TLR7 / 8 Antagonists and Their Use

Abstract

To provide novel TLR7 / 8 antagonists.SOLUTION: The present invention provides compounds of Formula (I) and pharmaceutically acceptable compositions thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Technical field of the present invention The present invention provides compounds represented by formula (I) as Toll-like receptor 7 / 8 (TLR7 / 8) antagonists, and their use in the treatment of immunodeficiency and other diseases related to TLR7 / 8 overexpression. [Background technology]

[0002] Background of the present invention Toll-like receptors (TLRs), currently comprising a family of 10 receptor genes with distinct specificities, are part of the cellular pathogen pattern recognition system that has evolved to defend against various infectious diseases (bacteria, viruses, and fungi). Activation of TLRs leads to cytokine responses, such as the release of interferons and the activation of specific immune cells. The functional expression of selected TLRs in tissues is highly diverse. Some receptors, such as TLR4 (stimulated by E. coli lipopolysaccharide LPS), are located on the cell surface, for example, on epithelial cells, while TLR3, 7, 8, and 9 are located in specific immune cells and on the endosomal membrane. The latter are all activated by nucleic acids, but recognize various types of nucleic acids. For example, TLR9 is activated by single-stranded DNA containing CpG sequences, TLR7 and 8 are activated by single-stranded RNA, and TLR3 is activated by double-stranded RNA.

[0003] TLRs are involved in a variety of autoimmune and inflammatory diseases, with the most obvious 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 polymorphisms are associated with rheumatoid arthritis (Enevold et al., J Rheumatol, 37:905-10, 2010). While various inhibitors of TLR7, TLR8, and TLR9 have been described, further TLR inhibitors are desired. In particular, polynucleotides with inhibitory motifs for one or more of TLR7, TLR8, and TLR9 are needed to strictly inhibit the immune response in subjects (e.g., patients with autoimmune diseases or inflammatory disorders).

[0004] A strong effort to utilize potent immune activation induced by TLR7, 8, or 9 agonists for cancer treatment has continued as a global endeavor in recent years. However, cancer immunotherapy has a long history of failures. In recent years, however, our knowledge of cancer immune surveillance and the resulting function of immune cell subsets has dramatically improved. TLR7 or TLR9 agonists are in clinical development for cancer monotherapy, combination therapy, or as vaccine adjuvants. The TLR agonist approach for cancer immunotherapy differs from previous efforts using cytokines, interferons, or monovalent vaccines, for example. Immune activation mediated by TLR agonists is multifaceted, mediated by specific immune cells (primarily dendritic cells and B cells, followed by other cells), and this activation leads to innate and adaptive immune responses. Moreover, not only one type of interferon, but rather many different isoforms are induced simultaneously, and not only type I (alpha, beta) but also type II (gamma, NK cells) are (indirectly) induced. [Overview of the Initiative]

[0005] Summary of the present invention In one aspect, the present invention relates to formula (I): [ka] The present invention provides compounds represented by [formula], and their pharmaceutically acceptable derivatives, solvates, salts, hydrates, and stereoisomers.

[0006] In another aspect, the present invention provides a compound represented by formula (I) that is a dual antagonist of TLR7 and TLR8. In another aspect, the present invention provides a compound represented by formula (I) suitable for treating and / or preventing disorders related to TLR7 / 8. In another aspect, the present invention provides compounds that can modulate, or in particular inhibit, the activity or function of TLR7 / 8 in mammalian, and especially human, pathological conditions. In one embodiment, the compounds are non-brain penetrant compounds. In another embodiment, the compounds are brain penetrant compounds due to the structure of the compounds of the present invention.

[0007] According to another aspect of the present invention, a method for treating and / or preventing autoimmune disorders is provided.

[0008] In another aspect, the present invention provides a compound represented by formula (I) that is selective for TLR7 or TLR8.

[0009] In another aspect, the present invention provides compounds represented by formula (I) that are selective for TLR7 and TLR8. [Modes for carrying out the invention]

[0010] Detailed description of a certain aspect 1. General description of the compounds of the present invention In some respects, the present invention provides antagonists of TLR7 / 8. In some embodiments, such compounds include compounds represented by the formulas described herein, or pharmaceutically acceptable salts thereof, where each variant is as defined and described herein.

[0011] 2. Compounds and Definitions The compounds of the present invention encompass those generally described above and are further described by the classes, subclasses, and species disclosed herein. When used herein, the following definitions may apply unless otherwise indicated. For the purposes of the present invention, chemical elements are as defined in Elements, CAS version, Handbook of Chemistry and Physics, 75 th They are identified according to Ed's periodic table. In addition, the general principles of organic chemistry are found in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5 th This is described in Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, and the entirety of this content is incorporated herein by reference.

[0012] The terms “aliphatic” or “aliphatic group,” as used herein, mean a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, or a monocyclic or bicyclic hydrocarbon, that is fully saturated or contains one or more unsaturated units, but is not aromatic (and is also referred herein as “carbocyclic,” “alicyclic,” or “cycloalkyl”), and has a single attachment site to the rest of the molecule. Unless otherwise specified, an aliphatic group comprises 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group comprises 1 to 5 aliphatic carbon atoms. In other embodiments, an aliphatic group comprises 1 to 4 aliphatic carbon atoms. In yet another embodiment, an aliphatic group comprises 1 to 3 aliphatic carbon atoms, and in yet another embodiment, an aliphatic group comprises 1 to 2 aliphatic carbon atoms. In some embodiments, “alicyclic” (or “carbocyclic” or “cycloalkyl”) refers to a monocyclic C3-C6 hydrocarbon that is either fully saturated or contains one or more unsaturated units, is not aromatic, and has a single attachment site to the rest of the molecule. Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C1-C8 alkyl groups, C2-C8 alkenyl groups, C2-C8 alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0013] The term "lower alkyl" refers to C 1~4 This refers to linear or branched alkyl groups. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0014] The term "lower haloalkyl" refers to a carbon atom substituted with one or more halogen atoms. 1~4 This refers to linear or branched alkyl groups.

[0015] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, or phosphorus (any oxidized form of nitrogen, sulfur, or phosphorus; any quaternized form of any basic nitrogen; or a substituteable nitrogen in a heterocycle, e.g., N (found in 3,4-dihydro-2H-pyrrolyl), NH (found in pyrrolidinyl), or NR + This means (including those found in N-substituted pyrrolidinyls).

[0016] The term "unsaturated" as used herein means that a moiety has one or more unsaturated units.

[0017] When used in this specification, the term "divalent C" 1~8 (or C 1~6 "Saturated or unsaturated, straight or branched hydrocarbon chains" means straight or branched, divalent alkylene, alkenylene, and alkynylene chains as defined herein.

[0018] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -wherein n is a positive integer, preferably from 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 methylene hydrogen atoms are replaced by substituents. Preferred substituents include those listed below for substituted aliphatic groups.

[0019] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Preferred substituents include those listed below for substituted aliphatic groups.

[0020] The term "halogen" refers to F, Cl, Br, or I.

[0021] The term “aryl,” used alone or as part of a larger phrase found in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic and bicyclic ring systems having a total of 5 to 14 ring members, where at least one ring in the system is aromatic, and where each ring in the system contains 3 to 7 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. Exemplary aryl groups include phenyl, biphenyl, naphthyl, anthrasyl, etc., which optionally contain one or more substituents. Also included within the scope of the term “aryl,” as used herein, are groups where the aromatic ring is condensed with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl.

[0022] Used alone or as part of a larger term, e.g., "heteroaryl" or "heteroar-", the terms "heteroaryl" and "heteroar-" refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in the cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and the quaternized form of basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthilidinyl, and pteridinyl. The terms “heteroaryl” and “hetero-arra-” also, as used herein, include groups in which a heteroaromatic ring is condensed with one or more aryl, alicyclic, or heterocyclyl rings, where the radical or attachment site is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one. Heteroaryl groups are optionally monocyclic or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," but any of these terms includes a ring that may optionally be substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, where the alkyl and heteroaryl moieties may be substituted independently and arbitrarily.

[0023] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety, wherein said heterocyclic moiety is either saturated or partially unsaturated, and contains, in addition to carbon atoms, one or more, preferably 1 to 4, heteroatoms as defined above. As used with respect to ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as found in 3,4-dihydro-2H-pyrrolyl), NH (as found in pyrrolidinyl), or + NR (as found in N-substituted pyrrolidinyl).

[0024] A heterocyclic ring may be attached to its pendant group by heteroatoms or carbon atoms, resulting in a stable structure in which any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranil, tetrahydrothiophenylpyrrolidinil, piperidinil, pyrrolinil, tetrahydroquinolinil, tetrahydroisoquinolinil, decahydroquinolinil, oxazolidinil, piperazinil, dioxanil, dioxolanil, diazepinyl, oxazepinyl, thiazepinyl, morpholinil, and quinuclidinil. The terms “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups to which the heterocyclyl ring is condensed with one or more aryl, heteroaryl, or alicyclic groups, such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl, where the radical or attachment site is on the heterocyclyl ring. The heterocyclyl group is optionally monocyclic or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, where the alkyl moiety and heterocyclyl moiety may be independently and optionally substituted.

[0025] As used herein, the term “partially unsaturated” refers to a ring portion containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated sites, but not to encompass aryl or heteroaryl moies as defined herein.

[0026] As described herein, certain compounds of the present invention include a “optionally substituted” portion. Generally, the term “substituted” means that one or more hydrogens in the specified portion are replaced with a preferred substituent, whether preceded by the term “optionally”. “substituted” means that the structure (for example, [ka] At least [ka] It refers to; and [ka] At least [ka] The term applies to one or more hydrogen atoms, either explicitly or implicitly, from (referring to). Unless otherwise indicated, a “optionally substituted” group has suitable substituents at each of its substituted positions, and when more than one position in any given structure is substituted with more than one substituent selected from a particular group, the substituents are either the same or different at every position. The substituent combinations envisioned by the present invention preferably result in the formation of stable or chemically feasible compounds. The term “stable” as used herein means a compound that is substantially unchanged when subjected to conditions that enable their production, detection, in some embodiments their recovery, purification, and use for one or more purposes disclosed herein.

[0027] Preferred monovalent substituents on the replaceable carbon atoms of the "optionally substituted" group are, independently, deuterium; halogen; -(CH2) 0~4 R ○ ;-(CH2) 0~4 Ure ○ ;-O(CH2) 0~4 R ○ -O-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 CH(OR ○ )2;-(CH2) 0~4 SR ○ ;R ○ -(CH2) can be arbitrarily substituted with 0~4 Ph;R ○ -(CH2) can be arbitrarily substituted with 0~4O(CH2) 0~1 Ph;R ○ -CH=CHPh;R is arbitrarily substituted. ○ -(CH2) can be arbitrarily substituted with 0~4 O(CH2) 0~1 -Pyridyl;-NO2;-CN;-N3;-(CH2) 0~4 N(R ○ )2;-(CH2) 0~4 N(R ○ )C(O)R ○ ;-N(R ○ )C(S)R ○ ;-(CH2) 0~4 N(R ○ )C(O)NR ○ 2;-N(R ○ )C(S)NR ○ 2;-(CH2) 0~4 N(R ○ )C(O)OR ○ ;-N(R ○ )N(R ○ )C(O)R ○ ;-N(R ○ )N(R ○ )C(O)NR ○ 2;-N(R ○ )N(R ○ )C(O)OR ○ ;-(CH2) 0~4 C(O)R ○ ;-C(S)R ○ ;-(CH2) 0~4 C(O)OR ○ ;-(CH2) 0~4 C(O)SR ○ ;-(CH2) 0~4 C(O)OSiR ○ 3;-(CH2) 0~4 OC(O)R ○ ;-OC(O)(CH2) 0~4 SR ○ SC(S)SR ○ ;-(CH2) 0~4 SC(O)R ○ ;-(CH2) 0~4 C(O)NR ○ 2;-C(S)NR ○ 2;-C(S)SR ○ ;-SC(S)SR○ , -(CH2) 0~4 OC(O)NR ○ 2; -C(O)N(OR ○ )R ○ ; -C(O)C(O)R ○ ; -C(O)CH2C(O)R ○ ; -C(NOR ○ )R ○ ; -(CH2) 0~4 SSR ○ ; -(CH2) 0~4 S(O)2R ○ ; -(CH2) 0~4 S(O)2OR ○ ; -(CH2) 0~4 OS(O)2R ○ ; -S(O)2NR ○ 2; -(CH2) 0~4 S(O)R ○ ; -N(R ○ )S(O)2NR ○ 2; -N(R ○ )S(O)2R ○ ; -N(OR ○ )R ○ ; -C(NH)NR ○ 2; -P(O)2R ○ ; -P(O)R ○ 2; -OP(O)R ○ 2; -OP(O)(OR ○ )2; SiR ○ 3; -(C 1~4 straight or branched alkylene)O-N(R ○ )2; or -(C 1~4 straight or branched alkylene)C(O)O-N(R ○ )2, wherein each R ○ is optionally substituted as defined below, and each R ○ is independently hydrogen, C 1~6 aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2-(5- to 6-membered heteroaryl ring), or a saturated, partially unsaturated or aryl 5- to 6-membered ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the definition above, R ○Two of these independently existing atoms, together with their intervening atoms (one or more), form saturated, partially unsaturated, or aryl 3- to 12-membered mono- or di-rings (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur), which may be optionally substituted as defined below.

[0028] R ○ (or R ○ A suitable monovalent substituent on the ring formed by two of the independently existing atoms joining with their intervening atoms is independently deuterium, halogen, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2;-O(HaroR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR ● ,-(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● ,-(C 1~4 Linear or branched alkylenes)C(O)OR ● , or -SSR ● However, here, each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and each R ● Independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1Ph, or selected from saturated, partially unsaturated, or aryl rings of 5-6 members (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur). ○ Suitable divalent substituents on the saturated carbon atom include =O and =S.

[0029] Preferred divalent substituents on the saturated carbon atom of the "optionally substituted" group are: =O, =S, =NNR * 2. =NNHC(O)R * ,=NNHC(O)OR * ,=NNHS(O)2R * ,=NR * 、=NOR * , -O(C(R * 2)) 2~3 O-, or -S(C(R * 2)) 2~3 S- is included, but here R * Each of these independent entities is selected from hydrogen, a substituted or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur) as defined below. A preferred divalent substituent bonded to the substituteable adjacent carbon of the "optionally substituted" group is:-O(CR * 2) 2~3 O- is included, but here R * Each of these independent entities is selected from hydrogen, a substituted or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur) as defined below.

[0030] R * Preferred substituents on the aliphatic group are halogens, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ●2, or -NO2, but where each R ● If it is unsubstituted, or if preceded by "halo", then it was one or more halogens that were unsubstituted, and each R ● Independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5-6 member saturated, partially unsaturated, or aryl ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur).

[0031] A suitable substituent on the substituted nitrogen of the group "may be optionally substituted" is -R † , -NR † 2, -C(O)R † , -C(O)OR † ,-C(O)C(O)R † -C(O)CH2C(O)R † -S(O)2R † -S(O)2NR † 2, -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † Includes; here, each R † These are, independently, hydrogen, and C which may be optionally substituted as defined below. 1~6 Aliphatic, unsubstituted -OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur), or, notwithstanding the above definition, R † Two of these independently existing atoms, together with their intervening atoms (one or more), form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or di-ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur).

[0032] R † Suitable substituents on the aliphatic group are, independently, halogens, -R ● ,-(HaroR ● ), -OH, -OR● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or -NO2, where each R ● It is either unsubstituted, or if preceded by "halo", it is substituted by only one or more halogens, and each R ● Independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 It is a 5-6 member saturated, partially unsaturated, or aryl ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur).

[0033] In some embodiments, as used herein, the terms “optionally substituted,” “optionally substituted alkyl,” “optionally substituted,” “optionally substituted alkenyl,” “optionally substituted alkynyl,” “optionally substituted carbocyclic,” “optionally substituted aryl,” “optionally substituted heteroaryl,” “optionally substituted heterocyclic,” and any other optionally substituted group refer to a group that is substituted or unsubstituted by the independent substitution of one, two, or three or more hydrogen atoms on the group with typical substituents, but such typical substituents include, but are not limited to, the following: -F, -Cl, -Br, -I, deuterium, -OH, protected hydroxyl, alkoxy, oxo, thiooxo, -NO2, -CN, CF3, N3, -NH2, protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -NH cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocyclic, -dialkylamino, -diarylamino, -diheteroarylamino, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclic -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)-carbocyrill, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocyclyl -CONH2, -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH-carbocyrill, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl -OCO2-alkyl, -OCO2-alkenyl, -OCO2-alkynyl, -OCO2-carbocykrill, -OCO2-aryl, -OCO2-heteroaryl, -OCO2-heterocyclyl, -OCONH2, -OCONH-alkyl, -OCONH-alkenyl, -OCONH-alkynyl, -OCONH-carbocykrill, -OCONH-aryl, -OCONH-heteroaryl, -OCONH-heterocyclyl, -NHC(O)-alkyl, -NHC(O)-alkenyl, -NHC(O)-alkynyl, -NHC(O)-carbocyrill, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclyl, -NHCO2-alkyl, -NHCO2-alkenyl, -NHCO2-alkynyl, -NHCO2-carbocyrill, -NHCO2-aryl, -NHCO2-heteroaryl, -NHCO2-heterocyclyl, -NHC(O)NH2, -NHC(O)NH-alkyl, -NHC(O)NH-alkenyl, -NHC( O)NH-alkenyl, -NHC(O)NH-carbocyrill, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocyclyl, NHC(S)NH2, -NHC(S)NH-alkyl, -NHC(S)NH-alkenyl, -NHC(S)NH-alkynyl, -NHC(S)NH-carbocyrill, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH-heterocyclyl, -NHC(NH)NH2, -NHC(NH)NH-alkyl, -NHC(NH)NH- -Alkenyl, -NHC(NH)NH-Alkenyl, -NHC(NH)NH-Carbocyclyl, -NHC(NH)NH-Aryl, -NHC(NH)NH-Heteroaryl, -NHC(NH)NH-Heterocyclyl, -NHC(NH)-Alkyl, -NHC(NH)-Alkenyl, -NHC(NH)-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-carbocyrill, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocyclyl -S(O)-alkyl, -S(O)-alkenyl, -S(O)-alkynyl, -S(O)-carbocyrill, -S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocyclyl-SO2NH2, -SO2NH-alkyl, -SO2NH-alkenyl, -SO2NH-alkynyl, -SO2NH-carbocyrill, -SO2NH-aryl, -SO2NH-heteroaryl, -SO2NH-heterocyclyl, -NHSO2-alkyl, -NHSO2-alkenyl, -NHSO2-alkynyl, -NHSO2-carbocyrill, -NHSO2-aryl, -NHSO2-heteroaryl, -NHSO2-heterocyclyl -CH2NH2, -CH2SO2CH3, -mono-, di-, or tri-alkylsilyl, -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-carbocykrill, -S-aryl, -S-heteroaryl, -S-heterocyclyl, or methylthiomethyl.

[0034] As used herein, the term “pharmaceutically acceptable salt” means, within reasonable limits of medical judgment, a salt that is suitable for use in contact with human and lower animal tissues, without excessive toxicity, irritation, allergic response, etc., and that is balanced by a reasonable benefit / risk ratio. pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19 (incorporated herein by reference). pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic acids and inorganic bases, as well as organic acids and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, bisulfic acid, boric acid, butyric acid, camphoric acid, camphor-sulfonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecyl sulfate, ethanesulfonic acid, formic acid, fumaric acid, glucoheptonic acid, glycerophosphate, gluconic acid, hemisulfic acid, heptanoic acid, hexanoic acid, hydroiodic acid, and 2-hydroxyethane. This includes sulfonic acid, lactobionic acid, lactic acid, lauric acid, lauryl sulfate, malic acid, maleic acid, malonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pectinic acid, persulfate, 3-phenylpropionic acid, phosphoric acid, pivalic acid, propionic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecanoic acid, valeric acid salts, etc.

[0035] Salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and N + (C1~4 This includes alkyl(4) salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts, when appropriate, include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylic acids, sulfuric acids, phosphoric acids, nitric acids, lower alkyl sulfonic acids, and aryl sulfonic acids.

[0036] Unless otherwise stated, the structures described herein also mean the forms of all isomers of that structure (e.g., enantiomers, diastereomers, and geometric isomers (or conformations)); for example, the R and S configurations, the Z and E double bond isomers, and the Z and E conformational isomers for each chiral center. Thus, isomers of a single stereochemistry, as well as mixtures of enantiomers, diastereomers, and geometric isomers (or conformations) of the compound, are within the scope of the invention. Unless otherwise stated, all forms of tautomers of the compounds of the invention are within the scope of the invention.

[0037] In addition, unless otherwise stated, the structures described herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the substitution of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure, in which carbon is replaced by carbon-enriched carbon, are within the scope of the present invention. In some embodiments, the group contains one or more deuterium atoms.

[0038] It is also intended that the compound represented by formula I encompasses its isotopically labeled form. The isotopically labeled form of the compound represented by formula I is identical to the compound, except that one or more atoms of the compound are replaced by one or more atoms having atomic masses or mass numbers different from those of atoms normally found in nature. Examples of isotopes that are commercially readily available and can be incorporated into the compound represented by formula I by known methods include 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 This invention encompasses CI. A compound represented by formula I, its prodrug, or any pharmaceutically acceptable salt thereof containing one or more other isotopes of the aforementioned isotopes and / or other atoms is intended to be part of the present invention. Isotope-labeled compounds represented by formula I can be used in a number of beneficial ways. For example, an isotope-labeled compound represented by formula I can be used, for example, 3 H or 14 Although radioactive isotopes such as 13C are incorporated into it, it is suitable for pharmaceutical and / or substrate tissue distribution assays. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 14 C) is particularly preferred due to its simple preparation and excellent detection ability. Heavier isotopes, for example, deuterium ( 2Incorporating H) into the compound represented by formula I offers therapeutic advantages due to the higher metabolic stability of the isotope-labeled compound. Higher metabolic stability directly translates to an increased in vivo half-life or a lower dosage, which, in most circumstances, represent preferred embodiments of the present invention. The isotope-labeled compound represented by formula I can typically be prepared by performing the procedures disclosed in the synthetic scheme and related descriptions in the examples and preparation sections of this text, and by replacing the isotope-unlabeled reactants with readily available isotope-labeled reactants.

[0039] deuterium( 2 H) can also be incorporated into the compound represented by formula I for the purpose of manipulating the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of heavier isotopes usually results in a decrease in the ground state energy of the chemical bond, thus causing a decrease in the rate-determining bond cleavage. If the bond cleavage occurs in or near the saddle point region in coordination with a multi-product reaction, the distribution ratio of the products can be substantially altered. For illustrative purposes: If deuterium is bonded to a carbon atom in an inexchangeable position, k M / k D The rate difference between 2 and 7 is typical. If this rate difference is successfully applied to compounds represented by formula I that are susceptible to oxidation, the in vivo profile of these compounds can be dramatically modified, potentially resulting in improved pharmacokinetic properties.

[0040] When a therapeutic agent is discovered and developed, it is reasonable for those skilled in the art to surmise that many compounds with poor pharmacokinetic profiles, which allow for optimization of pharmacokinetic parameters while maintaining desired in vitro properties, are susceptible to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information about the course of this type of oxidative metabolism, which in turn enables the rational design of deuterated compounds represented by formula I whose stability is improved through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profile of compounds represented by formula I are obtained thereby, and include improvements in in vivo half-life (t / 2) and concentration at maximum therapeutic effect (C). max It can be expressed quantitatively in terms of the area under the dose-response curve (AUC) and the increase at F; and in terms of reduced clearance, dose, and material costs.

[0041] The following is intended to explain the above: Compounds represented by formula I, which have multiple potential sites for oxidative metabolic attack (e.g., hydrogen atoms bonded to benzyl hydrogen atoms and nitrogen atoms), are prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms (so that some, almost all, or all of these hydrogen atoms are replaced by deuterium atoms). Determining the half-life allows for a preferred and correct determination of the degree to which the improvement in resistance to oxidative metabolism is achieved. Thus, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0042] Deuterium-hydrogen exchange in compounds represented by formula I can also be used to achieve a favorable modification of the metabolite spectrum of a starting compound in order to reduce or eliminate undesirable toxic metabolites. For example, if toxic metabolites arise through oxidative carbon-hydrogen (CH) bond cleavage, it can be reasonably inferred that deuterated analogs will greatly reduce or eliminate the generation of unwanted metabolites, even if the particular oxidation is not the rate-limiting step. Further information on the state of technology regarding 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. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al., Carcinogenesis 16(4), 683-688, 1993.

[0043] As used herein, the term “modulator” is defined as a compound that binds to and / or inhibits a target with measurable affinity. In one embodiment, the modulator is an IC 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. 50 It has and / or coupling constants.

[0044] When used herein, the terms “measurable affinity” and “measurable inhibition” mean a measurable change in TLR7 / 8 activity between a sample containing the compound or composition of the present invention and TLR7 / 8 (and an equivalent sample containing TLR7 / 8 in which the compound or composition is not present).

[0045] The substituents and heteromorphic combinations envisioned in this invention are limited to those that result in the formation of stable compounds. The term “stable” as used herein refers to a compound that possesses sufficient stability to enable production and maintains its integrity for a sufficient period useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0046] Any enumeration of chemical groups in any definition of a variant as used herein includes the definition of that variant as any single group or as a combination of the groups in the list. Any enumeration of embodiments for a variant as used herein includes that embodiment as any single embodiment or as a combination of any other embodiment or parts thereof.

[0047] 3. Exemplary compound description According to one aspect, the present invention relates to formula I, [ka] The present invention provides a compound represented by the formula, or a pharmaceutically acceptable salt thereof, wherein the formula is: Ring A is an aryl or a heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of them may be optionally substituted; Ring B is an aryl or a heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of them may be optionally substituted; R 1 -Me, -CF3, -OMe, -OEt, or -CN; Each R 2 These are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R 3These are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; X is C(R 4 )2, O, NR 4 , S, S(R 4 ), or S(R 4 )2; Each R 4 These are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R 5 These are independently -H, -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; Each R independently consists of hydrogen and C. 1~6 aliphatic, C 3~10 An aryl, a 3- to 8-membered saturated or partially unsaturated carbon ring, a 3- to 7-membered heteroring having 1- to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur), or a 5- to 6-membered monocyclic heteroaryl ring having 1- to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of these may be optionally substituted; or Two R groups on the same atom, together with the atom to which they are attached, form a C 3~10 They form aryl groups, 3-8 member saturated or partially unsaturated carbon rings, 3-7 member heterorings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur), or 5-6 member monocyclic heteroaryl rings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of these may be optionally substituted; k is either 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.

[0048] In one embodiment, R 1 It is -Me.

[0049] In one embodiment, R 1 It is -CF3.

[0050] In one embodiment, R 1 It is -OMe.

[0051] In one embodiment, R 1 It is -OEt.

[0052] In one embodiment, R 1 It is -CN.

[0053] In one embodiment, ring A is a C6 aryl, or a six-membered monocyclic heteroaryl having 1 to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of them may be optionally substituted.

[0054] In one embodiment, ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridadinyl, or triazinyl; each of these may be optionally substituted.

[0055] In one embodiment, ring A is phenyl, pyridyl, or pyrimidinyl; each of these may be optionally substituted.

[0056] In one embodiment, ring B is a C6 aryl or a 5-6 member monocyclic heteroaryl having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of them may be optionally substituted.

[0057] In one embodiment, ring B is phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrole, imidazole, isoxazole, oxazole, or thiazole; each of these may be optionally substituted.

[0058] In a certain configuration, ring A and ring B are, [ka] That is the case.

[0059] In a certain configuration, ring A and ring B are, [ka] That is the case.

[0060] In a certain configuration, ring A and ring B are, [ka] That is the case.

[0061] In a certain configuration, ring A and ring B are, [ka] That is the case.

[0062] In a certain configuration, ring A and ring B are, [ka] That is the case.

[0063] In a certain configuration, ring A and ring B are, [ka] That is the case.

[0064] In a certain configuration, ring A and ring B are, [ka] That is the case.

[0065] In one aspect, each R 2 It is independently -H.

[0066] In one aspect, each R 2 Independently, C 1~6 aliphatic, C 3~10 These are aryl rings, 3- to 8-membered saturated or partially unsaturated carbon rings, 3- to 7-membered heterorings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur), or 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of these may be optionally substituted.

[0067] In one aspect, each R 2 These are independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of these may be optionally substituted.

[0068] In one aspect, each R 2These are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanil, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2]bicyclooctanil, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, ku These are romanil, clomenil, cinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinil, dihydroflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indrenyl, indolinil, indolidinil, indolyl, 3H-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naphthilidinil, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, and 1,2,4-oxadiazolyl;-1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinil, Oxazolyl, Oxazolidinil, Pyrimidinil, Phenanthrolinil, Phenanthrolinil, Phenadinil, Phenothiazinil, Phenoxathiinil, Phenoxadinil, Phthalazinil, Piperadinil, Piperidinil, Pteridinil, Prinyl, Pyrazinil, Pyrazolidinil, Pyrazolyl, Pyridazinil, Pyridoxazole, Pyridoimidazole, Pyridhiazole, Pyridinil, Pyridyl, Pyrimidinil, Pyrrolidinil, Pyrrolidinil, 2H-Pyrrolyl, Pyrrolyl, Quinazolinil, Quinolinil, 4H-Quinolidinil, Quino These are xalinyl, quinuclidinyl, tetrahydrofuranil, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, 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 these may be optionally substituted.

[0069] In one aspect, each R 2 These are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0070] In one aspect, each R 2 These are F independently.

[0071] In one aspect, each R 3 It is independently -H.

[0072] In one aspect, each R 3 Independently, C 1~6 aliphatic, C3~10 These are aryl rings, 3- to 8-membered saturated or partially unsaturated carbon rings, 3- to 7-membered heterorings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur), or 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of these may be optionally substituted.

[0073] In one aspect, each R 3 These are independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of these may be optionally substituted.

[0074] In one aspect, each R 3 It is independently methyl.

[0075] In one aspect, each R 3These are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanil, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2]bicyclooctanil, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, ku These are romanil, clomenil, cinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinil, dihydroflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indrenyl, indolinil, indolidinil, indolyl, 3H-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naphthilidinil, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, and 1,2,4-oxadiazolyl;-1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinil, Oxazolyl, Oxazolidinil, Pyrimidinil, Phenanthrolinil, Phenanthrolinil, Phenadinil, Phenothiazinil, Phenoxathiinil, Phenoxadinil, Phthalazinil, Piperadinil, Piperidinil, Pteridinil, Prinyl, Pyrazinil, Pyrazolidinil, Pyrazolyl, Pyridazinil, Pyridoxazole, Pyridoimidazole, Pyridhiazole, Pyridinil, Pyridyl, Pyrimidinil, Pyrrolidinil, Pyrrolidinil, 2H-Pyrrolyl, Pyrrolyl, Quinazolinil, Quinolinil, 4H-Quinolidinil, Quino These are xalinyl, quinuclidinyl, tetrahydrofuranil, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, 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 these may be optionally substituted.

[0076] In one aspect, each R 3 These are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0077] In one aspect, each R 3 It is independently -F.

[0078] In one embodiment, X is C(R 4 )2, or O.

[0079] In one embodiment, X is C(R 4 )2. In one embodiment, X is CH2.

[0080] In one embodiment, X is O.

[0081] In one aspect, each R 4 It is independently -H.

[0082] In one aspect, each R 4 Independently, C 1~6 aliphatic, C 3~10 These are aryl rings, 3- to 8-membered saturated or partially unsaturated carbon rings, 3- to 7-membered heterorings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur), or 5- to 6-membered monocyclic heteroaryl rings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of these may be optionally substituted.

[0083] In one aspect, each R 4 These are independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of these may be optionally substituted.

[0084] In one aspect, each R 4These are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanil, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2]bicyclooctanil, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, ku These are romanil, clomenil, cinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinil, dihydroflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indrenyl, indolinil, indolidinil, indolyl, 3H-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naphthilidinil, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, and 1,2,4-oxadiazolyl;-1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinil, Oxazolyl, Oxazolidinil, Pyrimidinil, Phenanthrolinil, Phenanthrolinil, Phenadinil, Phenothiazinil, Phenoxathiinil, Phenoxadinil, Phthalazinil, Piperadinil, Piperidinil, Pteridinil, Prinyl, Pyrazinil, Pyrazolidinil, Pyrazolyl, Pyridazinil, Pyridoxazole, Pyridoimidazole, Pyridhiazole, Pyridinil, Pyridyl, Pyrimidinil, Pyrrolidinil, Pyrrolidinil, 2H-Pyrrolyl, Pyrrolyl, Quinazolinil, Quinolinil, 4H-Quinolidinil, Quino These are xalinyl, quinuclidinyl, tetrahydrofuranil, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, 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 these may be optionally substituted.

[0085] In one aspect, each R 4 These are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0086] In one aspect, each R 4 These are independently -H, C 1~6 The elements are aliphatic, -OR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2; each of these may be optionally substituted.

[0087] In one aspect, each R 4These are independently -H, C 1~6 It is aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted.

[0088] In one aspect, each R 4 Independently, [ka] [ka] [ka] [ka] [ka] [ka] [ka] That is the case.

[0089] In one aspect, each R 4 Independently, [ka] [ka] That is the case.

[0090] In one aspect, each R 5 It is independently -H.

[0091] In one aspect, each R 5 Independently, C 1~6 aliphatic, C 3~10The elements are aryls, 3-8 membered saturated or partially unsaturated carbon rings, 3-7 membered heterorings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur), or 5-6 membered monocyclic heteroaryl rings having 1-4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of these may be optionally substituted.

[0092] In one aspect, each R 5 These are independently methyl, ethyl, ethyl, propyl, i-propyl, butyl, s-butyl, t-butyl, linear or branched pentyl, or linear or branched hexyl; each of these may be optionally substituted.

[0093] In one aspect, each R 5These are independently phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanil, [4.3.0]bicyclononanil, [4.4.0]bicyclodecanil, [2.2.2]bicyclooctanil, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azosinyl, benzimidazolyl, benzofuranil, benzothiofuranil, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, ku These are romanil, clomenil, cinnolinil, decahydroquinolinil, 2H,6H-1,5,2-dithiadinil, dihydroflo[2,3-b]tetrahydrofuran, furanil, flazanil, imidazolidinil, imidazolinil, imidazolyl, 1H-indazolyl, indrenyl, indolinil, indolidinil, indolyl, 3H-indolyl, isoindolinil, isoindorenil, isobenzofuranil, isochromanil, isoindazolyl, isoindolinil, isoindolyl, isoquinolinil, isothiazolyl, isoxazolyl, morpholinil, naphthilidinil, octahydroisoquinolinil, oxadiazolyl, 1,2,3-oxadiazolyl, and 1,2,4-oxadiazolyl;-1,2,5-Oxadiazolyl, 1,3,4-Oxadiazolyl, Oxazolidinil, Oxazolyl, Oxazolidinil, Pyrimidinil, Phenanthrolinil, Phenanthrolinil, Phenadinil, Phenothiazinil, Phenoxathiinil, Phenoxadinil, Phthalazinil, Piperadinil, Piperidinil, Pteridinil, Prinyl, Pyrazinil, Pyrazolidinil, Pyrazolyl, Pyridazinil, Pyridoxazole, Pyridoimidazole, Pyridhiazole, Pyridinil, Pyridyl, Pyrimidinil, Pyrrolidinil, Pyrrolidinil, 2H-Pyrrolyl, Pyrrolyl, Quinazolinil, Quinolinil, 4H-Quinolidinil, Quino These are xalinyl, quinuclidinyl, tetrahydrofuranil, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiadinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, 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 these may be optionally substituted.

[0094] In one aspect, each R 5 These are independently halogen, -haloalkyl, -OR, -SR, -CN, -NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or -N(R)2.

[0095] In one aspect, each R 5 These are independently methyl, cyclopropyl, -F, or -CF3.

[0096] In one aspect, each R 5 Independently [ka] -F or -CF3.

[0097] In one embodiment, r=1. In one embodiment, t=1. In one embodiment, n=0. In one embodiment, p=0. In one embodiment, both n=0 and p=0. In one embodiment, r=1 and t=1. In one embodiment, r=1, t=1, and k=1. In one embodiment, r=1, t=1, k=1, n=0, and p=0.

[0098] In one configuration, X, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 5 Each of k, m, n, p, r, and t is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0099] In one aspect, the present invention relates to formula Ia [ka] The present invention provides a compound represented by or a pharmaceutically acceptable salt thereof, wherein R in the formula 1 , R 4 , R 5 Each of , r, and t is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0100] In one embodiment, R 1 is -Me, -CF3, -OMe, or -CN. In one embodiment, R 1 is -CF3 or -OMe. In one embodiment, R 1 is -CF3. In one embodiment, R 1 It is -OMe.

[0101] In one aspect, each R 4 These are independently -H, C 1~6It is an aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted. In one embodiment, each R 4 is -N(R)². In one embodiment, each R 4 Independently, [ka] In one aspect, each R 4 Independently, [ka] That is the case.

[0102] In one aspect, each R 5 R is independently methyl, -F, or -CF3. In one embodiment, each R 5 It is independently methyl.

[0103] In one embodiment, r=1 and t=1, that is, one substituent R 4 and one substituent R 5 In one embodiment, these single substituents R 4 and R 5 They have a cis-configuration relative to each other, that is, their orientation is [ka] and [ka] is, or [ka] and [ka] It is either one of the following. In some embodiments, their orientation is [ka] and [ka] That is the case.

[0104] In one embodiment, the compound represented by formula Ia is: [ka] A compound represented by ; or a pharmaceutically acceptable salt thereof, where R 1 , R 4 , and R 5 Each of these is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0105] In one embodiment, R 1 is -Me, -CF3, -OMe, or -CN. In one embodiment, R 1 is -CF3 or -OMe. In one embodiment, R 1 is -CF3. In one embodiment, R 1 It is -OMe.

[0106] In one embodiment, R 4 C 1~6 It is an aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted. In one embodiment, R 4 is -N(R)². In one embodiment, R 4 teeth, [ka] In one embodiment, R 4 teeth, [ka] That is the case.

[0107] In one embodiment, R 5is methyl, -F, or -CF3. In one embodiment, R 5 It is methyl.

[0108] In one embodiment, substituent R 4 and R 5 They have a cis-configuration relative to each other, that is, their orientation is [ka] and [ka] is, or [ka] and [ka] It is either one of the following. In some embodiments, their orientation is [ka] and [ka] That is the case.

[0109] In one embodiment, the present invention relates to formula Ib [ka] The present invention provides a compound represented by or a pharmaceutically acceptable salt thereof, wherein R in the formula 1 , R 4 , R 5 Each of , r, and t is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0110] In one embodiment, R 1is -Me, -CF3, -OMe, or -CN. In one embodiment, R 1 It is -OMe.

[0111] In one aspect, each R 4 These are independently -H, C 1~6 It is an aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted. In one embodiment, each R 4 is -N(R)². In one embodiment, each R 4 Independently, [ka] In one aspect, each R 4 Independently, [ka] That is the case.

[0112] In one aspect, each R 5 R is independently methyl, -F, or -CF3. In one embodiment, each R 5 It is independently methyl.

[0113] In one embodiment, r=1 and t=1, that is, one substituent R 4 and one substituent R 5 In one embodiment, these single substituents R 4 and R 5 They have a cis-configuration relative to each other, that is, their orientation is [ka] and [ka] is, or [ka] and [ka] It is either one of the following. In some embodiments, their orientation is [ka] and [ka] That is the case.

[0114] In one embodiment, the compound represented by formula Ib is: [ka] A compound represented by ; or a pharmaceutically acceptable salt thereof, where R 1 , R 4 , and R 5 Each of these is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0115] In one embodiment, R 1 is -Me, -CF3, -OMe, or -CN. In one embodiment, R 1 It is -OMe.

[0116] In one embodiment, R 4 C 1~6 It is an aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted. In one embodiment, R 4 is -N(R)². In one embodiment, R 4 teeth, [ka] In one embodiment, R 4 teeth, [ka] That is the case.

[0117] In one embodiment, R 5 is methyl, -F, or -CF3. In one embodiment, R 5 It is methyl.

[0118] In one embodiment, substituent R 4 and R 5 They have a cis-configuration relative to each other, that is, their orientation is [ka] and [ka] is, or [ka] and [ka] It is either one of the following. In some embodiments, their orientation is [ka] and [ka] That is the case.

[0119] In one embodiment, the present invention relates to formula Ic [ka] The present invention provides a compound represented by or a pharmaceutically acceptable salt thereof, wherein R in the formula 1 , R 4 , R 5 Each of , r, and t is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0120] In one embodiment, R 1 is -Me, -CF3, -OMe, or -CN. In one embodiment, R 1 It is -CN.

[0121] In one aspect, each R 4 These are independently -H, C 1~6 It is an aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted. In one embodiment, each R 4 is -NRC(O)R, or -N(R)2. In one embodiment, each R 4 This is -NRC(O)R.

[0122] In one aspect, each R 4 Independently, [ka] That is the case.

[0123] In one aspect, each R 5 R is independently methyl, -F, or -CF3. In one embodiment, each R 5 It is independently methyl.

[0124] In one embodiment, r=1 and t=1, that is, one substituent R 4 and one substituent R 5 In one embodiment, these single substituents R 4 and R 5 They have a cis-configuration relative to each other, that is, their orientation is [ka] and [ka] is, or [ka] and [ka] It is either one of the following. In some embodiments, their orientation is [ka] and [ka] That is the case.

[0125] In one aspect, a compound represented by formula Ic is a compound represented by formula I-ca: [ka] A compound represented by ; or a pharmaceutically acceptable salt thereof, where R 1 , R 4 , and R 5 Each of these is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0126] In one embodiment, R 1 is -Me, -CF3, -OMe, or -CN. In one embodiment, R 1 It is -CN.

[0127] In one embodiment, R 4 C 1~6 It is an aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted. In one embodiment, R 4 is -NRC(O)R, or -N(R)2. In one embodiment, each R 4 This is -NRC(O)R.

[0128] In one embodiment, R 4 Independently, [ka] That is the case.

[0129] In one embodiment, R 5 is methyl, -F, or -CF3. In one embodiment, R 5 It is methyl.

[0130] In one embodiment, substituent R 4 and R 5 They have a cis-configuration relative to each other, that is, their orientation is [ka] and [ka] is, or [ka] and [ka] It is either one of the following. In some embodiments, their orientation is [ka] and [ka] That is the case.

[0131] In one embodiment, the present invention relates to formula Id [ka] The present invention provides a compound represented by or a pharmaceutically acceptable salt thereof, wherein R in the formula 1 , R 4 , R 5Each of , r, and t is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0132] In one embodiment, R 1 is -Me, -CF3, -OMe, or -CN. In one embodiment, R 1 It is -CN.

[0133] In one aspect, each R 4 These are independently -H, C 1~6 It is an aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted. In one embodiment, each R 4 This is -C(O)N(R)2.

[0134] In one aspect, each R 4 Independently, [ka] That is the case.

[0135] In one aspect, each R 5 R is independently methyl, -F, or -CF3. In one embodiment, each R 5 It is independently methyl.

[0136] In one embodiment, r=1 and t=1, that is, one substituent R 4 and one substituent R 5 In one embodiment, these single substituents R 4 and R 5 They have a cis-configuration relative to each other, that is, their orientation is [ka] and [ka] is, or [ka] and [ka] It is either one of the following. In some embodiments, their orientation is [ka] and [ka] That is the case.

[0137] In one embodiment, a compound represented by formula Id is: [ka] A compound represented by ; or a pharmaceutically acceptable salt thereof, where R 1 , R 4 , and R 5 Each of these is as defined above and is described individually or in combination in the above embodiments, classes, and subclasses of this specification.

[0138] In one embodiment, R 1 is -Me, -CF3, -OMe, or -CN. In one embodiment, R 1 It is -CN.

[0139] In one embodiment, R 4 C 1~6 It is an aliphatic, -C(O)N(R)2, -NRC(O)R, or -N(R)2; each of these may be optionally substituted. In one embodiment, R 4 This is -C(O)N(R)2.

[0140] In one embodiment, R 4 Independently, [ka] That is the case.

[0141] In one embodiment, R 5 is methyl, -F, or -CF3. In one embodiment, R 5 It is methyl.

[0142] In one embodiment, R 4 and R 5 They have a cis-configuration relative to each other, that is, their orientation is [ka] and [ka] is, or [ka] and [ka] It is either one of the following. In some embodiments, their orientation is [ka] and [ka] That is the case.

[0143] In some embodiments, the present invention provides a selection of the compounds depicted above, or a pharmaceutically acceptable salt thereof.

[0144] Various structural descriptions may show heteroatoms without attached groups, radicals, charges, or counterions. Those skilled in the art will notice that such descriptions are intended to indicate that the heteroatom is attached to hydrogen. (For example, [ka] teeth, [ka] (It is understood to be so.)

[0145] In one embodiment, the compounds of the present invention were synthesized according to the scheme provided in the example below.

[0146] 4. Use, formulation, and administration Pharmacologically acceptable compositions In another embodiment, the present invention provides compositions comprising the compound of the present invention or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is such that it is effective in inhibiting TLR7 / 8 or its mutants to a measurable degree in a biological sample or in a patient. In one embodiment, the amount of the compound in the composition of the present invention is such that it is effective in inhibiting TLR7 / 8 or its mutants to a measurable degree in a biological sample or in a patient. In one embodiment, the composition of the present invention is formulated for administration to a patient requiring such a composition.

[0147] When used herein, the terms “patient” or “subject” mean an animal, preferably a mammal, most preferably a human.

[0148] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound formulated with it. The pharmaceutically acceptable carriers, adjuvants, or vehicles 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, buffers such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acid partial glyceride mixtures, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0149] "Pharmacologically acceptable derivatives" means any non-toxic salt, ester, ester salt or other derivative of the compound of the present invention that can directly or indirectly provide the compound of the present invention or its inhibitory active metabolite or residue to a recipient upon administration.

[0150] 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 “parenterally,” as used herein, encompasses subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intracisional, intrathecal, intrahepatic, intrafocal, 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 encompass aqueous or oily suspensions. These suspensions are formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, or as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterilized fixative oil has conventionally been used as a solvent or suspension medium.

[0151] For this purpose, any bland fixed oil employed includes synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, such as naturally pharmaceutically acceptable oils (especially their polyoxyethylated forms), such as olive oil or castor oil. Solutions or suspensions of these oils also contain diluents or dispersants for long-chain alcohols, such as carboxymethylcellulose or similar dispersants (commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions). Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, are also commonly used in the manufacture of pharmaceutically acceptable solids, liquids, or other dosage forms, but are used for formulation purposes.

[0152] The pharmaceutically acceptable compositions of the present invention are administered orally in any orally acceptable dosage form. Exemplary oral dosage forms include capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. Useful diluents for oral administration in capsule form include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweeteners, flavorings, or colorings may also be added.

[0153] Alternatively, the pharmaceutically acceptable compositions of the present invention are administered in the form of suppositories for transrectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature, and will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0154] The pharmaceutically acceptable compositions of the present invention are also administered topically, particularly when the target of a treatment encompassing diseases of the eyes, skin, or lower intestines includes areas or organs that are easily accessible by topical application. Suitable topical formulations are readily prepared for each of these areas or organs.

[0155] Topical application for the lower intestinal tract can be performed with transrectal suppositories (see above) or with suitable enema formulations. Topical transdermal patches are also used.

[0156] The pharmaceutically acceptable compositions provided for topical application are formulated into suitable ointments containing active components suspended or dissolved in one or more carriers. Exemplary carriers for topical administration of the compounds include mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided may be formulated into suitable lotions or creams containing active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0157] The pharmaceutically acceptable compositions of the present invention are optionally administered by nasal aerosol or inhalation. Such compositions are prepared according to well-known techniques in the art of pharmaceutical formulations, and are prepared as a solution in physiological saline, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorinated carbon, and / or other conventional solubilizers or dispersants.

[0158] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0159] The amount of the compound of the present invention, which can be optionally combined with a carrier material to produce a single-dosage-form composition, will vary depending on the host being treated and the specific mode of administration. Preferably, the compositions provided should be formulated so that a dosage of the compound between 0.01 and 100 mg / kg body weight / day can be administered to a patient receiving these compositions.

[0160] 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 activity of the specific compound used, age, weight, overall health, sex, diet, timing of administration, elimination rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0161] Use of compounds and pharmaceutically acceptable compositions The present invention further relates to a method for treating subjects suffering from TLR7 / 8-related disorders, the method comprising administering an effective amount of a compound represented by formula I and related formulas to the subject.

[0162] The compounds of the present invention are useful as anticancer agents for cancers that respond to TLR7 activation. In some embodiments, cancers include, but are not limited to, cancers of the breast, bladder, bone, brain, central and peripheral nervous system, colon, endocrine glands, esophagus, endometrium, germ cells, head and neck, kidney, liver, lung, larynx and hypopharynx, mesothelioma, sarcoma, ovarian, pancreas, prostate, rectum, renal, small intestine, soft tissue, testis, 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 syndromes, plasma cell neoplasms, paraneoplastic syndromes, cancers of unknown primary sites and AIDS-related malignancies.

[0163] In one embodiment, the compounds of the present invention are used to treat cancers of the skin or kidney. The sensitivity of a given cancer to TLR7 activation may be assessed by measuring a reduction (minor, partial, or complete reduction) of primary or metastatic tumor load, altered blood count, altered hormone or cytokine blood concentrations, inhibition of further increase in tumor load, stabilization of the disease in the patient, assessment of disease-related biomarkers or surrogate markers, prolonged overall survival in the patient, prolonged time to disease progression in the patient, prolonged survival without progression in the patient, prolonged disease-free survival in the patient, improved quality of life in the patient, or modulation of disease comorbidities (e.g., pain, cachexia, mobilization, hospitalization, altered blood count, weight loss, wound healing, fever).

[0164] The compounds according to the present invention may also be useful as immune response modifiers that can modulate immune responses from numerous different angles (making them useful in treating various disorders).

[0165] Provided herein are methods for inhibiting an individual's immune response, comprising administering an effective amount of a TLR7 and / or TLR8 inhibitor (e.g., TLR inhibitor) to the individual using the compounds described herein. In some variations, the TLR inhibitor inhibits a TLR7-dependent immune response. In some variations, the TLR inhibitor inhibits a TLR8-dependent immune response. In some variations, the TLR inhibitor inhibits both TLR7-dependent and TLR8-dependent immune responses. In some variations, the TLR inhibitor inhibits TLR7-dependent, TLR8-dependent, and other TLR-dependent immune responses. Unless otherwise noted, the term TLR inhibitor refers to any one of the TLR inhibitors disclosed herein. In some preferred embodiments, the individual is a human patient.

[0166] Methods of immunomodulation provided herein include suppressing and / or inhibiting immune responses, which include but are not limited to immune responses. The disclosure also provides methods for restoring conditions associated with unwanted immune activation, which include but are not limited to conditions associated with autoimmunity. Immunosuppression and / or inhibition by the methods herein may be practiced on individuals, including individuals suffering from disorders associated with unwanted activation of immune responses. The disclosure also provides methods for inhibiting responses induced by TLR7 and / or TLR8 (e.g., in vitro or in vivo). In some variations, cells are exposed to a TLR inhibitor in an amount effective in inhibiting the response from cells contributing to the immune response.

[0167] Inhibition of TLR7 and / or TLR8 is useful for treating and / or preventing a variety of cytokine-responsive diseases or disorders. Conditions for which TLR7 and / or TLR8 inhibitors may be used as treatment include, but are not limited to, autoimmune diseases and inflammatory disorders. Provided herein are methods for treating or preventing a disease or disorder in an individual, comprising administering an effective amount of a TLR7 and / or TLR8 inhibitor to the individual. Also provided are methods for restoring symptoms associated with a disease or disorder, comprising administering an effective amount of a TLR7 and / or TLR8 inhibitor to an individual having a disease or disorder. Methods for preventing or delaying the onset of a disease or disorder are also provided herein, the methods comprising administering an effective amount of one or more inhibitors from TLR7 and / or TLR8 to an individual having a disease or disorder. In some embodiments, the inhibitor is a compound as described herein.

[0168] Provided herein are methods for inhibiting an immune response in an individual, the methods comprising administering to the individual at least one TLR inhibitor as disclosed herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is associated with autoimmune diseases. In a further aspect, inhibiting the immune response herein restores one or more symptoms of an autoimmune disease. In yet another aspect, inhibiting the immune response herein treats an autoimmune disease. In yet another aspect, inhibiting the immune response herein prevents or delays the onset of an autoimmune disease. In some variations, the TLR inhibitor inhibits a TLR7-dependent immune response. In some variations, TLR inhibitors inhibit TLR8-dependent immune responses. In some variations, TLR inhibitors inhibit both TLR7-dependent and TLR8-dependent immune responses. In some aspects, at least one type of TLR inhibitor is administered in a dose effective to inhibit the immune response in an individual.

[0169] Also provided herein are methods for treating or preventing autoimmune diseases in an individual, which include administering an effective amount of TLR7 and / or TLR8 inhibitors to the individual. In some aspects, autoimmune diseases are characterized by arthralgia, positive antinuclear antibodies, cheek rash, or discoid rash. In some aspects, autoimmune diseases are related to the skin, muscle tissue, and / or connective tissue. In some embodiments, autoimmune diseases are not apparent in the individual from symptoms of the skin, muscle tissue, and / or connective tissue. In some embodiments, autoimmune diseases are systemic. Autoimmune diseases include, but are not limited to, rheumatoid arthritis (RA), autoimmune pancreatitis (AIP), systemic lupus erythematosus (SLE), type 1 diabetes mellitus, multiple sclerosis (MS), antiphospholipid syndrome (APS), sclerosing cholangitis, systemic onset arthritis, irritable bowel disease (IBD), scleroderma, Sjögren's disease, vitiligo, polymyositis, inflammatory bowel diseases including pemphigus vulgaris, pemphigus foliaceus, Crohn's disease and ulcerative colitis, autoimmune hepatitis, hypopituitarism, graft-versus-host disease (GvHD), autoimmune skin diseases, uveitis, pernicious anemia, and hypoparathyroidism. Autoimmune diseases may also include, but are not limited to, polyangiitis duplication syndrome, Kawasaki disease, sarcoidosis, glomerulonephritis, and cold sensitivity.

[0170] In some respects, autoimmune diseases are selected from a group consisting of arthritis, pancreatitis, mixed connective tissue disease (MCTD), lupus, antiphospholipid syndrome (APS), systemic arthritis, and irritable bowel syndrome.

[0171] In other respects, autoimmune diseases are selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune skin diseases, and multiple sclerosis.

[0172] In other aspects, autoimmune diseases are selected from the group consisting of pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type 1 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 pyelonephritis. 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-like disease or disorder. In some aspects, the rheumatoid-like disease or disorder is rheumatoid arthritis. In some aspects, the disease is diabetes and / or diabetes-related disease or disorder. In some aspects, here the autoimmune disease is related to RNA-containing immune complexes. In some aspects, the autoimmune disease is Sjögren's disease.

[0173] Provided herein are methods for inhibiting an immune response in an individual, the methods comprising administering to the individual at least one TLR inhibitor as disclosed herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is related to an inflammatory disorder. As used herein, the term “inflammatory disorder” encompasses inflammatory conditions without known autoimmune components (e.g., atherosclerosis, asthma, etc.). In a further aspect, inhibiting an immune response restores one or more symptoms of an inflammatory disorder. In yet another aspect, inhibiting an immune response treats an inflammatory disorder. In yet another aspect, inhibiting an immune response prevents or delays the onset of an inflammatory disorder. In some aspects, the inflammatory disorder is selected from the group consisting of non-rheumatoid arthritis, renal fibrosis, and hepatic fibrosis. In some aspects, the inflammatory disorder is interfacial dermatitis. In some further aspects, interfacial dermatitis is selected from the group consisting of lichen planus, lichenoid rash, lichenoid keratosis, linear lichen, chronic lichenoid keratosis, erythema multiforme, fixed drug eruption, pityriasis lichenoid, phototoxic dermatitis, radiodermatitis, viral exanthema, dermatomyositis, secondary syphilis, sclerosing atrophic lichen, mycosis fungoides, bullous pemphigoid, lichen yellow, porokeratosis, chronic atrophic acrodermatitis, and regressing melanoma. In some aspects, inflammatory conditions are skin disorders such as atopic dermatitis (eczema). In some aspects, inflammatory disorders are sterile inflammatory conditions such as drug-induced inflammation of the liver and / or pancreas. In some further aspects, inflammatory diseases are inflammatory liver disorders. In some other further aspects, inflammatory diseases are inflammatory pancreatic disorders.

[0174] Provided herein are methods for inhibiting an immune response in an individual, the methods comprising administering to the individual at least one TLR inhibitor as disclosed herein in an amount effective to inhibit the immune response in the individual. In some variations, the immune response is related to chronic pathogen stimulation. In some variations, the immune response is related to HIV infection. In a further aspect, inhibiting the immune response herein restores one or more symptoms of a viral disease or disorder resulting from HIV infection. In yet another aspect, inhibiting the immune response herein treats a viral disease or disorder resulting from HIV infection. In yet another aspect, inhibiting the immune response herein prevents or delays the onset of a viral disease or disorder resulting from HIV infection. Other variations provided herein relate to immunosuppressive treatment of individuals 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 several respects, at least one TLR inhibitor is administered in an effective dose to suppress HIV-induced cytokine production in individuals exposed to or infected with HIV.

[0175] Provided herein are methods for inhibiting a TLR7 and / or TLR8-dependent immune response in an individual, the method comprising administering a TLR inhibitor to the individual in an amount effective in inhibiting the immune response in the individual. In some variations, the immune response is associated with an autoimmune disease. In some aspects, the autoimmune disease is rheumatoid arthritis. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of rheumatoid arthritis. In some aspects, the autoimmune disease is multiple sclerosis. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of multiple sclerosis. In some aspects, the autoimmune disease is lupus. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of lupus. In some aspects, the autoimmune disease is pancreatitis. In some aspects, the TLR inhibitor is effective in suppressing one or more symptoms of pancreatitis. In some aspects, the autoimmune disease is diabetes mellitus. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of diabetes. In some aspects, the disease is Sjögren's disease. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of Sjögren's disease. In some variations, the immune response is associated with inflammatory disorders. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of inflammatory disorders. In some variations, the immune response is associated with chronic pathogen stimulation. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of chronic pathogen stimulation. In some variations, the immune response is associated with viral diseases resulting from HIV infection. In some aspects, TLR inhibitors are effective in suppressing one or more symptoms of viral diseases resulting from HIV infection. In any variation, the TLR inhibitor is a polynucleotide containing inhibitory motifs for one or more of TLR7, TLR8, and TLR9.

[0176] In some aspects of any method involving the administration of a TLR inhibitor to an individual (e.g., methods to inhibit an immune response, treat or prevent an autoimmune disease or inflammatory disorder), the TLR inhibitor has a therapeutically acceptable safety profile. The TLR inhibitor has a therapeutically acceptable histological profile that includes, for example, a tolerably low level of toxicity (if any) to the liver, kidneys, pancreas, or other organs. Occasionally, polynucleotides are associated with toxicity to certain organs, such as the liver, kidneys, and pancreas. In some aspects, the TLR inhibitor has an unexpected and advantageous safety profile. In some aspects, the safety profile includes an assessment of toxicity, histological profile, and / or necrosis (e.g., liver, kidneys, and / or heart). In some aspects, the TLR inhibitor has a therapeutically acceptable level of toxicity. In some aspects, the TLR inhibitor has a reduced level of toxicity compared to other TLR inhibitors. In some aspects, the TLR inhibitor induces a therapeutically acceptable reduction in body weight compared to the initial body weight of the treated individual. In some embodiments, the TLR inhibitor induces a reduction of less than 5%, 7.5%, 10%, 12.5%, or 15% in total body weight. In some embodiments, the TLR inhibitor has a therapeutically acceptable histological profile. In some embodiments, the TLR inhibitor has a better histological profile (e.g., a lower severity score) compared to, for example, a reference TLR inhibitor. In some embodiments, the TLR inhibitor has a better histological profile (e.g., a lower severity score) when, for example, evaluating the liver, kidneys, and / or heart. In some embodiments, the TLR inhibitor has a therapeutically acceptable necrosis score. In some embodiments, the TLR inhibitor has reduced necrosis and / or a better (e.g., a lower) necrosis score compared to, for example, a reference TLR inhibitor.In some embodiments, the TLR inhibitor has, for example, a reduced renal and / or hepatocyte necrosis score and / or a better renal and / or hepatocyte necrosis score compared to a reference TLR inhibitor.

[0177] In some embodiments, certain TLR inhibitors of the present invention are non-cerebral permeable compounds. These TLR inhibitors may be useful for the prevention and / or treatment of disorders or diseases in patients where penetration of the blood-brain barrier (BBB) ​​by a TLR inhibitor is not necessarily required or beneficial, or where BBB penetration is undesirable.

[0178] Consequently, the present invention provides a method for activating TLR7 in animals, particularly mammals, preferably humans, the method comprising administering an effective amount of a compound represented by formula I to the animal. As with all compositions for inhibiting immune responses, the effective amount of a specific TLR inhibitor formulation and the method of administration may vary based on the individual, the condition being treated, and other factors that are apparent to those skilled in the art. The effective amount of the compound will vary according to factors known in the art, but is expected to be in doses of 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.

[0179] The present invention also provides a method for treating viral infections in animals, comprising administering an effective amount of a compound represented by formula I to the animals. An effective amount for treating or inhibiting a viral infection is an amount that would cause a reduction of one or more of the signs of viral infection, such as viral lesions, viral load, viral production rate, and mortality, compared to an untreated control animal. The exact amount will vary according to factors known in the art, but is expected to be the dose indicated above with respect to TLR7 activation, or a dose of about 100 ng / kg to about 50 mg / kg, preferably about 10 μg / kg to about 5 mg / kg.

[0180] In various embodiments, compounds represented by formula (I) and related formulas are used for ICs to bind to TLR7 / 8 in concentrations of less than approximately 5 μM, preferably less than approximately 1 μM, and more preferably less than approximately 0.100 μM. 50 It exhibits the following characteristics.

[0181] The method of the present invention may be carried out either in vitro or in vivo. The sensitivity of specific cells to treatment with the compounds according to the present invention may be specifically determined by in vitro testing, whether in a research process or in clinical application. Typically, a culture of the cell is combined with the compounds according to the present invention at various concentrations for a period of time sufficient for the activator to inhibit TLR7 / 8 activity, usually about 1 hour to 1 week. In vitro treatment may be performed using biopsy samples or cultured cells from cell lines.

[0182] The host or patient may belong to any mammalian species, such as primates, specifically humans; rodents, including mice, rats, and hamsters; rabbits; horses, cattle, dogs, cats, etc. Animal models are the subject of experimental investigations and provide models for the treatment of human diseases.

[0183] To identify signaling pathways and detect interactions between various signaling pathways, scientists have developed suitable models or model systems, such as cell culture models and transgenic animal models. To determine a particular stage in a signaling cascade, interacting compounds can be used to modulate the signal. The compounds according to the present invention may also be used as reagents for testing TLR7 / 8-dependent signaling pathways in animal and / or cell culture models or in clinical diseases referred to in this application.

[0184] Furthermore, the following teachings herein regarding the use of compounds and derivatives of formula (I) for the production of pharmaceuticals for prophylactic or therapeutic treatment and / or monitoring are considered valid and applicable without limitation to the use of compounds for inhibition of TLR7 / 8 activity.

[0185] The present invention also relates to the use of compounds according to formula (I) and / or physiologically acceptable salts thereof for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or transmitted by TLR7 / 8 activity. Furthermore, the present invention relates to the use of compounds according to formula (I) and / or physiologically acceptable salts thereof for the production of pharmaceuticals for the prophylactic or therapeutic treatment and / or monitoring of diseases caused, mediated, and / or transmitted by TLR7 / 8 activity. In one embodiment, the present invention provides the use of compounds according to formula I or physiologically acceptable salts thereof for the production of pharmaceuticals for the prophylactic or therapeutic treatment of TLR7 / 8-mediated disorders.

[0186] The compound represented by formula (I) and / or physiologically acceptable salts thereof may also be used as intermediates for the preparation of further pharmaceutically active ingredients. The pharmaceuticals are preferably prepared in a non-chemical manner, for example, by combining the active ingredient with at least one solid, fluid, and / or semi-fluid carrier or excipient, optionally with one or more other active substances in a suitable dosage form.

[0187] Compounds represented by formula (I) according to the present invention may act therapeutically when administered once or several times before or after the onset of a disease. The aforementioned compounds and pharmaceuticals of use relating to the present invention are used specifically for therapeutic treatment. The therapeutically relevant effects include alleviating one or more symptoms of a disorder to some extent, or partially or completely restoring one or more physiological or biochemical parameters associated with or causing a disease or pathological condition to normal. Monitoring can be considered a type of treatment, for example, to boost the response and completely eliminate the pathogen and / or symptoms of the disease, provided that the compound is administered at distinguishable intervals. Either the same compound or different compounds may be applied. The methods of the present invention may also be used to reduce the likelihood of developing a disorder, or even to prevent the onset of a disorder related to TLR7 / 8 activity, or to treat the symptoms that have occurred and persist.

[0188] In the sense of the present invention, preventive measures are advisable if the subject has any of the aforementioned prerequisites for a physiological or pathological condition, such as a familial disposition, a genetic defect, or a pre-existing disease.

[0189] The present invention further relates to pharmaceuticals comprising (including mixtures thereof in any proportion) at least one compound according to the present invention and / or pharmaceutically usable derivatives, salts, solvates and stereoisomers thereof. In one embodiment, the present invention relates to pharmaceuticals comprising at least one compound according to the present invention and / or a physiologically acceptable salt thereof.

[0190] In the sense of the present invention, “pharmaceutical” means any agent in the medical field that comprises one or more compounds represented by formula (I) or preparations thereof (e.g., pharmaceutical compositions or pharmaceutical formulations) and can be used in the prevention, treatment, monitoring or aftercare of patients suffering from diseases associated with TLR7 / 8 activity, such that a pathogenic modification of their systemic condition or the condition of a specific region of their organism can only become established at least temporarily.

[0191] In various embodiments, the active ingredient may be administered alone or in combination with other treatments. Synergistic effects may be achieved by using one or more compounds in the pharmaceutical composition, i.e., the compound represented by formula (I) is combined with at least one other agent as the active ingredient (either another compound represented by formula (I) or a compound with a different structural framework). The active ingredients may be used simultaneously or sequentially.

[0192] The TLR inhibitors of this disclosure may be administered in combination with one or more additional therapeutic agents. As described herein, the TLR inhibitors may be combined with physiologically acceptable carriers. The methods described herein may be practiced in combination with other therapies that complement standard therapy for the disorder, such as the administration of anti-inflammatory agents.

[0193] In some embodiments, the TLR inhibitor described herein is administered in combination with a corticosteroid. In some embodiments, the corticosteroid is a glucocorticosteroid. In some embodiments, the corticosteroid is a mineralocorticoid. Corticosteroids include corticosterone and derivatives, their prodrugs, isomers and analogs; cortisone and derivatives, their prodrugs, isomers and analogs (i.e., Cortone); aldosterone and derivatives, their prodrugs, isomers and analogs; dexamethasone and derivatives, their prodrugs, isomers and analogs (i.e., Decadron); prednisone and derivatives, their prodrugs, isomers and analogs (i.e., Prelone); fludrocortisone and derivatives, their prodrugs, isomers and analogs; hydrocortisone and derivatives, their prodrugs, isomers and analogs (i.e., cortisol or Cortef); hydroxycortisone and derivatives, their prodrugs, isomers and analogs; betamethasone and derivatives, their prodrugs, isomers and analogs (i.e., Celestone); budesonide and derivatives, their prodrugs, isomers and analogs (i.e., Entocort This includes, but is not limited to, fludrocortisone (EC), methylprednisolone and its derivatives, their prodrugs, isomers and analogs (i.e., Medrol), prednisolone and its derivatives, their prodrugs, isomers and analogs (i.e., Deltasone, Crtan, Meticorten, Orasone, or Sterapred), triamcinolone and its derivatives, their prodrugs, isomers and analogs (i.e., Kenacort or Kenalog), etc. In some embodiments, the corticosteroid is fludrocortisone or its derivatives, its prodrugs, isomers or analogs. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the corticosteroid is hydroxycortisone or its derivatives, its prodrugs, isomers or analogs. In some embodiments, the corticosteroid is hydroxycortisone.

[0194] In some embodiments, corticosteroids are administered in doses between approximately 0.001 mg and 1 mg, 0.5 mg and 1 mg, 1 mg and 2 mg, 2 mg and 20 mg, 20 mg and 40 mg, 40 mg and 80 mg, 80 mg and 120 mg, 120 mg and 200 mg, 200 mg and 500 mg, or 500 mg and 1000 mg per day. In some embodiments, corticosteroids are administered in doses between approximately 0.1 mg / kg and 0.5 mg / kg, 0.5 mg / kg and 1 mg / kg, 1 mg / kg and 2 mg / kg, 2 mg / kg and 5 mg / kg, 5 mg / kg and 10 mg / kg, 10 mg / kg and 15 mg / kg, 15 mg / kg and 20 mg / kg, 20 mg / kg and 25 mg / kg, 25 mg / kg and 35 mg / kg, or 35 mg / kg and 50 mg / kg per day.

[0195] In some embodiments, the TLR inhibitor used in combination therapy is provided in the amount of TLR inhibitor delivered, which may be, for example, 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.

[0196] In some embodiments, the TLR inhibitor is administered concurrently with one or more additional therapeutic agents, including but not limited to corticosteroids (concurrent administration). In some embodiments, the TLR inhibitor is administered sequentially with one or more additional therapeutic agents, including but not limited to corticosteroids (sequential administration). In some embodiments, sequential administration involves administering the TLR inhibitor or additional therapeutic agent consecutively for one minute, five minutes, 30 minutes, one hour, five hours, 24 hours, 48 ​​hours, or within one week. In some embodiments, the TLR inhibitor is administered via the same route of administration as the additional therapeutic agent. In some embodiments, the TLR inhibitor is administered via a different route of administration than the additional therapeutic agent. In some embodiments, the additional therapeutic agent is administered parenterally (e.g., by central venous line, intra-arterial, intra-venous, intramuscular, intraperitoneal, intradermal, or subcutaneous injection), orally, gastrointestinal, topically, nasopharyngetally, and transpulmonaryly (e.g., by inhalation or intranasal). In some embodiments, the additional therapeutic agent is a corticosteroid.

[0197] The compounds of the disclosure represented by Formula I may be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term “anticancer agent” refers to any agent administered to a patient with cancer for the purpose of treating cancer.

[0198] The anticancer treatments defined above may be applied as monotherapy or in combination with conventional surgery, radiotherapy, or medicinal therapy in addition to the compound represented by Formula I disclosed herein. Such medicinal therapy (e.g., chemotherapy or targeted therapy) includes one or more of the following antitumor agents, preferably one of them: Alkylating agent:Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Chlormetine, Cyclophosphamide, Dacarbazine, Ifosfamide, Improsulfan, Tosilate, Lomustine, Melphalan, Mitobronitol, Mitractol, Nimustine, Ranimustine, Temozolomide, Thiotepa, Treosulfan, Mechloretamine, Carbocon; Apadicon, Fotemustine, Gluphosphamide, Paliphosphamide, Pipobroman, Trophosphamide, Uramustine, TH-302 4 VAL-083 4 etc; Platinum compounds: Carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lovaplatin, nedaplatin, picoplatin, satraplatin; lovaplatin, nedaplatin, picoplatin, satraplatin, etc. DNA modifiers: Amrubicin, Bisanthren, Decitabine, Mitoxantrone, Procarbazine, Trabectedin, Clofarabine; Amsacrin, Brostaricin, Pixantrone, Laromustine 1,3 etc; Topoisomerase inhibitor: Etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, berotecan, eriptinium acetate, boreroxine, etc. Microtubule modifier: Cabazitaxel, docetaxel, eribulin, ixabepirone, paclitaxel, vinplastin, vincristine, vinorelbine, vindesine, vinflunin; phospretabrine, tesetaxel, etc. Antimetabolites: Asparaginase 3 Azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, phloxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxyfluridine, ellacitabine, larcitrexed, cepacitabine, tegafur2,3 , trimethotrexate, etc. Anti-cancer antibiotics: Bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, rebamisol, miltefosine, mitomycin C, romidepsin, stereptozosin, barurubicin, dinostatin, zorubicin, daunorubicin, plicamycin; acralubicin, peplomycin, pirarubicin, etc. Hormones / Antagonists: Abarelix, abiraterone, bicalutamide, buserelin, carsterone, chlorotonianicene, degarelix, dexamethasone, estradiol, flutocortrone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megesterol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, triptorelin, diethylstilbestrol; acorbifen, danazol, deslorerin, epithiostanol, orteronel, enzalutamide 1,3 etc; Aromatase inhibitors: Aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestan, etc. Small molecule kinase inhibitors: Crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, ariseltib, dabrafenib, dacomitinib, dinaciclib, dovitinib, e Nzastaurin, Nintedanib, Lenvatinib, Linifanib, Lincitinib, Masitinib, Midostaurin, Motesanib, Neratinib, Orantinib, Perifosin, Ponatinib, Radotinib, Rigosatib, Tipifanib, Tivantinib, Tivozanib, Trametinib, Pimasertib, Brivanib, Alaninate, Cejilanib, Apatinib 4 Cabozantinib S-Marat 1,3 ibrutinib 1,3 , icotinib4 , Buparlisib 2 , cipatinib 4 Cobimetinib 1,3 , Ideralicib 1,3 , Fedratinib 1 XL-647 4 etc; Photosensitizer: Methoxsalen 3 ;Polyphymer sodium, talaporfin, temoporfin, etc.; antibody: Alemtuzumab, becilesomab, brentuximab, vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab 2,3 Katsumakisomab, elotuzumab, epratuzumab, faretuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, okalatuzumab, olegobomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zaltumumab, zanorimumab, matsuzumab, dalotuzumab 1,2,3 Onartuzumab 1,3 , racotumomab 1 Tabalumab 1,3 EMD-525797 4 nivolumab 1,3 etc; Cytokine: Aldesleukin, Interferon Alpha 2 Interferon alpha-2a 3 Interferon alpha-2b 2,3 ; Selmoleukin, Tasonelmin, Teseloukin, Operelbekin 1,3 Recombinant interferon beta-1a 4 etc; Drug conjugates:Deniloquin difutitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; syntredequin besudotox, edtreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technitium (99mTc) alsitumomab 1,3 , vintafolide 1,3 etc; vaccine: Siplücel 3 Vitespen 3 Emepepimto-S 3 OncoVAX 4 Lindpepim 3 troVax 4 MGN-1601 4 MGN-1703 4 etc; and others: Alitretinoin, Bexarotene, Bortezomib, Everolimus, Ibandronate, Imiquimod, Lenalidomide, Lentinan, Methylosine, Mifamlutide, Pamidronic Acid, Pegaspargase, Pentostatin, Cyprucel 3 Schizophyllan, Tamibarotene, Temsirolimus, Thalidomide, Tretinoin, Bismodegib, Zoledronic acid, Vorinostat; Celecoxib, Silenditide, Entinostat, Etanidazole, Ganetespib, Idronoxyl, Iniparib, Ixazomib, Ronidamine, Nimorazole, Parabinostat, Pelletinoin, Pritidepsin, Pomalidomide, Procodazole, Ridaforolimus, Tascinimod, Terotristat, Simalfasin, Tirapazamin, Tosedostat, Travedersen, Ubenimex, Valspodar, Gendicin 4 Picibanil 4 , Leolysine 4 Letaspimycin hydrochloride 1,3 Trevananib 2,3 bilirudin 4 , Carfilzomib 1,3 Endostatin 4immucothel 4 , Bellinostat 3 MGN-1703 4 . ( 1 Prop. INN (Proposed International Common Name); 2 Rec. INN (Recommended International Common Name); 3 USAN (United States Common Name); 4 (No INN)

[0199] In some embodiments, a combination of a TLR inhibitor and one or more additional therapeutic agents reduces the effective dose of the TLR inhibitor and / or one or more additional therapeutic agents administered to achieve the same result (including, but not limited to, dose volume, dose concentration, and / or total drug dose) compared to the effective dose administered when the TLR inhibitor or the additional therapeutic agent is administered alone. In some embodiments, a combination of a TLR inhibitor and a corticosteroid reduces the effective dose of the corticosteroid administered compared to the corticosteroid administered alone. In some embodiments, a combination of a TLR inhibitor and an additional therapeutic agent reduces the frequency of therapeutic agent administration compared to the additional therapeutic agent administered alone. In some embodiments, a combination of a TLR inhibitor and an additional therapeutic agent reduces the total duration of treatment compared to the additional therapeutic agent administered alone. In some embodiments, a combination of a TLR inhibitor and an additional therapeutic agent reduces the side effects associated with the additional therapeutic agent administered alone. In some embodiments, the additional therapeutic agent is a corticosteroid. In some embodiments, the corticosteroid is fludrocortisone or a derivative, its prodrug, isomer, or analog. In some embodiments, the corticosteroid is fludrocortisone. In some embodiments, the combination of an effective amount of TLR inhibitor and the additional therapeutic agent is more efficient than the effective amount of TLR inhibitor or the additional therapeutic agent alone.

[0200] TLR inhibitors may also be useful as vaccine adjuvants for use in conjunction with any material that modulates either humoral and / or cell-mediated immune responses (e.g., live viral, bacterial, or parasitic immunogens; inactivated viral, tumor-derived, protozoan, organism-derived, fungal, or bacterial immunogens, toxoids, toxins; autoantigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides; etc.). In some aspects, combination therapies, including but not limited to combinations of TLR inhibitors and vaccines, are used in the treatment of autoimmune diseases or inflammatory disorders. In some aspects, combination therapies, including but not limited to combinations of TLR inhibitors and vaccines, are used in the treatment of infectious diseases.

[0201] In some embodiments, combination therapies, including but not limited to combinations of TLR inhibitors and corticosteroids, are used in the treatment of autoimmune diseases or inflammatory disorders. In some embodiments, the autoimmune disease is selected from, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, autoimmune skin diseases, multiple sclerosis, pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type 1 diabetes. In some embodiments, the autoimmune disease is Sjögren's disease.

[0202] Also provided herein are TLR inhibitors as provided herein, and kits including instructions for their use in methods of inhibiting TLR7 and / or TLR8-dependent immune responses.

[0203] The kit may include one or more containers containing a TLR inhibitor (or a formulation containing a TLR inhibitor) as described herein, and a set of instructions, generally written instructions. However, an electronic storage medium (e.g., a magnetic diskette or optical disk) containing instructions regarding the use and dosage of the TLR inhibitor or formulation for the intended treatment (e.g., suppression of the response to a TLR7 and / or TLR8 agonist, suppression of a TLR7 and / or TLR8-dependent immune response, reversal of one or more symptoms of an autoimmune disease, reversal of symptoms of a chronic inflammatory disease, reduction of cytokine production in the response to a virus, and / or treatment and / or prevention of one or more symptoms of a disease or disorder mediated by TLR7 and / or TLR8) is also acceptable. The instructions included in the kit generally include information about the dosage, administration schedule, and route of administration for the intended treatment. The containers for TLR inhibitors (or formulations containing TLR inhibitors) may be unit doses, bulk packages (e.g., multi-dose packages), or sub-unit doses. The kit may further include a container for the adjuvant.

[0204] In another aspect, the present invention provides a kit comprising an effective amount of the compounds according to the present invention and / or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof (including mixtures thereof in any ratio), and optionally, a separate pack of an effective amount of further active ingredients. The kit includes a suitable container such as a box, individual bottles, bags or ampoules. The kit may include, for example, separate ampoules, each containing an effective amount of the compounds according to the present invention and / or their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers (including mixtures thereof in any ratio), and optionally, an effective amount of further active ingredients, in soluble or lyophilized form.

[0205] As used herein, the terms “treatment,” “to treat,” and “to treat” mean reversing, mitigating, delaying, or inhibiting the progression of a disease or disorder, or one or more of its symptoms, as described herein. In some embodiments, treatment is administered after the onset of one or more symptoms. In other embodiments, treatment is administered when there are no symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of the patient’s medical history and / or genetic or other susceptibility factors). Treatment may also be continued after the symptoms have subsided, for example, to prevent or delay their recurrence.

[0206] The compounds and compositions, according to the methods of the present invention, are administered using any amount and route of administration that is effective in treating or reducing the severity of the disorders described above. The exact amount required will vary depending on the subject, depending on the species, age, and overall condition of the subject, the severity of the infection, the specific agent, the mode of administration, etc. The compounds of the present invention are preferably formulated in dose unit form for ease of administration and uniformity of dosage. As used herein, the expression “dose unit form” refers to a physically individual unit of the agent appropriate for the patient to be treated. However, it will be understood that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician within reasonable medical judgment. The specific dose level effective for any particular patient or organism will depend on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound being employed; the specific compound being employed; the patient's age, weight, overall health, sex, and diet; the timing of administration, route of administration, and elimination rate of the specific compound being employed; the duration of treatment; any drugs used in combination with or concurrently with the specific compound being employed; and similar factors well known in medicine.

[0207] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisterna magna, intravaginally, intraperitoneally, topically (as powder, ointment, or drops), orally, depending on the severity of the infection being treated, as an oral spray or nasal spray or the like. In some embodiments, the compounds of the present invention are administered orally or parenterally once or twice a day at dosage levels ranging from about 0.01 mg / kg body weight (of the subject) to about 100 mg / kg per day, preferably from about 1 mg / kg body weight (of the subject) to about 50 mg / kg per day, in order to obtain the desired therapeutic effect.

[0208] In one embodiment, the therapeutically effective amount of the compound represented by formula (I) and related formulas, as well as the amount of other active ingredients, depends on a number of factors, including, for example, the age and weight of the animal, the exact disease state and its severity requiring treatment, the nature of the formulation, and the method of administration, and is ultimately determined by the physician or veterinarian administering the treatment. However, the effective amount of the compound generally ranges from 0.1 to 100 mg / kg body weight per day (of the recipient (mammal)), and specifically typically ranges from 1 to 10 mg / kg body weight per day. Thus, the practical daily dose for an adult mammal weighing 70 kg is usually between 70 mg and 700 mg, where this amount can be administered as individual daily doses or, usually, as partial daily doses of a formula (e.g., 2, 3, 4, 5, 6, etc.) so that the total daily dose is the same. The effective amount of the salt or solvate or the effective amount of its physiologically functional derivative can be determined as the effective amount of the compound itself.

[0209] In one embodiment, the pharmaceutical formulation may be administered in the form of dosage units containing a predetermined amount of the active ingredient per dosage unit. Depending on the state of the disease being treated, the method of administration, and the patient's age, weight, and condition, such units may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, specifically preferably 5 mg to 100 mg of the compound according to the present invention, or the pharmaceutical formulation may be administered in the form of dosage units containing a predetermined amount of the active ingredient per dosage unit. Preferred dosage unit formulations are those containing the daily dose or partial dose or the corresponding fraction of the active ingredient as indicated above. Furthermore, this type of pharmaceutical formulation may be prepared using processes commonly known in the pharmaceutical field.

[0210] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may optionally contain, for example, inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoic acid, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral composition also includes adjuvants such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and colorants.

[0211] Injectable preparations, such as sterile injectable aqueous or oily suspensions, are formulated according to known techniques (art) using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations are also sterile injectable solutions, suspensions or emulsions in non-toxic, parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, USP, and isotonic sodium chloride solutions. In addition, sterile fixatives have conventionally been employed as solvents or suspension media. Any harmless fixatives that may be employed for this purpose include synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in injectable preparations.

[0212] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0213] To extend the effects of the compounds of the present invention, it is often desirable to delay the absorption of the compounds from subcutaneous or intramuscular injection. This is achieved by using liquid suspensions of poorly soluble crystalline or amorphous materials. The absorption rate of the compound then depends on its dissolution rate, which may also depend on the crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound forms can also be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot formulations are made by forming a microencapsulation matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the compound-to-polymer ratio and the properties of the specific polymer employed, the compound release rate can be controlled. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with biological tissues.

[0214] The compositions for transrectal or vaginal administration are preferably suppositories that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier (such as cocoa butter or polyethylene glycol), or a suppository wax that is solid at ambient temperature but liquid at body temperature, and melts in the rectum or vaginal cavity to release the active compound.

[0215] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is at least one pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginic acid, gelatin, polyvinylpyrrolidinone, sucrose, and acacia gum, c) water-retaining agents such as glycerol, d) agar, calcium carbonate, potato or tapioca starch, alginic acid, The dosage form may also optionally include a buffer, in the case of capsules, tablets, and pills.

[0216] Similar types of solid compositions are also used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or lactose and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical technology field. They may optionally contain opacifying agents and may also be compositions that release only or preferentially the active ingredient(s) in a delayed manner in a portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and polymeric waxes. Similar types of solid compositions are also used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or lactose and high molecular weight polyethylene glycol.

[0217] The active compound may also be in microencapsulated form with one or more excipients as noted above. Solid dosage forms of tablets, sugar-coated tablets, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical technology. In such solid dosage forms, the active compound may be miscible with at least one inert diluent such as sucrose, lactose, or starch. Conventional dosage forms also include additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form also optionally includes a buffer. They may optionally contain opacifiers and may be compositions that release only the active ingredient(s) or preferentially the active ingredient(s) in a delayed manner in a portion of the intestinal tract. Examples of embedding compositions that may be used include polymeric substances and polymeric waxes.

[0218] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active components are mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservative or required buffer. Ophthalmic formulations, ear drops, and eye drops are also intended to be within the scope of the present invention. In addition, the present invention intends to use transdermal patches, which have the additional advantage of providing controlled delivery of the compounds to the body. Such dosage forms can be made by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flow of the compounds across the skin. The rate can be controlled either by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0219] According to one embodiment, the present invention relates to a method for inhibiting TLR7 / 8 activity in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition containing the compound.

[0220] In other embodiments, the present invention relates to a method for actively inhibiting TLR7 / 8 or its mutants or activity in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition containing the compound.

[0221] The compounds of the present invention are useful in vitro as unique tools for understanding the biological role of TLR7 / 8 (including the evaluation of numerous factors thought to influence, and be influenced by, TLR7 / 8 production and TLR7 / 8 interactions). These compounds are also useful for the development of other compounds that interact with TLR7 / 8, because they provide important structure-activity relationship (SAR) information that facilitates their development. The compounds of the present invention that bind to TLR7 / 8 can be used as reagents for detecting TLR7 / 8 from living cells, fixed cells, biological fluids, tissue homogenates, purified natural biomaterials, etc. For example, cells expressing TLR7 / 8 can be identified by labeling with such compounds. In addition, based on their binding ability to TLR7 / 8, the compounds of the present invention can be used in enzyme purification, such as in-situ staining, FACS (fluorescence-activated cell sorting), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and ELISA (enzyme-linked immunosorbent assay), or in the purification of cells expressing TLR7 / 8 within permeable cells. The compounds of the present invention can also be used as commercial research reagents for various medical research and diagnostic uses.Such uses include, but are not limited to: use as a calibration standard for quantifying the activity of candidate TLR7 / 8 inhibitors in various functional assays; use as a blocking reagent in random screening of compounds, i.e., in search of a new family of TLR7 / 8 ligands, the compound may be used to block the recovery of currently claimed TLR7 / 8 compounds; use in cocrystals with TLR7 / 8, i.e., the compound of the present invention will allow the determination of the enzyme / compound structure by X-ray crystallography by causing the formation of crystals of the compound bound to TLR7 / 8; other research and diagnostic applications, where TLR7 / 8 is preferably activated, or such activation is conveniently calibrated to known amounts such as TLR7 / 8 inhibitors; use in assays as a probe for determining the expression of TLR7 / 8 in cells; and developing assays for detecting compounds that bind to the same site as TLR7 / 8 binding ligands.

[0222] The compounds of the present invention may be applied either by themselves or in combination with physiometric measurements for diagnosing the effectiveness of treatment. Pharmaceutical compositions containing these compounds and the use of these compounds to treat TLR7 / 8-mediated conditions represent a promising novel approach to a wide range of treatments, whether in humans or animals, resulting in direct and immediate improvement of the state of health. The novel, orally administered bioavairavir and active chemical entities of the present invention improve patient convenience and physician compliance.

[0223] Compounds represented by formula (I), their salts, isomers, tautomers, enantiomers, diastereomers, racemic compounds, derivatives, prodrugs, and / or metabolites are characterized by high specificity and stability, low manufacturing costs, and favorable handling. These characteristics form the basis for a reproducible action (which includes the absence of cross-reactivity) and for a reliable and safe interaction with the target structure.

[0224] When used herein, the term “biological sample” includes, without limitation, cell cultures or extracts thereof; biopsy materials obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other bodily fluids, or extracts thereof.

[0225] Modulation of TLR7 / 8, or its mutants, and their activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, preservation of biological specimens, and biological assays.

[0226] Example As illustrated in the example below, in one exemplary embodiment, the compound is prepared according to the following general procedure. While the general method describes the synthesis of a compound of the present invention, it will be understood that the following general method and other methods known to those skilled in the art may also be applied to all compounds as described herein, and to each of their subclasses and species.

[0227] The symbols and conventions used in the processes, schemes, and examples described below are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[0228] Unless otherwise specified, all temperatures are expressed in degrees Celsius (°C).

[0229] All solvents used were commercially available and used without further purification. The reactions were typically carried out using anhydrous solvents under an inert nitrogen atmosphere. Flash column chromatography was generally performed using Silica gel 60 (0.035–0.070 mm particle size).

[0230] All NMR experiments were recorded on either a Bruker Mercury Plus 400 NMR Spectrometer equipped with a Bruker 400 BBFO probe at 400 MHz for proton NMR, or a Bruker Mercury Plus 300 NMR Spectrometer equipped with a Bruker 300 BBFO probe at 300 MHz for proton NMR. All deuterated solvents typically contain 0.03%–0.05% v / v tetramethylsilane, but this was used as a reference signal ( 1 H and 13 (Both C and δ were set to 0.00)

[0231] LC-MS analysis was performed on a SHIMADZU LC-MS instrument consisting of a UFLC 20-AD system and an LCMS 2020 MS detector. The column used was Shim-pack XR-ODS, 2.2 μm, 3.0 × 50 mm. A linear gradient was applied, starting at 95% A (A: 0.05% TFA in water) and ending at 100% B (B: 0.05% TFA in acetonitrile) over 2.2 min. The total run time was 3.6 min. The column temperature was 40°C and the flow rate was 1.0 mL / min. The Diode Array detector scanned at 200–400 nm. The mass spectrometer was equipped with an electrospray ion source (ES) operated in positive or negative mode. The mass spectrometer scanned between m / z 90–900 with a scan time of 0.6 s.

[0232] 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 may be prepared by standard synthetic techniques. In general, the synthetic route for any individual compound represented by formula (I) and related formulas will depend on the specific substituents of each molecule. Such factors will be understood by those skilled in the art. The following general methods and procedures described in the examples below may be employed to prepare compounds represented by formula (I) and related formulas. The reaction conditions described in the following scheme, such as temperature, solvent, or co-reagents, are given as examples only and are not limiting. If typical or preferred experimental conditions (i.e., reaction temperature, time, moles of reagent, solvent, etc.) are given, it will be understood that other experimental conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reagents or solvents used, but such conditions can be determined by those skilled in the art using routine optimization procedures. For all methods of protection and deprotection, see Philip J. Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and Theodora W. Greene and Peter GM Wuts in “Protective Groups in Organic Synthesis”, Wiley Interscience, 3 rd See Edition 1999. Preparation of intermediates Intermediate 1: 8-[cis-3-hydroxy-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile [ka]

[0233] 5-Methylpiperidine-3-ol: At room temperature, 5-methylpyridine-3-ol (9.50 g, 87.06 mmol), PtO2 (2767 mg, 12.19 mmol), and Rh / C (2866 mg, 27.86 mmol) were added to a 500 mL pressure tank, followed by the addition of AcOH (200 mL). The tank was evacuated and rinsed with hydrogen. The reaction mixture was hydrogenated at 60 °C for 16 hours under a 30 atm hydrogen atmosphere. After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to produce the title compound as brown oil (6.80 g, 68%). MS: 116 [M+H] + .

[0234] 8-[cis-3-hydroxy-5-methylpiperidine-1-yl]quinoxaline-5-carbonitride: To a solution of 8-bromoquinoxaline-5-carbonitride (450 mg, 1.92 mmol) in DMF (15 mL), 5-methylpiperidine-3-ol (246 mg, 2.13 mmol) and DIEA (593 mg, 4.60 mmol) were added at room temperature. The resulting mixture was stirred at 130 °C for 3 hours. After cooling to room temperature, the reaction mixture was quenched by adding water (50 mL). The resulting mixture was extracted with dichloromethane (100 mL x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 60% gradient). This separated the cis / trans isomers, and 8-[cis-3-hydroxy-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile was produced as a yellow solid (270 mg, 52%). MS: 269 [M+H] + . Intermediate 2: cis-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-ol [ka]

[0235] To a solution of 5-bromo-8-(trifluoromethyl)quinoline (950 mg, 3.44 mmol) in DMF (10 mL), 5-methylpiperidine-3-ol (600 mg, 5.21 mmol), K3PO4 (4161 mg, 19.60 mmol), Pd2(dba)3CHCl3 (676 mg, 0.65 mmol), and DavePhos (518 mg, 1.32 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 130 °C for 3 hours under a nitrogen atmosphere. After the reaction was complete, it was quenched by adding water (20 ml). The resulting mixture was extracted with ethyl acetate (50 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by reverse-phase chromatography with elution using acetonitrile in water (5% to 90% gradient over 40 min). This yielded cis-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-ol as a yellow solid (638 mg, 60%). MS: 311 [M+H] + Intermediate 3: 5-bromo-7-fluoro-8-methylquinoline [ka]

[0236] To 10.0 g (49.01 mmol) of 5-bromo-3-fluoro-2-methylphenylamine in a 200 ml flask, glycerol (14.44 ml; 196.04 mmol), iron(II) sulfate heptahydrate (2.73 g; 9.80 mmol), and sulfuric acid (16 ml; 294.06 mmol) were added. The mixture was stirred at 125 °C for 4 hours. The completed reaction was cooled to room temperature and diluted with 200 ml of DCM. 269 ml (539.11 mmol) of 2N sodium hydroxide was slowly added to the mixture cooled in an ice bath, followed by another 100 ml of DCM. The mixture was stirred at rt for 300 min. The separated organic layer was washed with brine, dried, and concentrated. The crude brown oil was purified by Biotage silica gel column (340 g, eluted with EA / hexane 10-35%), yielding the title compound as a white solid (6.0 g, 51% yield). MS: 241 [M+H] + . Intermediate 4: 5-bromo-7-fluoroquinoline-8-carbonitrile [ka]

[0237] 5-Bromo-8-dibromomethyl-7-fluoroquinoline: 5-bromo-7-fluoro-8-methylquinoline (2000 mg; 8.33 mmol) and N-bromosuccinimide (3744 mg; 20.83 mmol) were mixed with 60 ml of CCl4, followed by 2,2'-azobis(2-methylpropionitrile) (205 mg; 1.25 mmol). The mixture was stirred overnight at 80°C. The reaction mixture was cooled to rt and filtered to remove the solid. The filtrate was concentrated to produce the title compound as a white solid (2800 mg, yield 84.5%). MS: 397 / 399 [M+H] + .

[0238] 5-Bromo-7-fluoroquinoline-8-carbaldehyde: To a stirred solution of 5-bromo-8-dibromomethyl-7-fluoroquinoline (11.0 g; 27.65 mmol) in acetone (200 ml) and water (40 ml), AgNO3 (11.74 g; 69.12 mmol) was added at rt. The mixture was stirred at rt for 15 min. The precipitate was removed by filtration and washed with DCM (100 ml). The filtrate was concentrated to 1 / 3 volume and then extracted with DCM (100 ml x 2). Concentration of the combined organic phase produced the title compound as a yellow solid (7.0 g, 99%), which was used directly in the next step reaction. MS: 255 [M+H] + .

[0239] 5-Bromo-7-fluoroquinoline-8-carbaldehyde oxime: 5-bromo-7-fluoroquinoline-8-carbaldehyde (7.0 g; 27.55 mmol) was added to ethanol (300 ml) with NaOAc (4.52 g; 55.11 mmol), followed by NH2OH·HCl (2.30 g; 33.06 mmol). The mixture was stirred at 70°C for 2 hours. The completed reaction was cooled, filtered, and washed with ethanol to remove the solid. Concentration of the filtrate yielded the title compound as a pale yellow solid (7.2 g, 97% yield), which was used directly in the next step. MS: 270 [M+H] + .

[0240] 5-bromo-7-fluoro-quinoline-8-carbodehydroxime (6.0 g; 22.30 mmol) was added to 5-bromo-7-fluoro-quinoline-8-carbodehydroxime (ACN) (20 ml), to which Cu(OAc)2 (1.01 g; 5.57 mmol) and CH3COOH (1.28 ml; 22.30 mmol) were added. The mixture was refluxed for 2 hours. LC-MS showed the formation of the desired product (~60%) and byproducts. The reaction mixture was cooled and concentrated. The residue was dissolved in 100 ml of EA and 30 ml of 5% aq. NaHCO3. The separated aqueous layer was extracted with 50 ml of EA. The combined organic layers were washed with brine, dried, and concentrated. The crude sample was purified using a Biotage silica gel column (200 g, eluted with EA / hexane 0-60%) to produce the title compound (1230 mg, 22% yield). MS: 252 [M+H] + . Intermediate 5: 5-bromo-1,7-naphthyridine-8-carbonitrile [ka]

[0241] 5-Bromo-8-iodo-[1,7]naphthiridine: To a solution of 5-bromo-8-chloro-1,7-naphthiridine (4581 mg; 18.81 mmol; 1.0 eq.) and sodium iodide (8.46 g; 56.44 mmol; 3.0 eq.) in 10 ml of ACN, TMSCl (2.39 ml; 18.81 mmol; 1.0 eq.) was added. The suspension was heated under reflux for 2 hours. The yellowish-brown suspension was cooled to room temperature and poured into water (70 ml), and the brown suspension was stirred at room temperature for 1 hour. The beige solid was filtered, washed with water, and then dried under vacuum to obtain the title compound in quantitative yield. MS: 335 [M+H] + .

[0242] To a microwave vial containing 5-bromo-1,7-naphthirizine-8-carbonitrile:5-bromo-8-iodo-[1,7]naphthirizine (3.07 g; 9.17 mmol; 1.0 eq.), copper(i) cyanide (0.99 g; 11.0 mmol; 1.20 eq.) and MeCN (8.0 ml) were added. The mixture was stirred in a microwave at 90°C for 1 hour. The mixture was diluted with ELISA (50 ml), filtered, concentrated, and the residue was used directly in the next step. MS: 234 [M+H] + . Intermediate 6: 5-bromo-8-trifluoromethyl-[1,7]naphthyridine [ka]

[0243] To a solution of 5-bromo-8-iodo-[1,7]naphthirizine (1200 mg; 3.58 mmol; 1.0 eq.), cesium fluoride (1088 mg; 7.17 mmol; 2.0 eq.), and copper iodide (1365 mg, 7.17 mmol, 2 eq.) in DMF (10 mL), trimethyl-trifluoromethyl-silane (2.0 M in THF) (3.58 ml; 7.17 mmol; 2.0 eq.) was added, and the mixture was stirred at rt for 2 hours until the reaction was complete. The reaction was diluted with EA, filtered through Celite, the filtrate was concentrated, and the residue was subjected to a silica column for purification (eluted with 0-50% EA / hexane) to produce the title compound as a white solid (900 mg, yield 90.7%). LC-MS (M+1) = 278 / 280. Intermediate 7: 8-bromopyrido[3,4-b]pyrazine-5-carbonitrile [ka]

[0244] 5,8-Dibromopyrido[3,4-b]pyrazine: In a 100 ml round-bottom flask, 2,5-dibromopyridine-3,4-diamine (2.0 g; 7.493 mmol) was suspended in 1-butanol (50.0 ml), and a 40% solution of glyoxal in water (2.1 ml; 18.7 mmol) was added. The yellowish-brown suspension was heated to 80°C, and the yellow solution was stirred at 80°C for 1 hour and 30 minutes. The orange solution was cooled to room temperature. The beige suspension was filtered, the beige solid was washed with water and hexane, and dried under vacuum to obtain 1.32 g of 5,8-dibromopyrido[3,4-b]pyrazine (1.32 g; 59.1%). MS:290 [M+H] + .

[0245] 8-Bromo-5-iodopyrido[3,4-b]pyrazine: In a 50 ml round-bottom flask equipped with a condenser and under nitrogen, 5,8-dibromopyrido[3,4-b]pyrazine (750.0 mg; 2.518 mmol), sodium iodide (1.1 g; 7.554 mmol), and chlorotrimethylsilane (319.6 μl; 2.518 mmol) were added to anhydrous MeCN (5.0 ml). The brown suspension was heated under reflux, and the yellowish-brown suspension was stirred under reflux for 2 hours. The yellowish-brown suspension was cooled to room temperature and poured into water (70 ml), and the brown suspension was stirred at room temperature for 30 minutes. The beige solid was filtered, and the solid was dissolved in DCM and MeOH, adsorbed onto a PuriFlash 10g Celite column, and purified by chromatography on a PuriFlash 40g 30u column (DCM for 20 column volume). The major product eluted between 0.9 and 3.9 column volumes. The pure fraction was concentrated under reduced pressure, and the brown solid was dried under vacuum to give 492 mg of brown solid as the title compound (492.0 mg; 56.1%). MS:336 [M+H] + .

[0246] 8-Bromo-pyrido[3,4-b]pyrazine-5-carbonitrile: In a 10 ml microwave vial, 8-bromo-5-iodopyrido[3,4-b]pyrazine (200.0 mg; 0.575 mmol) and copper(i) cyanide (61.7 mg; 0.689 mmol) were suspended in anhydrous MeCN (5.0 ml) under nitrogen. The tube was sealed, and the mixture was rinsed with nitrogen for 10 min. The yellowish-brown suspension was microwaved at 80°C for 8 hours. The reaction mixture was concentrated under reduced pressure, the residue was suspended in DCM, filtered over Celite, and concentrated under reduced pressure. The residue was suspended in DCM, absorbed onto a PuriFlash Celite 2 g column, and purified by chromatography on a PuriFlash 12 g 30 u column (hexane-AcOEt 20% per 5 column volume, hexane-AcOEt 20-80% per 15 column volume). The major product was eluted with AcOEt at 20–39% (lambda up to 245 nm). The pure fraction was concentrated under reduced pressure, and the off-white solid was dried under vacuum to obtain 84 mg of a cream-colored solid as the title compound (84.0 mg; 54.5%). MS:235 [M+H] + . Intermediate 8: 8-bromo-5-methoxypyrido[3,4-b]pyrazine [ka]

[0247] In a 100 ml round-bottom flask, under nitrogen, 5,8-dibromopyrido[3,4-b]pyrazine (500.0 mg; 1.731 mmol) was dissolved in anhydrous methanol (50.0 ml). A 0.5 M solution of sodium methoxide (5.2 ml; 2.596 mmol) in methanol was added to the beige solution. The beige suspension was heated to 60°C, and the yellowish-brown solution was stirred at 60°C for 30 min. The yellowish-brown solution was cooled to room temperature, quenched with water (10 ml), and concentrated under reduced pressure. The residue was suspended in water (50 ml). The beige suspension was stirred at room temperature for 30 min. The beige solid was filtered, washed with water, and dried under vacuum to obtain 331 mg of the title compound (331.0 mg; 79.7%). MS:240 [M+H] + . Intermediate 9: [cis-6-(trifluoromethyl)morpholine-2-yl]methanol [ka]

[0248] 3-(benzyloxy)-2-chloropropanoic acid: At 0°C, a solution of (2R)-3-(benzyloxy)-2-[[(tert-butoxy)carbonyl]amino]propanoic acid (17.0 g, 57.90 mmol) in aqueous hydrogen chloride solution (12 N, 160 ml, 1.92 mol) was added dropwise to a solution of NaNO2 (15 g, 206.52 mmol) in water (20 ml) over a period of 0.5 hours. The resulting mixture was stirred at room temperature for 15 minutes. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (500 ml x 3). The combined organic phase was concentrated under reduced pressure, and the residue was diluted with water (300 ml). The pH of the resulting mixture was adjusted to 8 with sodium hydroxide solution (2 M). The mixture was extracted with ethyl acetate (300 ml x 3), and the aqueous layer was adjusted to pH=3 with HCl solution (3 N). The resulting mixture was extracted again with ethyl acetate (300 ml x 3). The organic layers were combined, dried on anhydrous sodium sulfate, and concentrated under vacuum to produce 3-(benzyloxy)-2-chloropropanoic acid as a light brown oil (8.0 g, 64%). MS: 213 [M+H] + .

[0249] 3-(benzylamino)-1,1,1-trifluoropropan-2-ol: At -10°C, 2-(trifluoromethyl)oxirane (6.17 g, 55.11 mmol) was slowly added to a solution of lithium trifluoromethanesulfonate (855 mg, 5.48 mmol) in acetonitrile (25 ml). Then, phenylmethaneamine (5.57 g, 52.13 mmol) was added dropwise at -10°C. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 10% gradient) to produce 3-(benzylamino)-1,1,1-trifluoropropan-2-ol as a white solid (7.89 g, 41%). MS: 220 [M+H] + .

[0250] Anti-2-N-benzyl-3-(benzyloxy)-2-chloro-N-[(2)-3,3,3-trifluoro-2-hydroxypropyl]propanamide: To a solution of 3-(benzyloxy)-2-chloropropanoic acid (6.20 g, 28.89 mmol) in dichloromethane (500 ml), DIEA (13.96 g, 108.05 mmol), HATU (12.35 g, 32.48 mmol), and 3-(benzylamino)-1,1,1-trifluoropropan-2-ol (4.93 g, 22.49 mmol) were sequentially added at room temperature. The resulting solution was stirred at room temperature for 16 hours. After the reaction was complete, it was quenched by adding water (300 ml). The resulting mixture was extracted with ethyl acetate (500 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 10% gradient) to produce anti-2-N-benzyl-3-(benzyloxy)-2-chloro-N-[(2)-3,3,3-trifluoro-2-hydroxypropyl]propanamide as a yellow solid (1.59 g, 17%). MS: 416 [M+H] + .

[0251] At -30°C, sodium hydride (600 mg, 25.0 mmol) was added in batches to a solution of anti-2-N-benzyl-3-(benzyloxy)-2-chloro-N-[(2)-3,3,3-trifluoro-2-hydroxypropyl]propanamide (883 mg, 2.12 mmol) in THF (150 ml). The resulting mixture was stirred at 130°C for 4 hours. After the reaction was complete, it was quenched by adding ice water (200 ml). The resulting mixture was extracted with ethyl acetate (300 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography with elution using ethyl acetate in hexane (0% to 10% gradient) to produce cis-4-benzyl-2-[(benzyloxy)methyl]-6-(trifluoromethyl)morpholin-3-one as a pale pink oil (639 mg, 79%). MS: 380 [M+H] + .

[0252] cis-4-benzyl-2-[(benzyloxy)methyl]-6-(trifluoromethyl)morpholine: To a solution of cis-4-benzyl-2-[(benzyloxy)methyl]-6-(trifluoromethyl)morpholine-3-one (639 mg, 1.68 mmol) in THF (20 ml), a solution of BH3 in THF (1 N, 12 ml, 12 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, it was quenched by adding EtOH (40 ml). The resulting mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 15% gradient) to produce cis-4-benzyl-2-[(benzyloxy)methyl]-6-(trifluoromethyl)morpholine as a pale yellow oil (354 mg, 58%).

[0253] [cis-6-(trifluoromethyl)morpholine-2-yl]methanol: At room temperature, palladium-carbon (87 mg, 0.82 mmol) and hydrogen chloride solution (0.5 ml, 6 mmol, 12N) were added to a solution of cis-4-benzyl-2-[(benzyloxy)methyl]-6-(trifluoromethyl)morpholine (177 mg, 0.48 mmol) in methanol (10 ml) under a nitrogen atmosphere. The reaction flask was evacuated and washed with hydrogen. The reaction mixture was hydrogenated at room temperature for 12 hours under a hydrogen atmosphere using a hydrogen balloon. After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to produce [cis-6-(trifluoromethyl)morpholine-2-yl]methanol as a pale yellow solid (88 mg, 98%). MS: 186 [M+H] + . Intermediate 10: 8-[cis-2-(hydroxymethyl)-6-(trifluoromethyl)morpholine-4-yl]quinoxaline-5-carbonitrile [ka]

[0254] To a solution of 8-bromoquinoxaline-5-carbonitrile (221 mg, 0.96 mmol) in DMF (25 ml), [cis-6-(trifluoromethyl)morpholine-2-yl]methanol (260 mg, 1.36 mmol) and DIEA (629 mg, 4.8 mmol) were added at room temperature. The resulting mixture was stirred at 130 °C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (20 ml). The resulting mixture was extracted with ethyl acetate (50 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate in hexane (0% to 30% gradient) to produce 8-[cis-2-(hydroxymethyl)-6-(trifluoromethyl)morpholine-4-yl]quinoxaline-5-carbonitrile as a pale yellow oil (100 mg, 31%). MS: 339 [M+H] + . Intermediate 11: 5-[cis-2-(hydroxymethyl)-6-(trifluoromethyl)morpholine-4-yl]quinoline-8-carbonitrile [ka]

[0255] To a solution of 5-bromoquinoline-8-carbonitride (600 mg, 2.57 mmol) in dioxane (30 ml), [cis-6-(trifluoromethyl)morpholine-2-yl]methanol (540 mg, 2.92 mmol), SPhos (210 mg, 0.51 mmol), SPhos Paradacycle Gen.3 (399 mg, 0.51 mmol), and Cs2CO3 (2510 mg, 7.71 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90°C for 13 hours under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was diluted with water (50 ml). The resulting mixture was extracted with ethyl acetate (150 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography with elution using toluene in hexane (0% to 40% gradient) to produce 5-[cis-2-(hydroxymethyl)-6-(trifluoromethyl)morpholine-4-yl]quinoline-8-carbonitrile as a yellow solid (300 mg, 34%). MS: 338 [M+H] + . Intermediate 12: 5-[cis-2-(hydroxymethyl)-6-(trifluoromethyl)morpholin-4-yl]-1,7-naphthyridine-8-carbonitrile [ka]

[0256] The title compound was prepared from 5-bromo-1,7-naphthyridine-8-carbonitrile and [cis-6-(trifluoromethyl)morpholine-2-yl]methanol as a yellow solid (60% yield) using the same method as for intermediate 11. MS: 339 [M+H] + . Intermediate 13: [(2R,6R)-4-(7-fluoro-8-methylquinoline-5-yl)-6-methylmorpholine-2-yl]methanol [ka]

[0257] In a 5 ml microwave vial, 5-bromo-7-fluoro-8-methylquinoline (200.0 mg; 0.83 mmol; 1.0 eq.), ((2R,6R)-6-methyl-morpholine-2-yl)-methanol (109.28 mg; 0.83 mmol; 1.0 eq.), RuPhos Pd (34.84 mg; 0.04 mmol; 0.05 eq.), RuPhos (38.87 mg; 0.08 mmol; 0.10 eq.), and potassium carbonate (345.41 mg; 2.50 mmol; 3.0 eq.) were dissolved in 20 ml of anhydrous dioxane. The vial was sealed and rinsed with nitrogen for 5 minutes, and the suspension was microwaved at 100°C for 8 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and redissolved in DCM. The solution was absorbed onto a 5g PuriFlash Celite column and purified by chromatography on a 12g PuriFlash 30u column (10% hexane-AcOEt per 5 column volume, 40-60% hexane-AcOEt for 18 minutes). The pure fraction was concentrated under reduced pressure, and the yellow, rubbery substance was dried under vacuum to obtain the title sample (45.0 mg; 0.17%). MS: 291 [M+H] + . Intermediate 14: [(2R,6R)-6-methyl-4-(8-methylquinoline-5-yl)morpholine-2-yl]methanol: [ka]

[0258] To a microwave vial, add 5-bromo-8-methylquinoline (532.0 mg; 2.40 mmol; 1.0 eq.), ((2R,6R)-6-methyl-morpholine-2-yl)-methanol hydrochloride (401.57 mg; 2.40 mmol; 1.0 eq.), chloro-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl Palladium(ii)-methyl-t-butyl ether adduct (58.7 mg; 0.07 mmol; 0.03 eq.), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (33.54 mg; 0.07 mmol; 0.03 eq.), cesium carbonate (1951.27 mg; 5.99 mmol; 2.50 eq.), and tBuOH (12.0 ml) were added. The mixture was heated in a microwave to 100°C for 4.5 hours, diluted with ELISA, and filtered. The filtrate was washed with water and brine, dried, and concentrated. The residue was purified by Biotage, giving the title compound as a white solid (103 mg, 15%). MS: 273 [M+H] + . Intermediate 15: 5-[(2R,6R)-2-(hydroxymethyl)-6-methylmorpholine-4-yl]-1,7-naphthyridine-8-carbonitrile [ka]

[0259] To a microwave vial containing 5-bromo-[1,7]naphthirizine-8-carbonitrile (1.07 g; 4.44 mmol; 1.0 eq.), ((2R,6R)-6-methyl-morpholine-2-yl)-methanol hydrochloride (0.74 g; 4.44 mmol; 1.0 eq.), triethylamine (1.25 ml; 8.89 mmol; 2.0 eq.), and DMF (10 ml) were added. The mixture was stirred in a microwave at 100°C for 2 hours. The mixture was diluted with SiO2 and filtered. The filtrate was washed with water and brine, dried, and concentrated. The residue was purified by flash chromatography (hexane in SiO2) to produce the title compound as a pale yellow solid (29.5 mg, 41%). MS: 285 [M+H] + . Intermediate 16: 5-((2R,6R)-2-hydroxymethyl-6-methylmorpholine-4-yl)-quinazoline-8-carbonitrile [ka]

[0260] In a 25 ml microwave vial, ((2R,6R)-6-methyl-morpholine-2-yl)-methanol (1.0 g; 5.97 mmol; 1.0 eq.), 5-bromo-quinazoline-8-carbonitrile (1.40 g; 5.97 mmol; 1.0 eq.), and DIEA (2.96 ml; 17.90 mmol; 3.0 eq.) were dissolved in anhydrous DMF (10.0 ml). The vial was sealed, and the yellow solution was microwaved at 120 °C for 5 hours. The yellow solution was concentrated under reduced pressure. Water (50 ml) was added to the residue, and the solid suspension was then filtered and dried to give 5-((2R,6R)-2-hydroxymethyl-6-methyl-morpholine-4-yl)-quinazoline-8-carbonitrile (1280.0 mg; 75%) as a brown solid. MS: 285 [M+H] + . Intermediate 17: [(2R,6R)-6-methyl-4-(8-trifluoromethyl-quinoline-5-yl)-morpholine-2-yl]methanol [ka]

[0261] In a 25 ml microwave vial, 5-bromo-8-trifluoromethylquinoline (500.0 mg; 1.81 mmol; 1.0 eq.), ((2R,6R)-6-methyl-morpholine-2-yl)-methanol (285.10 mg; 2.17 mmol; 1.20 eq.), and methanesulfonate (2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl) (2'- Amino-1,1'-biphenyl-2-yl)palladium(ii) (75.74 mg; 0.09 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (84.52 mg; 0.18 mmol; 0.10 eq.), and potassium carbonate (750.98 mg; 5.43 mmol; 3.0 eq.) were dissolved in anhydrous dioxane (10.0 ml). The tube was sealed and rinsed with nitrogen for 5 minutes, and the suspension was microwaved at 100°C for 8 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure and redissolved in DCM. The solution was absorbed onto a 5g PuriFlash Celite column and purified by chromatography on a 10g PuriFlash 30u column (10% hexane-AcOEt per 5 column volume, 40-60% hexane-AcOEt for 18 minutes). The pure fraction was concentrated under reduced pressure, and the pale yellow oil was dried under vacuum to give [(2R,6R)-6-methyl-4-(8-trifluoromethyl-quinoline-5-yl)-morpholine-2-yl]methanol (245.0 mg; 41%). MS:327 [M+H] + . Intermediate 18: (2R,6R)-4-(7-fluoro-8-methylquinoline-5-yl)-6-methylmorpholine-2-carboxylic acid [ka]

[0262] [(2R,6R)-4-(7-fluoro-8-methylquinoline-5-yl)-6-methylmorpholine-2-yl]methanol (140.0 mg; 0.48 mmol; 1.0 eq.) and DCM (15.0 ml) were added to a 50 ml round-bottom flask. The resulting solution was stirred in a water / ice bath at 0°C for 5 minutes, and then (diacetoxyiodo)benzene (0.31 g; 0.96 mmol; 2.0 eq.) was added. After raising the temperature to 10°C, tempo (15.07 mg; 0.10 mmol; 0.20 eq.) and water (0.60 ml) were added. The resulting solution was stirred for an additional 20 minutes while maintaining the temperature at 10°C in a water / ice bath. The reaction solution was stirred for an additional 2 hours at 25°C, after which the yellow solid suspension turned into a brown solution. LC / MS indicated that the reaction was complete. The reaction was then quenched with 0.5 ml of 10% sodium thiosulfate (aq) and stirred for another 45 minutes. The resulting mixture was concentrated under vacuum. The residue was dispersed in a 1:1 DCM / methanol mixture, filtered, and the filtrate was evaporated to give (2R,6R)-4-(7-fluoro-8-methylquinoline-5-yl)-6-methylmorpholine-2-carboxylic acid (106.0 mg; crude) as a yellow solid. MS: 305 [M+H] + . Intermediate 19: cis-4-(8-cyano-1,7-naphthyridine-5-yl)-6-(trifluoromethyl)morpholine-2-carboxylic acid [ka]

[0263] At 0°C, a mixture of 5-[cis-2-(hydroxymethyl)-6-(trifluoromethyl)morpholine-4-yl]-1,7-naphthirizine-8-carbonitrilate (313 mg, 0.93 mmol) in 38 ml of dichloromethane and 19 ml of water was mixed with (diacetoxyiodo)benzene (686 mg, 2.13 mmol) and TEMPO (36 mg, 0.23 mmol) at 0°C. The resulting mixture was stirred at 0°C for 8 hours. After the reaction was complete, it was quenched by adding MeOH (10 ml). The reaction mixture was concentrated under reduced pressure and then azeotropically mixed with toluene to remove most of the solvent. The residue was purified by flash chromatography using MeOH in DCM (0% to 15% gradient) to produce cis-4-(8-cyano-1,7-naphthyridine-5-yl)-6-(trifluoromethyl)morpholine-2-carboxylic acid as brown oil (134 mg, 78%). MS: 353 [M+H] + . Intermediate 20: cis-4-(8-cyanoquinoline-5-yl)-6-(trifluoromethyl)morpholine-2-carboxylic acid [ka]

[0264] The title compound was prepared from 5-[cis-2-(hydroxymethyl)-6-(trifluoromethyl)morpholine-4-yl]quinoline-8-carbonitrile as a yellow oil (48% yield) using the same method as for intermediate 19. MS: 352 [M+H] + . Intermediate 21: trans-5-methylpiperidine-3-yl-4-nitrobenzoate: [ka]

[0265] 5-Methylpiperidine-3-ol: At room temperature, 4.90 g of 5-methylpyridine-3-ol (44.90 mmol) was dissolved in 200 ml of acetic acid, to which Rh / C (1.42 g, 13.85 mmol) and PtO2 (1.42 g, 6.28 mmol) were added under a nitrogen atmosphere. The reaction tank was evacuated and washed with hydrogen. The reaction mixture was hydrogenated at room temperature for 12 hours under a hydrogen atmosphere (15 atm). After the reaction was complete, the reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to produce 5-methylpiperidine-3-ol as brown oil (4.50 g, cis / trans = 4:1, 87%). MS: 116.2 [M+H] + .

[0266] cis-tert-butyl 3-hydroxy-5-methylpiperidine-1-carboxylate: At 0°C, a solution of 5-methylpiperidine-3-ol (4.0 g, 34.73 mmol) in tetrahydrofuran (100 ml) was mixed with aqueous sodium hydroxide solution (2N, 30 ml, 60.0 mmol). To the mixed solution, a solution of (Boc)2O (10.29 g, 47.15 mmol) in tetrahydrofuran (50 ml) was added dropwise at room temperature over a period of 15 min. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with water (300 ml) and extracted with ethyl acetate (300 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography with elution using ethyl acetate in hexane (0% to 40% gradient) to produce cis-tert-butyl 3-hydroxy-5-methylpiperidine-1-carboxylate as a yellow solid (4.50 g, 60%). MS: 160.3 [M+H] + .

[0267] To a solution of cis-tert-butyl 3-hydroxy-5-methylpiperidine-1-carboxylate (2.70 g, 12.54 mmol) in tetrahydrofuran (60 ml), 4-nitrobenzoic acid (3.52 g, 21.06 mmol), PPh3 (5.85 g, 22.31 mmol), and DIAD (4.48 g, 22.18 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 4 hours. After the reaction was complete, it was quenched by adding saturated NH4Cl solution (200 ml). The resulting mixture was extracted with ethyl acetate (300 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography with elution using siRNA in hexane (0% to 50% gradient) to produce trans-tert-butyl 3-methyl-5-[(4-nitrophenyl)carbonyloxy]piperidine-1-carboxylate as a yellow solid (4.0 g, 92%). MS: 308.9 [M+H] + .

[0268] trans-5-methylpiperidine-3-yl-4-nitrobenzoate: To a solution of trans-tert-butyl 3-methyl-5-[(4-nitrophenyl)carbonyloxy]piperidine-1-carboxylate (4.0 g, 10.97 mmol) in dioxane (150 ml), aqueous hydrogen chloride solution (6 N, 15 ml, 90.0 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, the pH of the mixture was adjusted to 10 with saturated sodium carbonate solution, and the resulting mixture was concentrated under vacuum to remove the organic solvent. The remaining mixture was extracted with ethyl acetate (100 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. By removing the solvent under reduced pressure, trans-5-methylpiperidine-3-yl-4-nitrobenzoate was produced as a yellow solid (3.70 g, crude). MS: 265.0 [M+H] + . Intermediate 22: trans-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl-4-nitrobenzoate [ka]

[0269] To a solution of trans-5-methylpiperidine-3-yl-4-nitrobenzoate (3.70 g, crude) in N,N-dimethylformamide (100 ml), 8-bromoquinoxaline-5-carbonitrilate (3.08 g, 13.15 mmol) and DIEA (5.14 g, 39.77 mmol) were added at room temperature. The resulting mixture was stirred at 120°C for 3 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with ELISA in hexane (0% to 10% gradient) to produce trans-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl-4-nitrobenzoate as a yellow solid (2.62 g, 57% of the two steps). MS: 418.0 [M+H] + . Intermediate 23: trans-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl-4-nitrobenzoate [ka]

[0270] In a 50 ml shielded tube, a solution of 5-bromo-8-(trifluoromethyl)quinoxaline (450 mg, 1.62 mmol) in dioxane (15 ml) was mixed with trans-5-methylpiperidine-3-yl-4-nitrobenzoate (867 mg, 3.25 mmol), third-generation SPhos pre-catalyst (253 mg, 0.32 mmol), SPhos (373 mg, 0.91 mmol), and Cs2CO3 (1085 mg, 3.33 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C for 12 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with MeOH in DCM (0% to 10% gradient) to produce trans-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl-4-nitrobenzoate as a yellow solid (144 mg, 19%). MS: 461.0 [M+H] + . Example Preparation

[0271] Using the above intermediate or the intermediate in WO 2017 / 106607A1 and commercially available reagents, examples were prepared according to the following method. Example 1: 8-[(3S,5R)-3-methyl-5-[2-(4-methylpiperazine-1-yl)ethoxy]piperidine-1-yl]quinoxaline-5-carbonitrile [ka] [ka]

[0272] To a solution of 8-[cis-3-hydroxy-5-methylpiperidine-1-yl]quinoxaline-5-carbonitride (300 mg, 1.01 mmol, 1.0 equivalent) in tert-butyl 4-(2-[[cis-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]oxy]ethyl)piperazine-1-carboxylate: sodium hydride (804 mg, 33.50 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 20 minutes, and then tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (788 mg, 3.17 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. When the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography eluting with MeOH in DCM (0% to 40% gradient) to produce the title compound as a yellow solid (170 mg, 35%). MS: 481 [M+H] + .

[0273] 8-[cis-3-methyl-5-[2-(piperazine-1-yl)ethoxy]piperidine-1-yl]quinoxaline-5-carbonitric hydrochloride: To a solution of tert-butyl 4-(2-[[cis-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]oxy]ethyl)piperazine-1-carboxylate (145 mg, 0.30 mmol) in dioxane (50.0 ml), hydrogen chloride solution (12 N, 1 ml, 12 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to produce the title compound as a yellow solid (85 mg, 74%). MS: 381 [M+H] + .

[0274] 8-[cis-3-methyl-5-[2-(4-methylpiperazine-1-yl)ethoxy]piperidine-1-yl]quinoxaline-5-carbonitriel: At room temperature, 8-[cis-3-methyl-5-[2-(piperazine-1-yl)ethoxy]piperidine-1-yl]quinoxaline-5-carbonitriel hydrochloride (53 mg, 0.13 mmol) in methanol (10 ml) is mixed with NaOAc (308 mg, 3.75 mmol), (HCHO) n (108 mg, 1.20 mmol) and NaBH4 (33 mg, 0.87 mmol) were added sequentially. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 19 × 150 mm 5 μm; acetonitrile in water (with 10 mmol / L NH4HCO3 and 0.1% NH3·H2O), 35% to 65% gradient over 10 min; detector, UV 254 nm. The title compound was obtained as a pale yellow solid (11 mg, 21%). MS: 395 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.95 (d, J = 1.8 Hz, 1 H), 8.90 (d, J = 1.7 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 1 H), 4.64 - 4.56 (m, 1 H), 4.12 - 4.04 (m, 1 H), 3.85 - 3.70 (m, 3 H), 2.81 - 2.46 (m, 12 H), 2.35 - 2.31 (m, 1 H), 2.29 (s, 3 H), 2.06 - 2.01 (m, 1 H), 1.16 - 1.04 (m, 1 H), 1.05 (d, J = 6.6 Hz, 3 H).

[0275] The following compounds were synthesized using a similar method. Example 2: 5-[cis-3-methyl-5-[2-(4-methylpiperazine-1-yl)ethoxy]piperidine-1-yl]-8-(trifluoromethyl)quinoline [ka]

[0276] The title compound was prepared from cis-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-ol and tert-butyl-4-(2-chloroethyl)piperazine e-1-carboxylate. MS: 437 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.95 (dd, J = 4.2, 1.7 Hz, 1 H), 8.60 (dd, J = 8.6, 1.8 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.62 (dd, J = 8.6, 4.2 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 3.87 - 3.62 (m, 4 H), 3.39 - 3.33 (m, 1 H), 2.84 - 2.22 (m, 16 H), 2.17 - 2.06 (m, 1 H), 1.16 - 1.06 (m, 1 H), 1.04 (d, J = 6.6Hz, 3H). Example 3: 5-[cis-3-methyl-5-[2-(piperidine-1-yl)ethoxy]piperidine-1-yl]-8-(trifluoromethyl)quinolone [ka]

[0277] To a solution of cis-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-ol (85 mg, 0.27 mmol) in DMF (5 ml), sodium hydride (232 mg, 9.68 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 10 minutes, and then 1-(2-chloroethyl)piperidine hydrochloride (113 mg, 0.61 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with DCM (30 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD, 150 × 190 mm, 5 μm; acetonitrile in water (with 10 mmol / L NH4HCO3 and 0.1% NH3·H2O), 45% to 75% gradient over 8 min; detector, UV 254 nm. 5-[cis-3-methyl-5-[2-(piperidine-1-yl)ethoxy]piperidine-1-yl]-8-(trifluoromethyl)quinolone was obtained as a yellow solid (28 mg, 24%). MS: 422 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.95 (dd, J = 4.2, 1.8 Hz, 1 H), 8.60 (dd, J = 8.6, 1.8 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.62 (dd, J = 8.6, 4.2 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 3.89 - 3.59 (m, 4 H), 3.39 - 3.33 (m, 1 H), 2.64 - 2.39 (m, 8 H), 2.38 - 2.28 (m, 1 H), 2.16 - 2.06 (m, 1 H), 1.67 - 1.57 (m, 4H), 1.53 - 1.46 (m, 2 H), 1.16 - 1.06 (m, 1 H), 1.04 (d, J = 6.6 Hz, 3 H).

[0278] The following compounds were synthesized using a similar method. Example 4: Diethyl(2-[[cis-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]oxy]ethyl)amine [ka]

[0279] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-ol and (2-chloroethyl)diethylamine hydrochloride. MS: 410 [M+H] + . 1 H NMR (300 MHz, methanol-d4, ppm) δ 8.90 (dd, J = 4.2, 1.8 Hz, 1 H), 8.55 (dd, J = 8.6, 1.8 Hz, 1 H), 8.0 (d, J = 8.0 Hz, 1 H), 7.57 (dd, J = 8.6, 4.2 Hz, 1 H), 7.20 (d. H). Example 5: 8-[(3S,5R)-3-methyl-5-[2-(piperidine-1-yl)ethoxy]piperidine-1-yl]quinoxaline-5-carbonitrile [ka]

[0280] 8-[(3R,5S)-3-hydroxy-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile: At 0°C, a solution of 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile (178 mg, 0.67 mmol) in 5 ml of AcOH was dropwise added to a solution of NaNO2 (229 mg, 3.33 mmol) in 1 ml of water. The resulting solution was stirred at room temperature for 10 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: Column, XBridge BEH130 Prep C18 OBD column, 19 × 150 mm, 5 μm, 13 nm; Mobile phase, MeOH in water (with 10 mmol / L NH4HCO3), 30% to 80% gradient over 10 min; Detector, UV 254 nm. 8-[(3R,5S)-3-hydroxy-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile was obtained as a yellow solid (30 mg, 17%). MS: 269 [M+H] + .

[0281] 8-[(3S,5R)-3-methyl-5-[2-(piperidine-1-yl)ethoxy]piperidine-1-yl]quinoxaline-5-carbonitriel: At 0°C, sodium hydride (5 mg, 0.20 mmol) was added to a solution of 8-[(3R,5S)-3-hydroxy-5-methylpiperidine-1-yl]quinoxaline-5-carbonitriel (27 mg, 0.10 mmol) in DMF (5 ml). The resulting mixture was stirred at 0°C for 15 min, and then 1-(2-chloroethyl)piperidine (38 mg, 0.21 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. When the reaction was complete, it was quenched by adding water (20 ml). The resulting mixture was extracted with DCM (30 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: Column, XBridge Shield RP18 OBD column, 19 × 150 mm 5 μm; acetonitrile in water (with 10 mmol / L NH4HCO3 and 0.1% NH3·H2O), 40%–70% gradient over 10 min; detector, UV 254 nm. 8-[(3S,5R)-3-methyl-5-[2-(piperidine-1-yl)ethoxy]piperidine-1-yl]quinoxaline-5-carbonitrile was obtained as a pale yellow solid (14 mg, 36%). MS: 380 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 8.94 (d, J = 1.8 Hz, 1 H), 8.90 (d, J = 1.8 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 4.65 - 4.55 (m, 1 H), 4.12 - 4.03 (m, 1 H), 3.85 - 3.71 (m, 3 H), 2.79 - 2.45 (m, 8 H), 2.35 - 2.27 (m, 1 H), 2.05 - 2.01 (m, 1 H), 1.68 - 1.55 (m, 4 H), 1.54 - 1.45 (m, 2 H), 1.21 - 1.09 (m, 1 H), 1.05 (d, J = 6.7 Hz, 3 H).

[0282] The following compounds were synthesized using a similar method. Example 6: 8-[(3R,5S)-3-[2-(diethylamino)ethoxy]-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile [ka]

[0283] The title compound was prepared from 8-[(3R,5S)-3-hydroxy-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and (2-chloroethyl)diethylamine hydrochloride. MS: 368 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.94 (d, J = 1.8 Hz, 1 H), 8.90 (d, J = 1.8 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 4.66 - 4.56 (m, 1 H), 4.12 - 4.03 (m, 1 H), 3.82 - 3.68 (m, 3 H), 2.77 - 2.57 (m, 8 H), 2.35 - 2.27 (m, 1 H), 2.06 - 2.0 (m, 1 H), 1.21 - 1.02 (m, 10 H). Example 7: (3R,5S)-5-methyl-1-(8-trifluoromethyl-[1,7]naphthyrizin-5-yl)-piperidine-3-ylamine hydrochloride [ka]

[0284] [(3R,5S)-5-methyl-1-(8-trifluoromethyl-[1,7]naphthiridine-5-yl)-piperidine-3-yl]-carbamate tert-butyl ester: 5-bromo-8-trifluoromethyl-[1,7]naphthiridine (800 mg; 2.89 mmol; 1.0 eq.), ((3R,5S)-5-methyl-piperidine-3-yl)-carbamate tert-butyl ester in dioxane (10 ml): A solution of butyl ester (680 mg; 3.18 mmol; 1.10 eq.) and RuPhos (67.37 mg; 0.14 mmol; 0.05 eq.) was degassed, and then 2-methyl-propan-2-ol sodium (305 mg; 3.18 mmol; 1.10 eq.) and bis(tri-tert-butylphosphine)palladium(0) (74 mg; 0.14 mmol; 0.05 eq.) were added. The resulting mixture was stirred at 100°C for 2 hours. After the reaction was complete, the crude product was purified by silica column elution with 0-55% EA / hexane to produce the title compound (700 mg, yield 59%). LC-MS (M+1) = 411.

[0285] (3R,5S)-5-methyl-1-(8-trifluoromethyl-[1,7]naphthyridine-5-yl)-piperidine-3-ylamine hydrochloride: To a solution of [(3R,5S)-5-methyl-1-(8-trifluoromethyl-[1,7]naphthyridine-5-yl)-piperidine-3-yl]-carbamate tert-butyl ester (20 mg; 0.05 mmol; 1.0 eq.) in 1 ml of methanol, hydrogen chloride (4.0 M in dioxane) (0.60 ml; 2.40 mmol; 49.25 eq.) was added. The resulting mixture was stirred at rt for 1 hour until the reaction was complete. The reaction mixture was concentrated. The residue was suspended in ether and then filtered to produce the title compound as a yellow solid (16 mg, 94%). LC-MS (M+1) = 311. 1 H NMR (400 MHz, methanol-d4) δ 9.12 (d, J = 3.9 Hz, 1H), 8.60 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 7.86 (dd, J = 8.8, 4.1 Hz, 1H), 3.73 (dd, J = 39.3, 11.4 Hz, 2H), 3.53 (d, J = 12.0 Hz, 1H), 2.94 (t, J = 10.8 Hz, 1H), 2.62 (t, J = 11.5 Hz, 1H), 2.40 - 2.11 (m, 2H), 1.30 (q, J = 12.0 Hz, 1H), 1.10 (d, J = 6.4Hz, 3H). Example 8: 5-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-[1,7]naphthyridine-8-carbonitrile hydrochloride [ka] [ka]

[0286] [(3R,5S)-1-(8-cyano-[1,7]naphthirizine-5-yl)-5-methyl-piperizine-3-yl]-carbamate tert-butyl ester: In a 30 ml microwave vial, 5-bromo-[1,7]naphthirizine-8-carbonitrile (470 mg; 2.01 mmol; 1.0 eq.), ((3R,5S)-5-methyl-piperizine-3-yl)-carbamate tert-butyl ester (451 mg; 2.11 mmol; 1.05 eq.), triethylamine (0.56 ml; 4.02 mmol; 2.0 eq.), and DMF (4.7 ml) were added. The vial was sealed and microwaved at 130°C for 3 hours until the reaction was complete. The title compound (610 mg, 82.7%) was obtained by removing the solvent and purifying the residue by silica column elution with 0–55% EA / hexane. LC-MS (M+1) = 368.

[0287] 5-((3R,5S)-3-amino-5-methylpiperidine-1-yl)-[1,7]naphthirizine-8-carbonitrile hydrochloride (2): To a solution of [(3R,5S)-1-(8-cyano-[1,7]naphthirizine-5-yl)-5-methylpiperidine-3-yl]-carbamate tert-butyl (20 mg; 0.05 mmol; 1.0 eq.) in 1 ml of methanol, hydrogen chloride (4.0 M in dioxane) (0.27 ml; 1.09 mmol; 20.0 eq.) was added, and the reaction was stirred at rt for 3 hours until the reaction was complete. After removal of the solvent, a yellow product was produced in quantitative yield as the title compound. LC-MS (M+1) = 268. 1H NMR (400 MHz, methanol-d4) δ 9.15 (dd, J = 4.1, 1.2 Hz, 1H), 8.66 - 8.56 (m, 1H), 8.41 (s, 1H), 7.87 (dd, J = 8.6, 4.1 Hz, 1H), 3.87 (dd, J = 11.1, 3.1 Hz, 1H), 3.80 - 3.72 (m, 1H), 3.67 (s, 1H), 3.64 - 3.54 (m, 2H), 3.37 (s, 1H), 2.99 (t, J = 11.0 Hz, 1H), 2.68 (t, J = 11.6 Hz, 1H), 2.40 - 2.14 (m, 2H), 1.36 - 1.23 (m, 2H), 1.10 (d, J = 6.5 Hz, 3H). Example 9: 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-[1,7]naphthyridine-8-carbonitrile [ka]

[0288] [(3R,5S)-1-(8-chloro-[1,7]naphthirizine-5-yl)-5-trifluoromethyl-piperizine-3-yl]-carbamate tert-butyl ester: In a 20 ml microwave vial, 5-bromo-8-chloro-[1,7]naphthirizine (560 mg; 2.30 mmol; 1.0 eq.), ((3R,5S)-5-trifluoromethyl-piperizine-3-yl)-carbamate tert-butyl ester (617 mg; 2.30 mmol; 1.0 eq.), RuPhos (53 mg; 0.11 mmol; 0.05 eq.), and dioxane (10 ml) were added. The mixture was degassed, and then 2-methylpropan-2-ol sodium (243 mg; 2.53 mmol; 1.10 eq.) and bis(tri-tert-butylphosphine)palladium (0) (58.8 mg; 0.11 mmol; 0.05 eq.) were added. The resulting mixture was stirred at 90°C for 4 hours until the reaction was complete. The crude product was purified by silica column chromatography to produce the title compound (300 mg, 30% yield). LC-MS (M+1) = 431 / 433.

[0289] In 10 ml of microwave tube, a solution of [(3R,5S)-1-(8-chloro-[1,7]naphthirizine-5-yl)-5-trifluoromethyl-piperizine-3-yl]-carbamate tert-butyl ester (170 mg; 0.39 mmol; 1.0 eq.) in 1 ml of DMF was mixed with zinc cyanide (92 mg; 0.79 mmol; 2.0 eq.) and 1,1'-bis(diphenylphosphino)ferrocene (22 mg; 0.04 mmol; 0.10 eq.). The mixture was degassed, and then bis(tri-tert-butylphosphine)palladium(0) (10 mg; 0.02 mmol; 0.05 eq.) was added. The tube was capped, and the mixture was microwaved at 150°C for 2 hours until the reaction was complete. The crude product was purified by preparative HPLC elution with 20-70% ACN / water (containing 0.1% ammonia) to obtain the title compound. LC-MS (M+1) = 322. 1 H NMR (400 MHz, methanol-d4) δ 9.15 (dd, J = 4.2, 1.6 Hz, 1H), 8.59 (dd, J = 8.7, 1.6 Hz, 1H), 8.42 (s, 1H), 7.86 (dd, J = 8.7, 4.2 Hz, 1H), 4.56 (s, 1H), 3.81 - 3.64 (m, 2H), 3.25 (td, J = 10.9, 5.4 Hz, 1H), 3.07 - 2.90 (m, 1H), 2.72 (dd, J = 11.7, 10.7 Hz, 1H), 2.38 (d, J = 13.0 Hz, 1H), 1.43 (dd, J = 12.3, 4.9 Hz, 2H), 1.36 - 1.21 (m, 1H). Example 10: (3R,5S)-1-(8-ethoxy-[1,7]naphthyridine-5-yl)-5-trifluoromethylpiperidine-3-ylamine [ka]

[0290] To a solution of [(3R,5S)-1-(8-chloro-[1,7]naphthyrizin-5-yl)-5-trifluoromethyl-piperidine-3-yl]-carbamate tert-butyl ester (300 mg; 0.01 mmol; 1.0 eq.) in ethanol (0.4 ml), sodium hydroxide (2.0 M aqueous solution) (1.0 ml; 2.0 mmol; 287.23 eq.) was added. The resulting mixture was stirred at 130°C for 24 hours until the reaction was complete. The crude product was purified by preparative HPLC elution with 20-70% ACN / water (containing 0.1% ammonia) to provide the title compound. LC-MS (M+1) = 341. 1 H NMR (400 MHz,) δ 8.11 (dd, J = 4.2, 1.7 Hz, 1H), 7.73 (dd, J = 8.5, 1.7 Hz, 1H), 7.05 (s, 1H), 7.03 - 6.97 (m, 1H), 3.81 (q, J = 7.1 Hz, 2H), 2.66 - 2.54 (m, 2H), 2.52 (p, J = 1.6 Hz, 2H), 2.38 (ddd, J = 15.2, 10.6, 4.2 Hz, 1H), 2.16 - 2.01 (m, 2H), 1.74 (t, J = 10.8 Hz, 1H), 1.52 (d, J = 12.7 Hz, 1H), 0.73 (td, J = 7.1, 1.8 Hz, 3H), 0.63 - 0.48 (m, 1H). Example 11: 4-{[(3R,5S)-5-methyl-1-(8-trifluoromethyl-[1,7]naphthyridine-5-yl)-piperidine-3-ylamino]-methyl}tetrahydropyran-4-ol [ka]

[0291] A mixture of (3R,5S)-5-methyl-1-(8-trifluoromethyl-[1,7]naphthyrizin-5-yl)-piperidine-3-ylamine (50 mg; 0.16 mmol; 1.0 eq.), 4-bromomethyl-tetrahydropyran-4-ol (47 mg; 0.24 mmol; 1.50 eq.), and potassium carbonate (33 mg; 0.24 mmol; 1.50 eq.) in DMSO (1 ml) was stirred at 80°C for 24 hours. The reaction mixture was cooled to rt. The crude product was purified by preparative HPLC elution with 20-70% ACN (containing 0.1% ammonia) in water to produce the title compound. LC-MS (M+1) = 425. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 3.9 Hz, 1H), 8.55 (d, J = 8.6 Hz, 1H), 8.20 (s, 1H), 7.86 (dd, J = 8.8, 4.1 Hz, 1H), 4.29 (d, J = 12.2 Hz, 2H), 4.04 (dd, J = 11.7, 3.4 Hz, 1H), 3.66 - 3.49 (m, 4H), 2.81 (dd, J = 13.5, 8.2 Hz, 1H), 2.57 (d, J = 4.5 Hz, 2H), 2.08 (d, J = 12.1 Hz, 2H), 1.91 (s, 1H), 1.64 - 1.51 (m, 3H), 1.39 (d, J = 13.3 Hz, 2H), 0.93 (m, J = 7.3 Hz, 4H).

[0292] The following compounds were synthesized using a similar method. Example 12: 8-[(3R,5S)-3-(1,1-dioxo-1-lambda6-thietan-3-ylamino)-5-methyl-piperidine-1-yl]-quinoxaline-5-carbonitrile [ka]

[0293] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile hydrochloride (2) and 3-bromothietan 1,1-dioxide. LC-MS (M+1) = 372. 1 H NMR (400 MHz, DMSO-d6) δ 9.0 (dd, J = 27.4, 1.7 Hz, 2H), 8.17 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 4.52 - 4.24 (m, 3H), 4.13 (d, J = 12.4 Hz, 1H), 3.92 (dt, J = 13.0, 6.1 Hz, 2H), 3.76 (h, J = 7.1 Hz, 1H), 2.89 - 2.69 (m, 1H), 2.59 (dp, J = 11.7, 5.5 Hz, 3H), 2.10 - 1.98 (m, 1H), 1.88 (d, J = 6.6 Hz, 1H), 1.04 - 0.73 (m, 4H). Example 13: (1,1-Dioxo-1-lambda6-thietan-3-yl)-[(3R,5S)-5-methyl-1-(8-trifluoromethylquinoline-5-yl)-piperidine-3-yl]amine [ka]

[0294] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine and 3-bromothietan 1,1-dioxide. LC-MS (M+1) = 414. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 4.2 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.7, 4.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 4.32 (dt, J = 21.0, 10.3 Hz, 2H), 3.99 - 3.87 (m, 2H), 3.75 (q, J = 7.3 Hz, 1H), 3.51 (d, J = 11.2 Hz, 1H), 2.95 (d, J = 32.9 Hz, 1H), 2.59 (t, J = 6.8 Hz, 1H), 2.38 (q, J = 12.3, 11.8 Hz, 2H), 2.13 - 1.84 (m, 2H), 0.90 (dd, J = 26.8, 9.1 Hz, 3H). 0.85-0.9 (m, 1H). Example 14: 8-{(3R,5S)-3-[(4-hydroxy-tetrahydropyran-4-ylmethyl)-amino]-5-methyl-piperidine-1-yl}quinoxaline-5-carbonitrile [ka]

[0295] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile and 4-bromomethyl-tetrahydropyran-4-ol. LC-MS (M+1) = 382. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 34.5, 1.7 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.18 (d, J = 14.2 Hz, 2H), 3.60 (d, J = 12.6 Hz, 3H), 2.77 (s, 1H), 2.68 - 2.55 (m, 2H), 2.07 (d, J = 13.0 Hz, 1H), 1.88 (s, 2H), 1.57 (d, J = 13.0 Hz, 2H), 1.39 (d, J = 13.3 Hz, 2H), 1.01 - 0.83 (m, 3H). Example 15: 3-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-ylamino]-2-fluoro-2-methylpropionic acid [ka]

[0296] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrilate hydrochloride and 3-bromo-2-fluoro-2-methyl-propionate methyl ester. LC-MS (M+1) = 372. 1 H NMR (400 MHz, methanol-d4) δ 8.92 (dd, J = 12.8, 1.8 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.39 - 4.14 (m, 3H), 4.07 - 3.62 (m, 3H), 2.97 (dd, J = 11.7, 9.9 Hz, 1H), 2.74 (dd, J = 12.4, 10.3 Hz, 1H), 2.19 - 2.0 (m, 2H), 1.63 - 1.37 (m, 4H), 1.04 (d, J = 6.4 Hz, 3H). Example 16: 8-[(3R,5S)-3-(2-hydroxy-2-methylpropylamino)-5-methyl-piperidine-1-yl]-quinoxaline-5-carbonitrile formic acid [ka]

[0297] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile hydrochloride and 1-bromo-2-methylpropan-2-ol. LC-MS (M+1) = 340. 1 H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.24 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 4.45 (dd, J = 11.8, 2.7 Hz, 1H), 4.18 (dd, J = 13.1, 3.5 Hz, 1H), 2.79 (dq, J = 10.8, 5.3, 3.8 Hz, 1H), 2.62 (td, J = 11.7, 4.9 Hz, 2H), 2.55 - 2.52 (m, 2H), 2.07 (d, J = 12.3 Hz, 1H), 1.88 (dq, J = 10.8, 7.0 Hz, 1H), 1.09 (s, 6H), 1.0 - 0.80 (m, 4H). Example 17: 2-methyl-1-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-propane-2-ol [ka]

[0298] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethylquinoline-5-yl)-piperidine-3-ylamine hydrochloride and 1-bromo-2-methylpropan-2-ol. LC-MS (M+1) = 382. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.1, 1.7 Hz, 1H), 8.48 (dd, J = 8.6, 1.8 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 8.6, 4.1 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.12 (s, 1H), 3.54 (d, J = 10.9 Hz, 1H), 2.88 (d, J = 10.8 Hz, 1H), 2.64 - 2.22 (m, 5H), 2.18 - 1.93 (m, 2H), 1.52 (s, 1H), 1.07 (s, 6H), 1.03 - 0.55 (m, 4H). Example 18: 2-{[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]amino}-1-(morpholine-4-yl)ethane-1-one [ka]

[0299] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-aminium trifluoroacetate and 4-(bromoacetyl)morpholine. MS: 437 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.04 (dd, J = 4.2, 1.7 Hz, 1H), 8.42 (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), 7.08 (d, J = 7.9 Hz, 1H), 3.73 - 3.60 (m, 6H), 3.55 - 3.52 (m, 3H), 3.40 (t, J = 4.8 Hz, 2H), 3.36 - 3.30 (m, 1H), 3.10 - 3.02 (m, 1H), 2.66 (dd, J = 10.6, 7.6 Hz, 1H), 2.37 (t, J = 11.4 Hz, 1H), 2.25 - 2.17 (m, 1H), 1.09 (q, J = 11.9 Hz, 1H), 1.0 (d, J = 6.6 Hz, 3H). Example 19: N-(2-{[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]amino}ethyl)aminosulfonamide [ka]

[0300] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-aminium trifluoroacetate and [(2-bromoethyl)sulfamoyl]amine. MS: 432 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J = 4.1 Hz, 1H), 8.44 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.49 (dd, J = 8.6, 4.2 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 3.81 - 3.74 (m, 2H), 3.31 (d, J = 11.6 Hz, 1H), 3.13 - 3.07 (m, 2H), 2.93 - 2.84 (m, 2H), 2.53 (d, J = 12.0 Hz, 1H), 2.37 (t, J = 11.3 Hz, 1H), 2.28 (d, J = 12.4 Hz, 1H), 2.18 - 2.08 (m, 1H), 1.12 - 0.94 (m, 4H). Example 20: N-(2-{[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]amino}ethyl)methanesulfonamide [ka]

[0301] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-aminium trifluoroacetate and N-(2-bromoethyl)methanesulfonamide. MS: 431 [M+H] + . 1H NMR (400 MHz, CDCl3) δ 9.09 - 9.01 (m, 1H), 8.43 (dd, J = 8.5, 1.5 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 8.6, 4.2 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 3.56 (d, J = 11.2 Hz, 1H), 3.33 (d, J = 11.7 Hz, 1H), 3.21 (t, J = 5.6 Hz, 2H), 3.10 - 2.83 (m, 6H), 2.44 (t, J = 10.7 Hz, 1H), 2.36 (t, J = 11.3 Hz, 1H), 2.19 (d, J = 12.7 Hz, 1H), 2.13 - 2.03 (m, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.98 - 0.87 (m, 1H). Example 21: 8-[(3R,5S)-3-[(3-methanesulfonylpropyl)amino]-5-methylpiperidine-1-yl]quinoxaline-5-carbonnitrile methanesulfonamide [ka]

[0302] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-aminium trifluoroacetate and 1-bromo-3-methanesulfonylpropane. MS: 388 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 1.8 Hz, 1H), 8.94 (d, J = 1.8 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.14 (d, J = 12.2 Hz, 1H), 3.30 (d, J = 1.2 Hz, 2H), 3.16 (dd, J = 6.4, 4.0 Hz, 2H), 2.96 (s, 3H), 2.86 - 2.67 (m, 2H), 2.65 - 2.52 (m, 2H), 2.50 (p, J = 1.8 Hz, 4H), 2.05 (d, J = 12.5 Hz, 1H), 1.95 - 1.66 (m, 3H), 0.93 (t, J = 6.6 Hz, 4H). Example 22: 3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamino]-propionamide [ka]

[0303] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamine hydrochloride and 3-bromo-propionamide. LC-MS (M+1) = 382. 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 21.1, 1.8 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.34 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.73 (s, 1H), 4.28 (d, J = 11.4 Hz, 1H), 4.02 (d, J = 11.8 Hz, 1H), 2.80 (d, J = 6.4 Hz, 3H), 2.48 - 2.43 (m, 1H), 2.21 (t, J = 6.8 Hz, 2H), 2.05 (d, J = 12.5 Hz, 1H), 1.91 (s, 1H), 1.64 (d, J = 6.5 Hz, 1H), 1.01 - 0.76 (m, 4H). Example 23: N-{2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamino]-ethyl}methanesulfonamide [ka]

[0304] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamine hydrochloride and N-(2-bromo-ethyl)-methanesulfonamide. LC-MS (M+1) = 432. 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 21.3, 1.8 Hz, 2H), 8.04 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.5, 4.1 Hz, 1H), 6.92 (s, 1H), 4.30 (d, J = 11.0 Hz, 1H), 4.07 - 3.92 (m, 1H), 3.03 (t, J = 6.5 Hz, 2H), 2.91 (s, 3H), 2.83 (d, J = 10.7 Hz, 1H), 2.74 (t, J = 5.7 Hz, 2H), 2.48 - 2.43 (m, 2H), 2.06 (d, J = 13.1 Hz, 1H), 1.99 - 1.83 (m, 1H), 1.75 (s, 1H), 1.0 - 0.80 (m, 4H). Example 24: N-{2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamino]-ethyl}methanesulfonamide [ka]

[0305] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamine hydrochloride and N-(2-bromoethyl)ethane-1-sulfonamide. LC-MS (M+1) = 446. 1H NMR (400 MHz, DMSO-d6) δ 8.99 (d, J = 22.3 Hz, 2H), 8.04 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 4.31 (d, J = 11.7 Hz, 1H), 4.0 (d, J = 11.9 Hz, 1H), 3.08 - 2.93 (m, 4H), 2.83 (d, J = 11.2 Hz, 1H), 2.72 (s, 2H), 2.45 (d, J = 11.1 Hz, 2H), 2.05 (d, J = 12.2 Hz, 1H), 1.91 (s, 1H), 1.75 (s, 1H), 1.19 (td, J = 7.3, 2.0 Hz, 3H), 1.01 - 0.78 (m, 4H). Example 25: N-{2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamino]-ethyl}acetamidoformate [ka]

[0306] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamine hydrochloride and N-(2-chloro-ethyl)-acetamide. LC-MS (M+1) = 442. 1H NMR (400 MHz, methanol-d4) δ 9.0 - 8.87 (m, 2H), 8.54 (s, 1H), 8.08 (t, J = 6.5 Hz, 1H), 7.30 (t, J = 9.6 Hz, 1H), 4.31 (d, J = 11.8 Hz, 1H), 4.17 (q, J = 12.3 Hz, 1H), 3.97 (d, J = 12.0 Hz, 1H), 3.84 (d, J = 12.3 Hz, 1H), 3.77 (dt, J = 10.7, 5.2 Hz, 2H), 3.57 (d, J = 5.4 Hz, 1H), 3.45 (d, J = 5.6 Hz, 1H), 2.79 (t, J = 11.1 Hz, 1H), 2.74 - 2.59 (m, 1H), 2.37 (d, J = 2.2 Hz, 2H), 2.23 (q, J = 31.3, 22.4 Hz, 2H), 1.46 (q, J = 11.9 Hz, 1H), 1.30 (q, J = 11.9 Hz, 1H), 1.16 - 0.99 (m, 3H). Example 26: 4-{[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamino]-methyl}tetrahydropyran-4-ol [ka]

[0307] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamine hydrochloride and N-(2-chloro-ethyl)-acetamide. LC-MS (M+1) = 425. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 22.3 Hz, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 4.29 (d, J = 12.2 Hz, 2H), 4.04 (dd, J = 11.7, 3.4 Hz, 1H), 3.69 - 3.48 (m, 4H), 2.81 (dd, J = 13.5, 8.2 Hz, 2H), 2.57 (d, J = 4.5 Hz, 2H), 2.08 (d, J = 12.1 Hz, 1H), 1.91 (s, 1H), 1.61 - 1.45 (m, 2H), 1.39 (d, J = 13.3 Hz, 2H), 0.93 (t, J = 7.3 Hz, 4H). Example 27: 1-{2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-ethyl}imidazolidined-2-one [ka]

[0308] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride and 1-(2-bromo-ethyl)-imidazolidined-2-one. LC-MS (M+1) = 422. 1H NMR (400 MHz, DMSO-d6) δ 9.0 (d, J = 4.1 Hz, 1H), 8.49 (d, J = 8.6 Hz, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.6, 4.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.22 (s, 1H), 3.60 - 3.47 (m, 1H), 3.34 (dd, J = 8.9, 6.5 Hz, 2H), 3.20 (t, J = 7.9 Hz, 2H), 3.09 (hept, J = 6.6 Hz, 2H), 2.95 (s, 1H), 2.69 (s, 2H), 2.37 (td, J = 11.1, 7.1 Hz, 2H), 2.14 - 1.85 (m, 2H), 1.62 (s, 1H), 0.94 (d, J = 6.5 Hz, 3H), 0.84 (t, J = 11.7 Hz, 1H). Example 28: 5-{[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamino]-methyl}pyrrolidine-2-one [ka]

[0309] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamine hydrochloride and 5-bromomethyl-pyrrolidine-2-one. LC-MS (M+1) = 408. 1H NMR (400 MHz, methanol-d4) δ 9.05 - 8.89 (m, 2H), 8.42 (s, 1H), 8.08 (t, J = 8.5 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 4.50 (d, J = 11.2 Hz, 1H), 3.94 (d, J = 14.0 Hz, 2H), 3.75 (m, 1H), 3.37 (d, J = 11.7 Hz, 1H), 3.13 (d, J = 4.7 Hz, 1H), 2.99 (dd, J = 13.0, 7.6 Hz, 1H), 2.71 (t, J = 11.0 Hz, 1H), 2.61 (q, J = 11.9 Hz, 1H), 2.37 (td, J = 23.1, 19.0, 10.1 Hz, 3H), 2.13 (s, 1H), 1.91 (d, J = 11.4 Hz, 1H), 1.25 (dt, J = 46.9, 12.0 Hz, 1H), 1.09 (dd, J = 9.7, 7.2 Hz, 3H). Example 29: 3-{2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-ethyl}oxazolidine-2-one [ka]

[0310] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride and 3-(2-bromo-ethyl)-oxazolidine-2-one. LC-MS (M+1) = 423. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 3.9 Hz, 1H), 8.49 (dd, J = 8.6, 1.6 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 8.6, 4.2 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.23 (t, J = 8.0 Hz, 2H), 3.55 (q, J = 7.0, 5.7 Hz, 2H), 3.29 (s, 1H), 3.22 (td, J = 6.5, 2.9 Hz, 2H), 2.95 (s, 1H), 2.82 - 2.65 (m, 2H), 2.38 (td, J = 11.1, 5.2 Hz, 2H), 2.06 (dd, J = 32.7, 11.4 Hz, 2H), 1.75 (d, J = 6.6 Hz, 1H), 0.99 - 0.87 (m, 3H), 0.83 (d, J = 11.7 Hz, 1H). Example 30: 3-{2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-ethyl}pyrrolidine-2-one [ka]

[0311] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride and 3-(2-bromo-ethyl)-pyrrolidine-2-one. LC-MS (M+1) = 421. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 4.1 Hz, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 8.6, 4.2 Hz, 1H), 7.49 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 3.53 (d, J = 11.3 Hz, 1H), 3.21 - 3.04 (m, 2H), 2.92 (s, 1H), 2.64 (s, 2H), 2.44 - 2.30 (m, 2H), 2.25 (dd, J = 9.1, 4.6 Hz, 1H), 2.21 - 1.91 (m, 3H), 1.89 - 1.73 (m, 1H), 1.61 (d, J = 9.7 Hz, 2H), 1.32 (dt, J = 14.2, 7.9 Hz, 1H), 0.94 (d, J = 6.5 Hz, 3H), 0.89 - 0.76 (m, 1H). Example 31: 3-{2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamino]-ethyl}oxazolidine-2-ongformic acid [ka]

[0312] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamine hydrochloride and 3-(2-bromo-ethyl)-oxazolidine-2-one. LC-MS (M+1) = 424. 1H NMR (400 MHz, methanol-d4) δ 8.94 (d, J = 6.4 Hz, 2H), 8.47 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.41 (t, J = 8.1 Hz, 2H), 3.94 (d, J = 11.8 Hz, 1H), 3.71 (t, J = 8.3 Hz, 2H), 3.57 (s, 2H), 3.46 (s, 1H), 3.19 (d, J = 6.2 Hz, 2H), 2.74 (t, J = 11.0 Hz, 1H), 2.61 (t, J = 11.5 Hz, 1H), 2.31 (d, J = 12.5 Hz, 1H), 2.12 (s, 1H), 1.18 (q, J = 12.0 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H). Example 32: 3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-propane-1-sulfonate methylamide [ka]

[0313] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine and 3-chloropropane-1-sulfonic acid methylamide. LC-MS (M+1) = 445. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 10.3 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.86 (s, 1H), 3.53 (d, J = 11.2 Hz, 1H), 3.04 (t, J = 7.9 Hz, 1H), 2.90 (s, 1H), 2.68 (s, 2H), 2.56 (t, J = 2.7 Hz, 2H), 2.38 (d, J = 9.2 Hz, 3H), 2.17 - 1.90 (m, 3H), 1.87 (s, 1H), 1.83 - 1.64 (m, 2H), 1.03 - 0.91 (m, 3H), 0.91 - 0.79 (m, 1H). Example 33: 2-methyl-4-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-butan-2-ol [ka]

[0314] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethylquinoline-5-yl)-piperidine-3-ylamine hydrochloride and 4-bromo-2-methylbutan-2-ol. LC-MS (M+1) = 396. 1H NMR (400 MHz, methanol-d4) δ 9.0 - 8.83 (m, 1H), 8.61 (d, J = 8.6 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.61 (dt, J = 6.4, 3.0 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 3.64 (d, J = 11.3 Hz, 1H), 3.40 (s, 1H), 3.08 (d, J = 11.3 Hz, 1H), 2.87 (p, J = 9.8, 8.3 Hz, 2H), 2.48 (dt, J = 23.2, 11.1 Hz, 2H), 2.24 (d, J = 12.7 Hz, 1H), 2.13 (s, 2H), 1.70 (t, J = 7.6 Hz, 2H), 1.23 (s, 6H), 1.08 - 0.77 (m, 4H). Example 34: 3-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-ylamino]-propane-1-sulfonamide [ka]

[0315] 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile (50 mg; 0.19 mmol; 1.0 eq.), 3-bromo-propane-1-sulfonamide (56 mg; 0.28 mmol; 1.50 eq.), ethyl-diisopropylamine (0.08 ml; 0.47 mmol; 2.50 eq.), and NMP (1 ml) were placed in a microwave tube. The mixture was stirred at 80°C for 4 hours. The crude product was purified by preparative HPLC elution with 10-60% ACN / water (containing 0.1% ammonia) to obtain the title compound (33 mg, yield: 45%). LC-MS (M+1) = 389. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 31.1, 1.9 Hz, 2H), 8.16 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.75 (s, 2H), 4.50 - 4.36 (m, 1H), 4.20 - 4.09 (m, 1H), 3.03 (dd, J = 9.1, 6.5 Hz, 2H), 2.85 - 2.63 (m, 3H), 2.58 (dt, J = 15.5, 11.4 Hz, 2H), 2.05 (d, J = 12.6 Hz, 1H), 1.83 (p, J = 7.0 Hz, 3H), 1.01 - 0.85 (m, 3H).

[0316] The following compounds were synthesized using a similar method. Example 35: 5-[(3R,5S)-3-(2,3-dihydroxypropylamino)-5-methylpiperidine-1-yl]-[1,7]naphthyridine-8-carbonitrile [ka]

[0317] The title compound was prepared from 5-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-[1,7]naphthyridine-8-carbonitrile and 3-bromo-propane-1,2-diol. MS: 342.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 4.1 Hz, 1H), 8.48 (d, J = 8.6 Hz, 1H), 8.36 (s, 1H), 7.86 (dd, J = 8.7, 4.2 Hz, 1H), 5.75 (s, 3H), 3.81 - 3.72 (m, 2H), 3.57 - 3.48 (m, 3H), 2.92 (s, 1H), 2.73 (dd, J = 11.9, 4.5 Hz, 1H), 2.60 (q, J = 10.6 Hz, 2H), 2.54 (s, 1H), 2.09 (d, J = 12.6 Hz, 1H), 1.99 (s, 1H), 0.95 (d, J = 6.6 Hz, 3H). Example 36: N-hydroxy-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-propionamide [ka]

[0318] A mixture of (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine (55.0 mg; 0.18 mmol; 1.0 eq.), 3-chloro-N-hydroxypropionamide (32.95 mg; 0.27 mmol; 1.50 eq.), and triethylamine (44.98 mg; 0.44 mmol; 2.50 eq.) in DMSO (1 ml) was stirred overnight at 80°C. Once complete, the reaction was purified by preparative HPLC on an acetonitrile / water (0.1% NH4OH modified) gradient to produce the title compound (4.50 mg; 0.01 mmol; 6.4%). MS: 397.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.1, 1.7 Hz, 1H), 8.48 (dt, J = 10.1, 3.1 Hz, 1H), 8.08 - 8.02 (m, 1H), 7.68 - 7.63 (m, 1H), 7.34 (s, 1H), 7.19 (d, J = 8.1 Hz, 1H), 3.57 - 3.48 (m, 1H), 3.32 (s, 2H), 2.99 - 2.89 (m, 1H), 2.85 - 2.72 (m, 1H), 2.37 (td, J = 10.9, 4.7 Hz, 2H), 2.20 (t, J = 6.8 Hz, 1H), 2.12 - 1.95 (m, 2H), 0.93 (dd, J = 6.5, 3.5 Hz, 3H), 0.86 (q, J = 11.5 Hz, 1H). Example 37: N-{2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-ethyl}acetamidoformate [ka]

[0319] In a 10 ml microwave tube, a mixture of (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride (300 mg; 0.87 mmol; 1.0 eq.), N-(2-chloro-ethyl)-acetamide (166 mg; 1.30 mmol; 1.50 eq.), sodium iodide (39.01 mg; 0.26 mmol; 0.30 eq.), and triethylamine (0.30 ml; 2.17 mmol; 2.50 eq.) in ACN (3 ml) was stirred at 80°C for 72 hours until the reaction was complete. The reaction mixture was cooled to rt. The crude product was purified by preparative HPLC elution with 20-60% CAN / water (containing 0.1% ammonia) to produce the title compound (150 mg, yield 39%). LC-MS (M+1) = 372. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 4.1 Hz, 1H), 8.58 (dd, J = 24.6, 8.7 Hz, 1H), 8.42 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 8.7, 4.2 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.18 (d, J = 25.1 Hz, 1H), 4.0 (s, 1H), 3.69 - 3.46 (m, 4H), 2.79 (t, J = 10.9 Hz, 1H), 2.64 (d, J = 10.4 Hz, 1H), 2.40 (t, J = 9.8 Hz, 1H), 2.33 (s, 1H), 2.24 (s, 1H), 2.20 - 2.06 (m, 2H), 1.33 (d, J = 12.4 Hz, 1H), 1.16 (q, J = 13.2, 12.3 Hz, 1H), 0.97 (d, J = 6.3 Hz, 3H).

[0320] The following compounds were synthesized using a similar method. Example 38: 3-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-trifluoromethylpiperidine-3-ylamino]-propane-1-sulfonamide [ka]

[0321] The title compound was prepared from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrile and 3-bromo-propane-1-sulfonamide. LC-MS (M+1) = 442. 1H NMR (400 MHz, DMSO-d6) δ 9.06 (d, J = 4.2 Hz, 1H), 8.51 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.71 (dd, J = 8.9, 4.2 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.74 (s, 2H), 3.57 (t, J = 13.5 Hz, 3H), 3.02 (dd, J = 9.1, 6.7 Hz, 4H), 2.88 (t, J = 11.4 Hz, 1H), 2.70 (d, J = 6.8 Hz, 2H), 2.29 (d, J = 12.2 Hz, 1H), 2.03 (d, J = 47.9 Hz, 1H), 1.81 (t, J = 7.8 Hz, 2H), 1.25 (q, J = 12.0 Hz, 1H), 0.95 (d, J = 6.6 Hz, 1H). Example 39: 3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-propane-1-sulfonamide [ka]

[0322] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine and 3-bromo-propane-1-sulfonamide. LC-MS (M+1) = 431. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.1, 1.9 Hz, 1H), 8.56 - 8.45 (m, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.8, 4.2 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.74 (s, 2H), 3.53 (d, J = 11.7 Hz, 1H), 3.02 (dd, J = 9.2, 6.4 Hz, 2H), 2.91 (s, 1H), 2.69 (h, J = 5.2 Hz, 2H), 2.37 (td, J = 11.3, 4.0 Hz, 2H), 2.15 - 1.90 (m, 2H), 1.82 (q, J = 7.3 Hz, 2H), 0.94 (d, J = 6.4 Hz, 3H), 0.86 (q, J = 11.9 Hz, 1H). Example 40: {2-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-trifluoromethylpiperidine-3-ylamino]-ethyl}urea [ka]

[0323] The title compound was prepared from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrile and (2-chloro-ethyl)-urea. LC-MS (M+1) = 407. 1H NMR (400 MHz, DMSO-d6) δ 9.10 - 8.99 (m, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.72 (dd, J = 8.6, 4.2 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 5.89 (d, J = 5.9 Hz, 1H), 5.42 (s, 2H), 3.57 (t, J = 12.6 Hz, 2H), 3.03 (q, J = 6.4 Hz, 3H), 2.88 (t, J = 11.4 Hz, 1H), 2.63 (d, J = 6.5 Hz, 2H), 2.29 (d, J = 12.5 Hz, 1H), 1.87 (s, 1H), 1.25 (q, J = 12.0 Hz, 1H). Example 41: N-{2-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-ylamino]-ethyl}methanesulfonamide [ka]

[0324] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile hydrochloride (2) and N-(2-bromo-ethyl)-methanesulfonamide. LC-MS (M+1) = 389. 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (dd, J = 32.5, 1.7 Hz, 2H), 8.17 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.92 (s, 1H), 4.46 (d, J = 12.3 Hz, 1H), 4.14 (d, J = 12.2 Hz, 1H), 3.02 (t, J = 6.5 Hz, 2H), 2.91 (s, 3H), 2.83 - 2.67 (m, 2H), 2.59 (dt, J = 17.0, 11.3 Hz, 3H), 2.05 (d, J = 12.4 Hz, 1H), 1.82 (d, J = 44.5 Hz, 2H), 1.04 - 0.84 (m, 3H). Example 42: 8-{(3R,5S)-3-[(1,1-dioxotetrahydro-1-lambda6-thiophen-3-ylmethyl)-amino]-5-methyl-piperidine-1-yl}quinoxaline-5-carbonitrile [ka]

[0325] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile hydrochloride (2) and 3-bromomethyl-tetrahydrothiophene 1,1-dioxide. LC-MS (M+1) = 400. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 - 8.86 (m, 2H), 8.16 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H), 4.15 (d, J = 12.4 Hz, 1H), 3.26 - 3.10 (m, 2H), 3.04 (q, J = 12.2, 10.6 Hz, 1H), 2.86 - 2.65 (m, 3H), 2.65 - 2.54 (m, 2H), 2.22 (s, 1H), 2.05 (d, J = 13.1 Hz, 1H), 1.94 - 1.70 (m, 3H), 0.93 (d, J = 6.8 Hz, 4H). Example 43: 8-{(3R,5S)-3-[2-(1,1-dioxo-1-lambda6-thietan-3-yl)-ethylamino]-5-methyl-piperidine-1-yl}quinoxaline-5-carbonitrile [ka]

[0326] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile hydrochloride (2) and 3-(2-bromo-ethyl)thietan 1,1-dioxide. LC-MS (M+1) = 400. 1H NMR (400 MHz, methanol-d4) δ 8.92 (d, J = 17.1 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.58 (d, J = 11.9 Hz, 1H), 4.26 (dd, J = 14.1, 9.6 Hz, 2H), 4.21 - 4.07 (m, 1H), 3.86 (dd, J = 14.2, 6.6 Hz, 2H), 3.02 (t, J = 10.9 Hz, 1H), 2.73 (q, J = 6.6 Hz, 1H), 2.63 (dt, J = 13.5, 6.6 Hz, 2H), 2.20 (d, J = 12.5 Hz, 1H), 1.93 (q, J = 7.4 Hz, 2H), 1.04 (d, J = 6.8 Hz, 3H). Example 44: N-{2-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-trifluoromethylpiperidine-3-ylamino]-ethyl}acetamide [ka]

[0327] The title compound was prepared from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrile and N-(2-chloro-ethyl)-acetamide. LC-MS (M+1) = 406. 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (d, J = 4.3 Hz, 1H), 8.70 - 8.52 (m, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.5, 4.2 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 6.37 (s, 1H), 4.02 (s, 1H), 3.69 (s, 1H), 3.56 (d, J = 11.1 Hz, 1H), 3.44 (s, 2H), 3.13 (s, 3H), 2.93 (s, 1H), 2.68 (s, 1H), 2.01 (d, J = 19.4 Hz, 1H), 1.96 - 1.66 (m, 3H), 1.60 - 1.30 (m, 1H). Example 45: {2-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-ethyl}urea [ka]

[0328] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine and (2-chloro-ethyl)-urea. LC-MS (M+1) = 396. 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d, J = 4.2 Hz, 1H), 8.54 - 8.42 (m, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.67 (dd, J = 8.6, 4.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 5.94 (d, J = 34.6 Hz, 1H), 5.45 (d, J = 22.7 Hz, 2H), 3.53 (d, J = 11.1 Hz, 1H), 3.03 (q, J = 6.1 Hz, 2H), 2.92 (s, 1H), 2.67 - 2.54 (m, 2H), 2.37 (q, J = 10.2, 9.5 Hz, 2H), 2.18 - 1.89 (m, 2H), 1.65 (s, 1H), 0.94 (d, J = 6.5 Hz, 3H), 0.86 (q, J = 11.8 Hz, 1H). Example 46: Ethanesulfonic acid {2-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-ylamino]-ethyl}amide [ka]

[0329] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile and ethanesulfonic acid (2-bromo-ethyl)amide. LC-MS (M+1) = 403. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 33.6 Hz, 2H), 8.16 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 6.95 (s, 1H), 4.46 (d, J = 11.8 Hz, 1H), 4.13 (d, J = 12.3 Hz, 1H), 3.01 (q, J = 7.4 Hz, 3H), 2.76 (d, J = 36.2 Hz, 3H), 2.59 (dd, J = 20.2, 10.9 Hz, 1H), 2.04 (d, J = 12.7 Hz, 1H), 1.83 (d, J = 41.6Hz, 2H), 1.25 - 1.11 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H). Example 47: 8-{(3S,5R)-3-methyl-5-[(oxetan-3-ylmethyl)-amino]-piperidine-1-yl}quinoxaline-5-carbonitrile [ka]

[0330] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrine and 3-bromomethyl-oxetane. LC-MS (M+1) = 338. 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (d, J = 31.1 Hz, 2H), 8.16 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 4.62 (t, J = 6.9 Hz, 2H), 4.44 (d, J = 12.5 Hz, 1H), 4.27 (s, 2H), 4.16 (d, J = 12.7 Hz, 1H), 3.0 (p, J = 7.0 Hz, 1H), 2.88 (d, J = 7.4 Hz, 2H), 2.77 (s, 1H), 2.58 (q, J = 11.2, 10.8 Hz, 2H), 2.06 (d, J = 12.6 Hz, 1H), 1.88 (s, 1H), 1.69 (s, 1H), 0.99 - 0.84 (m, 3H). Example 48: 5-{[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-methyl}pyrrolidine-2-one [ka]

[0331] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride and 5-bromomethyl-pyrrolidine-2-one. LC-MS (M+1) = 407. 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.1, 1.7 Hz, 1H), 8.48 (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), 7.60 (s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 3.63 - 3.46 (m, 3H), 2.93 (s, 1H), 2.58 (tt, J = 11.8, 6.9 Hz, 2H), 2.38 (t, J = 10.9 Hz, 2H), 2.19 - 1.89 (m, 4H), 1.81 - 1.56 (m, 2H), 0.94 (d, J = 6.5 Hz, 3H), 0.84 (t, J = 11.8 Hz, 1H). Example 49: N-{2-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-ylamino]-ethyl}acetamide [ka]

[0332] The title compound was prepared from 8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonitrile hydrochloride and N-(2-chloro-ethyl)-acetamide. LC-MS (M+1) = 353. 1H NMR (400 MHz, methanol-d4) δ 8.92 (dd, J = 15.3, 1.8 Hz, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.66 - 4.52 (m, 1H), 4.21 - 4.04 (m, 1H), 3.36 (t, J = 6.5 Hz, 2H), 3.10 - 2.98 (m, 1H), 2.85 (td, J = 6.5, 2.4 Hz, 2H), 2.70 - 2.54 (m, 2H), 2.19 (d, J = 12.8 Hz, 1H), 2.12 - 2.01 (m, 1H), 1.97 (s, 3H), 1.15 (t, J = 7.3 Hz, 1H), 1.11 - 0.99 (m, 3H). Example 50: 4-{[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-methyl}tetrahydropyran-4-ol [ka]

[0333] The title compound was prepared from (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride and 4-bromomethyl-tetrahydropyran-4-ol. LC-MS (M+1) = 424. 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.1, 1.7 Hz, 1H), 8.53 - 8.44 (m, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.66 (dd, J = 8.6, 4.1 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.19 (s, 1H), 3.59 (q, J = 13.3, 11.9 Hz, 4H), 2.90 (s, 1H), 2.55 (s, 3H), 2.39 (t, J = 11.6 Hz, 2H), 2.17 - 1.96 (m, 2H), 1.53 (dd, J = 17.0, 7.6 Hz, 2H), 1.37 (d, J = 13.4 Hz, 2H), 1.04 - 0.82 (m, 4H). Example 51: 1-(3-hydroxyazetidine-1-yl)-2-[(3R,5S)-5-methyl-1-(8-trifluoromethylquinoline-5-yl)-piperidine-3-ylamino]-ethanone [ka]

[0334] {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]-amino}methyl acetate: In a 10 ml microwave tube, a mixture of (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride (220 mg; 0.64 mmol; 1.0 eq.), bromo-methyl acetate (146 mg; 0.95 mmol; 1.50 eq.), triethylamine (0.27 ml; 1.91 mmol; 3.0 eq.), and ACN (3 ml) was stirred at 80°C for 7 hours until the reaction was complete. The reaction mixture was cooled to rt, and then tert-butoxycarbonyl tert-butylcarbonate (208 mg; 0.95 mmol; 1.50 eq.) was added. The mixture was stirred overnight at rt until the reaction was complete. The solvent was removed, and the residue was loaded onto a 25 g silica column eluted with hexane / EA 0-50% to produce the title compound (128 mg, yield: 42%). LC-MS (M+1) = 482.

[0335] A mixture of {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]-amino}-lithium acetate (128 mg; 0.27 mmol; 1.0 eq.) and lithium hydroxide hydrate (22 mg; 0.53 mmol; 2.0 eq.) in THF (2 ml) and water (2 ml) was stirred overnight at rt. After removal of the solvent, a yellow solid was produced as the title compound. LC-MS (M+1) = 467.

[0336] To a solution of {tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-ethanone:DMF (1 ml), HATU (60 mg; 0.16 mmol; 1.50 eq.) was added. The resulting mixture was stirred at rt for 20 min, and then ethyl-diisopropylamine (0.03 ml; 0.16 mmol; 1.50 eq.) and azetidine-3-ol (0.02 ml; 0.21 mmol; 2.0 eq.) were added. The mixture was stirred for an additional 1 hour until the reaction was complete. The reaction was diluted with water (30 ml) and extracted with EA (30 ml x 2). The combined organic layer was washed with 10% citric acid, brine, 5% NaHCO3, then brine, dried over Na2SO4, and concentrated. The residue was dissolved in 1 ml of methanol and hydrogen chloride (4.0 M in dioxane) (0.18 ml; 0.74 mmol; 7.0 eq.) was added. The mixture was stirred at rt for 2 hours until the reaction was complete. The solvent was removed and the residue was purified by preparative HPLC eluting with 0-60% CAN / water (containing 0.1% ammonia) to provide the title compound (18 mg, yield: 40%). LC-MS (M+1) = 423. 1H NMR (400 MHz, methanol-d4) δ 9.03 - 8.83 (m, 1H), 8.58 (d, J = 8.7 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 5.0 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.60 (d, J = 6.3 Hz, 1H), 4.40 (s, 1H), 4.24 (s, 1H), 4.02 - 3.88 (m, 1H), 3.80 (s, 1H), 3.61 (d, J = 11.5 Hz, 1H), 3.33 (s, 1H), 3.07 (d, J = 11.4Hz, 1H), 2.48 (dt, J = 31.4, 11.2 Hz, 2H), 2.29 - 1.96 (m, 2H), 1.12 - 0.85 (m, 4H).

[0337] The following compounds were synthesized using a similar method. Example 52: N-Methoxy-4-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-ylamino]-butylamide [ka]

[0338] The title compound was prepared from 4-{tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoxaline-5-yl)-piperidine-3-yl]-amino}butyrate lithium and O-methyl-hydroxylamine hydrochloride. LC-MS (M+1) = 426. 1H NMR (400 MHz, methanol-d4) δ 8.92 (d, J = 4.4 Hz, 2H), 8.04 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 5.50-5.31 (m, 1H), 4.40 (d, J = 11.8 Hz, 1H), 4.06 - 3.91 (m, 1H), 3.70 (s, 3H), 3.09 (s, 2H), 2.86 - 2.67 (m, 2H), 2.54 (t, J = 11.3 Hz, 2H), 2.17 (d, J = 8.2 Hz, 2H), 2.07 (s, 1H), 1.87 (s, 2H), 1.17 (s, 1H), 1.04 (d, J = 6.2 Hz, 3H). Example 53: 1-(3-hydroxy-azetidine-1-yl)-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-propan-1-one [ka]

[0339] The title compound was prepared from lithium 3-{tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]-amino}propionate and azetidine-3-ol. LC-MS (M+1) = 437. 1H NMR (400 MHz, DMSO-d6) δ 9.01 (dd, J = 4.1, 1.9 Hz, 1H), 8.49 (dd, J = 8.7, 2.1 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 8.7, 3.9 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 5.68 (d, J = 6.2 Hz, 1H), 4.43 (d, J = 6.3 Hz, 1H), 4.27 (t, J = 7.9 Hz, 1H), 4.0 (t, J = 8.6 Hz, 1H), 3.82 (d, J = 8.3 Hz, 1H), 3.55 (d, J = 5.0 Hz, 2H), 3.18 (s, 1H), 2.96 (s, 1H), 2.80 (s, 2H), 2.38 (d, J = 9.3 Hz, 2H), 2.18 (d, J = 8.0 Hz, 2H), 2.13 - 1.83 (m, 2H), 0.94 (d, J = 6.1 Hz, 3H), 0.86 (d, J = 12.0 Hz, 1H). Example 54: N-(1,1-dioxo-1-lambda6-thietan-3-yl)-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-propionamide [ka]

[0340] The title compound was prepared from lithium 3-{tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]-amino}propionate and 1,1-dioxo-1-lambda6-thietan-3-ylamine. LC-MS (M+1) = 485. 1H NMR (400 MHz, DMSO-d6) δ 9.11 - 8.96 (m, 1H), 8.77 (s, 1H), 8.50 (d, J = 8.9 Hz, 1H), 8.22 - 8.0 (m, 2H), 7.68 (s, 1H), 7.22 (d, J = 8.6 Hz, 1H), 4.52 (t, J = 11.3 Hz, 2H), 4.34 (d, J = 7.9 Hz, 1H), 4.03 (d, J = 11.8 Hz, 3H), 3.59 (d, J = 11.4 Hz, 2H), 3.13 (s, 1H), 2.95 (s, 2H), 2.35 (s, 2H), 2.10 (dd, J = 37.0, 14.6 Hz, 2H), 0.96 (d, J = 6.9 Hz, 3H). Example 55: N-Methoxy-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-propionamide [ka]

[0341] The title compound was prepared from lithium 3-{tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]-amino}propionate and O-methyl-hydroxylamine hydrochloride. LC-MS (M+1) = 411. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (d, J = 4.1 Hz, 1H), 8.53 (t, J = 7.2 Hz, 1H), 8.16 - 8.03 (m, 1H), 7.69 (dd, J = 8.8, 4.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 3.60 (s, 4H), 3.13 (s, 1H), 2.82 - 2.57 (m, 2H), 2.40 - 2.15 (m, 2H), 2.06 (s, 1H), 1.22 - 1.02 (m, 1H), 0.98 (d, J = 6.5 Hz, 2H). Example 56: N-methyl-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamino]-propionamide [ka]

[0342] The title compound was prepared from lithium 3-{tert-butoxycarbonyl-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]-amino}propionate and methanamine hydrochloride. LC-MS (M+1) = 395. 1 H NMR (400 MHz, methanol-d4) δ 8.97 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 7.5 Hz, 1H), 7.64 (s, 1H), 7.30 (d, J = 7.9 Hz, 1H), 3.72 (s, 1H), 3.56 - 3.37 (m, 2H), 3.23 (s, 2H), 2.76 (s, 3H), 2.63 - 2.42 (m, 2H), 2.35 (d, J = 12.5 Hz, 1H), 2.20 (s, 1H), 1.17 (d, J = 12.2 Hz, 1H), 1.14 - 0.93 (m, 3H). Example 57: 5-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-7-fluoroquinoline-8-carbonitrile [ka] [ka]

[0343] [(3R,5S)-1-(8-cyano-7-fluoroquinoline-5-yl)-5-methylpiperidine-3-yl]-carbamate tert-butyl ester: 5 ml microwave tube containing 5-bromo-7-fluoroquinoline-8-carbonilicate (100 mg; 0.40 mmol; 1.0 eq.), ((3R,5S)-5-methylpiperidine-3-yl)-carbamate tert-butyl ester (85 mg; 0.40 mmol; 1.0 eq.), and chloro(2-dicyclohexylphosphino-2',6'-di-i-p A mixture of propyl-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii), methyl-t-butyl ether adduct (16 mg; 0.02 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (9 mg, 0.02 mmol, 0.05 eq.), sodium tert-butoxide (42 mg, 0.44 mmol, 1.1 eq.), and dioxane (2 ml) was degassed and then microwaved at 100°C for 600 min. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a 50 g silica column eluted with EA / hexane 20-80% to produce the title compound, which was used directly in the next step. LC-MS (M+1) = 385.

[0344] [(3R,5S)-3-amino-5-methyl-piperidine-1-yl)-7-fluoroquinoline-8-carbonitrile:DCM (0.6 ml) was mixed with [(3R,5S)-1-(8-cyano-7-fluoroquinoline-5-yl)-5-methyl-piperidine-3-yl]-carbamate tert-butyl ester (110 mg; 0.29 mmol; 1.0 eq.) and trifluoroacetic acid (652 mg; 5.72 mmol; 20.0 eq.). The mixture was stirred at rt for 10 min until the reaction was complete. The solvent was removed, and the residue was purified by prep waters eluted with 10-50% ACN / water (containing 0.1% ammonia) to obtain the title compound. LC-MS (M+1) = 285. 1H NMR (400 MHz, DMSO-d6) δ 9.05 (ddd, J = 15.7, 4.2, 1.6 Hz, 1H), 8.43 (dd, J = 8.6, 1.7 Hz, 1H), 7.63 (dd, J = 8.6, 4.3 Hz, 1H), 7.15 (d, J = 12.4 Hz, 1H), 3.57 (d, J = 13.0 Hz, 1H), 3.44 (d, J = 12.1 Hz, 1H), 3.0 (td, J = 10.7, 5.4 Hz, 2H), 2.50-2.54 (m, 1H), 2.05 - 1.86 (m, 2H), 1.60 (s, 2H), 0.93 (d, J = 6.4 Hz, 3H), 0.85 (d, J = 12.3 Hz, 1H). Example 58: N-[(3R,5S)-1-(8-cyano-7-fluoroquinoline-5-yl)-5-methylpiperidine-3-yl]-2-(1-methyl-1H-pyrazole-4-yl)-acetamide [ka]

[0345] Benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (93 mg; 0.21 mmol; 1.50 eq.) was added to a solution of 5-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-7-fluoroquinoline-8-carbonitrili (40 mg; 0.14 mmol; 1.0 eq.), (1-methyl-1H-pyrazole-4-yl)-acetic acid (29 mg; 0.21 mmol; 1.50 eq.), and DIEPA (0.05 ml; 0.28 mmol; 2.0 eq.) in DMSO (2 ml). The resulting mixture was stirred at rt for 1 hour until the reaction was complete. The crude product was purified by preparative HPLC elution with 20-60% ACN / water (containing 0.1% ammonia) to produce the title compound. LC-MS (M+1) = 407. 1H NMR (400 MHz, methanol-d4) δ 9.04 - 8.91 (m, 1H), 8.59 (dd, J = 8.6, 1.6 Hz, 1H), 7.61 (dd, J = 8.6, 4.3 Hz, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 7.10 (d, J = 11.8 Hz, 1H), 4.19 (t, J = 11.3 Hz, 1H), 3.85 (s, 3H), 3.79 (d, J = 11.8 Hz, 1H), 3.52 (d, J = 12.1 Hz, 1H), 3.38 (s, 2H), 2.58 (q, J = 11.0 Hz, 2H), 2.13 (d, J = 11.6 Hz, 1H), 1.22 (q, J = 12.5 Hz, 2H), 1.05 (d, J = 6.3 Hz, 3H). Example 59: N-[(3R,5S)-1-(8-cyano-7-fluoroquinoline-5-yl)-5-methylpiperidine-3-yl]-2-(1-methylazetidine-3-yl)-acetamide [ka]

[0346] To a solution of 5-((3R,5S)-3-amino-5-methylpiperidine-1-yl)-7-fluoroquinoline-8-carbonitrile (20 mg; 0.07 mmol; 1.0 eq.) in DMF (1 ml), HATU (45 mg; 0.12 mmol; 1.70 eq.) was added. After stirring at rt for 100 min, ethyl-isopropylamine (0.04 ml; 0.21 mmol; 3.0 eq.) and 5-((3R,5S)-3-amino-5-methylpiperidine-1-yl)-7-fluoroquinoline-8-carbonitrile (20 mg; 0.07 mmol; 1.0 eq.) were added. The resulting mixture was stirred at rt for 1 hour until the reaction was complete. The title compound was produced by removing the solvent and purifying the residue by preparative HPLC elution with 20-60% ACN / water (containing 0.1% ammonia). LC-MS (M+1) = 396. 1H NMR (400 MHz, methanol-d4) δ 8.97 (dd, J = 4.3, 1.6 Hz, 1H), 8.59 (dd, J = 8.6, 1.7 Hz, 1H), 7.62 (dd, J = 8.6, 4.3 Hz, 1H), 7.11 (d, J = 11.8 Hz, 1H), 4.24 - 4.11 (m, 1H), 3.78 (d, J = 12.3 Hz, 1H), 3.51 (q, J = 7.4 Hz, 2H), 3.05 - 2.92 (m, 3H), 2.80 (p, J = 7.5 Hz, 1H), 2.61 - 2.50 (m, 2H), 2.47 (dd, J = 7.7, 2.1 Hz, 2H), 2.32 (d, J = 3.9 Hz, 3H), 2.18 - 2.02 (m, 2H), 1.22 (t, J = 12.6 Hz, 1H), 1.05 (d, J = 6.4 Hz, 3H).

[0347] The following compounds were synthesized using a similar method. Example 60: N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-trifluoromethylpiperidine-3-yl]-2,3-dihydroxypropionamide [ka]

[0348] The title compound was prepared from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrili trifluoroacetate and 2,3-dihydroxy-propionic acid. MS: 409 [M+H] +. 1H NMR (400 MHz, methanol-d4) d 8.99 (s, 1H), 8.65 (d, J = 7.9 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.68 (dd, J = 8.1, 3.9 Hz, 1H), 7.30 (dd, J = 8.2, 2.5 Hz, 1H), 4.44 - 4.29 (m, 1H), 4.09 (p, J = 4.3 Hz, 1H), 3.82 - 3.61 (m, 4H), 3.0 (q, J = 13.7, 11.3 Hz, 2H), 2.72 (q, J = 10.9 Hz, 1H), 2.36 (d, J = 12.5 Hz, 1H), 1.77 - 1.62 (m, 1H). Example 61: 1-Methyl-piperidine-4-carboxylic acid [(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-trifluoromethyl-piperidine-3-yl]amide [ka]

[0349] The title compound was prepared from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrili trifluoroacetate and 1-methyl-piperidine-4-carboxylic acid. MS: 446 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 9.0 (dd, J = 4.3, 1.5 Hz, 1H), 8.66 (dd, J = 8.7, 1.6 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.70 (dd, J = 8.6, 4.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.39 - 4.23 (m, 1H), 3.75 - 3.60 (m, 2H), 3.14 - 2.89 (m, 4H), 2.60 (t, J = 11.2 Hz, 1H), 2.35 (d, J = 12.6 Hz, 1H), 2.28 (s, 3H), 2.24 - 2.15 (m, 1H), 2.06 (ddd, J = 14.9, 11.6, 7.0 Hz, 2H), 1.93 - 1.68 (m, 4H), 1.60 (q, J = 12.1 Hz, 1H). Example 62: N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-trifluoromethylpiperidine-3-yl]-2-hydroxyacetamide [ka]

[0350] The title compound was prepared from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrili trifluoroacetate and glycolic acid. MS: 379 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 8.99 (dd, J = 4.2, 1.4 Hz, 1H), 8.73 - 8.57 (m, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.6, 4.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 4.46 - 4.32 (m, 1H), 4.02 (s, 2H), 3.66 (d, J = 8.5 Hz, 2H), 3.14 - 2.92 (m, 2H), 2.74 (t, J = 11.3 Hz, 1H), 2.35 (d, J = 12.2 Hz, 1H), 1.73 (q, J = 12.2 Hz, 1H), 1.41 - 1.27 (m, 1H),. Example 63: 2-(4-hydroxy-1-methylpiperidine-4-yl)-N-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl]acetamide [ka]

[0351] The title compound was prepared from cis-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-amine hydrogen chloride and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 520 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.98 - 8.91 (m, 2 H), 8.08 (d, J = 8.3 Hz, 1 H), 7.35 (d, J = 8.3 Hz, 1 H), 4.50 - 4.44 (m, 1 H), 4.33 - 4.21 (m, 1 H), 4.20 - 4.11 (m, 1 H), 3.0 - 2.90 (m, 2 H), 2.80 (t, J = 11.2 Hz, 1 H), 2.68 - 2.60 (m, 2 H), 2.54 - 2.42 (m, 2 H), 2.39 (s, Example 64: 3-(dimethylamino)-N-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]propanamide [ka] The title compound was prepared from (3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 3-(dimethylamino)propanoic acid. MS: 463 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.97 (dd, J = 4.2, 1.7 Hz, 1 H), 8.69 (dd, J = 8.6, 1.8 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.67 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32 (d, J = 8.1 Hz, 1 H), 4.39 - 4.26 (m, 1 H), 3.71 - 3.58 (m, 2 H), 3.12 - 2.90 (m, 2 H), 2.71 - 2.62 (m, 2 H), 2.58 (t, J = 11.1 Hz, 1 H), 2.49 - 2.33 (m, 3H), 2.28 (s, 6 H), 1.63 - 1.50 (m, 1 H). Example 65: N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-3-(dimethylamino)propanamide [ka]

[0352] The title compound was prepared from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitrile and 3-(dimethylamino)propanoic acid. MS: 420 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 9.01 (dd, J = 4.2, 1.6 Hz, 1 H), 8.68 (dd, J = 8.6, 1.7 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.2 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.38 - 4.26 (m, 1 H), 3.80 - 3.64 (m, 2 H), 3.14 - 2.96 (m, 2 H), 2.74 - 2.66 (m, 2 H), 2.61 (t, J = 11.2 Hz, 1 H), 2.48 - 2.35 (m, 3H), 2.31 (s, 6 H), 1.65 - 1.52 (m, 1 H). Example 66: 2-(4-methylpiperazine-1-yl)-N-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]acetamide [ka]

[0353] The title compound was prepared from (3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 2-(4-methylpiperazine-1-yl)acetic acid. MS: 504 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.0 - 8.94 (m, 1 H), 8.69 (dd, J = 8.6, 1.8 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.40 - 4.35 (m, 1 H), 3.65 - 3.57 (m, 2 H), 3.09 - 3.06 (m, 3 H), 3.02 - 2.91 (m, 1 H), 2.75 - 2.39 (m, 9 H), 2.39 - 2.32 (m, 1 H), 2.32 (s, 3H), 1.75 - 1.61 (m, 1 H). Example 67: 2-(4-hydroxy-1-methylpiperidine-4-yl)-N-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]acetamide [ka]

[0354] The title compound was prepared from (3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 519 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.97 (dd, J = 4.2, 1.7 Hz, 1 H), 8.68 (dd, J = 8.7, 1.8 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.66 (dd, J = 8.6, 4.2 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 4.40 - 4.28 (m, 1 H), 3.73 - 3.55 (m, 2 H), 3.14 - 2.88 (m, 2 H), 2.64 - 2.54 (m, 3 H), 2.52 - 2.38 (m, 3 H), 2.36 (s, 2 H), 2.29 (s, 3 H), 1.78 - 1.64 (m, 4 H), 1.63-1.56 (m, 1 H). Example 68: (3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-amine hydrochloride [ka]

[0355] The title compound was prepared from (3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-amine and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 483 [M+H] + .1 H NMR (400 MHz, methanol-d4, ppm) δ 9.43 - 9.37 (m, 1 H), 9.20 - 9.15 (m, 1 H), 8.14 - 8.07 (m, 1 H), 7.51 (d, J = 11.1 Hz, 1 H), 4.40 - 4.28 (m, 1 H), 3.68 - 3.55 (m, 2 H), 3.36 - 3.32 (m, 2 H), 3.32 - 3.27 (m, 2 H), 3.15 - 2.96 (m, 2 H), 2.86 (s, 3 H), 2.76 - 2.66 (m, 4 H), 2.46 (s, 2 H), 2.43 - 2.33 (m, 1 H), 2.07 - 1.88 (m, 4 H), 1.71 - 1.57 (m, 1 H). Example 69: N-[(3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-yl]-2-(4-hydroxy-1-methylpiperidine-4-yl)acetamide [ka]

[0356] The title compound was prepared from (3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-amine and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 429 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 9.36 (dd, J = 8.5, 1.5 Hz, 1 H), 9.13 (dd, J = 5.5, 1.6 Hz, 1 H), 8.07 (dd, J = 8.5, 5.5 Hz, 1 H), 7.38 (d, J = 11.5 Hz, 1 H), 4.27 - 4.23 (m, 1 H), 3.69 - 3.62 (m, 1 H), 3.43 - 3.35 (m, 3 H), 3.32 - 3.24 (m, 2 H), 2.87 (s, 3 H), 2.65 (s, 3 H), 2.63 - 2.53 (m, 2 H), 2.45 (s, 2 H), 2.19 - 2.11 (m, 2 H), 2.04 - 1.87 (m, 4 H), 1.33 - 1.15 (m, 1 H), 1.06 (d, J = 6.4 Hz, 3 H). Example 70: N-[(3R,5S)-1-(8-methyl-1,7-naphthyridine-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-methylpiperazine-1-yl)acetamide [ka]

[0357] The title compound was prepared from (3R,5S)-1-(8-methyl-1,7-naphthyridine-5-yl)-5-(trifluoromethyl)piperidine-3-amine and 2-(4-methylpiperazine-1-yl)acetic acid. MS: 451 [M+H] + . 1H NMR (300 MHz, chloroform-d, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.42 (dd, J = 8.5, 1.8 Hz, 1 H), 8.16 (s, 1 H), 7.65 (dd, J = 8.5, 4.1 Hz, 1 H), 7.19 (d, J = 8.6 Hz, 1 H), 4.42 - 4.31 (m, 1 H), 3.62 - 3.46 (m, 2 H), 3.19 - 2.69 (m, 7 H), 2.65 - 2.33 (m, 9 H), 2.37 - 2.34 (m, 1 H), 2.29 (s, 3 H), 1.75 - 1.65 (m, 1 H). Example 71: N-[(3R,5S)-1-(8-cyanoquinazoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-fluoro-1-methylpiperidine-4-yl)acetamide [ka]

[0358] The title compound was prepared from 5-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidine-1-yl]quinazoline-8-carbonitrile and 2-(4-fluoro-1-methylpiperidine-4-yl)acetic acid. MS: 479 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.73 (s, 1 H), 9.32 (s, 1 H), 8.31 (d, J = 8.2 Hz, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 4.38 - 4.26 (m, 1 H), 3.90 - 3.77 (m, 2 H), 3.17 - 3.06 (m, 2 H), 2.83 - 2.65 (m, 3 H), 2.59 - 2.50 (m, 2 H), 2.41 - 2.30 (m, 3 H), 2.28 (s, 3 H), 1.99 - 1.76 (m, 4 H), 1.72 - 1.57 (m, 1 H). Example 72: N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-hydroxy-1-methylpiperidine-4-yl)acetamide hydrochloride [ka]

[0359] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 423 [M+H] + . 1 H NMR (300 MHz, methanol-d4, ppm) δ 8.93 (d, J = 1.8 Hz, 1 H), 8.88 (d, J = 1.8 Hz, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.43 - 4.26 (m, 2 H), 4.23 - 4.06 (m, 1 H), 3.39 - 3.31 (m, 2 H), 2.88 (s, 3 H), 2.84 - 2.62 (m, 2 H), 2.45 (s, 2 H), 2.17 - 1.78 (m, 7 H), 1.40 - 1.14 (m, 2 H), 1.01 (d, J = 6.4 Hz, 3 H). Example 73: N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-hydroxy-1-methylpiperidine-4-yl)acetamide [ka]

[0360] The title compound was prepared from 8-[(3R,5S)-3-amino-5-trifluoromethylpiperidine-1-yl]quinoxaline-5-carbonitrile and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 467 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 9.05 - 8.98 (m, 1 H), 8.67 (dd, J = 8.6, 1.7 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.39 - 4.27 (m, 1 H), 3.80 - 3.70 (m, 1 H), 3.70 - 3.63 (m, 1 H), 3.13 - 2.92 (m, 2 H), 2.68 - 2.53 (m, 3 H), 2.48 - 2.37 (m, 2 H), 2.36 (s, 3H), 2.28 (s, 3 H), 1.78 - 1.53 (m, 5 H). Example 74: N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(3-methyl-1,2-oxazole-5-yl)acetamide [ka]

[0361] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and 2-(3-methyl-1,2-oxazole-5-yl)acetic acid. MS: 391 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.04 (d, J = 1.8 Hz, 1 H), 8.96 (d, J = 1.8 Hz, 1 H), 8.33 (d, J = 7.3 Hz, 1 H), 8.21 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.5 Hz, 1 H), 6.21 (s, 1 H), 4.44 - 4.21 (m, 2 H), 3.95 - 3.89 (m, 1 H), 3.67 (s, 2 H), 2.85 - 2.64 (m, 2 H), 2.21 (s, 3 H), 2.06 - 1.82 (m, 2 H), 1.27 - 1.09 (m, 1H), 0.94 (d, J = 6.5 Hz, 3 H). Example 75: N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-3-(dimethylamino)propenamide [ka]

[0362] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and 3-(dimethylamino)propanoic acid. MS: 421 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.96 - 8.91 (m, 2 H), 8.14 (d, J = 8.3 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 4.72 - 4.55 (m, 1 H), 4.36 - 4.16 (m, 2 H), 3.12 - 2.80 (m, 3 H), 2.68 (t, J = 7.3 Hz, 2 H), 2.43 (t, J = 7.6, 6.5 Hz, 2 H), 2.39 - 2.32 (m, 1 H), 2.30 (s, 6 H), 1.69 - 1.55 (m, 1 H). Example 76: N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-hydroxy-1-methylpiperidine-4-yl)acetamide [ka]

[0363] The title compound was prepared from 8-[(3R,5S)-3-amino-5-trifluoromethylpiperidine-1-yl]quinoxaline-5-carbonitrile and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 477 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 8.96 (d, J = 1.8 Hz, 1 H), 8.92 (d, J = 1.8 Hz, 1 H), 8.13 (d, J = 8.3 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 4.71 - 4.63 (m, 1 H), 4.31- 4.16 (m, 2 H), 3.16 - 2.82 (m, 3 H), 2.69 - 2.62 (m, 2 H), 2.57 - 2.46 (m, 2 H), 2.39 (s, 2 H), 2.37 - 2.35 (m, 1 H), 2.34 (s, 3 H), 1.83- 1.68 (m, 4H), 1.71 - 1.57 (m, 1 H). Example 77: 2-(4-fluoro-1-methylpiperidine-4-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]acetamide [ka]

[0364] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and 2-(4-fluoro-1-methylpiperidine-4-yl)acetic acid. MS: 479 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.96 (d, J = 1.8 Hz, 1 H), 8.92 (d, J = 1.8 Hz, 1 H), 8.13 (d, J = 8.3 Hz, 1 H), 7.33 (d, J = 8.3 Hz, 1 H), 4.69 - 4.61 (m, 1 H), 4.34 - 4.16 (m, 2 H), 3.06 (t, J = 11.7 Hz, 1 H), 2.99 - 2.82 (m, 3 H), 2.70 - 2.55 (m, 4 H), 2.49 (s, 3 H), 2.40 - 2.31 (m, 1 H), 2.13 - 1.89 (m, 4 H), 1.71 - 1.57 (m, 1 H), 1.49 - 1.40 (m, 1 H). Example 78: 3-(dimethylamino)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl]propenamide [ka]

[0365] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-amine and 3-(dimethylamino)propanoic acid. MS: 410 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.94 - 8.87 (m, 2 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.3 Hz, 1 H), 4.59 (br s, 1 H), 4.28 - 4.07 (m, 3 H), 2.71 - 2.62 (m, 3 H), 2.62 - 2.52 (m, 1 H), 2.45 - 2.37 (m, 2 H), 2.29 (s, 6 H), 2.17 - 2.02 (m, 2 H), 1.23 - 1.10 (m, 1 H), 1.02 (d, J = 6.4 Hz, 3 H). Example 79: N-((3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl)-3-(dimethylamino)propenamide [ka]

[0366] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and 3-(dimethylamino)propanoic acid. MS: 367 [M+H] + . 1H NMR (300 MHz, methanol-d4, ppm) δ 8.93 - 8.88 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.35 (dd, J = 23.1, 10.0 Hz, 2 H), 4.17 - 4.11 (m, 1 H), 2.81 - 2.60 (m, 4 H), 2.46 - 2.35 (m, 2 H), 2.29 (s, 6 H), 2.16 - 2.0 (m, 2 H), 1.33 - 1.11 (m, 1 H), 1.01 (d, J = 6.5 Hz, 3 H). Example 80: 2-(4-hydroxy-1-methylpiperidine-4-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl]acetamide hydrochloride [ka]

[0367] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-amine and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 466 [M+H] + . 1 H NMR (300 MHz, methanol-d4, ppm) δ 9.10 - 9.0 (m, 2 H), 8.22 (d, J = 8.3 Hz, 1 H), 7.84 (d, J = 8.3 Hz, 1 H), 4.47 - 4.32 (m, 1 H), 4.19 - 4.09 (m, 1 H), 4.04 - 3.95 (m, 1 H), 3.57-3.42 (m, 2 H), 3.36 - 3.30 (m, 1 H), 3.21 - 2.98 (m, 3 H), 2.85 (s, 3 H), 2.45 (s, 2 H), 2.32 - 2.23 (m, 1 H), 2.21 - 2.11 (m, 1 H), 2.05 - 1.84 (m, 4 H), 1.43 - 1.30 (m, 1 H), 1.07 (d, J = 6.6 Hz, 3 H). Example 81: N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-hydroxy-1-methylpiperidine-4-yl)acetamide [ka]

[0368] The title compound was prepared from 5-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidine-1-yl]quinoline-8-carbonitrile and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 467 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.05 - 8.98 (m, 1 H), 8.67 (dd, J = 8.6, 1.7 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.39 - 4.27 (m, 1 H), 3.80 - 3.70 (m, 1 H), 3.70 - 3.63 (m, 1 H), 3.13 - 2.92 (m, 2 H), 2.68 - 2.53 (m, 3 H), 2.48 - 2.37 (m, 2 H), 2.36 (s, 3H), 2.28 (s, 3 H), 1.78 - 1.53 (m, 5 H). Example 82: N-((3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl)-2-(4-methylpiperazine-1-yl)acetamide [ka]

[0369] The title compound was prepared from 5-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidine-1-yl]quinoline-8-carbonitrile 2-(4-methylpiperazine-1-yl)acetic acid. MS: 461 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 9.01 (dd, J = 4.3, 1.7 Hz, 1 H), 8.68 (dd, J = 8.6, 1.7 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.3 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.42 - 4.31 (m, 1 H), 3.70 - 3.65 (m, 2 H), 3.07 (s, 2 H), 3.05 - 2.95 (m, 2 H), 2.78 - 2.43 (m, 9 H), 2.39 - 2.32 (m, 1 H), 2.30 (s, 3 H), 1.77 - 1.63 (m, 1 H). Example 83: 2-(4-fluoro-1-methylpiperidine-4-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]acetamide [ka]

[0370] The title compound was derived from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 2-(4-fluoro-1-methylpiperidine-4-yl)acetic acid. MS: 468 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 8.97 - 8.91 (m, 1 H), 8.66 (dd, J = 8.6, 1.8 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 4.26 - 4.22 (m, 1 H), 3.68 - 3.60 (m, 1 H), 3.43 - 3.36 (m, 1 H), 2.73 - 2.65 (m, 2 H), 2.58 - 2.44 (m, 4 H), 2.35 - 2.31 (m, 2 H), 2.29 (s, 3 H), 2.22 - 2.08 (m, 2 H), 2.0 - 1.77 (m, 4 H), 1.24 - 1.10 (m, 1 H), 1.05 (d, J = 6.4 Hz, 3 H). Example 84: 2-(4-hydroxy-1-methylpiperidine-4-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]acetamide [ka]

[0371] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 465 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 8.94 (dd, J = 4.2, 1.8 Hz, 1 H), 8.66 (dd, J = 8.6, 1.8 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 4.30 - 4.19 (m, 1 H), 3.70 - 3.62 (m, 1 H), 3.43 - 3.36 (m, 1 H), 2.64 - 2.56 (m, 2 H), 2.56 - 2.40 (m, 4 H), 2.35 (s, 2 H), 2.29 (s, 3 H), 2.25 - 2.11 (m, 2 H), 1.78 - 1.62 (m, 4 H), 1.24 - 1.10 (m, 1 H), 1.08 - 1.02 (m, 3 H). Example 85: 2-(4-hydroxy-1-methylpiperidine-4-yl)-N-[(3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)piperidine-3-yl]acetamide hydrochloride [ka]

[0372] The title compound was prepared with (3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)piperidine-3-amine and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 411 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 10.15 (br s, 1 H), 9.19 - 9.13 (m, 1 H), 9.09 - 9.02 (m, 1 H), 8.18 (d, J = 7.4 Hz, 1 H), 8.03 - 7.95 (m, 1 H), 7.82 (d, J = 7.7 Hz, 1 H), 7.37 (d, J = 8.1 Hz, 1 H), 4.07 (d, J = 10.6 Hz, 1 H), 3.45 - 3.37 (m, 1 H), 3.26 - 3.17 (m, 3 H), 3.15 - 3.01 (m, 2 H), 2.76 - 2.68 (m, 6 H), 2.51 - 2.36 (m, 2 H), 2.31 (s, 2 H), 2.17 - 1.82 (m, 4 H), 1.73 - 1.65 (m, 2 H), 1.18 - 1.03 (m, 1 H), 0.95 (d, J = 6.4 Hz, 3 H). Example 86: N-[(3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)piperidine-3-yl]-2-(4-methylpiperazine-1-yl)acetamide [ka]

[0373] The title compound was prepared from (3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)piperidine-3-amine and 2-(4-methylpiperazine-1-yl)acetic acid. MS: 396 [M+H] + . 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.90 (dd, J = 4.1, 1.8 Hz, 1 H), 8.46 (dd, J = 8.5, 1.8 Hz, 1 H), 7.62 - 7.46 (m, 3 H), 7.08 (d, J = 7.6 Hz, 1 H), 4.11 - 4.03 (m, 1 H), 3.33 - 3.23 (m, 1 H), 3.20 - 3.10 (m, 1 H), 2.89 (s, 2 H), 2.64 (s, 3 H), 2.47 - 2.24 (m, 10 H), 2.14 (s, 3 H), 2.09 - 1.86 (m, 2 H), 1.22 - 1.04 (m, 1 H), 0.94 (d, J = 6.5 Hz, 3 H). Example 87: 2-(4-hydroxy-1-methylpiperidine-4-yl)-N-[(3R,5S)-1-(8-methylquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]acetamide [ka]

[0374] The title compound was prepared from (3R,5S)-1-(8-methylquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-amine and 2-(4-hydroxy-1-methylpiperidine-4-yl)acetic acid. MS: 465 [M+H] + . 1 H NMR (300 MHz, methanol-d4, ppm) δ 8.86 (dd, J = 4.3, 1.7 Hz, 1 H), 8.65 (dd, J = 8.6, 1.7 Hz, 1 H), 7.61 - 7.49 (m, 2 H), 7.19 (d, J = 7.6 Hz, 1 H), 4.35 - 4.22 (m, 1 H), 3.52 - 3.37 (m, 2 H), 3.04 - 2.93 (m, 2 H), 2.89 - 2.75 (m, 1 H), 2.69 (s, 3 H), 2.62 - 2.29 (m, 7 H), 2.25 (s, 3 H), 1.78 - 1.63 (m, 4 H), 1.59 - 1.41 (m, 1 H). Example 88: N-[(3R,5S)-1-(8-cyanoquinazoline-5-yl)-5-methylpiperidine-3-yl]-2-(4-fluoro-1-methylpiperidine-4-yl)acetamide [ka]

[0375] The title compound was prepared from 5-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinazoline-8-carbonitrile and 2-(4-fluoro-1-methylpiperidine-4-yl)acetic acid. MS: 425 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.68 (s, 1 H), 9.30 (s, 1 H), 8.28 (d, J = 8.3 Hz, 1 H), 7.30 (d, J = 8.3 Hz, 1 H), 4.26 - 4.14 (m, 1 H), 3.95 - 3.87 (m, 1 H), 3.70 - 3.63 (m, 1 H), 3.10 - 3.06 (m, 2 H), 2.93 - 2.67 (m, 4 H), 2.65 - 2.56 (m, 5 H), 2.24 - 1.84 (m, 6 H), 1.31 - 1.17 (m, 1 H), 1.05 (d, J = 6.4 Hz, 3H). Example 89: N-[(3R,5S)-1-(8-cyanoquinazoline-5-yl)-5-methylpiperidine-3-yl]-2-(4-methylpiperazine-1-yl)acetamide [ka]

[0376] The title compound was prepared from 5-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinazoline-8-carbonitrile and 2-(4-methylpiperazine-1-yl)acetic acid. MS: 408 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.60 (s, 1 H), 9.37 (s, 1 H), 8.37 (d, J = 8.3 Hz, 1 H), 7.77 (d, J = 7.7 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 4.07 - 4.03 (m, 1 H), 3.79 - 3.72 (m, 1 H), 3.66 - 3.59 (m, 1 H), 2.97 (s, 2 H), 2.82 - 2.52 (m, 9 H), 2.38 - 2.34 (m, 3 H), 2.13 - 1.91 (m, 2 H), 1.33 - 1.20 (m, 2 H), 0.95 (d, J = 6.5 Hz, 3 H). Example 90: (2R)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-methylpiperazine-1-yl)propanamide & Example 91: (2S)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-methylpiperazine-1-yl)propanamide [ka]

[0377] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and 2-(4-methylpiperazine-1-yl)propanoic acid, and subsequently separated on chiral-HPLC under the following conditions: Column: Repaired CHIRALPAK IC-3, 0.46 × 10 cm, 3 μm; Mobile phase: MtBE in EtOH (with 0.1% DEA), 70% homogeneous concentration over 20 min; Detector: UV 220 nm. (The chirality of 2-(4-methylpiperazine-1-yl)propanamide was randomly assigned.) Example 90: MS: 422 [M+H] + . 1H NMR (300 MHz, methanol-d4, ppm) δ 8.92 (d, J = 1.8 Hz, 1 H), 8.88 (d, J = 1.8 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.4 Hz, 1 H), 4.69 - 4.52 (m, 1 H), 4.34 - 4.23 (m, 2 H), 4.21 - 4.05 (m, 1 H), 3.08 - 2.96 (m, 1 H), 2.88 - 2.75 (m, 1 H), 2.76 - 2.39 (m, 8 H), 2.28 (s, 3 H), 2.15 - 1.94 (m, 2 H), 1.35 - 1.16 (m, 4 H), 1.01 (d, J = 6.4 Hz, 3 H). Example 91: MS: 422 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.91 (d, J = 1.8 Hz, 1 H), 8.88 (d, J = 1.8 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 4.62 - 4.58 (m, 1 H), 4.40 - 4.25 (m, 2 H), 4.21 - 4.09 (m, 1 H), 3.09 - 2.99 (m, 1 H), 2.88 - 2.78 (m, 1 H), 2.76 - 2.44 (m, 8 H), 2.29 (s, 3 H), 2.14 - 1.92 (m, 2 H), 1.34 - 1.21 (m, 4 H), 1.03 (d, J = 6.5 Hz, 3 H). Example 92: (2R)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]-2-(4-methylpiperazine-1-yl)propanamide & Example 93: (2S)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]-2-(4-methylpiperazine-1-yl)propanamide [ka]

[0378] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 2-(4-methylpiperazine-1-yl)propanoic acid, and subsequently separated on chiral-HPLC under the following conditions: column, CHIRALPAK ADH, 0.46 × 10 cm, 3 μm; mobile phase, hexane in EtOH (with 0.1% DEA), 90% homogeneous concentration at 20 min; detector, UV 220 nm. The chirality of (2-(4-methylpiperazine-1-yl)propanamide was randomly assigned. ) Example 92: MS: 464 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.94 (dd, J = 4.3, 1.8 Hz, 1 H), 8.67 (dd, J = 8.6, 1.8 Hz, 1 H), 8.04 (d, J = 8.2 Hz, 1 H), 7.63 (dd, J = 8.6, 4.3 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 4.26 - 4.22 (m, 1 H), 3.67 - 3.60 (m, 1 H), 3.43 - 3.36 (m, 1 H), 3.09 - 3.0 (m, 1 H), 2.76 - 2.38 (m, 10 H), 2.29 (s, 3 H), 2.23 - 2.04 (m, 2 H), 1.28 - 1.14 (m, 4 H), 1.06 (d, J = 6.5 Hz, 3 H). Example 93: MS: 464 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 8.94 (dd, J = 4.3, 1.8 Hz, 1 H), 8.67 (dd, J = 8.6, 1.8 Hz, 1 H), 8.04 (d, J = 8.2 Hz, 1 H), 7.62 (dd, J = 8.6, 4.3 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 1 H), 4.26 - 4.22 (m, 1 H), 3.67 - 3.60 (m, 1 H), 3.43 - 3.36 (m, 1 H), 3.09 - 3.0 (m, 1 H), 2.76 - 2.38 (m, 10 H), 2.29 (s, 3 H), 2.23 - 2.04 (m, 2 H), 1.28 - 1.14 (m, 4 H), 1.05 (d, J = 6.5 Hz, 3 H). Example 94: (2R)-2-(4-methylpiperazine-1-yl)-N-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]propanamide & Example 95: (2S)-2-(4-methylpiperazine-1-yl)-N-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]propanamide [ka]

[0379] The title compound was prepared from (3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 2-(4-methylpiperazine-1-yl)propanoic acid, and subsequently separated on chiral-HPLC under the following conditions: column, CHIRALPAK IC-3, 0.46 × 5 cm, 3 μm; mobile phase, EtOH hexane (with 0.1% DEA), 93% homogeneous concentration at 20 min; detector, UV 254 nm. (The chirality of 2-(4-methylpiperazine-1-yl)propanamide was randomly assigned.) Example 94: MS: 518 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 8.97 (dd, J = 4.3, 1.7 Hz, 1H), 8.68 (dd, J = 8.6, 1.8 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.67 (dd, J = 8.6, 4.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.34 (m, J = 15.5, 10.8, 4.2 Hz, 1H), 3.60 (d, J = 11.1 Hz, 2H), 3.06 (m, J = 6.9 Hz, 2H), 2.96 (m, J = 11.2 Hz, 1H), 2.84-2.17 (m, 13H), 1.65 (m, J = 12.3 Hz, 1H), 1.24 (d, J = 6.9 Hz, 3H). Example 95: MS: 518 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.0 - 8.94 (m, 1 H), 8.68 (dd, J = 8.6, 1.8 Hz, 1 H), 8.08 (d, J = 8.1 Hz, 1 H), 7.67 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.41 - 4.28 (m, 1 H), 3.64 - 3.57 (m, 2 H), 3.14 - 3.0 (m, 2 H), 2.96 (t, J = 11.2 Hz, 1 H), 2.76 - 2.45 (m, 9 H), 2.40 -2.35 (m, 1 H), 2.34 (s, 3 H), 1.72 - 1.59 (m, 1 H), 1.24 (d, J = 6.9 Hz, 3 H). Example 96: (2R)-N-[(3R,5S)-5-amino-1-(8-cyanoquinazoline-5-yl)piperidine-3-yl]-2-(4-methylpiperazine-1-yl)propanamide & Example 97: (2S)-N-[(3R,5S)-5-amino-1-(8-cyanoquinazoline-5-yl)piperidine-3-yl]-2-(4-methylpiperazine-1-yl)propanamide [ka]

[0380] The title compound was prepared from 5-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinazoline-8-carbonitrile and 2-(4-methylpiperazine-1-yl)propanoic acid, and subsequently separated by chiral HPLC under the following conditions: Column: Repaired CHIRALPAK IC-3, 0.46 × 10 cm, 3 μm; Mobile phase: MtBE in EtOH (with 0.1% DEA), 70% homogeneous concentration at 20 min; Column: Repaired Chiral Cellulose-SB, 0.46 × 10 cm, 3 μm; Mobile phase: Hexane (20 mmol NH3) in EtOH, 70% homogeneous concentration at 20 min; Detector: UV 254 nm. (The chirality of 2-(4-methylpiperazine-1-yl)propanamide was randomly assigned.) Example 96: MS: 422 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.61 (s, 1 H), 9.37 (s, 1 H), 8.38 (d, J = 8.3 Hz, 1 H), 7.72 (d, J = 7.5 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 4.07 - 3.99 (m, 1 H), 3.81 - 3.73 (m, 1 H), 3.66 - 3.58 (m, 1 H), 3.06 - 2.96 (m, 1 H), 2.80 - 2.66 (m, 2 H), 2.49 - 2.19 (m, 8 H), 2.13 (s, 3 H), 2.09 - 1.89 (m, 2 H), 1.32 - 1.18 (m, 1 H), 1.08 (d, J = 6.9 Hz, 3 H), 0.95 (d, J = 6.5 Hz, 3 H). Example 97: MS: 422 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.61 (s, 1H), 9.36 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 4.08-3.98 (m, 1H), 3.75 (d, J = 12.7 Hz, 1H), 3.63 (d, J = 11.7 Hz, 1H), 3.01 (q, J = 6.9 Hz, 1H), 2.72 (dt, J = 23.2, 11.5 Hz, 2H), 2.44 (d, J = 14.7 Hz, 4H), 2.33 (s, 4H), 2.15 (s, 3H), 2.05 (s, 1H), 1.97 (d, J = 12.8 Hz, 1H), 1.25 (q, J = 12.0 Hz, 1H), 1.08 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H). Example 98: (2R)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-methylpiperazine-1-yl)propanamide & Example 99: (2S)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-methylpiperazine-1-yl)propenamide [ka]

[0381] The title compound was prepared from 8-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidine-1-yl]quinoxaline-5-carbonitrile and 2-(4-methylpiperazine-1-yl)propanoic acid, and subsequently separated on chiral-HPLC under the following conditions: Column, Repaired Chiral-ADH, 0.46 × 10 cm, 3 μm; Mobile phase, Hexane (0.2% IPA) in EtOH, 85% homogeneous concentration at 20 min; Detector, UV 220 nm. (The chirality of 2-(4-methylpiperazine-1-yl)propanamide was randomly assigned.) Example 98: MS: 476 [M+H]+ . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.0 - 8.91 (m, 2 H), 8.15 (d, J = 8.3, 1.1 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 4.68 - 4.60 (m, 1 H), 4.30 - 4.18 (m, 2 H), 3.16 - 3.03 (m, 2 H), 2.98 - 2.87 (m, 2 H), 2.69 - 2.64 (m, 8 H), 2.40 (s, 3 H), 2.37 - 2.29 (m, 1 H), 1.78 - 1.65 (m, 1 H), 1.27 (d, J = 6.9 Hz, 3 H). Example 99: MS: 476 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.97-8.91 (m, 2 H), 8.14 (d, J = 8.2 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 4.69 - 4.61 (m, 1 H), 4.26 - 4.19 (m, 2 H), 3.15 - 3.03 (m, 2 H), 2.98 - 2.87 (m, 2 H), 2.80 - 2.52 (m, 8 H), 2.42 (s, 3 H), 2.36 - 2.29 (m, 1 H), 1.79 - 1.66 (m, 1 H), 1.28 (d, J = 6.9 Hz, 3 H). Example 100: (2R)-N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-methylpiperazine-1-yl)propanamide & Example 101: (2S)-N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-methylpiperazine-1-yl)propenamide [ka]

[0382] The title compound was prepared from 5-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidine-1-yl]quinoline-8-carbonitrile and 2-(4-methylpiperazine-1-yl)propanoic acid, and subsequently separated on chiral-HPLC under the following conditions: Column: Repaired ADH, 0.46 × 10 cm, 3 μm; Mobile phase: Hexane in EtOH (with 0.1% DEA), 90% homogeneous concentration at 20 min; Detector: UV 220 nm. (The chirality of 2-(4-methylpiperazine-1-yl)propanamide was randomly assigned.) Example 100: MS: 475 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.04 - 8.98 (m, 1 H), 8.68 (dd, J = 8.6, 1.7 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.3 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.39 - 4.27 (m, 1 H), 3.74 - 3.63 (m, 2 H), 3.11 - 2.95 (m, 3 H), 2.73 - 2.41 (m, 9 H), 2.38 - 2.31 (m, 1 H), 2.30 (s, 3 H), 1.74 - 1.61 (m, 1H), 1.25 (d, J = 6.9 Hz, 3 H). Example 101: MS: 475 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 9.04 - 8.98 (m, 1 H), 8.68 (dd, J = 8.6, 1.7 Hz, 1 H), 8.16 (d, J = 8.0 Hz, 1 H), 7.70 (dd, J = 8.6, 4.3 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.39 - 4.27 (m, 1 H), 3.74 - 3.63 (m, 2 H), 3.11 - 2.95 (m, 3 H), 2.73 - 2.41 (m, 9 H), 2.38 - 2.31 (m, 1 H), 2.30 (s, 3 H), 1.74 - 1.61 (m, 1H), 1.25 (d, J = 6.9 Hz, 3 H). Example 102: (2S)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-hydroxypiperidine-1-yl)propanamide & Example 103: (2R)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-hydroxypiperidine-1-yl)propanamide [ka]

[0383] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and 2-(4-hydroxypiperidine-1-yl)propanoic acid, and subsequently separated on chiral-HPLC under the following conditions: Column, CHIRALPAK IE-3, 0.46 × 10 cm, 3 μm; Mobile phase, hexane in EtOH (with 0.1% DEA), 90% homogeneous concentration at 20 min; Detector, UV 254 nm. (The chirality of 2-(4-hydroxypiperidine-1-yl)propenamide was randomly assigned.) Example 102: MS: 423 [M+H] + . 11H NMR (400 MHz, methanol-d4, ppm) δ 8.93 - 8.88 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.86 (br s, 1 H), 4.41 - 4.23 (m, 2 H), 4.18 - 4.13 (m, 1 H), 3.66 - 3.57 (m, 1 H), 3.14 - 3.05 (m, 1 H), 2.89 - 2.79 (m, 2 H), 2.71 (t, J = 11.7 Hz, 1 H), 2.45 - 2.35 (m, 1 H), 2.33 - 2.23 (m, 1 H), 2.14 - 2.03 (m, 3 H), 1.91 - 1.85 (m, 2 H), 1.65 - 1.51 (m, 2 H), 1.37 - 1.21 (m, 4 H), 1.03 (d, J = 6.4 Hz, 3 H). Example 103: MS: 423 [M+H] + . 1 1H NMR (400 MHz, methanol-d4, ppm) δ 8.94- 8.87 (m, 2H), 8.10 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 4.60 (s, 1H), 4.32 (dd, J = 22.5, 12.3 Hz, 2H), 4.14 (m, J = 8.4, 5.7, 4.1 Hz, 1H), 3.62 (m, J = 9.2, 4.8 Hz, 1H), 3.05 (t, J = 6.9 Hz, 1H), 2.87 -2.78 (m, 2H), 2.78 - 2.69 (m, 1H), 2.37 (t, J = 10.6 Hz, 1H), 2.27 (t, J = 10.7 Hz, 1H), 2.15 -2.05 (m, 2H), 1.96 - 1.77 (m, 2H), 1.59 (t, J = 11.0 Hz, 2H), 1.33- 1.28 (m, 1H), 1.24 (s, 3H), 1.03 (d, J = 6.4 Hz, 3H). Example 104: (2S)-2-(4-hydroxypiperidine-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]propanamide & Example 105: (2R)-2-(4-hydroxypiperidine-1-yl)-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]propanamide [ka]

[0384] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 2-(4-hydroxypiperidine-1-yl)propanoic acid, and subsequently separated on chiral-HPLC under the following conditions: Column, CHIRALPAK IE-3, 0.46 × 5 cm, 3 μm; Mobile phase, hexane (20 mmol NH3) in EtOH, 85% homogeneous concentration over 20 min; Detector, UV 254 nm. (The chirality of 2-(4-hydroxypiperidine-1-yl)propenamide was randomly assigned.) Example 104: MS: 465 [M+H] + . 1¹H NMR (400 MHz, methanol-d₄, ppm) δ 8.94 (dd, J = 4.2, 1.8 Hz, 1 H), 8.66 (dd, J = 8.6, 1.8 Hz, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 4.31 - 4.18 (m, 1 H), 3.68 - 3.56 (m, 2 H), 3.43 - 3.35 (m, 1 H), 3.13 - 3.04 (m, 1 H), 2.88 - 2.76 (m, 2 H), 2.60 - 2.45 (m, 2 H), 2.46 - 2.24 (m, 2 H), 2.22 - 2.09 (m, 2 H), 1.91 - 1.87 (m, 2 H), 1.65 - 1.52 (m, 2 H), 1.26 - 1.14 (m, 4 H), 1.05 (d, J = 6.5 Hz, 3 H). Example 105: MS: 465 [M+H] + . 1 ¹H NMR (400 MHz, methanol-d₄, ppm) δ 8.94 (dd, J = 4.2, 1.8 Hz, 1H), 8.66 (dd, J = 8.6, 1.8 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.63 (dd, J = 8.6, 4.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 4.31-4.18 (m, 1H), 3.62 (m, J = 12.8, 11.2, 4.4 Hz, 2H), 3.43-3.35 (m, 1H), 3.09 (m, J = 6.9 Hz, 1H), 2.82 (m, J = 12.2, 5.7 Hz, 2H), 2.53 (m, J = 22.2, 11.1 Hz, 2H), 2.35 (m, J = 46.2, 10.7 Hz, 2H), 2.21-2.09 (m, 2H), 1.87 (d, J = 13.3 Hz, 2H), 1.59 (m, J = 12.6, 8.0, 3.3 Hz, 2H), 1.27-1.14 (m, 4H), 1.05 (d, J = 6.5 Hz, 3H). Example 106: N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]-2-[(1R,5S,6s)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl]acetamide & Example 107: N-((3S,5R)-5-methyl-1-(8-(trifluoromethyl)quinoline-5-yl)piperidine-3-yl)-2-((1R,5S,6r)-3-methyl-3-azabicyclo[3.1.1]heptan-6-yl)acetamide [ka]

[0385] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and 2-(4-hydroxypiperidine-1-yl)propanoic acid, and subsequently separated by preparative HPLC under the following conditions: Column, XBridge Prep C18 OBD column, 150 × 19 mm, 5 μm; Mobile phase, acetonitrile in water (with 10 mmol / L NH4HCO3 and 0.1% NH3·H2O), 32% to 68% gradient over 8 min; Detector, UV 254 nm. Example 106: MS: 461 [M+H] + . 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.01 (dd, J = 4.2, 1.7 Hz, 1 H), 8.52 (dd, J = 8.6, 1.8 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.88 (d, J = 7.4 Hz, 1 H), 7.66 (dd. (m, 2 H), 2.48 - 2.22 (m, 6 H), 2.18 - 2.12 (m, 1 H), 2.05 - 1.93 (m, 5 H), 1.54 - 1.48 (m, 1 H), 1.27 - 1.21 (m, 1 H), 1.12 - 1.05 (m, 1 H), 0.94 (d, J = 6.4 Hz, 3 H). Example 107: MS: 461 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 8.95 (dd, J = 4.3, 1.7 Hz, 1H), 8.66 (dd, J = 8.6, 1.8 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.6, 4.2 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.23 (s, 1H), 3.64 (d, J = 11.4 Hz, 2H), 3.45 (m, 1H), 3.16 (d, J = 11.6 Hz, 2H), 2.67 (d, J = 25.2 Hz, 4H), 2.58-2.31 (m, 6H), 2.16 (s, 3H), 1.81 (d, J = 9.9 Hz, 1H), 1.39-1.02 (m, 5H). Example 108: 2-(1-isopropyl-piperidine-4-yl)-N-[(3R,5S)-5-methyl-1-(8-methyl-quinoline-5-yl)-piperidine-3-yl]acetamide [ka]

[0386] The title compound was synthesized from (3R,5S)-5-methyl-1-(8-methyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride (2) and (1-isopropyl-piperidine-4-yl)-acetic acid. MS: 423.6 [M+H] + . H NMR (400 MHz, DMSO-d6) 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), 7.55 (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), 4.10 - 3.98 (m, 1H), 3.16 (d, J = 10.6 Hz, 1H), 2.75 - 2.65 (m, 3H), 2.65 (d, J = 1.0 Hz, 3H), 2.64 - 2.58 (m, 1H), 2.32 (dt, J = 18.3, 10.9 Hz, 2H), 2.08 - 1.99 (m, 3H), 1.97 (d, J = 6.8 Hz, 3H), 1.56 (t, J = 12.8Hz, 3H), 1.06 (dq, J = 24.1, 11.9 Hz, 4H), 0.93 (dd, J = 6.5, 3.5 Hz, 9H). Example 109: 2-(1-isopropyl-piperidine-4-yl)-N-[(3R,5S)-1-(8-methyl-quinoline-5-yl)-5-trifluoromethyl-piperidine-3-yl]acetamide [ka]

[0387] The title compound was synthesized from (3R,5S)-1-(8-methyl-quinoline-5-yl)-5-trifluoromethyl-piperidine-3-ylamine hydrochloride (2) and (1-isopropyl-piperidine-4-yl)acetic acid. MS: 477.6. [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 4.1, 1.8 Hz, 1H), 8.53 (dd, J = 8.5, 1.8 Hz, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.58 (dd, J = 8.5, 4.1 Hz, 1H), 7.54 (dd. (d, J = 12.2 Hz, 1H), 2.08 - 1.99 (m, 2H), 1.97 (s, 2H), 1.57 (t, J = 12.5 Hz, 3H), 1.44 (q, J = 12.3 Hz, 1H), 1.08 (s, 2H), 0.93 (d, J = 6.6 Hz, 6H). Example 110: N-[(R)-5,5-difluoro-1-(8-methylquinoline-5-yl)-piperidine-3-yl]-2-(1-isopropyl-piperidine-4-yl)-acetamide & Example 111: N-[(S)-5,5-difluoro-1-(8-methylquinoline-5-yl)-piperidine-3-yl]-2-(1-isopropyl-piperidine-4-yl)-acetamide & Example [ka]

[0388] The title compound was synthesized from 5,5-difluoro-1-(8-methylquinoline-5-yl)-piperidine-3-ylamine hydrochloride and (1-isopropyl-piperidine-4-yl)-acetic acid, followed by chiral SFC separation under the following conditions: column, IA, Prep SFC-P100; mobile phase, 0.5% dimethylethylamine (DMEA) in ethanol, 40°C / 80 bar, 70 g / min; wavelength: 240 nm. Example 110: MS: 44.6 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J = 4.1, 1.8 Hz, 1H), 8.51 (dd, J = 8.5, 1.8 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 8.5, 4.1 Hz, 1H), 7.55 (dd, J = 7.6, 1.1 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 4.24 (d, J = 5.7 Hz, 0H), 2.70 (d, J = 9.9 Hz, 2H), 2.67 (d, J = 0.9 Hz, 3H), 2.61 (p, J = 6.7 Hz, 1H), 2.44 (d, J = 11.5 Hz, 1H), 2.06 - 1.95 (m, 5H), 1.57 (s, 3H), 1.16 - 1.02 (m, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 111: MS: 445.6 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J = 4.1, 1.8 Hz, 1H), 8.51 (dd, J = 8.5, 1.8 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.59 (dd, J = 8.5, 4.1 Hz, 1H), 7.55 (dd, J = 7.6, 1.1 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 4.23 (d, J = 5.7 Hz, 0H), 2.70 (d, J = 9.9 Hz, 2H), 2.67 (d, J = 0.9 Hz, 3H), 2.61 (p, J = 6.7 Hz, 1H), 2.44 (d, J = 11.5 Hz, 1H), 2.06 - 1.95 (m, 5H), 1.56 (s, 3H), 1.16 - 1.02 (m, 2H), 0.92 (d, J = 6.6 Hz, 6H). Example 112: N-[(3R,5S)-1-(7-フルオロ-8-メチル-キノリン-5-イル)-5-メチル-ピペリジン-3-イル]-2-(3-メチル-3-アザ-ビシクロ[3.1.1]へプタ-6-イル)-アセトアミド

change

[0389] The title compound was synthesized from (3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-ylamine hydrochloride and (3-methyl-3-azabicyclo[3.1.1]hepta-6-yl)acetic acid. MS: 425.6 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.44 (dt, J = 8.4, 1.6 Hz, 1H), 7.81 (dd, J = 23.9, 7.5 Hz, 1H), 7.52 (dd, J = 8.5, 4.2 Hz, 1H), 7.04 (d, J = 11.5 Hz, 1H), 4.08 - 3.93 (m, 1H), 3.20 (d, J = 11.4 Hz, 1H), 2.90 - 2.71 (m, 4H), 2.64 - 2.58 (m, 1H), 2.53 (d, J = 2.3 Hz, 3H), 2.41 - 2.31 (m, 3H), 2.29 (d, J = 6.4 Hz, 3H), 2.25 - 2.12 (m, 3H), 2.04 - 1.92 (m, 3H), 1.57 - 1.48 (m, 1H), 1.05 (q, J =12.0 Hz, 1H), 0.94 (d, J = 6.5 Hz, 3H). Example 113: N-[(3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-trifluoromethylpiperidine-3-yl]-2-(3-methyl-3-azabicyclo[3.1.1]hepta-6-yl)-acetamide [ka]

[0390] The title compound was synthesized from (3R,5S)-1-(7-fluoro-8-methyl-quinoline-5-yl)-5-trifluoromethyl-piperidine-3-ylamine and (3-methyl-3-azabicyclo[3.1.1]hepta-6-yl)acetic acid. MS: 479.5 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.49 (dd, J = 8.5, 1.7 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.55 (dd, J = 8.5, 4.2 Hz, 1H), 7.20 (d, J = 11.3 Hz, 1H), 4.11 (dd, J = 10.8, 5.0 Hz, 2H), 3.14 (s, 1H), 2.90 - 2.70 (m, 5H), 2.62 (d, J = 13.4 Hz, 1H), 2.55 (d, J = 2.4 Hz, 3H), 2.48 - 2.34 (m, 2H), 2.29 (s, 2H), 2.25 - 2.09 (m, 4H), 1.77 - 1.70 (m, 1H), 1.53 (d, J = 8.3 Hz, 1H), 1.45 (q, J = 12.3 Hz, 1H). Example 114: N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-fluoropiperidine-4-yl)acetamide [ka]

[0391] To a solution of 8-[(3R)-3-amino-5-methyl-1,2,3,6-tetrahydropyridine-3-yl]quinoxaline-5-carbonitride (61 mg, 0.23 mmol) in tert-butyl 4-([[(3R)-1-(8-cyanoquinoxaline-5-yl)-5-methyl-1,2,3,6-tetrahydropyridine-3-yl]carbamoyl]methyl)-4-fluoropiperidine-1-carboxylate:DMF (3 ml), 2-[1-[(tert-butoxy)carbonyl]-4-fluoropiperidine-4-yl]acetic acid (211 mg, 0.81 mmol), DIEA (184 mg, 1.43 mmol), and HATU (361 mg, 0.95 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. Once the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. By removing the solvent under reduced pressure, N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-fluoropiperidine-4-yl)acetamide was produced as a yellow solid (60 mg, crude), which was used in the next step without further purification.

[0392] N-[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidine-3-yl]-2-(4-fluoropiperidine-4-yl)acetamide: To a solution of tert-butyl 4-([[(3R,5S)-1-(8-cyanoquinoxalin-5-yl)-5-methylpiperidine-3-yl]carbamoyl]methyl)-4-fluoropiperidine-1-carboxylate (60 mg, crude) in methanol (3 ml), an aqueous solution of hydrogen chloride (6N, 1 ml, 6.0 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After the reaction was complete, it was quenched by adding water (10 ml). The resulting mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: Column, XBridge Prep C18 OBD, 150 × 19 mm, 5 μm; Mobile phase, acetonitrile in water (with mmol / L NH4HCO3 and 0.1% NH3·H2O), 15% to 45% gradient over 8 min; Detector, UV 254 nm. N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-2-(4-fluoropiperidine-4-yl)acetamide was obtained as a yellow solid (26 mg, 30% for 2 steps). MS: 411 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 8.93 (d, J = 1.8 Hz, 1 H), 8.89 (d, J = 1.8 Hz, 1 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 4.44 - 4.27 (m, 2 H), 4.17 - 4.12 (m, 1 H), 2.93 - 2.86 (m, 4 H), 2.78 (t, J = 11.3 Hz, 1 H), 2.68 (t, J = 11.6 Hz, 1 H), 2.53 (d, J = 16.0 Hz, 2 H), 2.17 - 1.67 (m, 6 H), 1.33 - 1.16 (m, 1 H), 1.02 (d, J = 6.5 Hz, 3 H).

[0393] The following compounds were synthesized using a similar method. Example 115: (2S)-N-[(3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]pyrrolidine-2-carboxamide [ka]

[0394] The title compound was prepared from (3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-(trifluoromethyl)piperidine-3-amine and (2S)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid. MS: 425 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.98 - 8.93 (m, 1 H), 8.50 (dd, J = 8.4, 1.8 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.55 (dd, J = 8.5, 4.2 Hz, 1 H), 7.21 (d, J = 11.3 Hz, 1 H), 4.17 - 4.12 (m, 1 H), 3.54 -3.46 (m, 1 H), 3.27 - 3.06 (m, 3 H), 2.87 - 2.75 (m, 3 H), 2.66 - 2.57 (m, 1 H), 2.55 (d, J = 2.3 Hz, 3 H), 2.17 - 2.09 (m, 1 H), 2.02 - 1.87 (m, 1 H), 1.72 -1.51 (m, 4 H). Example 116: (2S,4S)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-4-hydroxypyrrolidine-2-carboxamide [ka]

[0395] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitride and (2S,4S)-1-[(tert-butoxy)carbonyl]-4-hydroxypyrrolidine-2-carboxylic acid. MS: 381 [M+H] + . 1 H NMR (300 MHz, methanol-d4, ppm) δ 8.91 - 8.87 (m, 2 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.28 (d, J = 8.5 Hz, 1 H), 4.45 - 4.23 (m, 3 H), 4.15 - 4.09 (m, 1 H), 3.71 - 3.61 (m, 1 H), 3.05 - 2.90 (m, 2 H), 2.86 - 2.57 (m, 2 H), 2.40 - 2.25 (m, 1 H), 2.16 - 2.01 (m, 2 H), 1.91 - 1.81 (m, 1 H), 1.37 -1.23 (m, 1 H), 1.02 (d, J = 6.4 Hz, 3 H). Example 117: 2-(4-fluoropiperidine-4-yl)-N-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]acetamide [ka]

[0396] The title compound was prepared from tert-butyl 4-fluoro-4-({[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamoyl}methyl)piperidine-1-carboxylate and hydrogen chloride in dioxane. MS: 507 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.07 - 9.01 (m, 1 H), 8.60 (dd, J = 8.6, 1.8 Hz, 1 H), 8.11 (dd, J = 16.0, 7.7 Hz, 2 H), 7.71 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32 (d. Hz, 2H), 2.22 - 2.14 (m, 1 H), 1.78 - 1.45 (m, 5 H). Example 118: N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-2-(4-fluoropiperidine-4-yl)acetamide [ka]

[0397] The title compound was prepared from tert-butyl 4-({[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]carbamoyl}methyl)-4-fluoropiperidine-1-carboxylate and hydrogen chloride in dioxane. MS: 465 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.04 (d, J = 1.8 Hz, 1 H), 8.96 (d, J = 1.8 Hz, 1 H), 8.24 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 7.2 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1 H), 4.71 - 4.61 (m, 1 H), 4.17 - 3.90 (m, 2 H), 3.10 (t, J = 11.9 Hz, 1 H), 2.99 - 2.93 (m, 1 H), 2.84 (t, J = 11.5 Hz, 1 H), 2.76 - 2.59 (m, 4 H), 2.51-2.40 (m, 2 H), 2.17 - 2.08 (m, 2 H), 1.80 - 1.45 (m, 5 H). Example 119: 2-(1-aminocyclopropyl)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]acetamide [ka]

[0398] The title compound was prepared from tert-butyl N-[1-({[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]carbamoyl}methyl)cyclopropyl]carbamate and hydrogen chloride in dioxane. MS: 419 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 9.0 - 8.91 (m, 2 H), 8.14 (d, J = 8.4, 1.8 Hz, 1 H), 7.35 (d, J = 8.4, 1.5 Hz, 1 H), 4.67 (d, J = 11.7 Hz, 1 H), 4.31 - 4.17 (m, 2 H), 3.15 - 2.78 (m, 3 H), 2.37 - 2.33 (m, 3 H), 1.66 - 1.57 (m, 1 H), 0.70 - 0.63 (m, 2 H), 0.63 - 0.53 (m, 2 H). Example 120: 2-(1-aminocyclopropyl)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]acetamide [ka]

[0399] The title compound was prepared from tert-butyl N-[1-({[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]carbamoyl}methyl)cyclopropyl]carbamate and hydrogen chloride in dioxane. MS: 365 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.02 - 8.86 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 4.43 - 4.29 (m, 2 H), 4.23 - 4.11 (m, 1 H), 2.85 - 2.61 (m, 2 H), 2.57 (s, 2 H), 2.16 - 2.03 (m, 2 H), 1.26 - 1.16 (m, 1 H),1.08 - 0.96 (m, 5 H), 0.95 -0.82 (m, 2 H). Example 121: 2-(1-aminocyclopropyl)-N-[(3R,5S)-5-methyl-1-(8-methyl-1,7-naphthyridine-5-yl)piperidine-3-yl]acetamide [ka]

[0400] The title compound was prepared from tert-butyl N-[1-({[(3R,5S)-5-methyl-1-(8-methyl-1,7-naphthyridine-5-yl)piperidine-3-yl]carbamoyl}methyl)cyclopropyl]carbamate and hydrogen chloride in dioxane. MS: 354 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.02 (dd, J = 4.1, 1.7 Hz, 1 H), 8.61 (dd, J = 8.6, 1.7 Hz, 1 H), 8.05 (s, 1 H), 7.79 (dd, J = 8.6, 4.2 Hz, 1 H), 4.30 -4.17 (m, 1 H), 3.62 - 3.54 (m, 1 H), 3.33 - 3.29 (m, 1 H), 2.96 (s, 3 H), 2.58 - 2.42 (m, 2 H), 2.33 (s, 2 H), 2.22 - 2.07 (m, 2 H), 1.25 - 1.11 (m, 1 H), 1.05 (d, J = 6.4 Hz, 3 H), 0.66 - 0.61 (m, 2 H), 0.59 - 0.49 (m, 2 H). Example 122: (2S)-N-[(3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)piperidine-3-yl]pyrrolidine-2-carboxamide [ka]

[0401] The title compound was prepared from tert-butyl(2S)-2-{[(3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)piperidine-3-yl]carbamoyl}pyrrolidine-1-carboxylate and hydrogen chloride in dioxane. MS: 353 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.91 (dd, J = 4.1, 1.8 Hz, 1 H), 8.47 (dd, J = 8.5, 1.8 Hz, 1 H), 7.84 (d, J = 8.1 Hz, 1 H), 7.59 - 7.48 (m, 2 H), 7.09 (d, J = 7.6 Hz, 1 H), 4.03 - 3.98 (m, 1 H), 3.51 - 3.43 (m, 1 H), 3.30 - 3.23 (m, 1 H), 3.19 - 3.12 (m, 1 H), 2.85 - 2.72 (m, 3 H), 2.64 (s, 3 H), 2.44 (t, J = 10.7Hz, 1 H), 2.30 (t, J = 11.2 Hz, 1 H), 2.12 - 1.86 (m, 2 H), 1.68 - 1.50 (m, 3 H), 1.18 - 1.05 (m, 1 H), 0.94 (d, J = 6.5 Hz, 3 H). Example 123: (2S)-N-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]pyrrolidine-2-carboxamide [ka]

[0402] The title compound was prepared from tert-butyl(2S)-2-{[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamoyl}pyrrolidine-1-carboxylate and hydrogen chloride in dioxane. MS: 461 [M+H] + . 1H NMR (400 MHz, methanol-d4, ppm) δ 9.0 - 8.94 (m, 1 H), 8.69 (dd, J = 8.6, 1.8 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.67 (dd, J = 8.6, 4.2 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 4.37 - 4.26 (m, 1 H), 3.67 - 3.57 (m, 3 H), 3.19 - 2.80 (m, 4 H), 2.65 (t, J = 11.1 Hz, 1 H), 2.40 - 2.32 (m, 1 H), 2.21 - 2.09 (m, 1 H), 1.85 - 1.70 (m, 3 H), 1.70 - 1.56 (m, 1 H). Example 124: (2S)-N-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]pyrrolidine-2-carboxamide [ka]

[0403] The title compound was prepared from tert-butyl(2S)-2-{[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamoyl}pyrrolidine-1-carboxylate and hydrogen chloride in dioxane. MS: 419 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.94 (dd, J = 16.6, 1.8 Hz, 2 H), 8.13 (d, J = 8.3 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 4.67 -4.59 (m, 1 H), 4.27 - 4.15 (m, 2 H), 3.71 - 3.63 (m, 1 H), 3.11 - 2.82 (m, 5 H), 2.37 - 2.30 (m, 1 H), 2.25 - 2.09 (m, 1 H), 1.88 - 1.57 (m, 4 H). Example 125: (2S)-N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]pyrrolidine-2-carboxamide [ka]

[0404] The title compound was prepared from tert-butyl(2S)-2-{[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]carbamoyl}pyrrolidine-1-carboxylate and hydrogen chloride in dioxane. MS: 418 [M+H] + . 1 H NMR (300 MHz, methanol-d4, ppm) δ 8.99 (dd, J = 4.3, 1.7 Hz, 1 H), 8.66 (dd, J = 8.6, 1.7 Hz, 1 H), 8.15 (d, J = 8.0 Hz, 1 H), 7.68 (dd, J = 8.6, 4.3 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 4.43 - 4.21 (m, 1 H), 3.69 - 3.56 (m, 3 H), 3.15 - 2.82 (m, 4 H), 2.65 (t, J = 11.2 Hz, 1 H), 2.39 - 2.29 (m, 1 H), 2.21 - 2.06 (m, 1H), 1.87 - 1.50 (m, 4 H). Example 126: (2R)-N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]pyrrolidine-2-carboxamide [ka]

[0405] The title compound was prepared from tert-butyl(2R)-2-{[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]carbamoyl}pyrrolidine-1-carboxylate and hydrogen chloride in dioxane. MS: 418 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 9.01 (dd, J = 4.3, 1.7 Hz, 1 H), 8.67 (dd, J = 8.6, 1.7 Hz, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.69 (dd, J = 8.6, 4.2 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 4.37 - 4.25 (m, 1 H), 3.74 - 3.59 (m, 3 H), 3.17 - 2.86 (m, 4 H), 2.67 (t, J = 11.2 Hz, 1 H), 2.39 - 2.32 (m, 1 H), 2.19 - 2.07 (m, 1 H), 1.87 - 1.50 (m, 4 H). Example 127: (2S)-2-amino-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl]butanediamide [ka]

[0406] The title compound was prepared from tert-butyl N-[(1S)-2-carbamoyl-1-{[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl]carbamoyl}ethyl]carbamate and hydrogen chloride in dioxane. MS: 425 [M+H] + . 1 H NMR (300 MHz, methanol-d4, ppm) δ 8.94 - 8.83 (m, 2 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 1 H), 4.27 - 3.97 (m, 3 H), 3.70 - 3.59 (m, 1 H), 2.77 - 2.41 (m, 4 H), 2.17 - 2.04 (m, 2 H), 1.31 - 1.15 (m, 1 H), 1.01 (d, J = 6.4 Hz, 3 H). Example 128: (2S)-2-amino-N-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]butanediamide [ka]

[0407] The title compound was prepared from tert-butyl N-[(1S)-2-carbamoyl-1-{[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl]carbamoyl}ethyl]carbamate and hydrogen chloride in dioxane. MS: 424 [M+H] + . 1 H NMR (400 MHz, methanol-d4, ppm) δ 8.97 - 8.91 (m, 1 H), 8.66 (dd, J = 8.6, 1.8 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.63 (dd, J = 8.6, 4.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 1 H), 4.25 - 4.21 (m, 1 H), 3.68 - 3.59 (m, 2 H), 3.43 - 3.36 (m, 1 H), 2.67 - 2.44 (m, 4 H), 2.20 - 2.11 (m, 2 H), 1.26 - 1.13 (m, 1 H), 1.05 (d, J = 6.4 Hz, 3 H). Example 129: (2S)-2-amino-N-[(3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-yl]butanediamide [ka]

[0408] The title compound was prepared from tert-butyl N-[(1S)-2-carbamoyl-1-{[(3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-yl]carbamoyl}ethyl]carbamate and hydrogen chloride in dioxane. MS: 388 [M+H] + .1 H NMR (300 MHz, DMSO-d6, ppm) δ 8.95 - 8.87 (m, 1 H), 8.46 - 8.37 (m, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.50 (dd, J = 8.5, 4.2 Hz, 1 H), 7.35 (br s, 1 H), 7.01 (d. H), 2.21 -1.89 (m, 3 H), 1.83 (br s, 2 H), 1.17 - 0.99 (m, 1 H), 0.91 (d, J = 6.4 Hz, 3 H). Example 130: (2S)-2-amino-N-[(3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)piperidine-3-yl]butanediamide [ka]

[0409] The title compound was prepared from tert-butyl N-[(1S)-2-carbamoyl-1-{[(3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)piperidine-3-yl]carbamoyl}ethyl]carbamate and hydrogen chloride in dioxane. MS: 370 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 8.93 - 8.87 (m, 1 H), 8.47 (dd, J = 8.5, 1.8 Hz, 1 H), 7.83 (d, J = 7.9 Hz, 1 H), 7.58 - 7.47 (m, 2 H), 7.36 (br s, 1 H), 7.07 (d. (m, 3H), 1.15 - 1.02 (m, 1 H), 0.93 (d, J = 6.5 Hz, 3 H). Example 131: N-[(3R,5S)-1-(8-cyanoquinazoline-5-yl)-5-methylpiperidine-3-yl]-2-[(3R,4S)-3-fluoropiperidine-4-yl]acetamide & Example 132: N-[(3R,5S)-1-(8-cyanoquinazoline-5-yl)-5-methylpiperidine-3-yl]-2-[(3S,4R)-3-fluoropiperidine-4-yl]acetamide [ka]

[0410] The title compound was prepared from 5-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinazoline-8-carbonitrile and 2-{1-[(tert-butoxy)carbonyl]-3-fluoropiperidine-4-yl}acetic acid, and subsequently separated by preparative HPLC under the following conditions: Column, Repaired CHIRALPAK ID-3, 0.46 × 10 cm, 3 μm; Mobile phase, MtBE in EtOH (with 0.1% DEA), 80% homogeneous concentration at 20 min; Detector, UV 254 nm. Example 131: MS: 411 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.61 (s, 1H), 9.36 (s, 1H), 8.41 - 8.33 (m, 1H), 8.06 - 7.95 (m, 1H), 7.30 - 7.21 (m, 1H), 4.52 (s, 0H), 4.40 (s, 0H), 4.10 - 3.91 (m, 0H), 3.85 - 3.76 (m, 1H), 3.67 - 3.57 (m, 1H), 3.10 - 2.99 (m, 1H), 2.90 - 2.79 (m, 1H), 2.76 - 2.59 (m, 3H), 2.50 - 2.37 (m, 2H), 2.28 - 1.91 (m, 5H), 1.37 - 1.04 (m, 3H), 0.94 (d, J = 6.4 H, 3H). Example 132: MS: 411 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.61 (s, 1 H), 9.36 (s, 1 H), 8.37 (d, J = 8.3 Hz, 1 H), 8.0 (d, J = 7.1 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 1 H), 4.46 (d, J = 49.4 Hz, 1 H), 4.04 - 4.0 (m, 1 H), 3.85 - 3.78 (m, 1 H), 3.67 - 3.59 (m, 1 H), 3.09 - 2.98 (m, 1 H), 2.92 - 2.84 (m, 1 H), 2.76 - 2.55 (m, 5 H), 2.25 - 2.15 (m, 1H), 2.13 - 1.89 (m, 4 H), 1.37 - 1.32 (m, 2 H), 1.22 -1.09 (m, 1 H), 0.94 (d, J = 6.4 Hz, 3 H). Example 133: 2-amino-2-cyclopropyl-N-[(3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)-piperidine-3-yl]acetamide [ka]

[0411] The title compound was prepared from (3R,5S)-5-methyl-1-(8-methylquinoline-5-yl)-piperidine-3-ylamine hydrochloride and tert-butoxycarbonylaminocyclopropylacetic acid. MS: 353.5 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.91 (dd, J = 4.1, 1.8 Hz, 1H), 8.48 (ddd, J = 8.4, 1.8, 0.8 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.55 (dd, J = 8.5, 4.1 Hz, 1H), 7.52 (dt, J = 7.6, 1.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 1H), 4.05 (s, 1H), 3.17 (d, J = 11.3 Hz, 1H), 2.69 - 2.64 (m, 3H), 2.36 (dtd, J = 30.4, 10.9, 5.1 Hz, 3H), 1.98 (d, J = 12.7 Hz, 1H), 1.67 (s, 1H), 1.09 (qd, J = 12.0, 4.6 Hz, 1H), 0.95 (dd, J = 6.5, 1.2 Hz, 3H), 0.88 (dddd, J = 9.9, 7.8, 4.8, 2.4 Hz, 1H), 0.41 - 0.27 (m, 3H), 0.25 - 0.13 (m, 1H). Example 134: (2S,3R)-2-amino-N-[(3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-yl]-3-hydroxybutylamide [ka]

[0412] The title compound was prepared from (3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-ylamine hydrochloride and (2S,3R)-2-tert-butoxycarbonylamino-3-hydroxybutyrate. MS: 375.5 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.97 (d, J = 3.6 Hz, 1H), 8.61 (s, 1H), 8.50 (s, 1H), 8.10 (s, 3H), 7.56 (s, 1H), 7.07 (d, J = 11.5 Hz, 1H), 4.10 (s, 1H), 3.88 (q, J = 6.6 Hz, 1H), 3.45 (s, 3H), 3.39 (q, J = 7.0 Hz, 1H), 3.24 (d, J = 10.7 Hz, 1H), 2.55 (d, J = 2.2 Hz, 3H), 2.48 - 2.37 (m, 1H), 2.03 (d, J = 14.4 Hz, 2H), 1.20 - 1.03 (m, 5H), 0.96 (d, J = 6.4 Hz, 3H). Example 135: (R)-2-amino-N-[(3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-yl]-3-hydroxypropionamide [ka]

[0413] The title compound was synthesized from (3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-ylamine hydrochloride and boc-D-Ser-OH. MS: 361.4 [M+H] +. 1H NMR (400 MHz, deuterium oxide) δ 9.23 (dd, J = 8.5, 1.6 Hz, 1H), 8.98 (dd, J = 5.6, 1.5 Hz, 1H), 7.94 (dd, J = 8.5, 5.6 Hz, 1H), 7.31 (d, J = 11.5 Hz, 1H), 4.22 (s, 1H), 4.06 (dd, J = 5.5, 4.1 Hz, 1H), 3.97 - 3.82 (m, 2H), 3.71 (s, 1H), 3.51 (d, J = 8.7 Hz, 1H), 3.34 (d, J = 11.9 Hz, 1H), 2.64 (t, J = 11.0 Hz, 1H), 2.55 (d, J = 1.7 Hz, 3H), 2.47 (t, J = 11.5 Hz, 1H), 2.14 (d, J = 11.5 Hz, 2H), 1.15 (q, J = 12.6 Hz, 1H), 0.95 (d, J = 6.3 Hz, 3H). Example 136: 2-(3-fluoropiperidine-4-yl)-N-[(3R,5S)-1-(8-methyl-[1,7]naphthyridine-5-yl)-5-trifluoromethyl-piperidine-3-yl]acetamide [ka]

[0414] The title compound was synthesized from (3R,5S)-1-(8-methyl-[1,7]naphthyridine-5-yl)-5-trifluoromethylpiperidine-3-ylamine and 4-carboxymethyl-3-fluoropiperidine-1-carboxylate tert-butyl ester. MS: 454.3 [M+H] + . Example 137: 2-Fluoro-N-[(3R,5S)-1-(8-methyl-[1,7]naphthyridine-5-yl)-5-trifluoromethyl-piperidine-3-yl]-2-pyrrolidine-3-yl-acetamide [ka]

[0415] The title compound was prepared from (3R,5S)-1-(8-methyl-[1,7]naphthyridine-5-yl)-5-trifluoromethylpiperidine-3-ylamine and 3-(carboxy-fluoro-methyl)-pyrrolidine-1-carboxylate tert-butyl ester. MS: 439.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.98 - 8.94 (m, 1H), 8.49 - 8.44 (m, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 2.7 Hz, 1H), 7.83 (ddd, J = 8.5, 4.2, 1.5 Hz, 1H), 7.41 - 7.36 (m, 1H), 4.20 (s, 2H), 4.04 (s, 3H), 2.90 - 2.64 (m, 6H), 2.11 (s, 2H), 1.65 (s, 3H), 1.15 (s, 3H), 0.84 (s, 3H). Example 138: N-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-trifluoromethylpiperidine-3-yl]-2-(3-fluoropiperidine-4-yl)-acetamide [ka]

[0416] Prepared by a similar method from 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-1-yl)-quinoline-8-carbonitride and 4-carboxymethyl-3-fluoro-piperidine-1-carboxylate tert-butyl ester. MS: 464.3 [M+H] +. 1H 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), 8.09 (d, J = 7.3 Hz, 1H), 7.72 (dd, J = 8.5, 4.2 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 4.15 (s, 2H), 3.57 (d, J = 11.7 Hz, 2H), 3.20 (s, 2H), 2.94 (t, J = 11.6 Hz, 2H), 2.13 (dt, J = 49.4, 7.2 Hz, 5H), 1.50 (q, J = 12.1 Hz, 2H), 1.30 (s, 3H). Example 139: 1-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-3-[2-(dimethylamino)ethyl]urea [ka]

[0417] 8-[(3R,5S)-3-isocyanate-5-(trifluoromethyl)piperidine-1-yl]quinoxaline-5-carbonitrile: At 0°C, triphosgene (70 mg, 0.24 mmol) was added dropwise at 0°C to a solution of 8-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidine-1-yl]quinoxaline-5-carbonitrile (94 mg, 0.29 mmol) and DIEA (115 mg, 0.89 mmol) in dichloromethane (8 ml). The resulting mixture was stirred at 0°C for 3 hours and then concentrated under reduced pressure to produce 8-[(3R,5S)-3-isocyanate-5-(trifluoromethyl)piperidine-1-yl]quinoxaline-5-carbonitrile as a pale yellow solid (54 mg, crude), which was used in the next step without further purification. MS: 348.2 [M+H] + .

[0418] To a solution of 8-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-3-[2-(dimethylamino)ethyl]urea:8-[(3R,5S)-3-isocyanate-5-(trifluoromethyl)piperidine-1-yl]quinoxaline-5-carbonitrile (54 mg, crude) in dichloromethane (8 ml), DIEA (115 mg, 0.89 mmol) and (2-aminoethyl)dimethylamine (6 mg, 0.07 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 16 hours. After the reaction was complete, it was quenched by adding water (5 ml). The resulting mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were combined, washed with brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: Column, XBridge Prep C18 OBD column, 150 × 19 mm, 5 μm; Mobile phase, acetonitrile in water (with 10 mmol / L NH4HCO3 and 0.1% NH3·H2O), 15% to 40% gradient over 8 min; Detector, UV 254 nm. 1-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-3-[2-(dimethylamino)ethyl]urea was obtained as a pale yellow solid (23 mg, 18% for 2 steps). MS: 436 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.07 (d, J = 1.8 Hz, 1 H), 8.99 (d, J = 1.8 Hz, 1 H), 8.26 (d, J = 8.4 Hz, 1 H), 7.39 (d, J = 8.5 Hz, 1 H), 6.32 (d, J = 7.3 Hz, 1 H), 5.89 - 5.79 (m, 1 H), 4.78 - 4.68 (m, 1 H), 4.20 - 4.10 (m, 1 H), 3.91 - 3.76 (m, 1 H), 3.27 - 2.75 (m, 5 H), 2.33 - 2.23 (m, 2 H), 2.19 - 2.13 (m, 7 H), 1.57 - 1.43 (m, 1 H).

[0419] The following compounds were synthesized using a similar method. Example 140: 1-[(3R,5S)-1-(8-cyanoquinoxaline-5-yl)-5-methylpiperidine-3-yl]-3-[2-(dimethylamino)ethyl]urea [ka]

[0420] The title compound was prepared from 8-[(3R,5S)-3-amino-5-methylpiperidine-1-yl]quinoxaline-5-carbonitrile and (2-aminoethyl)dimethylamine. MS: 382 [M+H] + . 1 H NMR (400 MHz, DMSO-d6, ppm) δ 9.03 (d, J = 1.8 Hz, 1 H), 8.94 (d, J = 1.8 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.6 Hz, 1 H), 6.14 (d, J = 7.3 Hz, 1 H), 5.79 - 5.72 (m, 1 H), 4.43 - 4.36 (m, 1 H), 4.30 - 4.22 (m, 1 H), 3.72 - 3.68 (m, 1 H), 3.16 - 3.0 (m, 2 H), 2.75 - 2.63 (m, 2 H), 2.29 - 2.22 (m, 2H), 2.14 (s, 6 H), 2.0 -1.76 (m, 2 H), 1.12 - 0.98 (m, 1 H), 0.90 (d, J = 6.5 Hz, 3 H). Example 141: 3-[2-(dimethylamino)ethyl]-1-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl]urea [ka]

[0421] The title compound was prepared from (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-amine and (2-aminoethyl)dimethylamine. MS: 425 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.01 - 8.95 (m, 2 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 6.12 (d, J = 7.5 Hz, 1 H), 5.81 - 5.71 (m, 1 H), 4.26 - 4.10 (m, 2 H), 3.77 - 3.71 (m, 1 H), 3.19 - 3.01 (m, 2 H), 2.66 - 2.52 (m, 2 H), 2.32 - 2.22 (m, 2 H), 2.15 (s, 6 H), 1.98 - 1.92 (m, 2 H), 1.10 - 0.96 (m, 1 H), 0.92 (d, J = 6.3 Hz, 3 H). Example 142: 3-[2-(dimethylamino)ethyl]-1-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-yl]urea [ka]

[0422] The title compound was prepared from (3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoxaline-5-yl]piperidine-3-amine and (2-aminoethyl)dimethylamine. MS: 479 [M+H] + . 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.04 - 8.98 (m, 2 H), 8.10 (d, J = 8.4 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 6.30 (d, J = 7.5 Hz, 1 H), 5.83 (t, J = 5.3 Hz, 1 H), 4.59 - 4.50 (m, 1 H), 4.12 - 4.01 (m, 1 H), 3.90 - 3.84 (m, 1 H), 3.22 - 2.85 (m, 4 H), 2.75 (t, J = 11.3 Hz, 1 H), 2.32 - 2.22 (m, 2 H), 2.22 - 2.19 (m, 1H), 2.15 (s, 6 H), 1.53 - 1.36 (m, 1 H). Example 143: 1-[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-(trifluoromethyl)piperidine-3-yl]-3-[2-(dimethylamino)ethyl]urea [ka]

[0423] The title compound was prepared from 5-[(3R,5S)-3-amino-5-(trifluoromethyl)piperidine-1-yl]quinoline-8-carbonitrile and (2-aminoethyl)dimethylamine. MS: 435 [M+H] + . 1H NMR (400 MHz, DMSO-d6, ppm) δ 9.09 - 9.03 (m, 1 H), 8.58 (dd, J = 8.6, 1.7 Hz, 1 H), 8.25 (d, J = 8.0 Hz, 1 H), 7.71 (dd, J = 8.6, 4.2 Hz, 1 H), 7.31 (d, J = 8.1 Hz, 1 H), 6.28 (d, J = 7.3 Hz, 1 H), 5.79 (t, J = 5.4 Hz, 1 H), 3.99 - 3.94 (m, 1 H), 3.59 - 3.56 (m, 2 H), 3.25 - 3.01 (m, 3 H), 2.93 (t, J = 11.5 Hz, 1H), 2.57 (t, J = 11.1 Hz, 1 H), 2.31 - 2.17 (m, 3 H), 2.12 (s, 6 H), 1.46 - 1.33 (m, 1 H). Example 144: 3-[2-(dimethylamino)ethyl]-1-[(3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]urea [ka]

[0424] The title compound was prepared from (3R,5S)-5-(trifluoromethyl)-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine and (2-aminoethyl)dimethylamine. MS: 478 [M+H] + . 1H NMR (300 MHz, DMSO-d6, ppm) δ 9.08 - 9.0 (m, 1 H), 8.60 (dd, J = 8.6, 1.8 Hz, 1 H), 8.08 (d, J = 8.1 Hz, 1 H), 7.71 (dd, J = 8.6, 4.1 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 6.31 (d, J = 7.5 Hz, 1 H), 5.83 (t, J = 5.4 Hz, 1 H), 4.02 - 3.96 (m, 1 H), 3.55 - 3.46 (m, 2 H), 3.27 - 3.03 (m, 3 H), 2.87 (t, J = 11.4 Hz, 1H), 2.61 - 2.51 (m, 1 H), 2.36 - 2.25 (m, 2 H), 2.25 - 2.20 (m, 1 H), 2.17 (s, 6 H), 1.49 - 1.30 (m, 1 H). Example 145: 3-[2-(dimethylamino)ethyl]-1-[(3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-yl]urea [ka]

[0425] The title compound was prepared from (3R,5S)-1-(7-fluoro-8-methylquinoline-5-yl)-5-methylpiperidine-3-amine and (2-aminoethyl)dimethylamine. MS: 388 [M+H] + . 1H NMR (300 MHz, DMSO-d6, ppm) δ 8.98 - 8.90 (m, 1 H), 8.44 (dd, J = 8.5, 1.8 Hz, 1 H), 7.53 (dd, J = 8.5, 4.2 Hz, 1 H), 7.04 (d, J = 11.5 Hz, 1 H), 6.09 (d, J = 7.5 Hz, 1 H), 5.73 (t, J = 5.4 Hz, 1 H), 3.88 - 3.79 (m, 1 H), 3.48 - 3.39 (m, 1 H), 3.25 - 3.16 (m, 1 H), 3.16 - 2.98 (m, 2 H), 2.57 - 2.51 (m, 3 H), 2.41 - 2.21 (m, 4 H), 2.13 (s, 6 H), 2.03 - 1.93 (m, 2 H), 1.02 - 0.84 (m, 4 H). Example 146: 3-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]-1-[(3R)-piperidine-3-yl]urea [ka]

[0426] At 0°C, tert-butyl(3R)-3-([[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamoyl]amino)piperidine-1-carboxylate was added dropwise to a solution of (3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-amine (92 mg, 0.28 mmol) and DIEA (77 mg, 0.60 mmol) in 10 ml of dichloromethane, to a solution of triphosgene (29 mg, 0.10 mmol) in 5 ml of dichloromethane. The resulting mixture was stirred at 0°C for 3 hours, and then tert-butyl(3R)-3-aminopiperidine-1-carboxylate (60 mg, 0.30 mmol) was added. The resulting solution was stirred at room temperature for an additional 16 hours. The reaction mixture was concentrated under reduced pressure to produce tert-butyl(3R)-3-([[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamoyl]amino)piperidine-1-carboxylate as a pale yellow solid (110 mg, crude), which was used in the next step without further purification.

[0427] 3-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]-1-[(3R)-piperidine-3-yl]urea: To a solution of tert-butyl(3R)-3-([[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]carbamoyl]amino)piperidine-1-carboxylate (110 mg, crude) in methanol (10 ml), aqueous HCl solution (6N, 3.3 ml, 19.99 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 5 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: Column, XBridge Prep C18 OBD column, 150 × 19 mm, 5 μm; Mobile phase, acetonitrile in water (with 10 mmol / L NH4HCO3 and 0.1% NH3·H2O), 25% to 45% gradient over 8 min; Detector, UV 254 nm. 3-[(3R,5S)-5-methyl-1-[8-(trifluoromethyl)quinoline-5-yl]piperidine-3-yl]-1-[(3R)-piperidine-3-yl]urea was obtained as a white solid (59 mg, 45% for 2 steps). MS: 436 [M+H] + . 1 H NMR (300 MHz, DMSO-d6, ppm) δ 9.06 - 8.98 (m, 1 H), 8.53 (dd, J = 8.6, 1.8 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.67 (dd, J = 8.6, 4.2 Hz, 1 H), 7.20 (d, J = 8.1 Hz, 1 H), 5.99 - 5.69 (m, 2 H), 3.88 - 3.80 (m, 1 H), 3.63 - 3.54 (m, 1 H), 3.52 - 3.37 (m, 2 H), 2.92 - 2.82 (m, 1 H), 2.74 - 2.64 (m, 1 H), 2.49 - 2.33 (m, 3 H), 2.30 - 2.17 (m, 1 H), 2.10 - 1.95 (m, 2 H), 1.72 - 1.66 (m, 1 H), 1.56 - 1.50 (m, 1 H), 1.39 - 1.13 (m, 2 H), 1.07 - 0.91 (m, 4 H). Example 147: 1-(1-methyl-piperidine-4-yl)-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]-urea [ka]

[0428] 1-(1-methyl-piperidine-4-yl)-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]-urea: In a scintillation vial, under nitrogen, (3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-ylamine hydrochloride (2) (53.10 mg; 0.14 mmol; 1.0 eq.) was suspended in a solution of diisopropylethylamine (0.12 ml; 0.69 mmol; 5.0 eq.) in anhydrous THF (3.0 ml). The suspension was stirred at room temperature for 5 minutes, and then phenyl 4-nitrochloroformate (42.0 mg; 0.21 mmol; 1.50 eq.) was added. The reaction mixture was stirred for 2 hours, then 4-amino-1-methylpiperidine (0.03 ml; 0.28 mmol, 2.0 eq.) was added. The reaction was stirred overnight.

[0429] The reaction was concentrated to 1 ml and purified by preparative HPLC under the following conditions: column, XBridge BEH130 Prep C18 OBD column, 19 × 150 mm 5 μm 13 nm; mobile phase, CAN / water with 0.1% NH4OH as a modifier; detector, UV 254 nm. The pure fraction was frozen and lyophilized to give 1-(1-methyl-piperidine-4-yl)-3-[(3R,5S)-5-methyl-1-(8-trifluoromethyl-quinoline-5-yl)-piperidine-3-yl]urea (31.40 mg; 0.07 mmol; 50.3%) as a white solid. MS: 450 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 9.0 (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), 7.66 (dd, J = 8.6, 4.2 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 5.76 (t, J = 7.2 Hz, 2H), 3.85 (s, 1H), 3.34 (s, 5H), 2.60 (d, J = 8.7 Hz, 2H), 2.40 (q, J = 11.4 Hz, 2H), 2.12 (s, 3H), 1.95 (q, J = 14.2, 11.2 Hz, 4H), 1.78 - 1.61 (m, 2H), 1.39 - 1.20 (m, 2H), 1.03 - 0.88 (m, 3H). Example 148: N-[(3R,5S)-1-(8-cyano-[1,7]naphthyridine-5-yl)-5-methyl-piperidine-3-yl]-2-[3-fluoro-1-(2-hydroxyethyl)-piperidine-4-yl]-acetamide [ka]

[0430] The title compound was prepared from N-[(3R,5S)-1-(8-cyano-[1,7]naphthiridine-5-yl)-5-methylpiperidine-3-yl]-2-(3-fluoropiperidine-4-yl)-acetamide:(3R,5S)-1-(8-cyano-[1,7]naphthiridine-5-yl)-5-methylpiperidine-3-ylamine and 4-carboxymethyl-3-fluoropiperidine-1-carboxylate tert-butyl ester by a similar method (e.g., 136).

[0431] In DMSO (1 ml), N-[(3R,5S)-1-(8-cyano-[1,7]naphthirizin-5-yl)-5-methylpiperidine-3-yl]-2-[3-fluoro-1-(2-hydroxyethyl)-piperidine-4-yl]-acetamide:N-[(3R,5S)-1-(8-cyano-[1,7]naphthirizin-5-yl)-5-methylpiperidine-3-yl]-2-(3-fluoropiperidine-4-yl)-acetamide (50 mg; 0.11 mmol; 1.0 eq.), 2-bromo-ethanol (21 mg; 0.17 mmol; 1.50 eq.), and potassium carbonate (38 mg; 0.28 mmol; 2.50 eq.) were combined in a vial. The reaction was stirred overnight at 100°C. The reaction was purified by preparative HPLC on an acetonitrile / water (0.1% NH4OH-modified) gradient to obtain the title compound (28 mg; 0.06 mmol; 55.9%). MS: 455.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.17 (dd, J = 4.1, 1.5 Hz, 1H), 8.55 (dd, J = 8.7, 1.6 Hz, 1H), 8.39 (s, 1H), 8.10 (d, J = 7.1 Hz, 1H), 7.87 (dd. Hz, 2H), 2.31 (dt, J = 12.7, 5.4 Hz, 2H), 2.16 (d, J = 12.6 Hz, 2H), 2.07 - 1.95 (m, 2H), 1.77 - 1.64 (m, 2H), 1.15 (q, J = 12.2 Hz, 1H), 0.96 (d, J = 6.4 Hz, 3H). Example 149: 4-{[(3R,5S)-1-(8-cyano-[1,7]naphthyridine-5-yl)-5-methyl-piperidine-3-ylcarbamoyl]-methyl}-3-fluoro-piperidine-1-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide [ka] [ka]

[0432] N-[(3R,5S)-1-(8-cyano-[1,7]naphthyrizin-5-yl)-5-methylpiperidine-3-yl]-2-(3-fluoropiperidine-4-yl)-acetamide (200 mg; 0.49 mmol; 1.0 eq.), 2-amino-2-methylpropan-1-ol (65 mg; 0.73 mmol; 1.50 eq.), and diimidazole-1-ylmethanone (158 mg; 0.97 mmol; 2.0 eq.) were added to the vial. Then, DMF (1 ml) and triethylamine (147 mg; 1.46 mmol; 3.0 eq.) were added. The reaction was stirred for 1 hour. The crude product was purified by preparative HPLC using acetonitrile / water gradient (modified with 0.1% NH4OH) to obtain the title compound (18.5 mg; 0.04 mmol; 7.2%). MS: 526.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.17 (dd, J = 4.1, 1.6 Hz, 1H), 8.55 (dd, J = 8.7, 1.6 Hz, 1H), 8.38 (d, J = 1.7 Hz, 1H), 8.04 (d, J = 7.1 Hz, 1H), 7.93 (s, 2H), 7.87 (dd, J = 8.7, 4.2 Hz, 1H), 4.21 (s, 2H), 4.01 (d, J = 16.0 Hz, 3H), 3.75 (d, J = 11.7 Hz, 1H), 3.06 (d, J = 14.6 Hz, 2H), 2.83 (s, 1H), 2.70 - 2.60 (m, 2H), 2.32 - 2.21 (m, 1H), 1.99 (d, J = 12.7 Hz, 2H), 1.49 (d, J = 6.2 Hz, 1H), 1.38 (s, 1H), 1.25 (d, J =3.6 Hz, 6H), 1.15 (q, J = 12.2 Hz, 2H), 0.96 (d, J = 6.4 Hz, 3H). Example 150: 2-[(2-amino-ethyl)-(2-hydroxy-ethyl)-amino]-N-[(3R,5S)-1-(8-cyano-quinoxaline-5-yl)-5-methyl-piperidine-3-yl]acetamide [ka] [ka]

[0433] The title compound was prepared from 2-bromo-N-[(3R,5S)-1-(8-cyano-quinoxaline-5-yl)-5-methyl-piperidine-3-yl]acetamide:8-((3R,5S)-3-amino-5-methyl-piperidine-1-yl)-quinoxaline-5-carbonnitrile and bromoacetic acid by a similar method (e.g., 59).

[0434] 2-[(2-amino-ethyl)-(2-hydroxy-ethyl)-amino]-N-[(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidine-3-yl]acetamide: In DMSO (1 ml), 2-bromo-N-[(3R,5S)-1-(8-cyano-quinoxalin-5-yl)-5-methyl-piperidine-3-yl]acetamide (27 mg; 0.07 mmol; 1.0 eq.), 2-(2-amino-ethylamino)-ethanol (9 mg; 0.08 mmol; 1.20 eq.), and ethyl-diisopropylamine (19 mg; 0.21 mmol; 3.0 eq.) were combined in a vial. The reaction was heated overnight to 100°C. Once the reaction was complete, the compound was purified by preparative HPLC on an acetonitrile / water (0.1% NH4OH-modified) gradient to obtain the title compound (5.1 mg; 0.01 mmol; 17.8%). MS: 412.4 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.94 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 4.43 (s, 1H), 4.27 (dd, J = 24.8, 13.0 Hz, 3H), 3.95 (s, 2H), 3.44 (s, 2H), 3.09 (s, 2H), 2.83 (t, J = 11.5 Hz, 2H), 2.69 (t, J = 11.4 Hz, 2H), 2.56 (d, J = 5.3 Hz, 5H), 1.96 (d, J = 13.9 Hz, 3H), 1.23 (d, J = 12.0 Hz, 2H), 0.93 (d, J = 6.2 Hz, 3H). Example 151: (3R,5S)-1-(8-methoxy-[1,7]naphthyridine-5-yl)-5-methylpiperidine-3-ylamine [ka] [ka]

[0435] [(3R,5S)-1-(8-methoxy-[1,7]naphthiridine-5-yl)-5-methyl-piperidine-3-yl]-carbamate tert-butyl ester: In a microwave vial, 5-bromo-8-methoxy-[1,7]naphthiridine (0.58 g; 2.43 mmol; 1.0 eq.), ((3R,5S)-5-methyl-piperidine-3-yl)-carbamate tert-butyl ester (0.62 g; 2.91 mmol; 1.20 eq.), chloro(2-dicyclohexyl Phosphino-2',6'-di-i-propoxy-1,1'-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii), methyl-t-butyl ether adduct (99 mg; 0.12 mmol; 0.05 eq.), 2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl (56 mg; 0.12 mmol; 0.05 eq.), and cesium carbonate (1.58 g; 4.85 mmol; 2.0 eq.) were dissolved in anhydrous dioxane (11 ml). The reaction was carried out under nitrogen and heated to 85°C in a microwave for 8 hours. The reaction was purified on silica using an ethyl acetate / hexane gradient to produce the title compound (578 mg; 1.55 mmol; 64.0%). MS: 373.5 [M+H] + .

[0436] (3R,5S)-1-(8-methoxy-[1,7]naphthiridine-5-yl)-5-methyl-piperidine-3-ylamine:[(3R,5S)-1-(8-methoxy-[1,7]naphthiridine-5-yl)-5-methyl-piperidine-3-yl]-carbamate tert-butyl ester (185.0 mg; 0.50 mmol; 1.0 eq.) was dissolved in dioxane (2 ml) in a reaction vial. Trifluoroacetic acid (4 ml; 2.48 mmol; 5.0 eq.) was added, and the reaction was stirred for 4 hours. The mixture was purified by preparative HPLC on an acetonitrile / water (0.1% NH4OH modified) gradient to produce the title compound (114.0 mg; 0.42 mmol; 84.3%). MS: 273.4 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (dd, J = 4.3, 2.1 Hz, 1H), 8.38 - 8.33 (m, 1H), 7.78 (dd, J = 8.8, 4.0 Hz, 1H), 7.73 (s, 1H), 4.02 (d, J = 1.8 Hz, 3H), 3.27 - 3.18 (m, 1H), 3.10 (d, J = 11.4 Hz, 2H), 2.98 (s, 2H), 2.28 (t, J = 10.8 Hz, 2H), 1.94 (s, 2H), 0.91 (d, J = 6.3 Hz, 3H), 0.80 (q, J = 12.1 Hz, 1H). Example 152: 5-{(3R,5S)-3-[(piperidine-3-ylmethyl)-amino]-5-trifluoromethyl-piperidine-1-yl}quinoline-8-carbonitrile [ka]

[0437] A solution of 5-((3R,5S)-3-amino-5-trifluoromethyl-piperidine-3-ylamino)-quinoline-8-carbonitride hydrochloride (3) (199.0 mg; 0.46 mmol; 1.0 eq.), tert-butyl 3-formylpiperidine-1-carboxylate (118.53 mg; 0.56 mmol; 1.20 eq.), and glacial acetic acid (0.003 ml; 0.05 mmol; 0.10 eq.) in 3-{[(3R,5S)-1-(8-cyano-quinoline-5-yl)-5-trifluoromethyl-piperidine-3-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester:DCE (5 ml) was stirred for 1 hour, followed by the addition of sodium triacetoxyborohydride (147.23 mg; 0.69 mmol; 1.50 eq.). The resulting solution was stirred to completion under argon at ambient temperature. The crude product was purified on a flash system using a 20–100% siRNA gradient in hexane, yielding 3-{[(3R,5S)-1-(8-cyanoquinoline-5-yl)-5-trifluoromethyl-piperidine-3-ylamino]-methyl}piperidine-1-carboxylic acid tert-butyl ester (72.30 mg; 0.14 mmol; 30.2%) as an oily residue after concentration. MS:518 [M+H] + .

[0438] 5-{(3R...

Claims

[Claim 1] Equation I-a, 【Chemistry 1】 A compound represented by the formula: R １ -CF ３ , -OMe, or -OEt; 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 These are 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 It is; Each R is independently hydrogen, C １～６ aliphatic, C ３～１０ An aryl ring, a 3- to 8-membered saturated or partially unsaturated carbon ring, a 3- to 7-membered heteroring having 1- to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur), or a 5- to 6-membered monocyclic heteroaryl ring having 1- to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of these may be optionally substituted; or Two R groups on the same atom, together with the atom to which they are attached, form C ３～１０ They form aryl groups, 3- to 8-membered saturated or partially unsaturated carbon rings, 3- to 7-membered heterorings having 1- to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur), or 5- to 6-membered monocyclic heteroaryl rings having 1- to 4 heteroatoms (independently selected from nitrogen, oxygen, or sulfur); each of these may be optionally substituted; r is 0, 1, or 2; and t is 0, 1, or 2, the compound, or its solvates, hydrates, tautomers or stereoisomers, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion.

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