 (s, 1H), 4.26 (s, 1H), 4.11 (d, J=12.9 Hz, 1H), 3.81 (dd, J=28.3 , 13.6 Hz, 2H), 3.25 (dd, J=12.9, 10.0 Hz, 2H), 2.50 (s, 2H), 2.19 (dtd, J=30.2, 12.3, 6.4 Hz, 1H), 1.31 (s, 6H). MS: m/z=389 [M+H] ⁺ .

Example 131: Synthesis of Compound 507 and Compound 508 ]-propionamide and 2-azetidin-1-yl-N-[(R)-1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide)

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: 2-Chloro-N-[1-(8-cyano-quinoxaline) mixture -5-yl)-5,5-difluoro-piperidin-3-yl]-propionamide (30 mg; 0.08 mmol) and azetidine (45 mg; 0.79 mmol) in acetoneitrile was stirred at 100° C. for 2 hours. The reaction mixture was purified by reverse phase chromatography (XBridge column) eluting with acetonitrile in water (0.1%NH ₃ .H ₂ O) to give 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: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (d, J=1.8 Hz, 1H), 9.02 (d, J=1.8 Hz, 1H), 8, 31 (d, J=8.3 Hz, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 4.50- 4.32 (m, 1H), 4.21 (s, 1H), 3.89-3.68 (m, 2H), 3.62 (dd, J=12.9, 7.7 Hz, 1H) , 3.21 (q.v., J=6.8 Hz, 2H), 3.09 (q.v., J=6.8 Hz, 2H), 2.79 (q.v., J=6.8 Hz, 1H ), 2.33 (s, 2H), 1.96 (n, J=6.9 Hz, 2H), 1.02 (d, J=6.8 Hz, 3H). MS: m/z=401 [M+H] ⁺ .

Isomer 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (d, J=1.8 Hz, 1H), 9.04 (d, J=1.8 Hz, 1H), 8, 31 (dd, J=7.7, 4.0 Hz, 2H), 7.42 (d, J=8.3 Hz, 1H), 4.31 (td, J=15.0, 14.5, 6.6 Hz, 1H), 4.19 (d, J=7.2 Hz, 1H), 3.81 (s, 1H), 3.65 (d, J=5.0 Hz, 1H), 3 .28-3.19(m, 1H), 3.18(q, J=6.9Hz, 2H), 3.09(q, J=6.8Hz, 2H), 2.77( sq., J=6.8 Hz, 1H), 2.39-2.16 (m, 2H), 1.83 (p, J=6.9 Hz, 2H), 1.07 (d, J= 6.8 Hz, 3H). MS: m/z =401 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

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. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.11 (t, J=1.9 Hz, 1H), 9.01 (dd, J=8.7, 1.8 Hz, 1H), 8 .37-8.16 (m, 2H), 7.43 (dd, J=8.4, 3.9 Hz, 1H), 4.44-4.14 (m, 2H), 4.01-3 .85 (m, 1H), 3.82-3.71 (m, 1H), 3.65 (dt, J=13.2, 6.8 Hz, 1H), 3.46 (sq., J= 4.3 Hz, 4H), 2.97 (sq., J=6.9 Hz, 1H), 2.51-2.23 (m, 6H), 1.14 (dd, J=10.9, 7.0 Hz, 3H). MS: m/z=431 [M+H] ⁺ .

Example 132: Synthesis of Compound 518

1-Cyclopropyl-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-urea: (3R,5S)-5-methyl mixture -1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride (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%NH ₃ .H ₂ O) to give 1-cyclopropyl-3-[(3R,5S)-5-methyl-1-( 8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-urea as a white solid.

Compound 518: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.54 (dd, J=8.6, 1, 8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (d, J= 8.1 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 5.80 (d, J=7.5 Hz, 1H), 3.56 (d, J=8, 9 Hz, 1H), 2.48-2.35 (m, 3H), 2.14-1.82 (m, 2H), 1.06 (sq., J=11.9 Hz, 1H), 0 .95 (d, J=6.4 Hz, 3H), 0.56 (dd, J=7.0, 2.1 Hz, 2H), 0.32 (dd, J=3.7, 2.3 Hz, 2H). 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)

4-bromo-7-dibromomethyl-benzo[1.2.5]thiadiazole: Mixture of 4-bromo-7-methyl-benzo[1.2.5]thiadiazole (5.00 g; 21.8 mmol), N- Bromosuccinimide (8.24 g; 45.8 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.54 g; 3.27 mmol) in carbon tetrachloride (150 ml) were stirred at 80° C. overnight. The suspension was filtered, the filtrate was diluted with ethyl acetate and washed with brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 4-bromo-7-dibromomethyl-benzo[1,2,5]thiadiazole (8.36 g quantitative yield) as a yellow solid. MS: m/z=386 [M+H] ⁺ .

7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde: A solution of 4-bromo-7-dibromomethyl-benzo[1,2,5]thiadiazole (8.36 g; 21.61 mmol) and silver nitrate (9.18 g; 54.02 mmol) in acetone (100 ml) and water (20 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the resulting solid was washed with water and dried to give 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde. MS: m/z=242 [M+H] ⁺ .

7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde oxime:A mixture of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde (5.25 g; 21.6 mmol) and sodium acetate (1.95 g; 23.77 mmol) in ethanol (200 ml) and ammonium chloride solution (1.58 mg; 22.7 mmol) was stirred at 70° C. for 1 hour. The reaction mixture was cooled, filtered and the solid was washed with ethanol. The filtrate was concentrated under reduced pressure to give 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde oxime (4.30 g, 78%) as a yellow solid. MS: m/z=257 [M+H]⁺.

7-bromo-benzo[1,2,5]thiadiazole-4-carbonitrile: A mixture of 7-bromo-benzo[1,2,5]thiadiazole-4-carbaldehyde oxime (4.30 g; 16.7 mmol), acetate copper(II) (302 mg; 1.67 mmol) and acetic acid (2.00 ml; 35.0 mmol) in acetoneitrile (20 ml) were refluxed over the weekend. The reaction mixture was cooled, water (20 ml) was added and a solution of 2M sodium hydroxide (17.5 ml) was added slowly. 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 give 7-bromo-benzo[1,2,5]thiadiazole-4-carbonitrile (3.0 g, 75%) as a light green solid. MS: m/z=239 [M+H] ⁺ .

[(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 mmol), tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl]carbamate (1 .80 g; 8.25 mmol) and ethyl-diisopropyl-amine (1.61 ml; 9.00 mmol) in DMSO (2 ml) were heated under microwave irradiation at 120° C. for 60 minutes. The reaction mixture was diluted with methanol (10 ml). A brown solid precipitated and was filtered to give [(3R,5S)-1-(7-cyano-benzo[1,2,5]thiadiazol-4-yl)-5-methyl-piperidine- 3-yl]-carbamic acid (2.16 mg, 77%). MS: m/z=374 [M+H] ⁺ .

[(3R,5S)-1-(2,3-diamino-4-cyano-phenyl)-5-methyl-piperidin-3-yl]-carbamic acid tert-butyl ester: Mixture of tert-butyl ester [(3R, 5S)-1-(7-cyano-benzo[1,2,5]thiadiazol-4-yl)-5-methyl-piperidin-3-yl]-carbamic acid (2.16 g; 5.78 mmol) and sodium borohydride (0.24 g; 6.36 mmol) in ethanol (130 ml) was refluxed for 2 days. Added additional amount of sodium borohydride during the reaction until its 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 give tert-butyl ester [(3R,5S)-1-(2,3-diamino-4-cyano-phenyl)-5-methyl-piperidin-3-yl ]-carbamic acid (1.6 g, 80%) as a brown solid. MS: m/z=346 [M+H] ⁺ .

8-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-3-methyl-quinoxaline-5-carbonitrile: To a solution of utet-butyl ether [(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). 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%NH ₃ .H ₂ O) to give 8-((3R,5S)-3-amino- 5-methyl-piperidin-1-yl)-3-methyl-quinoxaline-5-carbonitrile as a white solid.

Compound 525: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.83 (s, 1H), 8.08 (dd, J=9.7, 8.4 Hz, 1H), 7.13 (t , J=8.7 Hz, 1H), 4.21 (s, 2H), 3.01-2.79 (m, 1H), 2.73 (d, J=2.8 Hz, 3H), 2 .57 (dt, J=11.3, 5.5 Hz, 1H), 2.02-1.47 (m, 4H), 0.99-0.75 (m, 3H). MS: m/z=282 [M+H] ⁺ .

Example 134: Synthesis of Compound 529

1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid methyl ester: 1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro methyl ester -piperidine-3-carboxylic acid was prepared from 8-bromo-quinoxaline-5-carbonitrile and 5,5-difluoro-piperidine-3-carboxylic acid methyl ester hydrochloride using Method H. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.09 (d, J=1.8 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 4.39 (d, J=12.5 Hz, 1H), 3.83-3.72 (m, 1H), 3.69 (s , 3H), 3.49-3.33 (m, 1H), 3.20 (s, 1H), 2.31 (dtd, J=31.9, 12.8, 6.4 Hz, 1H). MS: m/z=333 [M+H] ⁺ .

Lithium salt of 1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid: A mixture of methyl ester 1-(8-cyano-quinoxalin-5-yl)-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) were stirred at room temperature in within 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting solid was dried to give 1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid lithium salt as a yellow solid. MS: m/z=319 [M+H] ⁺ .

1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid (1-methyl-piperidin-4-yl)-amide: (1-methyl-piperidin-4-yl )-amide of 1-(8-cyano-quinoxalin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid was obtained from the lithium salt of 1-(8-cyano-quinoxalin-5-yl)-5.5 -difluoro-piperidine-3-carboxylic acid and 4-amino-1-methylpiperidine as a white solid using Method J.

Compound 529: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (d, J=1.8 Hz, 1H), 8.99 (d, J=1.8 Hz, 1H), 8, 26 (d, J=8.4 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 4.73 ( s, 2H), 4.16 (d, J=13.3 Hz, 1H), 3.77-3.40 (m, 4H), 3.01 (s, 2H), 2.71 (s, 2H ), 2.33 (s, 1H), 2.15 (s, 3H), 1.93 (t, J=11.1 Hz, 2H), 1.73 (d, J=12.3 Hz, 2H ), 1.53-1.32 (m, 2H). MS: m/z=415 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

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, methyl ester of 5,5-difluoro-piperidine-3-carboxylic acid hydrochloride and 4-amino-1-methylpiperidine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (dd, J=4.2, 1.6 Hz, 1H), 8.56 (dd, J=8.6, 1.7 Hz, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.04 (d, J=7.6 Hz, 1H), 7.75 (dd, J=8.6, 4.2 Hz, 1H), 7.36 (d, J=8.1 Hz, 1H), 3.67 (s, 1H), 3.55-3.34 (m, 3H), 3.18-2.93 (m, 2H), 2.77-2.58 (m, 2H), 2.37 (d, J=12.3 Hz, 1H), 2.30 (s, 1H), 2.13 (s, 3H), 1.92 (tdd, J=10.9, 5.3, 2.2 Hz, 2H), 1.78-1.60 (m, 2H), 1.47-1.26 (m, 2H). MS: m/z=414 [M+H] ⁺ .

Compound 531 ((1-methyl-piperidin-4-ylmethyl)-amide 1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid): from 5-bromo-quinoline -8-carbonitrile, methyl ester of 5,5-difluoro-piperidine-3-carboxylic acid hydrochloride and C-(1-methyl-piperidin-4-yl)-methylamine. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.69 (dd, J=8.6, 1.7 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.69 (dd, J=8.6, 4.3 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 3.79-3.52 (m, 2H), 3.26-3.07 (m, 4H), 2.88 (d, J=11.8 Hz, 2H), 2.46 (s, 1H), 2.33 (dd, J=13.6, 6.1 Hz, 1H), 2.27 (s, 3H), 2.07-1.91 (m, 2H), 1, 71 (dd, J=13.3, 3.2 Hz, 2H), 1.52 (dd, J=14.3, 7.6, 6.5, 4.1 Hz, 1H), 1.29 ( dkv., J=12.1, 3.9 Hz, 2H). MS: m/z=428 [M+H] ⁺ .

Compound 532 ((1-ethyl-piperidin-4-yl)-amide 1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidine-3-carboxylic acid): from 5-bromo-quinoline -8-carbonitrile, methyl ester of 5,5-difluoro-piperidine-3-carboxylic acid hydrochloride and 1-ethyl-piperidin-4-ylamine. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 9.02 (dd, J=4.3, 1.7 Hz, 1H), 8.69 (dd, J=8.6, 1.7 Hz, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.69 (dd, J=8.6, 4.3 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 3.77-3.64 (m, 2H), 3.60 (d, J=10.2 Hz, 1H), 3.26-3.09 (m, 3H), 2.98 (d, J=25.7 Hz, 3H), 2.45 (sq., J=7.2 Hz, 3H), 2.39-2.17 (m, 1H), 2.10 (dp, J =7.0, 3.5, 3.0 Hz, 2H), 1.90 (t, J=13.7 Hz, 2H), 1.57 (dd, J=12.4, 8.9 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H). MS: m/z=428 [M+H] ⁺ .

Compound 537 and Compound 538 ([2-(4-methyl-piperazin-1-yl)-ethyl]-amide acids and trans-1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidine-3-carboxylic acid [2-(4-methyl-piperazin-1-yl)-ethyl]-amide): 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: ¹ H NMR (400 MHz, Methanol-d4) δ 8.92 (dd, J=19.8, 1.8 Hz, 2H), 8.10 (d, J=8.4 Hz, 1H) , 7.24 (d, J=8.4 Hz, 1H), 4.41 (ddt, J=12.3, 3.6, 1.7 Hz, 1H), 4.17 (ddd, J=10 .4, 4.5, 2.5 Hz, 1H), 3.37 (d, J=6.8 Hz, 2H), 3.09 (dd, J=12.3, 11.3 Hz, 1H) , 2.90-2.75 (m, 1H), 2.67 (dd, J=12.5, 10.9 Hz, 2H), 2.54 (sq., J=10.2, 6.8 Hz, 8H), 2.29 (s, 3H), 2.13-1.98 (m, 2H), 1.45 (sq., J=13.1, 12.7 Hz, 1H), 1, 03 (d, J=6.4 Hz, 3H). MS: m/z=422 [M+H] ⁺ . Isomer 2: ¹ H NMR (400 MHz, Methanol-d4) δ 9.03 (dd, J=24.4, 1.8 Hz, 2H), 8.22 (d, J=8.3 Hz, 1H) , 7.40 (d, J=8.3 Hz, 1H), 4.60-4.48 (m, 1H), 3.67-3.46 (m, 2H), 3.46-3.34 (m, 3H), 3.14 (dd, J=13.2, 3.3 Hz, 1H), 2.96-2.83 (m, 1H), 2.75 (s, 1H), 2, 49 (td, J=6.5, 1.3 Hz, 3H), 2.43-2.27 (m, 4H), 2.10 (s, 5H), 1.50 (ddd, J=13, 2, 11.3, 5.1 Hz, 1H), 1.06 (dd, J=10.1, 6.7 Hz, 3H).

Compound 539 ((1-methyl-piperidin-4-ylmethyl)-amide 1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidine-3-carboxylic acid): from 8-bromo-quinoxaline-5 -carbonitrile, 5-methyl-piperidine-3-carboxylic acid hydrochloride methyl ester and C-(1-methyl-piperidin-4-yl)-methylamine. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 9.06 (d, J=1.8 Hz, 1H), 8.98 (d, J=1.9 Hz, 1H), 8.20 (d , J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 4.39 (dd, J=13.3, 3.5 Hz, 1H), 3.62 -3.38 (m, 2H), 3.17-3.05 (m, 2H), 2.97-2.85 (m, 2H), 2.85-2.71 (m, 2H), 2 .24(s, 3H). 2.14-1.84 (m, 4H), 1.71 (t, J=16.2 Hz, 2H), 1.56-1.43 (m, 2H), 1.37-1.18 ( m, 2H), 1.08 (d, J=6.6 Hz, 3H). MS: m/z=407 [M+H] ⁺ .

Compound 540 ((1-ethyl-piperidin-4-yl)-amide 1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidine-3-carboxylic acid): from 8-bromo-quinoxaline-5 -carbonitrile, 5-methyl-piperidine-3-carboxylic acid hydrochloride methyl ester and 1-ethyl-piperidin-4-ylamine. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 9.07 (s, 2H), 8.20 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.4 Hz , 1H), 4.45 (d, J=12.4 Hz, 1H), 3.85 (ddd, J=15.5, 11.4, 4.3 Hz, 1H), 3.59-3, 46 (m, 1H), 3.13 (dd, J=13.1, 3.2 Hz, 1H), 3.01 (d, J=10.2 Hz, 1H), 2.91 (dd, J =11.4, 9.8 Hz, 2H), 2.75 (t, J=4.3 Hz, 1H), 2.44 (sq., J=7.2 Hz, 2H), 2.18- 1.91 (m, 4H), 1.82 (d, J=13.0 Hz, 1H), 1.65 (dq, J=12.0, 3.9 Hz, 1H), 1.57- 1.39 (m, 2H), 1.18-1.00 (m, 5H). MS: m/z=407 [M+H] ⁺ .

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) methylamide) -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: ¹ H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.8 Hz, 1H), 8.96 (d, J=1.8 Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.84 (d, J=5.1 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 4.34 (d , J=12.8 Hz, 1H), 4.18 (d, J=12.2 Hz, 1H), 3.05 (t, J=12.0 Hz, 1H), 2.76-2.63 (m, 2H), 2.58 (d, J=4.6 Hz, 3H), 1.91 (t, J=15.5 Hz, 2H), 1.35 (square, J=12.1 Hz, 1H), 1.04-0.86 (m, 3H). MS: m/z=310 [M+H] ⁺ . Isomer 2: ¹ H NMR (400 MHz, DMSO-d6) δ 9.12-9.03 (m, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.43 (d, J=5.2Hz, 1H), 8.23(d, J=8.4Hz, 1H), 7.27(d, J=8.4Hz, 1H), 3.92(dd, J= 12.9, 6.4 Hz, 1H), 3.48 (ddd, J=20.3, 12.5, 3.6 Hz, 2H), 2.82-2.68 (m, 1H), 2 .64 (d, J=4.4 Hz, 3H), 2.20-1.91 (m, 2H), 1.48 (ddd, J=12.5, 7.7, 4.7 Hz, 1H ), 1.00 (d, J=6.7 Hz, 3H). MS: m/z=310 [M+H] ⁺ .

Compound 543 and Compound 544 (cis-1-(8-cyanoquinoxalin-5-yl)-5-methyl-N-(1-methyl-3-piperidyl)piperidine-3-carboxamide and 5-yl)-5-methyl-N-(1-methyl-3-piperidyl)piperidine-3-carboxamide): from 8-bromo-quinoxaline-5-carbonitrile, 5-methyl-piperidine-3-carboxylic acid methyl ester hydrochloride and 1-methyl-piperidin-3-ylamine. Isomer 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (dd, J=1.8, 0.7 Hz, 1H), 8.95 (t, J=1.8 Hz, 1H ), 8.18 (dd, J=8.5, 1.3 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.5 Hz , 2H), 4.30 (s, 1H), 4.19 (d, J=12.3 Hz, 1H), 3.69 (s, 1H), 3.07 (t, J=12.0 Hz , 1H), 2.75-2.59 (m, 3H), 2.55 (s, 2H), 2.14 (d, J=1.5 Hz, 2H), 1.89 (s, 3H) , 1.64 (s, 3H), 1.43 (d, J=31.3 Hz, 1H), 1.13 (d, J=11.1 Hz, 2H), 0.94 (d, J= 6.0 Hz, 3H). MS: m/z=393 [M+H] ⁺ . Isomer 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (d, J=1.8 Hz, 1H), 8.97 (d, J=1.8 Hz, 1H), 8, 22 (d, J=8.4 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.5 Hz, 1H), 4.11- 3.99 (m, 1H), 3.71 (d, J=9.5 Hz, 2H), 3.57-3.44 (m, 2H), 2.73 (s, 2H), 2.60 (s, 1H), 2.08 (s, 4H), 1.93-1.62 (m, 3H), 1.45 (d, J=47.0 Hz, 4H), 1.01 (d, J=6.6 Hz, 3H). MS: m/z=393 [M+H] ⁺ .

Compound 547 and Compound 548 -piperidin-4-ylmethyl)-amide trans-5-methyl-1(8-trifluoromethyl-quinolin-5-yl)-piperidine-3-carboxylic acid): from 5-bromo-8-trifluoromethyl-quinoline, methyl ester 5 ,5-difluoro-piperidine-3-carboxylic acid hydrochloride and C-(1-methyl-piperidin-4-yl)-methylamine. Isomer 1: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.65 (dd, J=8.6, 1 .8 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.85 (t, J=5.9 Hz, 1H), 7.66 (dd, J=8.5 , 4.2 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 3.21-3.05 (m, 2H), 2.98 (hept., J=6.4 Hz, 2H), 2.79 (s, 2H), 2.66-2.56 (m, 2H), 2.26 (s, 1H), 2.05-1.96 (m, 1H), 1 .64 (dt, J=22.8, 11.5 Hz, 2H), 1.51 (t, J=13.0 Hz, 1H), 1.29 (dt, J=7.7, 4.1 Hz, 1H), 1.12 (d, J=6.9 Hz, 1H), 1.10-0.98 (m, 1H). Isomer 2 : ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.52 (dd, J=8.6, 1, 8 Hz, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.90 (t, J=5.8 Hz, 1H), 7.66 (dd, J=8.6, 4.1 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 3.45-3.32 (m, 2H), 3.06-2.86 (m, 2H), 2.82 (t, J=11.7 Hz, 2H), 2.71 (d, J=11.3 Hz, 2H), 2.41 (t, J=11.3 Hz, 1H), 2. 12 (s, 3H), 1.99 (t, J=14.9 Hz, 2H), 1.76 (td, J=11.6, 2.5 Hz, 2H), 1.57 (d, J =12.9 Hz, 2H), 1.30 (dd, J=16.6, 8.1 Hz, 2H), 1.12 (tt, J=13.0, 6.5 Hz, 2H), 0 .95 (dd, J=6.5, 3.9 Hz, 3H). MS: m/z=449 [M+H] ⁺ .

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 hydrochloride methyl ester and 1-methyl-piperazine. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.2, 1.7 Hz, 1H), 8.62 (dd, J=48.2, 8.6, 1 .8 Hz, 1H), 8.07 (d, J=8.1 Hz, 1H), 7.67 (ddd, J=8.6, 4.1, 1.7 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 3.68-3.40 (m, 4H), 3.12-3.01 (m, 1H), 2.85 (t, J=11.3 Hz, 1H), 2.44 (t, J=11.5 Hz, 1H), 2.32 (d, J=5.3 Hz, 4H), 2.18 (d, J=1.7 Hz, 3H), 2.10 (s, 1H), 1.93 (d, J=13.3 Hz, 1H), 1.56 (d, J=13.5 Hz, 1H), 1.23 (d, J=7.2 Hz, 2H), 0.95 (d, J=6.6 Hz, 3H). 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 methyl-5-(4-methyl-piperazin-1-ylmethyl)-piperidin-1-yl]-8-trifluoromethyl-quinoline)

[5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-methanol: To a solution of methyl ester 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 mmol) 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 adjusted 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 give [5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-methanol as light -yellow solid. ¹ H NMR (400 MHz, Chloroform-d) δ 9.06 (dd, J=4.2, 1.8 Hz, 1H), 8.50 (dd, J=8.6, 1.8 Hz, 1H ), 7.99 (ddd, J=8.0, 4.1, 0.9 Hz, 1H), 7.49 (ddd, J=8.5, 4.2, 1.0 Hz, 1H), 7.11 (t, J=7.4 Hz, 1H), 4.07-3.80 (m, 1H), 3.73-3.61 (m, 1H), 3.58 (ddd, J= 8.4, 7.2, 3.2 Hz, 1H), 3.39 (ddt, J=11.7, 3.9, 1.8 Hz, 1H), 3.28-3.05 (m, 1H), 2.27-2.16(m, 1H), 2.16-2.05(m, 1H), 2.06-1.93(m, 1H), 1.38(s, 1H) , 1.11 (d, J=6.7 Hz, 1H), 1.01 (d, J=6.6 Hz, 2H), 0.88 (q, J=12.2 Hz, 1H). MS: m/z=325 [M+H] ⁺ .

5-Methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylmethyl ester of methanesulfonic acid: Mixture of [5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3 -yl]-methanol (175 mg; 0.54 mmol), methanesulfonyl chloride (0.05 ml; 0.70 mmol) and ethyl-diisopropylamine (0.15 ml; 0.81 mmol) in THF (2 ml) was stirred at room temperature for 1 hour. The reaction mixture was used directly in the next step without any further purification. MS: m/z=403 [M+H] ⁺ .

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-ylmethyl ester of methanesulfonic acid ( 100 mg; 0.25 mmol) and 1-methyl-piperazine (0.31 ml; 2.48 mmol) in THF (1 ml) and DMSO (1 ml) were heated at 80° C. overnight. The reaction mixture was purified by reverse phase chromatography (XBridge column) eluting with acetonitrile in water (0.1%NH ₃ .H ₂ O) to give cis-5-[3-methyl-5-(4-methyl-piperazine-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 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.2, 1.6 Hz, 1H), 8.48 (dd, J=8.6, 1.8 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.64 (dd, J=8.6, 4.1 Hz, 1H), 7.18 (d, J=8.1 Hz, 1H), 3.60-3.45(m, 1H), 2.49-2.33(m, 3H), 2.28(square, J=16.3, 13 .4 Hz, 5H), 2.21-2.15 (m, 2H), 2.12 (s, 3H), 2.01 (d, J=12.3 Hz, 1H), 1.88 (d , J=12.8 Hz, 1H), 0.94 (dd, J=6.6, 1.9 Hz, 3H), 0.74 (sq., J=11.8, 11.3 Hz, 1H ). MS: m/z=407 [M+H] ⁺ .

Isomer 2: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.73 (dd, J=8.6, 1, 8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.63 (dd, J=8.6, 4.1 Hz, 1H), 7.20 (d, J= 8.1 Hz, 1H), 3.18 (d, J=9.0 Hz, 1H), 2.95 (d, J=11.5 Hz, 1H), 2.73 (s, 2H), 2 .42-2.17 (m, 6H), 2.15 (s, 3H), 1.60 (d, J=13.0 Hz, 1H), 1.40 (s, 1H), 1.04 ( e, J=6.6 Hz, 3H). MS: m/z=407 [M+H] ⁺ .

The following compounds were synthesized in a similar manner:

Compound 535 and compound 536 (cis-5-[3-methyl-5-(4-morpholin-4-yl-piperidin-1-ylmethyl)-piperidin-1-yl]-8-trifluoromethylquinoline 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, methyl ester 5-methyl-piperidine-3-carboxylic acid hydrochloride and 4-piperidin-4-yl-morpholine. Isomer 1: ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.93 (dd, J=4.2, 1.7 Hz, 1H), 8.60 (dd, J=8.6, 1, 8 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.60 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (d, J= 8.0 Hz, 1H), 3.70 (t, J=4.7 Hz, 4H), 3.62 (d, J=11.5 Hz, 1H), 3.41 (d, J=11, 5 Hz, 1H), 3.14 (d, J=11.7 Hz, 1H), 2.94 (d, J=11.7 Hz, 1H), 2.57 (t, J=4.7 Hz , 4H), 2.40 (dt, J=16.9, 11.1 Hz, 2H), 2.33-2.15 (m, 4H), 2.15-1.79 (m, 6H), 1.60-1.40 (m, 2H), 1.01 (d, J=6.6 Hz, 3H), 0.82 (sq., J=11.7 Hz, 1H). MS: m/z=477 [M+H] ⁺ . Isomer 2: ¹ H NMR (400 MHz, Methanol-d ₄ ) δ 8.93 (dd, J=4.2, 1.7 Hz, 1H), 8.79 (dd, J=8.6, 1, 8 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.61 (dd, J=8.6, 4.2 Hz, 1H), 7.23 (d, J= 8.0 Hz, 1H), 3.79-3.63 (m, 3H), 3.26 (d, J=12.9 Hz, 1H), 3.10 (s, 2H), 2.96 ( e, J=11.7 Hz, 1H), 2.75 (s, 2H), 2.58 (t, J=4.7 Hz, 3H), 2.41-2.11 (m, 4H), 2.07 (t, J=11.5 Hz, 1H), 1.92 (d, J=10.7 Hz, 2H), 1.72 (d, J=12.8 Hz, 1H), 1, 60-1.40 (m, 3H), 1.11 (d, J=6.6 Hz, 3H). MS: m/z=477 [M+H] ⁺ .

Example 136: Separation of Compound 545 and Compound 546 and (1-methyl-piperidin-4-ylmethyl)-amide (S)-1-(8-cyano-quinolin-5-yl)-5,5-difluoro-piperidin-3-carboxylic acid)

The title compounds were isolated by chiral SLC chromatography of compound 531. (Column: CHIRALPAK 10×250 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)-benzo[1,2,5]thiadiazole-4-carbonitrile hydrochloride)

7-((3R,5S)-3-amino-5-methyl-piperidin-1-yl)-benzo[1,2,5]thiadiazole-4-carbonitrile hydrochloride: 7-((3R,5S)-3- amino-5-methyl-piperidin-1-yl)-benzo[1,2,5]thiadiazole-4-carbonitrile hydrochloride was obtained from tert-butyl ether [(3R,5S)-1-(7-cyano-benzo[1 ,2,5]thiadiazol-4-yl)-5-methyl-piperidin-3-yl]-carbamic acid using Method Q.

Compound 552: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.32 (s, 2H), 8.16 (dd, J=8.3, 1.2 Hz, 1H), 6.95 (d , J=8.3 Hz, 1H), 4.94 (d, J=12.1 Hz, 1H), 4.65 (d, J=11.9 Hz, 1H), 3.13 (sq., J=12.6, 11.8Hz, 1H), 2.75(t, J=12.3Hz, 1H), 2.16(d, J=12.3Hz, 1H), 1.88( s, 1H), 1.33 (q, J=12.0 Hz, 1H), 0.99 (d, J=6.5 Hz, 3H). MS: m/z=354 [M+H] ⁺ .

Example 138: Synthesis of Compound 567

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 acid was obtained from (3R,5S)-5-methyl-1-(8- methyl-[1,7]naphthyridin-5-yl)-piperidin-3-ylamine dihydrochloride and mono-methylsuccinate using Method 37 followed by saponification of the ester to a carboxylic acid using Method I to give N-[(3R,5S )-5-methyl-1-(8-methyl-[1,7]naphthyridin-5-yl)-piperidin-3-yl]-succinamic acid in 71% yield for 2 steps.

Compound 567: MS: m/z=357 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.02 (dd, J=4.1, 1.7 Hz, 1H), 8.44 (dd, J=8.5, 1 .8 Hz, 1H), 8.10 (s, 1H), 7.90 (d, J=7.5 Hz, 1H), 7.80 (dd, J=8.5, 4.1 Hz, 1H ), 4.04-3.97 (m, 1H), 3.42-3.37 (m, 1H), 3.27-3.20 (m, 1H), 2.88 (s, 3H), 2.47-2.35(m, 4H), 2.35-2.25(m, 2H), 2.09-1.91(m, 2H), 1.06(q, J=12, 1 Hz, 1H), 0.95 (d, J=6.4 Hz, 3H).

Example 139: Synthesis of compound 568

[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester: 5-Bromo-8-trifluoromethyl-quinoline mixture ( 600 mg; 2.0 mmol), tert-butyl N-[(3R,5S)-5-methylpiperidin-3-yl] carbamate (486 mg; 2.27 mmol), cesium carbonate (1345 mg; 4.1 mmol ), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (48 mg; 0.1 mmol), chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1 adduct '-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) with methyl tert-butyl ether (84 mg; 0.1 mmol) and tBuOH (15 ml) in a 20 ml microwave tube was degassed and placed in a microwave oven at 85°C for 8 hours. The reaction mixture was filtered. The filtrate was concentrated. The crude material was purified by silica gel chromatography eluting with ethyl acetate and hexane to give [(3R5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-carbamic acid tert-butyl ester (764 mg; 90%). MS: m/z=410 [M+H] ⁺ .

{tert-Butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid methyl ester: bis(trimethylsilyl)amide lithium (2.3 ml; 2.38 mmol) was added to a solution of tert-butyl ether [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl] α-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 minutes. Methyl bromoacetate (0.8 ml, 9.1 mmol) 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 quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The separated organic layer was washed with brine, dried and concentrated. The crude material was purified by preparative HPLC (XBridge Prep C18 column, 10 μM, OBD 30×250 mm, 50-95% ACN in water with 0.1% NH ₄ OH) to give the methyl ester {tert-butoxycarbonyl-[(3R,5S) -5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid (160 mg; 19%). MS: m/z=482 [M+H] ⁺ .

tert-Butyl ether ]-carbamic acid: A mixture of {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid methyl ester (25 mg; 0.05 mmol) and azetidine (0.14 ml; 2.0 mmol) in methanol (1 ml) were stirred at room temperature for 2 days. The reaction mixture was concentrated to dryness to give crude (2-azetidin-1-yl-2-oxo-ethyl)-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl) tert-butyl ester )-piperidin-3-yl]-carbamic acid (25 mg), which was used directly for the next reaction. MS: m/z=507 [M+H] ⁺ .

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 obtained from tert-butyl ether (2-azetidine-1- yl-2-oxo-ethyl)-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-carbamic acid using Method Q. Crude material purified by preparative HPLC (XBridge Prep C18 column, 10 μM, OBD 30×250 mm, 10-60% ACN in water with 0.1% NH ₄ OH) to give 1-azetidin-1-yl-2-[(3R,5S )-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-ethanone (18 mg; 90%).

Compound 568: MS: m/z=407 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4, ppm) δ 8.96 (dd, J=4.2, 1.8 Hz, 1H), 8.59 (dd, J=8.6, 1 .8 Hz, 1H), 8.49 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.6, 4.2 Hz, 1H ), 7.28 (d, J=8.0 Hz, 1H), 4.24 (t, J=7.7 Hz, 2H), 4.08 (t, J=7.8 Hz, 2H), 3.74-3.65(m, 1H), 3.62(s, 2H), 3.45-3.35(m, 2H), 2.69(t, J=10.9Hz, 1H) , 2.47 (t, J=11.4 Hz, 1H), 2.38 (q.v., J=7.8 Hz, 2H), 2.34-2.26 (m, 1H), 2.23 -2.06 (m, 1H), 1.15 (q, J=11.9 Hz, 1H), 1.06 (d, J=6.6 Hz, 3H).

The following compounds were synthesized in a similar manner:

Compound 569 (1-Azetidin-1-yl-2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-ethanone): from methyl {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid ester and methylamine. MS: m/z=381 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4, ppm) δ 8.95 (dd, J=4.3, 1.7 Hz, 1H), 8.58 (dd, J=8.6, 1 .8 Hz, 1H), 8.46 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.62 (dd, J=8.6, 4.2 Hz, 1H ), 7.26 (d, J=8.0 Hz, 1H), 3.72-3.63 (m, 1H), 3.59 (br.s, 2H), 3.43-3.35 ( m, 1H), 3.32-3.27 (m, 1H), 2.80 (s, 3H), 2.67 (t, J=10.9 Hz, 1H), 2.46 (t, J =11.4Hz, 1H), 2.28(d, J=12.4Hz, 1H), 2.22-2.07(m, 1H), 1.13(square, J=11.8 Hz, 1H), 1.05 (d, J=6.6 Hz, 3H).

Compound 570 (1-Azetidin-1-yl-2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-ethanone): from methyl {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid ester and ammonia. MS: m/z=367 [M+H] ⁺ . ¹ H NMR (400 MHz, Methanol-d4, ppm) δ 8.96 (dd, J=4.2, 1.7 Hz, 1H), 8.59 (dd, J=8.6, 1 .8 Hz, 1H), 8.46 (s, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.63 (dd, J=8.6, 4.2 Hz, 1H ), 7.27 (d, J=8.0 Hz, 1H), 3.78-3.56 (m, 3H), 3.39 (dd, J=11.9, 4.0 Hz, 2H) , 2.69 (t, J=10.8 Hz, 1H), 2.47 (t, J=11.4 Hz, 1H), 2.30 (d, J=12.3 Hz, 1H), 2 .22-2.10 (m, 1H), 1.15 (sq., J=11.9 Hz, 1H), 1.06 (d, J=6.6 Hz, 3H).

Example 140: Synthesis of compound 571 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid)

[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid methyl ester dihydrochloride: {tert-Butoxycarbonyl-[(3R, 5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amino}-acetic acid (18 mg; 0.04 mmol) and 4.0M 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 crude [(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid dihydrochloride methyl ester (17 mg; >99 %), which was used directly for the next reaction. MS: m/z=382 [M+H] ⁺ .

[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid: [(3R,5S)-5-methyl-1 methyl ester solution -(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamino]-acetic acid dihydrochloride (17 mg; 0.04 mmol) and lithium hydroxide monohydrate (9.4 mg; 0.2 mmol) in THF ( 1 ml) and water (1 ml) were stirred at room temperature for 1 hour. The reaction mixture was concentrated and then purified by preparative HPLC (XBridge Prep C18 column, 10 μM, OBD 30×250 mm, 5-60% ACN in water with 0.1% formic acid) to give [(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] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (dd, J=4.2, 1.7 Hz, 1H), 8.49 (dd, J=8.6, 1 .8 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.67 (dd, J=8.6, 4.1 Hz, 1H), 7.23 (d, J =8.0 Hz, 1H), 3.73-3.64 (m, 1H), 3.48-3.41 (m, 1H), 3.34-3.30 (m, 1H), 3, 28 (d, J=4.6 Hz, 2H), 2.62 (t, J=11.0 Hz, 1H), 2.41 (t, J=11.4 Hz, 1H), 2.20 ( d, J=12.3 Hz, 1H), 2.07-1.95 (m, 1H), 1.09 (sq., J=12.0 Hz, 1H), 0.96 (d, J= 6.6 Hz, 3H).

Example 141: Synthesis of compound 580 urea)

1-[(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-3-(3,3-difluoro-cyclobutylmethyl)-urea: Solution 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 1 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: XBridge C18 OBD Prep Column, 5 μm, 19 mm x 250 mm; Mobile phase: acetonitrile in water (with 10 mmol/l NH ₄ OH), 10% - 80% gradient over 25 min; 254 nm UV detector, yielding 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.

Compound 580: HPLC: <99% purity, RT=4.03 min. MS: m/z=468.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6, ppm) θ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.58 (dd, J=8.6, 1 .7 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.71 (dd, J=8.6, 4.2 Hz, 1H), 7.32 (d, J =8.1 Hz, 1H), 6.13 (d, J=7.7 Hz, 2H), 3.99 (s, 1H), 3.58 (t, J=10.3 Hz, 2H), 3.12(kw, J=13.2, 6.0Hz, 3H), 2.93(t, J=11.5Hz, 1H), 2.64-2.54(m, 2H) , 2.35-2.16 (m, 4H), 1.46 (sq., J=12.2 Hz, 1H).

The following compounds were synthesized in a similar manner:

Compound 581 ([(3R,5S)-1-(8-cyano-quinolin-5-yl)-5-trifluoromethyl-piperidin-3-yl]-amide 1-carboxylic acid):from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidin-1-yl)-quinoline-8-carbonitrile hydrochloride and (3R,4S)-3,4-difluoro-pyrrolidine hydrochloride. HPLC: <99% purity, RT=3.73 min. MS: m/z=454.5 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6) δ 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.59 (dd, J=8.6, 1.7 Hz, 1H) , 8.25 (d, J=8.0 Hz, 1H), 7.72 (dd, J=8.6, 4.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 6.39 (d, J=7.4 Hz, 1H), 5.40-5.18 (m, 3H), 4.06 (s, 2H), 3.68 (dd, J=12 .6, 5.9 Hz, 2H), 3.64-3.55 (m, 3H), 3.47-3.35 (m, 3H), 2.92 (t, J=11.6 Hz, 2H), 2.64 (t, J=11.3 Hz, 1H), 2.20 (d, J=12.0 Hz, 1H), 1.63 (q., J=12.4 Hz, 2H ).

Compound 582 ):from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride and C-(3,3-difluoro-cyclobutyl)-methylamine hydrochloride. HPLC: <99% purity, RT=4.39 min. MS: m/z=457.4 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1, 8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.66 (dd, J=8.6, 4.2 Hz, 1H), 7.20 (d, J= 8.1 Hz, 1H), 6.02 (t, J=5.9 Hz, 1H), 5.93 (d, J=7.5 Hz, 1H), 3.61-3.51 (m, 1H), 3.35 (s, 1H), 3.11 (kw, J=13.3, 6.1 Hz, 2H), 2.62-2.52 (m, 2H), 2.41 (t, J=11.0 Hz, 2H), 2.32-2.16 (m, 3H), 2.02 (s, 2H), 1.02 (sq., J=11.9 Hz, 1H ), 0.95 (d, J=6.4 Hz, 3H).

Compound 583 ([(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-yl]-amide 1-carboxylic acid):from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinolin-5-yl)-piperidin-3-ylamine hydrochloride; and (3R,4S)-3,4-difluoro-pyrrolidine hydrochloride. HPLC: <99% purity, RT=4.08 min. MS: m/z=44.3.4 [M+H]⁺.^oneH NMR (400 MHz, DMSO-d6, ppm) δ 9.01 (dd, J=4.2, 1.7 Hz, 1H), 8.53 (dd, J=8.6, 1, 8 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.67 (dd, J=8.6, 4.2 Hz, 1H), 7.21 (d, J= 8.1 Hz, 1H), 6.23 (d, J=7.5 Hz, 1H), 5.21 (dd, J=9.6, 5.5 Hz, 2H), 3.94 (s, 1H), 3.73-3.49 (m, 3H), 3.49-3.32 (m, 4H), 2.48 (s, 3H), 2.40 (t, J=11.3 Hz , 1H), 2.12-1.96(m, 2H), 1.20(q, J=12.1Hz, 1H), 0.96(d, J=6.4Hz, 3H).

Example 142: HEK cell analysis

TLR7/NFKb HEK cells were added to 384-well culture plates (Corning 3707) at 5000 cells/well in 30 µl of DMEM free of Phenyl Red (gibco#31053) and 10% inactivated FCS and 2 mM L-Z Glutamine. Cells were incubated for 24 hours at 37°C, 10% carbon dioxide and 90% relative humidity. 3 μl of controls, standards and compounds were dispensed into wells, incubated for 30 minutes, then 3 μl of R*48 agonist in 20 mM Hepes was added. After incubation for 5 hours, the plates were allowed to stand at room temperature for 15 minutes. Then 10 µl of Steady-Glo substrate was added and the assay plate was shaken for 5 minutes at 1500 rpm. The assay plate was allowed to stand for 30 minutes at room temperature and then the plate was read on EnVision.

The results are presented in the following table.

A: IC _{50 <} 1 µM

B: IC ₅₀ : 1 µM -10 µM

C: IC ₅₀ >10 μM

table 2 Example Compound Activity one one C one 2 B 2 3 B 3 four B four 5 B 5 6 B 6 7 C 7 eight B eight 9 C 9 ten A 9 eleven B 9 12 A ten 13 C ten fourteen C ten fifteen C eleven 16 A eleven 17 C 12 eighteen C 12 19 A ten twenty A ten 21 A ten 22 B ten 23 C 13 24 A 13 25 A 13 26 B

13 27 B 13 28 A 13 29 C 13 thirty C 13 31 B ten 32 A ten 33 B 13 34 C 13 35 A ten 36 B ten 37 C 12 38 A 12 39 B ten 40 A ten 41 B fourteen 42 C fifteen 43 C 16 44 A 16 45 C 17 46 C eighteen 47 B 19 48 B twenty 49 C 21 fifty A 22 51 C 22 52 A 22 53 A 22 54 A 22 55 A 22 56 B 22 57 A 22 58 A 22 59 A 22 60 B

23 61 B 24 62 B 25 63 C 25 64 B 25 65 A 26 66 A 27 67 A 28 68 A 29 69 B 29 70 A thirty 71 A 31 72 A 31 73 A 32 74 A 33 75 A 33 76 B 34 77 A 35 78 A 36 79 B 37 80 B 38 81 A 39 82 A 39 83 A 39 84 B 40 85 A 40 86 C 41 87 A 41 88 A 41 89 C 41 90 C 42 91 A 42 92 B 42 93 C 42 94 C

42 95 B 42 96 C ten 97 A 43 98 A 43 99 A 43 100 B 43 101 B 13 102 A 13 103 A 13 104 C 13 105 A 13 106 A 13 107 C ten 108 A ten 109 A ten 110 C ten 111 A 44 112 B 44 113 A 44 114 C 44 115 C 13 116 A 13 117 A 13 118 B 13 119 A ten 120 C 12 121 C 12 122 A 45 123 A 46 124 A 46 125 A 12 126 C 45 127 C 13 128 C

13 129 B ten 130 A ten 131 C ten 132 A ten 133 C ten 134 B 42 135 A 42 136 A 42 137 A 42 138 A 42 139 C ten 140 A ten 141 C ten 142 A ten 143 C ten 144 A ten 145 C 41 146 A 41 147 A 41 148 C 41 149 C 41 150 A 41 151 A 41 152 B 41 153 B 41 154 A 41 155 B 41 156 C 41 157 C 41 158 B 41 159 B 41 160 C 41 161 C 47 162 B

ten 163 A ten 164 C ten 165 A ten 166 A ten 167 A ten 168 C ten 169 A ten 170 C ten 171 A ten 172 B 41 173 B 41 174 C ten 175 B 12 176 B 48 177 B 48 178 B ten 179 B 49 180 A fifty 181 C fifty 182 B 51 183 C 52 184 C 52 185 C 42 186 C 53 187 A 54 188 A 54 189 B 55 190 A 56 191 B 56 192 B 54 193 B 57 194 A 57 195 A 58 196 A

59 197 B 59 198 A 57 199 A 60 200 A 27 201 B 27 202 B 27 203 B 61 204 A 61 205 A 62 206 A 63 207 B 63 208 A 61 209 A 64 210 A 65 211 B 65 212 B 66 213 A 66 214 B 66 215 A 67 216 A 66 217 A 66 218 B 67 219 A 66 220 B 68 221 B 40 222 A 40 223 B 69 224 B 69 225 B 69 226 A 69 227 B 40 228 B 40 229 A ten 230 A

70 231 A ten 232 A ten 233 A ten 234 A ten 235 A ten 236 A 69 237 A 69 238 A 57 239 A 57 240 A 57 241 A 70 242 B 57 243 A 57 244 A 57 245 A 57 246 A 57 247 A 57 248 A 71 249 A 71 250 A 71 251 B 70 252 B 71 253 A 71 254 A 71 255 A 71 256 A 71 257 B 71 258 A 71 259 A 72 260 A 72 261 A 73 262 A 73 263 A 73 264 A

ten 265 A ten 266 A 74 267 A 13 268 A ten 269 A 75 270 A 75 271 A 76 272 A 75 273 B 77 274 A 75 275 A 78 276 A 13 277 A 57 278 A 57 279 A 79 280 A 80 281 A 80 282 A 57 283 A 75 284 A 75 285 A 76 286 A 57 287 A 80 288 A 57 289 A 78 290 A 80 291 A 71 292 B 71 293 A 81 294 A 71 295 A 75 296 A 75 297 A 76 298 A

71 299 B 81 300 A 81 301 A 61 302 B 61 303 A 82 304 A 83 305 A 83 306 A 61 307 A 75 308 B 75 309 A 76 310 A 61 311 B 83 312 B 61 313 A 78 314 A 83 315 A 61 316 A 61 317 C 61 318 A 61 319 A 75 320 B 75 321 B 76 322 B 61 323 B 83 324 B 61 325 B 78 326 A 83 327 A 61 328 A 61 329 B 84 330 A 84 331 A 85 332 A

84 333 A 84 334 A 86 335 C 86 336 C 87 337 C 86 338 A 88 339 A 88 340 B 89 341 A 90 342 B 91 343 B 95 344 B 93 345 C 93 346 C 94 347 B 95 348 A 96 349 A 95 350 A 96 351 A 97 352 A 98 353 A 95 354 B 96 355 A 98 356 A 99 357 A 99 358 A 100 359 A 100 360 A 82 361 A 78 362 A 100 363 A 100 364 A 82 365 B 101 366 B

102 367 C 103 368 C 104 369 A 104 370 A 104 371 A 104 372 A 105 373 B 106 374 B 106 375 B 106 376 B 106 377 B 106 378 B 105 379 B 105 380 B 106 381 B 106 382 B 106 383 B 106 384 B 106 385 B 106 386 B 106 387 B 7 388 B 106 389 B 7 390 B 7 391 C 7 392 C 107 393 B 7 394 B 108 395 B 7 396 C 108 397 B 108 398 A 7 399 C 7 400 C

106 401 B 7 402 B 108 403 A 109 404 C 7 405 B 109 406 B 108 407 A 7 408 B 7 409 A 7 410 A 7 411 B 7 412 C 109 413 A one 414 A one 415 A one 416 A 7 417 A 7 418 A one 419 B one 420 A one 421 A one 422 A thirty 423 A 40 424 B 110 425 A 40 426 A one 427 B 40 428 A 41 429 C 41 430 A 40 431 A 105 432 A one 433 A one 434 A

one 435 A 111 436 A 41 437 B 41 438 B one 439 A one 440 A 111 441 A 111 442 A 112 443 A 113 444 A 113 445 A 111 446 A 114 447 A 112 448 B 115 449 A 115 450 B 116 451 A 117 452 A 118 453 A one 454 B 107 455 C one 456 C 32 457 A 119 458 C 32 459 B 114 460 C 119 461 A 89 462 A 118 463 A 120 464 A 121 465 A 114 466 B 22 467 A 25 468 A

114 469 B 114 470 B 114 471 A 57 472 A 57 473 A 57 474 B 57 475 80 476 A 121 477 A 122 478 A 123 479 A 124 480 B 122 481 B 124 482 B 123 483 A 122 484 A 122 485 A 123 486 A 123 487 A 125 488 A 125 489 A 122 490 A 122 491 A 124 492 B 123 493 A 126 494 C 126 495 B 122 496 A 126 497 A 126 498 A 127 499 B 127 500 B 127 501 C 128 502 B

129 503 A 129 504 A 130 505 B 129 506 B 131 507 A 131 508 B 131 509 C thirty 510 A 40 511 A 40 512 B 40 513 B 80 514 A 57 515 A 57 516 A 57 517 A 132 518 A 57 519 A 126 520 A 126 521 A 126 522 A 126 523 A thirty 524 B 133 525 A 57 526 A 126 527 A 126 528 B 134 529 A 134 530 A 134 531 A 134 532 A 135 533 A 135 534 B 135 535 A 135 536 B

134 537 A 134 538 A 134 539 A 134 540 A 134 541 B 134 542 B 134 543 A 134 544 A 136 545 B 136 546 A 134 547 A 134 548 A 134 549 B 57 550 57 551 137 552 A thirty 553 A 122 554 A 122 555 B 122 556 B 122 557 B 122 558 B 122 559 B 122 560 A 123 561 A 123 562 A 123 563 A 124 564 C 124 565 B 124 566 B 138 567 C 139 568 A 139 569 A 139 570 A

140 571 B 57 572 A 57 573 A 57 574 A 57 575 B 40 576 A 40 577 A 40 578 A 40 579 B 141 580 B 141 581 B 141 582 B 141 583 B 40 584 A 40 585 A 89 586 A

Example 77 Pharmaceuticals

(A) Injection vials: A solution of 100 g of the active ingredient according to the invention and 5 g of disodium hydrogen phosphate in 3 l of bidistilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred to injection vials, lyophilized under sterile conditions and sealed under sterile conditions. Each injection vial contained 5 mg of the active ingredient.

(B) Suppositories: A mixture of 20 g of the active ingredient according to the invention was melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contained 20 mg of the active ingredient.

(C) Solution: The solution was prepared from 1 g of the active ingredient according to the invention, 9.38 g of NaH ₂ PO ₄ ⋅ 2H ₂ O, 28.48 g of Na ₂ HPO ₄ ⋅ 12 H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH was adjusted to 6.8 and the solution was obtained in a volume of 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

(D) Ointment: 500 mg of the active ingredient according to the invention were mixed with 99.5 g of vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of the 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 magnesium stearate was compressed into tablets in the usual way so that each tablet contains 10 mg active ingredient.

(F) Coated Tablets: Tablets were compressed in the same manner as Example E and then coated in the usual manner using a coating of sucrose, potato starch, talc, tragacanth, and dye.

(G) Capsules: 2 kg of the active ingredient according to the invention were filled into hard gelatin capsules in the usual way so that each capsule contained 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of the active ingredient according to the invention in 60 liters of bidistilled water was sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contained 10 mg of the active ingredient.

(I) Inhalation spray: 14 g of the active ingredient according to the invention was dissolved in 10 L of isotonic NaCl solution and the solution was transferred into commercially available pump spray containers. The solution can be sprayed into the mouth or nose. One injection (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Although this application describes a number of embodiments of the present invention, it is obvious that the basic examples can be changed to obtain other embodiments that use the compounds and methods of the present invention. Therefore, it should be understood that the scope of the present invention is to be determined by the appended claims and not by the specific embodiments that have been presented by way of example.

Claims (9)

1. Connection

or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, represented by the structure

or a pharmaceutically acceptable salt thereof. 3. A pharmaceutical composition that inhibits TLR7/8 activity, comprising an effective amount of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or excipient. 4. A method of inhibiting the activity of TLR7/8 or its mutant in a patient or biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof. 5. A method of treating a TLR7/8-mediated disorder selected from lupus, polymyositis, dermatomyositis, Sjogren's disease and rheumatoid arthritis in a patient in need thereof, comprising the step of administering to said patient a compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof.