TW201414704A - Biaryl-containing compounds as inverse agonists of ROR-gamma receptors - Google Patents

Abstract

The present invention relates to biaryl-containing inverse agonists of ROR-gamma receptors. The invention also provides pharmaceutical compositions comprising these biaryl-containing inverse agonists, and methods of modulating ROR-gamma receptors using these inverse agonists. Also provided are methods of using biaryl-containing inverse agonists to treat ROR-gamma mediated diseases.

Description

Biaryl compound as a reverse agonist of ROR-γ receptor Cross-reference to related applications

The present application claims the benefit of U.S. Provisional Patent Application No. 61/667,334, filed on Jul. 2, 2012, and U.S. Provisional Patent Application No. 61/799,894, filed on Mar. The disclosure is hereby incorporated by reference in its entirety.

The present invention relates to a biaryl-containing inverse agonist for ROR-gamma receptors. The invention also provides pharmaceutical compositions comprising such inverse agonists. Methods of treating ROR-γ mediated diseases using such inverse agonists are also provided.

Abnormal regulation of the immune system is a common cause of human disease. Autoimmune diseases occur when the immune system attacks and destroys healthy body tissues. Other inflammatory diseases such as asthma are not necessarily caused by improper or uncontrolled immune response caused by direct attack on healthy tissue. An agent that modulates the development and function of cells of the immune system can be used as a therapy for such diseases.

One way to achieve this regulation is by targeting the function of nuclear receptors expressed in the immune system. Nuclear receptors are a superfamily of ligands that regulate DNA-binding transcription factors, which are expressed by many cell types and control a wide range of physiological processes. Drugs that target nuclear receptors are used to treat a wide range of human diseases. Such as tamoxigen against estrogen receptors (targeted in breast cancer) Tamoxifen, thiazolidinedione against peroxisome proliferator-activated receptor-gamma (PPARγ) (targeted in type 2 diabetes), or against glucocorticoid receptor (targeted in inflammatory diseases) The pharmaceutical nuclear receptor agonist or antagonist of dexamethasone is especially the most commonly used drug. The nuclear receptor RAR-associated orphan receptor C (RORC, ROR-γ, ROR-γ-t, RORγ) is expressed in cells of the immune system and plays an important role in the function of the immune system. Disclosed herein are biaryl containing compounds useful as reverse agonists for ROR-γ.

In one aspect, the invention provides a biaryl-containing inverse agonist of a ROR-gamma receptor, wherein the inverse agonist is a compound of formula I:

Or a pharmaceutically acceptable salt thereof, wherein: R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, Optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl And optionally substituted cycloalkyl-alkyl, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^2a , R ^2b , R ^2c and R ^2d are each independently H , halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ , optionally substituted heteroaryl or optionally substituted heterocycloalkyl; R ⁴ , R ⁵ and R ⁶ are each independently substituted as appropriate Alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form as appropriate 4 to 7 members Heterocycle; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN, or any of R ^8a , R ^8b , R ^8c , R ^8d and R ^8e The two adjacent substituents may together form a 4- to 7-membered cycloaliphatic ring or a 4- to 7-membered heterocyclic ring which may be optionally substituted; X is CH or N; and J is a bond or C _1-4 alkyl.

In some embodiments of this aspect, R ³ and R ⁷ together form an optionally substituted 5 to 7 membered heterocyclic ring; and J is a bond. In some such embodiments, the compound of Formula I is a compound of Formula Ia:

Wherein: W is CR ^7c R ^7d , O or NR ^7a ; R ^7a and R ^7b are each independently H or C _1-4 alkyl, and R ^7c and R ^7d are each independently H, C _1-4 alkane. Base or halogen; and n is 1, 2 or 3.

In some embodiments, R ³ is H, alkyl, substituted alkyl, halo, NR ⁵ R ⁶ or optionally substituted heterocycloalkyl; and R ⁷ is alkyl.

In other embodiments of this aspect, R ³ is OR ⁴ .

In other embodiments of this aspect, R ³ is SR ⁴ or S(O) ₂ R ⁴ .

In some embodiments of Formula I, two adjacent substituents of R ^8a , R ^8b , R ^8c , R ^{8d ,} and R ^8e may together form an optionally substituted 4 to 7 membered cycloaliphatic ring or, as appropriate, substituted 4 to 7 member heterocyclic ring.

In some embodiments, the compound is a compound of Formula Ib:

Or a pharmaceutically acceptable salt thereof, wherein: R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-3 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ or optionally substituted heterocycloalkyl; R ⁴ , R lines ⁵ and R ⁶ are each independently of the optionally substituted alkyl, optionally substituted cycloalkyl or the optionally substituted heterocyclic group of; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN; X is CH or N; and J is a bond or a C _1-4 alkylene group.

In another aspect, the invention includes a compound of formula II:

Or a pharmaceutically acceptable salt thereof, wherein: J is a bond or a C _1-4 alkylene group; or ;B is , , , , or ; the restriction is that when J is C _1-4 alkyl and B is When R ^{10 is} not a hydroxyl group; X ¹ is CH or N; X ² is CR ^2a or N; X ³ is CR ^2b or N; X ⁴ is CR ^2d or N; X ⁵ is S or O; Z ¹ and Z ² is independently H or an optionally substituted alkyl; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halo, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ , optionally substituted a heteroaryl or optionally substituted heterocycloalkyl; each R ⁴ is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl or, as appropriate Substituted heterocycloalkyl; R ⁵ and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or, optionally substituted heterocycloalkyl; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form an optionally substituted 5 to 7 membered heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen. , C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN; R ⁹ is a bond, optionally substituted alkyl or a substituted cycloalkylene group; R ¹⁰ is NR ^1a R ^1b , a hydroxy group or an optionally substituted alkyl group; R ^12a and R ^12b are each independently an optionally substituted alkyl group, or R ^12a and R ^12b may together form an optionally substituted 4 to 7 membered heterocyclic ring; and R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclic An alkyl-alkyl group, optionally substituted cycloalkyl-alkyl group, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring.

In another aspect, the invention includes a compound comprising Formula I, Formula Ia, Formula Ib, Formula II, Formula II-k ₁ or Formula II-k _2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable A pharmaceutical composition that accepts a carrier or adjuvant.

In another aspect, the invention comprises a method of modulating the activity of a ROR-gamma receptor with a reverse agonist comprising reacting the receptor with Formula I, Formula Ia, Formula Ib, Formula II, Formula II- The k ₁ or a compound of the formula II-k ₂ or a pharmaceutically acceptable salt thereof is contacted.

In one embodiment of this aspect, the compound of Formula I, Formula Ia, Formula Ib, Formula II, Formula II-k ₁ or Formula II-k ₂ or a pharmaceutically acceptable salt thereof modulates ROR-γ in vitro Receptor activity. In another embodiment, a compound of Formula I, Formula Ia, Formula Ib, Formula II, Formula II-k ₁ or Formula II-k _2, or a pharmaceutically acceptable salt thereof, modulates ROR-γ receptor in vivo active. In one embodiment, the compound of Formula I, Formula Ia, Formula Ib, Formula II, Formula II-k ₁ , Formula II-k ₂ or a pharmaceutically acceptable salt thereof is a reverse agonist of the ROR-γ receptor Agent.

In another aspect, the invention comprises a method of treating a ROR-gamma receptor mediated disease in a patient or reducing the severity of a ROR-gamma receptor mediated disease in a patient, comprising administering to a patient in need thereof And a compound of formula I, formula Ia, formula Ib, formula II, formula II-k ₁ , formula II-k ₂ or a pharmaceutically acceptable salt thereof.

In one embodiment of this aspect, the ROR-gamma receptor mediated disease can comprise an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of: articular adhesion vertebrate, asthma, Behcet's disease, chronic obstructive pulmonary disease, Crohn's disease , type 1 diabetes, multiple sclerosis, neuromyelitis optica, rheumatic polymyalgia, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome , systemic lupus erythematosus, systemic sclerosis, transplant rejection, inflammatory bowel disease, ulcerative colitis, and uveitis.

definition

As used herein, the following definitions apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Handbook of Chemistry and Physics, 75th Edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolito: 1999 and "March's Advanced Organic Chemistry", 5th edition, Smith, MB and March, J. ed., John Wiley & Sons In New York: 2001, the entire contents of such books are hereby incorporated by reference.

As used herein, the term "aliphatic" encompasses the terms alkyl, alkenyl, alkynyl. Unless otherwise stated, aliphatic may include substituted alkyl, alkenyl and alkynyl groups with both unsubstituted alkyl, alkenyl and alkynyl groups.

As used herein, "alkyl" refers to a saturated aliphatic hydrocarbon group containing 1-8 (eg, 1-6, 1-4, or 1, 2, 3, 4, 5, 6, 7, or 8) carbon atoms. . As used herein, the term C1 _- nalkyl refers to an alkyl group containing from 1 to n carbon atoms. For example, C _1-5 alkyl means an alkyl group containing 1, 2, 3, 4 or 5 carbon atoms. The alkyl group can be a straight or branched chain. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, n-pentyl, n-heptyl or 2- Ethylhexyl.

As used herein, the term "alkylene" refers to an alkyl group as defined above wherein one hydrogen atom of the alkyl group has been replaced by a bond. The alkyl group may be a straight chain or a branched chain. Non-limiting examples of alkylene groups include -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH(CH ₃ )CH ₂ CH ₂ - and -CH ₂ CH(CH ₃ )CH ₂ -. As used herein, the term "cycloalkylene" refers to a cycloalkyl substituent wherein the same carbon atom or a hydrogen atom at a different carbon atom is replaced by a bond, for example or . In other examples, the "heterocycloalkylene group" is a heterocycloalkyl substituent in which hydrogen is replaced by a bond or the like.

As used herein, "alkenyl" refers to an aliphatic carbon group containing 2-8 (eg, 2-6 or 2-4) carbon atoms and at least one double bond. As the alkyl group, the alkenyl group may be a straight chain or a branched chain. Examples of alkenyl groups include, but are not limited to, allyl, isopentenyl, 2-butenyl, and 2-hexenyl.

As used herein, "alkynyl" refers to an aliphatic carbon group containing 2-8 (eg, 2-6 or 2-4) carbon atoms and at least one reference bond. Like an alkyl group, an alkynyl group can be a straight or branched chain.

As used herein, "amino" refers to -NR ^X R ^Y , wherein each of R ^X and R ^Y is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aryl Alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl or carbonyl, each of which is defined herein. Examples of the amine group include an alkylcarbonylamino group, an alkylsulfonylamino group, an alkoxycarbonylamino group, an (azacycloalkylcarbonyl)amino group, a heteroaralkylcarbonylamino group, a heteroarylcarbonylamine. , carbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, (ring Alkyl)alkylcarbonylamino, cycloalkylcarbonylamino. When the term "amino" is not a terminal group (e.g., an alkylcarbonylamino group), it is represented by -NR ^X -. R ^X has the same meaning as defined above. A non-exhaustive list of possible R ^X and R ^Y includes sulfonylamino, alkylamino, carbonylamino, carboxy, pendant oxy, hydroxy, sulfonate, decyl, alkylsulfonyl, alkyl Sulfonyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylane A carbonyl group, a heteroarylcarbonyl group or a heteroarylalkylcarbonyl group.

As used herein, "carbonyl" means when used alone or as part of another configuration of use - (CO) R ^X, wherein R ^X based on defined above. When the term "carbonyl" is not a terminal group (e.g., an arylaminoalkylcarbonyl group), it is represented by -C(O)R ^X . The carbonyl group may include, without limitation, an optionally substituted aminocarbonyl group, an alkoxyalkoxycarbonyl group, an alkylaminocarbonyl group, an arylcarbonyl group (e.g., a halogen arylcarbonyl group), a heterocycloalkylcarbonyl group, a heterocycloalkenyl group. a carbonyl group, an arylaminocarbonyl group (e.g., a halogen arylaminocarbonyl group), a cyanoalkylarylcarbonyl group, a heterocycloalkoxycarbonyl group, an alkynyloxycarbonyl group, a cycloalkoxycarbonyl group, a heterobicyclic arylcarbonyl group, Alkylheteroarylaminocarbonyl, alkoxyarylcarbonyl (eg haloalkoxyarylcarbonyl), (alkylheterocyclo)alkenylcarbonyl, heteroarylcarbonyl, arylcarbonyl, heteroarylcarbonyl, Alkoxycarbonyl (e.g., haloalkoxycarbonyl), alkylarylcarbonyl, cycloalkylcarbonyl, alkylheteroarylcarbonyl, arylsulfonylcarbonyl, aminocarbonyl, sulfonylcarbonyl, alkylcarbonyl An alkylsulfonylcarbonyl group, an alkylcarbonyl group, an arylaminocarbonyl group or the like. A non-exhaustive list of possible R ^X and R ^Y includes sulfonylaminocarbonyl, alkylcarbonyl, carbonylamino, carboxy, pendant oxy, hydroxy, sulfonate, decyl, alkylsulfonyl, alkyl Sulfonyl, alkylsulfonyl, aminocarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heterocycloalkylcarbonyl, heterocycloalkylane A carbonyl group, a heteroarylcarbonyl group or a heteroarylalkylcarbonyl group.

As used herein, "aryl" as used alone as part of a larger portion, such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to an aromatic monocyclic ring (eg, benzene). An aromatic bicyclic ring (eg, anthracenyl, naphthyl, tetrahydronaphthyl, tetrahydroindenyl); an aromatic tricyclic (eg, anthracenyl, tetrahydroindenyl, fluorenyl or tetrahydroindenyl); or 2-3 carbon rings, wherein one or more of the rings are aromatic benzofused groups. For example, a benzo-fused group includes a phenyl group fused to two or more C _4-8 carbocyclic moieties.

As used herein, "aralkyl" refers to an alkyl group substituted with an aryl group (eg, _C1-4 alkyl). Both "alkyl" and "aryl" are defined herein. An example of one of the aralkyl groups is a benzyl group.

"Heteroaralkyl" means an alkyl group substituted with a heteroaryl group. Both "alkyl" and "heteroaryl" are defined herein.

The term "cycloaliphatic" means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic hydrocarbon ring having a single point of attachment to the rest of the molecule. The cycloaliphatic ring is a 3-8 member single ring (eg 3-6 Member ring). The cycloaliphatic ring also includes an 8-12 membered bicyclic hydrocarbon ring (e.g., a 10-membered bicyclic hydrocarbon ring). The cycloaliphatic group encompasses "cycloalkyl" and "cycloalkenyl".

As used herein, "cycloalkyl" refers to a saturated carbocyclic monocyclic ring having 3-10 (eg, 4-6, 5-10, 3, 4, 5, 6, 7, 8, 9 or 10) carbon atoms. , bicyclic, tricyclic or polycyclic (fused, snail or bridged). Examples of the monocyclic cycloalkyl group include, without limitation, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or the like. Examples of bicyclic cycloalkyl groups include, without limitation, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, Bicyclo[3.3.2.]nonyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptyl or the like. The polycyclic group includes, without limitation, an adamantyl group, a cubic alkyl group, a norbornyl group, or the like.

"Cycloalkenyl" as used herein refers to a non-aromatic carbocyclic ring having from 3 to 10 (eg, 4 to 8) carbon atoms having one or more double bonds. Examples of cycloalkenyl groups include cyclopentenyl, 1,4-cyclohex-di-alkenyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl, octahydro-naphthyl, cyclohexenyl, Cyclopentenyl, bicyclo[2.2.2]octenyl and bicyclo[3.3.1]nonenyl.

As used herein, the terms "heterocycloaliphatic" and "heterocycle" encompass heterocycloalkyl and heterocycloalkenyl.

As used herein, "heterocycloalkyl" refers to a 3-10 membered monocyclic or bicyclic (fused, spiro or bridged) (eg, 4-6, 5-10, 3, 4, 5, 6, 7, 8, A 9 or 10 membered monocyclic or bicyclic) saturated ring structure in which one or more ring atoms are heteroatoms (eg, N, O, S, or a combination thereof). Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, tetrahydropentanyl, tetrahydrofuranyl, 1,4-dioxolanyl, 1,4-dithiaalkyl, 1,3-di Oxolylcycloalkyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, octahydro-benzofuranyl, octahydro- Alkenyl, octahydro-thio Alkenyl, octahydro-indenyl, octahydro-pyridyl, decahydro-quinolinyl, octahydro-benzo[ b ]thienyl, 2-oxa-bicyclo[2.2.2]octyl, 1- Aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, 2,6-dioxa-tricyclo[3.3.1.0 ^3,7 ]decyl, decane .

The monocyclic heterocycloalkyl group can be fused to a phenyl moiety such as tetrahydroisoquinoline. Heterocycloalkyl The ring structure may optionally be substituted at any chemically feasible position on one or more of the rings.

"Heterocyclenyl" as used herein refers to a monocyclic or bicyclic ring having one or more double bonds, wherein one or more ring atoms are heteroatoms (eg, N, O or S) (eg, 5 to 10 members) Monocyclic or bicyclic) non-aromatic ring structures.

Examples of heterocycloalkenyl groups include 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl or 2-pyrazolyl. Monocyclic heteroaliphatic compounds are numbered according to standard chemical nomenclature. E.g:

As used herein, "heteroaryl" means having from 4 to 15 (eg, 5-9, 6-13, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) a ring atom in which one or more ring atoms are heteroatoms (eg, N, O, S, or a combination thereof), and wherein one or more of the bicyclic or tricyclic structures are aromatic monocyclic, bicyclic or tricyclic structures . Heteroaryl groups include benzofused ring systems having 2 to 3 rings. For example, a benzo-fused group includes one or two C _4-8 heterocyclic moieties (eg, pyridazinyl, fluorenyl, isodecyl, 3H-indenyl, porphyrinyl, Benzo[ b ]furanyl, benzo[ b ]phenylthio, quinolinyl or isoquinolinyl) is benzofused. Some examples of heteroaryl groups are azetidinyl, pyridyl, 1H-carbazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuranyl , isoquinolinyl, benzothiazolyl, ,sulfur , phenothiazine, indoline, benzo[1,3]dioxin, benzo[ b ]furanyl, benzo[ b ]phenylthio, oxazolyl, benzimidazolyl, benzothiazole Base, base, Lolinyl, quinolyl, quinazolinyl, Orolinyl, pyridazinyl, quinazolinyl, quinoxalinyl, isoquinolinyl, 4H-quinolizinyl, benzo-1,2,5-thiadiazolyl or 1,8- Pyridyl.

Monocyclic heteroaryl includes, without limitation, furyl, phenylthio, 2H-pyrrolyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1, 3,4-thiadiazolyl, 2H-piperidyl, 4-H-piperidyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazolyl, pyrazinyl or 1,3,5-triazinyl . Monocyclic heteroaryls are numbered according to standard chemical nomenclature. E.g:

Bicyclic heteroaryl includes, without limitation, pyridazinyl, fluorenyl, isodecyl, 3H-indenyl, porphyrinyl, benzo[ b ]furanyl, benzo[ b ]phenylthio , quinolyl, tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolinyl, pyridazinyl, isodecyl, oxazolyl, benzimidazolyl, benzothiazolyl, fluorenyl, 4H-quinolizinyl, quinolyl, isoquinolinyl, Lolinyl, pyridazinyl, quinazolinyl, quinoxalinyl, 1,8- Pyridyl, pyridazinyl, imidazopyridyl, tetrahydrobenzoazinyl, tetrahydrobenzoxazino, benzo[1,4]oxazinyl, benzodihydro[1,4] Oxazinyl, benzo[1,3]oxazinyl, benzodihydro[1,3]oxazinyl, fused pyrido[1,4]oxazinyl, fused pyridine[1,3] Oxazinyl, fused pyrido[1,4]dihydrooxazinyl, fused pyrido[1,3]dihydrooxazinyl, fused pyrimido[1,4]oxazinyl, fused pyrimidine And [1,3]oxazinyl, fused pyrimido[1,4]dihydrooxazinyl, fused pyrimido[1,3]dihydrooxazinyl, fused pyrazino[1,4] Oxazinyl, fused pyrazino[1,3]oxazinyl, fused pyrazino[1,4]dihydrooxazinyl or fused pyrazino[1,3]dihydrooxazinyl or Acridine. Bicyclic heteroaryls are numbered according to standard chemical nomenclature. E.g:

As used herein, "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group (e.g., _C1-4 alkyl). Both "alkyl" and "heteroaryl" have been defined above.

As used herein, "cyclic moiety" includes cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, aryl or heteroaryl, each of which has been previously defined.

As used herein, "mercapto" is a nail base or alkyl-C(=O)- (also known as "alkylcarbonyl"), wherein "alkyl" has been previously defined. Ethyl thiol and trimethylethenyl are examples of fluorenyl groups.

As used herein, "aminomethane" refers to a group having the structure -O-CO-NR ^x R ^y or -NR ^x -CO-OR ^z wherein R ^x and R ^y have been defined above and R ^z It can be an alkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl group.

As used herein, "carboxy" and "sulfonic acid group" mean -COOH or -COOR ^X and -SO ₃ H or -SO ₃ R ^{X , respectively} .

As used herein, "hydroxyl" refers to -OH.

As used herein, "alkoxy" refers to an alkyl-O- group in which "alkyl" has been previously defined. Further, an alkoxy group includes a structure comprising two alkoxy groups on the same atom or a neighboring atom forming a ring together with the atom to which it is bonded.

As used herein, "thiooxy" refers to -O-SO-R ^X or -SO-OR ^X , wherein R ^X has been defined above.

As used herein, "mercapto" refers to -SH.

As used herein, "sulfonyl" refers to -S(O) ₂ -R ^X , wherein R ^X has been defined above. Examples of the sulfonyl group include an optionally substituted alkylsulfonyl group, an arylsulfonyl group (e.g., a halogenarylsulfonyl group), a heteroarylsulfonyl group (e.g., an alkylheteroarylsulfonyl group) or Its similar group.

As used herein, "sulfinyl" refers to -S(O)-R ^X , wherein R ^X has been defined above. Examples of the sulfinyl group include an alkylsulfinyl group.

As used herein, "sulfonyl" refers to -SR ^X , wherein R ^X has been defined above. Examples of the sulfonyl group include an alkylsulfonyl group.

As used herein, "halogen" or "halo" refers to fluoro, chloro, bromo or iodo.

As used herein, "haloaliphatic" group refers to an aliphatic group substituted with 1-3 halogens. For example, the term haloalkyl includes the group -CF _3.

As used herein, "amine sulfonyl" refers to the structure -S(O) ₂ -NR ^x R ^y or -NR ^x -S(O) ₂ -R ^z , wherein R ^x , R ^y and R ^z are already present Define it.

As used herein, "sulfonamide" group refers to the structure -NR ^X -S(O) ₂ -NR ^Y R ^Z , wherein R ^X , R ^Y and R ^Z have been defined above.

As used herein, alone or in association with another group of "carbonyl group" means such as ^{Rx-C (O) -NR X} - of the acyl group. For example, an alkylcarbonylamino group includes alkyl-C(O)-NR ^X -, wherein R ^x has been defined above.

As used herein, "aminocarbonyl", alone or in connection with another group, refers to a guanamine group such as N(Rx) _2- C(O)-.

As used herein, "alkoxycarbonyl", alone or in connection with another group, refers to a carbonyl group such as alkyl-O-C(O)-.

As used herein, "carboxyalkoxy", used alone or in association with another group, refers to a carboxyl group (COOH-) bonded to an alkoxy-CO-( _C2-4 alkyl) group, such as -CO ( C _2-4 alkyl) COOH.

As used herein, "alkoxyalkyl" refers to an alkyl group such as alkyl-O-alkyl- (wherein alkyl is as defined above).

As used herein, "aminocarbonyl" refers to a guanamine group such as -NR ^X -C(O)-, wherein R ^x has been defined above.

As used herein, "sulfo acyl group" means the structure _{^{-N (R X) 2 -S (}} O) 2 -, wherein R ^x has been defined above.

As used herein, "sideoxy" refers to =0.

As used herein, "aminoalkyl" refers to the structure N(RX)2-alkyl-.

As used herein, "cyanoalkyl" refers to the structure (CN)-alkyl-.

As used herein, "alkylsulfonyl" refers to the structure alkyl-S(O)2-.

As used herein, "sulfonylamino" refers to the structure Rx-S(O)2-N(RX)2- wherein Rx has been defined above.

As used herein, "urea" refers to the structure -NRX-CO-NRYRZ and "thiourea" refers to the structure -NRX-CS-NRYRZ. RX, RY and RZ have been defined above.

As used herein, the depicted substituents drawn with a single unconnected wavy line drawn perpendicular to the bond of the substituent are intended to show the point of attachment of the substituent. For example, pyrrole substituents Shown by a ring nitrogen attached to the main core structure, while the pyrrole substituent It is shown to be attached to the main core structure by a carbon atom adjacent to the ring nitrogen.

As used herein, the depicted ring structure of a bond with a substituent superimposed on a ring bond indicates that the substituent can be at any substitutable atom of the entire ring structure, whether the ring structure is monocyclic or polycyclic. For example, structure The R substituent above may be substituted at any atom of the piperidine ring, and in the structure The R substituent above may be substituted on any atom of the phenyl ring or piperidine ring.

As used herein, the depicted structures with methyl substituents are drawn to show their methyl substituents as external bonds. In detail, structure And structure the same.

As described herein, a divalent substituent such as the guanamine shown as -C(O)N(Rx)- is intended to include a substituent in both directions. For example, a generic structure (wherein X is an unsubstituted guanamine) can be or . Some examples of general divalent substituents include, but are not limited to, -CO-, -CS-, -CONQ2-, -CO2-, -OCO-, -NQ2-, -NQ2CO2-, -O-, -NQ2CONQ2-, -OCONQ2-, -NQ2CO-, -S-, -SO-, -SO2-, -SO2NQ2-, -NQ2SO2-, and -NQ2SO2NQ2-.

In general, the term "substituted" whether or not preceded by the term "optionally" includes, but is not limited to, a group in a given structure (eg, a hydrogen group) is replaced by a group of a specified substituent or is directed to an atom (eg, sulfur). Or phosphorus) to add a designated group substituent. For example, sulfur may be optionally substituted with one or more pendant oxy substituents. Particular substituents are as defined above and below in the description of the compounds and their examples. Unless otherwise indicated, optionally substituted groups may have substituents at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the specified group The substituents at each position may be the same or different. A substituent may be bonded to the same atom (C, S, N or O) or two or more different atoms. A ring substituent such as a heterocycloalkyl group can be bonded to another ring such as a cycloalkyl group to form a spiro bicyclic system, for example, two rings share a common atom. As will be recognized by those of ordinary skill in the art, combinations of substituents contemplated by the present invention are those which result in the formation of stable or chemically feasible compounds.

Substituents may include, but are not limited to, alkyl, cycloalkyl, alkenyl, amine, carbonyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, hetero Aryl, heteroaralkyl, fluorenyl, amine carbaryl, carboxy, hydroxy, alkoxy, thiooxy, decyl, sulfonate, sulfonyl, sulfinyl, sulfonyl, halogen, halogen Aliphatic, sulfonyl, sulfonamide, carbonylamino, aminocarbonyl, alkoxycarbonyl, carboxyalkoxy, alkoxyalkyl, aminocarbonyl, alkylcarbonylamino, alkylsulfonate An amino group, an aminosulfonyl group, a pendant oxy group, a cyano group, an aminoalkyl group, a cyanoalkyl group, an alkylsulfonyl group, and a sulfonylamino group, wherein the cycloalkyl group of any of the above substituents, The cycloalkyl moiety, the alkyl group or the alkyl moiety may further be at least one of an amine group, a halogen group, a hydroxyl group, a carboxyl group, a sulfonic acid group, a sulfonyl group, a pendant oxy group, a cyano group and a carbonyl group, preferably 1 to 3 Replaced by.

In general, the term "unsubstituted" means that the chemical moiety does not include a substituent.

As used herein, the phrase "stable or chemically feasible" means that the compound is subjected to one or more of the purposes of allowing it to be produced, detected, and preferably recovered, purified, and used herein. The condition does not change substantially. In some embodiments, the stabilizing compound or chemically feasible compound is a compound that does not substantially change when kept at a temperature of 40 ° C or less at least for one week in the absence of moisture or other chemically reactive conditions.

As used herein, an effective amount is defined as the amount required to confer a therapeutic effect on a patient being treated, and is typically determined based on the age, body surface area, weight, and condition of the patient. The correlation between animal and human doses (based on the number of milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother. Rep., 50: 219 (1966). The body surface area can be approximated by the patient's height and weight. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, New York, 537 (1970). As used herein, "patient" refers to a mammal, including a human.

Unless otherwise stated, structures described herein are also intended to include all isomeric forms of the structure (eg, mirror image, non-image, and geometry (or configuration)); for example, R and S configurations of asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) configuration isomers. Thus, single stereochemical isomers as well as mirror image, non-image, and geometric (or configuration) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The compounds disclosed herein also include all pharmaceutically acceptable isotopic variations in which at least one atom has the same atomic number, but the atomic mass differs from the atomic substitution of the most common atomic mass in nature. Examples of isotopes suitable for inclusion in the disclosed compound include, without limitation, hydrogen isotopes such as ² H and ³ H; carbon isotopes such as ¹³ C and ¹⁴ C; nitrogen isotopes such as ¹⁵ N; oxygen isotopes such as ¹⁷ O And ¹⁸ O; phosphorus isotope such as ³¹ P and ³² P; sulfur isotope such as ³⁵ S; fluorine isotope such as ¹⁸ F; and chlorine isotope such as ³⁶ Cl. Certain isotopic variations of the disclosed compounds may be compatible with radioisotopes (e.g., 氚³ H or ¹⁴ C) in drug and/or matrix tissue distribution studies.

In addition, unless otherwise stated, isotopically-labeled structures encompassed by the present invention are also intended to include all isomeric forms of isotopically-labeled structures (eg, mirror-isomerism, non-mirror Structure and geometry (or configuration)); for example, R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) configuration isomers. Thus, single stereochemically isomeric and isotopically labeled structures of the isotope-labeled structures, such as mirror image isomerism, non-image isomerism, and geometric (or conformational) mixtures are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the isotopically-labeled structures of the invention are within the scope of the invention.

ROR-γ receptor containing biaryl counter agonist

In one aspect, the invention provides a biaryl-containing inverse agonist of a ROR-gamma receptor, wherein the inverse agonist is a compound of formula I:

Or a pharmaceutically acceptable salt thereof, wherein: R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, Optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl And optionally substituted cycloalkyl-alkyl, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^2a , R ^2b , R ^2c and R ^2d are each independently H , halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ , optionally substituted heteroaryl or optionally substituted heterocycloalkyl; R ⁴ , R ⁵ and R ⁶ are each independently substituted as appropriate Alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form as appropriate 4 to 7 members Heterocycle; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN, or any of R ^8a , R ^8b , R ^8c , R ^8d and R ^8e The two adjacent substituents may together form a 4- to 7-membered cycloaliphatic ring or a 4- to 7-membered heterocyclic ring which may be optionally substituted; X is CH or N; and J is a bond or C _1-4 alkyl.

In another embodiment of this aspect, the invention includes a compound of formula I, wherein: R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, Optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl -alkyl, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halo, C _1-4 alkyl , OC _1-3 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ or optionally substituted Heterocycloalkyl; R ⁴ , R ⁵ and R ⁶ are each independently optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R ⁷ is C _{1 -4} alkyl, or R ³ and R ⁷ may together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 ^{alkyl, oR 4, NR 5 R 6} , CF 3 or CN; X is CH N; and J is a bond or C _1-4 alkylene.

In some embodiments of Formula I, R ³ and R ⁷ together form an optionally substituted 5 to 7 membered heterocyclic ring; and J is a bond. In some such embodiments, the compound of Formula I is a compound of Formula Ia:

Wherein: W is CR ^7c R ^7d , O or NR ^7a ; R ^7a and R ^7b are each independently H or C _1-4 alkyl, and R ^7c and R ^7d are each independently H, C _1-4 alkane. Base or halogen; and n is 1, 2 or 3.

In some embodiments, R ³ is H, alkyl, substituted alkyl, halo, NR ⁵ R ⁶ or optionally substituted heterocycloalkyl; and R ⁷ is alkyl.

In other embodiments of this aspect, R ³ is OR ⁴ .

In other embodiments of this aspect, R ³ is SR ⁴ or S(O) ₂ R ⁴ .

In another aspect, the invention includes a compound of formula Ib:

Or a pharmaceutically acceptable salt thereof, wherein: R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl , optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-3 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ or optionally substituted heterocycloalkyl; R ⁴ , R lines ⁵ and R ⁶ are each independently of the optionally substituted alkyl, optionally substituted cycloalkyl or the optionally substituted heterocyclic group of; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN; X is CH or N; and J is a bond or a C _1-4 alkylene group.

In another aspect, the invention includes a compound of formula II

Or a pharmaceutically acceptable salt thereof, wherein: J is a bond or a C _1-4 alkylene group; or ;B is , , , , or ; the restriction is that when J is C _1-4 alkyl and B is When R ^{10 is} not a hydroxyl group; X ¹ is CH or N; X ² is CR ^2a or N; X ³ is CR ^2b or N; X ⁴ is CR ^2d or N; X ⁵ is S or O; Z ¹ and Z ² is independently H or an optionally substituted alkyl; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halo, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ , optionally substituted a heteroaryl or optionally substituted heterocycloalkyl; each R ⁴ is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl or, as appropriate The substituted heterocycloalkyl groups R ⁵ and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form an optionally substituted 5 to 7 membered heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN; R ⁹ is a bond, optionally substituted alkyl or as appropriate a cyclic alkyl group substituted; R ¹⁰ is NR ^1a R ^1b , a hydroxy group or an optionally substituted alkyl group; R ^12a and R ^12b are each independently an optionally substituted alkyl group, or R ^12a and R ^12b may together form an optionally substituted 4 to 7 membered heterocyclic ring; and R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclic An alkyl-alkyl group, optionally substituted cycloalkyl-alkyl group, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring. In another aspect, the invention includes a compound of formula II-k ₁

Or a pharmaceutically acceptable salt thereof, wherein: J is a bond or a C _1-4 alkylene group; or ;B is X ¹ is CH or N; X ² is CR ^2a or N; X ³ is CR ^2b or N; X ⁴ is CR ^2d or N; X ⁵ is S or O; R ^2a , R ^2b , R ^2c and R ^2d Each is independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, SR ⁴ , S(O ₂ R ⁴ , NR ⁵ R ⁶ , optionally substituted heteroaryl or optionally substituted heterocycloalkyl; each R ⁴ is independently optionally substituted alkyl, optionally substituted ring Alkyl, optionally substituted heteroaryl or optionally substituted heterocycloalkyl; R ⁵ and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl Or optionally substituted heterocycloalkyl; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form an optionally substituted 5 to 7 membered heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN; R ⁹ is a bond, optionally substituted alkyl or cycloalkyl substituted with the substituted alkylene group; R ¹⁰ or NR ^1a R ^1b is hydroxyl; and R ^1a and R ^1b are each independently based H, optionally substituted Alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl An alkyl group, optionally substituted cycloalkyl-alkyl group, or R ^1a and R ^1b together form a optionally substituted 4 to 7 membered heterocyclic ring.

In another embodiment, the invention includes a compound of formula II-k ₂ :

Or a pharmaceutically acceptable salt thereof, wherein: J is a bond; or ;B is , , , ,

X ¹ is CH or N; X ² is CR ^2a or N; X ³ is CR ^2b or N; X ⁴ is CR ^2d or N; X ⁵ is S or O; Z ¹ and Z ² are each independently H or Optionally substituted alkyl; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halo, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, Optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ , optionally substituted heteroaryl or, as appropriate, Substituted heterocycloalkyl; each R ⁴ is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl or, optionally substituted heterocycloalkyl; R ⁵ and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or, optionally substituted heterocycloalkyl; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form an optionally substituted 5 to 7 membered heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, ^{oR 4, NR 5 R 6,} CF 3 or CN; R ⁹ is a bond, optionally substituted alkylene group or the optionally substituted ring extension Group; R ¹⁰ is NR ^1a R ^1b, or optionally substituted hydroxyl group of alkyl; R ^12a and R ^12b are each independently system optionally substituted alkyl group of, or R ^12a and R ^12b together may form an optionally Substituted 4 to 7 membered heterocyclic ring; and R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally Substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted The substituted cycloalkyl-alkyl group, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring.

In some embodiments of Formula II, R ⁵ and R ⁶ are each independently an optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

In some embodiments of Formula I or Formula II, R ³ and R ⁷ together form an optionally substituted 4 to 7 membered heterocyclic ring; and J is a bond. In such an aspect, a representative compound of formula I is of formula Ia:

Wherein: W is CR ^7c R ^7d , O or NR ^7a ; R ^7a and R ^7b are each independently H or C _1-4 alkyl, and R ^7c and R ^7d are each independently H, C _1-4 alkane. Base or halogen; and n is 1, 2 or 3.

In the following examples, the following substituents: R ^1a , R ^1b , R ^2a , R ^2b , R ^2c , R ^2d , R ⁴ , R ⁵ , R ⁶ , R ^8a , R ^8b , R ^8c , R ^8d and R ^8e description and definitions of X, and be adapted to provide a compound of formula I, formula II, formula II-k _1, of formula II-k ₂ and formula Ia as described previously herein and herein after. In the following examples, the following substituents: R ³ and R ^{7 are} recited and defined to apply to compounds of Formula I or Formula II, Formula II-k ₁ and Formula II-k ₂ as provided herein before and after. In the following examples, the following substituents: R ^7a , R ^7b , R ^7c , R ^7d and W are described and defined to apply to the compounds of formula Ia as provided herein before and after.

In some embodiments, R ^1a and R ^1b are each independently: H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted Heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted The cycloalkyl-alkyl group, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring.

In some embodiments, R ^1a and R ^1b are each independently: H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted Arylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl, or R ^1a and R ^1b together, as appropriate Substituted 4- to 7-membered heterocyclic ring.

In some embodiments, R ^1a and R ^1b are each independently an optionally substituted alkyl group, wherein the alkyl group may be optionally substituted with one or three of the following: hydroxy, carboxy, amine, sulfonyl, sulfonic acid Alkyl, alkoxy, _{C2-4carboxyalkoxy} , _C2-4 alkoxycarbonyl, aminocarbonyl, _C1-4 alkyl and heteroaryl. In some embodiments, the substituted amino C ₁ - ₄ alkyl group is an alkyl carbonyl group, N (CH _{3) 2} NH ₂ or a substituted alkyl group of C _1-4.

In some embodiments, R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring wherein the 4 to 7 membered heterocyclic ring is optionally substituted with one or three of the following: OH, an amine group, an alkyl group, a carboxyl group. And alkoxy groups. In some embodiments, the 4 to 7 membered heterocyclic ring optionally substituted with an alkyl group is an alkyl substituted 4 to 7 membered heterocyclic ring wherein the alkyl group is further substituted with a hydroxy group. In some embodiments, the 4 to 7 membered heterocyclic ring is optionally substituted with a hydroxy substituted C _1-4 alkyl group. In some embodiments, the 4 to 7 membered heterocyclic ring optionally substituted with an amine group is a 4 to 7 membered heterocyclic ring substituted with NH ₂ , alkylsulfonylamino or alkylcarbonylamino. In some embodiments, the 4 to 7 membered heterocyclic ring optionally substituted with an alkoxy group is a 4 to 7 membered heterocyclic ring substituted with an alkoxy group, wherein the alkoxy group is further substituted with a hydroxy group.

In some embodiments, R ^1a and R ^1b are each independently: H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted Arylalkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl, optionally substituted cycloalkyl-alkyl, or R ^1a and R ^1b together, as appropriate a substituted 4 to 7 membered heterocyclic ring wherein the 4 to 7 membered heterocyclic ring is substituted by one or more of the following: OH, NH ₂ , CH ₃ , , ,

In some such embodiments, R ^1a and R ^1b are each independently: H, C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxa heterocycle. Butane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, diazetidine, piperazine, morpholine, thiocyclobutane, tetrahydrogen Thiophene, tetrahydrothiopyran, tetrahydrofuran, tetrahydropyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiopyran dioxide, tetrazole, C _1-6 aralkyl, furanyl -C _1-6 alkyl, phenylthio-C _1-6 alkyl, 2H-pyrrolyl-C _1-6 alkyl, pyrrolyl-C _1-6 alkyl, oxazolyl-C _1-6 alkane , thiazolyl-C _1-6 alkyl, imidazolyl-C _1-6 alkyl, pyrazolyl-C _1-6 alkyl, isoxazolyl-C _1-6 alkyl, isothiazolyl-C _1-6 alkyl, 1,3,4-thiadiazolyl-C _1-6 alkyl, 2H-piperidyl-C _1-6 alkyl, 4-H-piperidyl-C _1-6 alkane , pyridyl-C _1-6 alkyl, pyridazinyl-C _1-6 alkyl, pyrimidinyl-C _1-6 alkyl, pyrazinyl-C _1-6 alkyl, 1,3,5- Triazinyl-C _1-6 alkyl, and Or R ^1a and R ^1b together form azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, morpholine, diazetidine or piperazine; wherein each of the aforementioned non-H parts is optionally Substituted by one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen .

Or R ^1a and R ^1b are formed together: , , ,

In some such embodiments, R ^1a and R ^1b are each independently: H, C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxa heterocycle. Butane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, diazetidine, piperazine, morpholine, thiocyclobutane, tetrahydrogen Thiophene, tetrahydrothiopyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiopyran dioxide, C _1-6 aralkyl, furyl-C _1-6 alkyl, benzene sulfide -C _1-6 alkyl, 2H-pyrrolyl-C _1-6 alkyl, pyrrolyl-C _1-6 alkyl, oxazolyl-C _1-6 alkyl, thiazolyl-C _1-6 alkane , imidazolyl-C _1-6 alkyl, pyrazolyl-C _1-6 alkyl, isoxazolyl-C _1-6 alkyl, isothiazolyl-C _1-6 alkyl, 1,3, 4-thiadiazolyl-C _1-6 alkyl, 2H-piperidyl-C _1-6 alkyl, 4-H-piperidyl-C _1-6 alkyl, pyridyl-C _1-6 alkane , pyridazinyl-C _1-6 alkyl, pyrimidinyl-C _1-6 alkyl, pyrazinyl-C _1-6 alkyl, 1,3,5-triazinyl-C _1-6 alkyl Or R ^1a and R ^1b together form azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, morpholine , diazetidine or piperazine; wherein each of said non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl Alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen.

In one embodiment, R ^1a and R ^1b are each independently: , ,

In some such embodiments, R ^1a and R ^1b are each independently: H, C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxa heterocycle. Butane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, diazetidine, piperazine, morpholine, thiocyclobutane, tetrahydrogen Thiophene, tetrahydrothiopyran, tetrahydrofuran, tetrahydropyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiopyran dioxide, tetrazole, C _1-6 aralkyl, furanyl -C _1-6 alkyl, phenylthio-C _1-6 alkyl, 2H-pyrrolyl-C _1-6 alkyl, pyrrolyl-C _1-6 alkyl, oxazolyl-C _1-6 alkane , thiazolyl-C _1-6 alkyl, imidazolyl-C _1-6 alkyl, pyrazolyl-C _1-6 alkyl, isoxazolyl-C _1-6 alkyl, isothiazolyl-C _1-6 alkyl, 1,3,4-thiadiazolyl-C _1-6 alkyl, 2H-piperidyl-C _1-6 alkyl, 4-H-piperidyl-C _1-6 alkane , pyridyl-C _1-6 alkyl, pyridazinyl-C _1-6 alkyl, pyrimidinyl-C _1-6 alkyl, pyrazinyl-C _1-6 alkyl, 1,3,5- Triazinyl-C _1-6 alkyl, and Or R ^1a and R ^1b together form azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, morpholine, diazetidine or piperazine; wherein each of the aforementioned azetidines , pyrrolidine, piperidine, pyrrolidone, piperidone, morpholine, diazetidine or piperazine may be substituted by one or more of the following: OH, NH ₂ , CH ₃ , , , , ,

In some embodiments, R ^1a and R ^1b may together form a 4 to 7 membered heterocyclic ring, optionally substituted by one or more of the following: OH, OR ^1c , NR ^1c R ^{1d ,} and optionally substituted alkyl, wherein R ^1c and R ^1d are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

In some embodiments, R ^1a and R ^1b together form an azetidine ring, optionally substituted by one or more of the following: OH, OR ^1c , NR ^1c R ^{1d ,} and optionally substituted alkyl, wherein R ^1c and R ^1d are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

In some embodiments, R ^1a and R ^1b together form a optionally substituted by one or more of the piperidine ^{ring: OH, OR 1c, NR 1c} R 1d , and optionally of substituted alkyl, wherein R ^1c and R ^1d are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

In some embodiments, R ^1a and R ^1b together form a pyrrolidine ring, optionally substituted by one or more of the following: OH, OR ^1c , NR ^1c R ^{1d ,} and optionally substituted alkyl, wherein R ^1c and R ^1d are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

In some embodiments, R ^1a and R ^1b together form the following optionally substituted by one or more of the morpholine ^{ring: OH, OR 1c, NR 1c} R 1d , and optionally of substituted alkyl, wherein R ^1c and R ^1d are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

In some embodiments, R ^1a and R ^1b together form a optionally substituted by one or more of the piperazine ^{ring: OH, OR 1c, NR 1c} R 1d , and optionally of substituted alkyl, wherein R ^1c and R ^1d are each independently H, optionally substituted alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl.

In one embodiment, R ^1a and R ^1b are formed together: , ,

In another embodiment, R ^1a and R ^1b are formed together , , or

In one embodiment, R ^1a and R ^1b are each independently: H, C _1-4 alkyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, Azetidine, pyrrolidine, piperidine, tetrahydrothiophene dioxide, C _1-4 aralkyl, pyrrolyl-C _1-4 alkyl, imidazolyl-C _1-4 alkyl, pyrazolyl -C _1-4 alkyl, pyridyl-C _1-4 alkyl, pyridazinyl-C _1-4 alkyl, pyrimidinyl-C _1-4 alkyl, pyrazinyl-C _1-4 alkyl; Or R ^1a and R ^1b together form azetidine, pyrrolidine, piperidine, morpholine, diazetidine or piperazine; wherein each of the aforementioned non-H moieties is optionally selected from one or more selected from the group consisting of Substituted unsubstituted substituents: C _1-4 alkyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone , diazetidine, piperazine, morpholine, thiocyclobutane, tetrahydrothiophene, tetrahydrothiopyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiopyran dioxide And a hydroxyl group, an OC _1-4 alkyl group, a C _1-4 carboxyl group, and an N(C _1-4 alkyl) group (C _1-4 alkyl group).

In another embodiment, R ^1a and R ^1b are each independently: H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydrogen Piper, piperidine, tetrahydrothiophene dioxide, phenyl or pyridyl; or R ^1a and R ^1b together form azetidine, pyrrolidine, morpholine or piperazine; wherein each of the aforementioned non-H moieties is optionally Substituted by one or more unsubstituted substituents selected from the group consisting of CH ₃ , C ₂ H ₅ , OH, OCH ₃ , OC ₂ H ₅ , CH ₂ COOH, C ₂ H ₄ COOH, C ₃ H ₆ COOH, N(Me)(Me), N(Me)(Et), N(Et)(Et), tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine and pyrrolidone.

In some embodiments, at least one of R ^1a and R ^1b is an unsubstituted non-H moiety; or R ^1a and R ^1b together form an unsubstituted heterocyclic ring.

In other embodiments, at least one of R ^1a and R ^1b is a substituted non-H moiety; or R ^1a and R ^1b together form a substituted heterocyclic ring.

In some embodiments, R ^1a and R ^1b are each independently selected from the group consisting of H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentyl, cyclohexyl, oxetane, Tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , and Or R ^1a and R ^1b together , , or

In one embodiment, R ^1a and R ^1b are H. In another embodiment, R ^1a and R ^1b are each independently H, CH ₃ , C ₂ H ₅ or C ₃ H ₇ .

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is

In another embodiment, one of R ^1a and R ^1b is CH ₃ , and the other of R ^1a and R ^1b is

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is cyclopentyl, cyclohexyl or .

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide Object or

In another embodiment, R ^1a and R ^1b are H, and the other of R ^1a and R ^1b is phenyl,

In one embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is 2-pyridyl, 3-pyridyl, 4-pyridyl.

In some embodiments, R ^2a , R ^2b , R ^{2c ,} and R ^2d are each independently H, halo, C _1-4 alkyl, OC _1-4 alkyl, or CF ₃ . In other embodiments, R ^2a , R ^2b , R ^{2c ,} and R ^2d are each independently H, halo, C _1-4 alkyl, OC _1-3 alkyl, or CF ₃ .

In other embodiments, R ^2a , R ^2b , R ^{2c ,} and R ^2d are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ , OC ₃ H ₇ or CF. ₃ . In other embodiments, R ^2a , R ^2b , R ^{2c ,} and R ^2d are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H _{5 ,} or CF ₃ . In other embodiments, R ^2a , R ^2c and R ^2d are each independently H or F; and R ^2b is H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ or OC ₂ H ₅ . In some exemplary embodiments: R ^2a , R ^2b , R ^{2c ,} and R ^2d are each H; R ^2a , R ^{2c ,} and R ^2d are each H, and R ^2b is F; and each of R ^2a , R ^{2b ,} and R ^2c Is H, and R ^2d is F; R ^2a , R ^2c and R ^2d are each H, and R ^2b is OCH ₃ ; R ^2a , R ^2c and R ^2d are each H, and R ^2b is CH ₃ ; R ^2a , R ^2c and R ^2d are each H and R ^2b is Cl; R ^2a , R ^2b and R ^2d are each H and R ^2c is F; R ^2a and R ^2b are each F, and R ^2c and R ^2d are each H; or R ^2a and R ^2c are each H, R ^2c is Cl, and R ^2d is F.

In some embodiments, R ^8a , R ^8b , R ^8c , R ^{8d ,} and R ^8e are each independently H, F, Cl, C _1-4 alkyl, OC _1-4 alkyl, NR ⁵ R ⁶ , CF ₃ or CN. In other embodiments, R ^8a , R ^8b , R ^8c , R ^{8d ,} and R ^8e are each independently F, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH _{3 ,} or CF ₃ . In other embodiments, R ^8a and R ^8e are each independently H, F, Cl or CH ₃ ; R ^8b and R ^8d are each independently H, Cl, F, CH ₃ , OCH ₃ or CF ₃ ; And R ^8c is H, Cl, CH ₃ or OCH ₃ . In some exemplary embodiments: R ^8a , R ^8b , R ^8c , R ^{8d ,} and R ^8e are each H; R ^8a , R ^8b , R ^{8d ,} and R ^8e are each H, and R ^8c is Cl; R ^8a , R ^8b , R ^8d and R ^8e are each H and R ^8c is CH ₃ ; R ^8a , R ^8b , R ^8d and R ^8e are each H, and R ^8c is OCH ₃ ; R ^8a , R ^8c , R ^8d and R ^{8e is} each H and R ^8b is Cl; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is CF ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is CH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is OCH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is F; R ^8b , R ^8c , R ^8d and R ^8e are each H and R ^8a is Cl; R ^8b , R ^8c , R ^8d and R ^8e are each H, and R ^8a is CH ₃ ; each of R ^8b , R ^8c and R ^8d Is H, R ^8a is F, and R ^8e is Cl; R ^8a , R ^8d and R ^8e are each H, and R ^8b and R ^8c are each Cl; R ^8b , R ^8d and R ^8e are each H, and R ^8a and R ^8c are each Cl; or R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F.

In some embodiments, X is N. In other embodiments, X is CH.

In some embodiments of Formula Ia, R ^7a and R ^7b are each independently H or C _1-3 alkyl. In one embodiment, R ^7a and R ^7b are each independently H or CH ₃ or CH ₂ CH ₃ . In another embodiment, R ^7a and R ^7b are each independently H or CH ₃ .

In some embodiments of Formula Ia, W is CR ^7c R ^7d . In some such embodiments, R ^7c and R ^7d are each independently H, C _1-3 alkyl or F. In other such embodiments, R ^7c and R ^7d are each independently H, CH ₃ or F. For example, R ^7c and R ^7d are both H, both CH ₃ or both.

In some embodiments of Formula Ia, W is O. In other embodiments, W is NR ^7a ; and R ^7a is C _1-3 alkyl, such as CH ₃ .

In some embodiments of Formula I-a, n is one. In other embodiments, n is two. In other embodiments, n is 3.

In some embodiments: R ^1a and R ^1b are each independently: H, C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxetane , tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, diazetidine, piperazine, morpholine, thiocyclobutane, tetrahydrothiophene, Tetrahydrothiopyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiopyran dioxide, C _1-6 aralkyl, furyl-C _1-6 alkyl, phenylthio- C _1-6 alkyl, 2H-pyrrolyl-C _1-6 alkyl, pyrrolyl-C _1-6 alkyl, oxazolyl-C _1-6 alkyl, thiazolyl-C _1-6 alkyl, Imidazolyl-C _1-6 alkyl, pyrazolyl-C _1-6 alkyl, isoxazolyl-C _1-6 alkyl, isothiazolyl-C _1-6 alkyl, 1,3,4- Thiadiazolyl-C _1-6 alkyl, 2H-piperidyl-C _1-6 alkyl, 4-H-piperidyl-C _1-6 alkyl, pyridyl-C _1-6 alkyl, pyridazinyl-C _1-6 alkyl, pyrimidinyl-C _1-6 alkyl, pyrazinyl-C _1-6 alkyl, 1,3,5-triazinyl-C _1-6 alkyl; R ^1a and R ^1b together form azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, morpholine, Azetidine or piperazine; wherein each of said non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl a base, an alkynyl group, a hydroxyl group, an alkoxy group, a carboxyl group, an amine group and a halogen; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkane Or a group of CF ₃ ; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, C _1-4 alkyl, OC _1-4 alkyl, NR ⁵ R ⁶ , CF ₃ or CN.

In other embodiments: R ^1a and R ^1b are each independently: H, C _1-4 alkyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, Azetidine, pyrrolidine, piperidine, tetrahydrothiophene dioxide; C _1-4 aralkyl, pyrrolyl-C _1-4 alkyl, imidazolyl-C _1-4 alkyl, pyrazolyl -C _1-4 alkyl, pyridyl-C _1-4 alkyl, pyridazinyl-C _1-4 alkyl, pyrimidinyl-C _1-4 alkyl, pyrazinyl-C _1-4 alkyl; Or R ^1a and R ^1b together form azetidine, pyrrolidine, piperidine, morpholine, diazetidine or piperazine; wherein each of the aforementioned non-H moieties is optionally selected from one or more selected from the group consisting of Substituted unsubstituted substituents: C _1-4 alkyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone , diazetidine, piperazine, morpholine, thiocyclobutane, tetrahydrothiophene, tetrahydrothiopyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiopyran dioxide , hydroxy, OC _1-4 alkyl, C _1-4 carboxyl and N(C _1-4 alkyl)(C _1-4 alkyl); R ^2a , R ^{2 b} , R ^2c and R ^2d are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CF ₃ ; R ^7a and R ^7b are each independently H or C _1-3 alkyl; R ^7c and R ^7d are each independently H, C _1-3 alkyl or F; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently F, Cl , CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ or CF ₃ .

In other embodiments: R ^1a and R ^1b are each independently: H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetrahydroperidine Or a piperidine, a tetrahydrothiophene dioxide, a phenyl or a pyridyl group; or R ^1a and R ^1b together form an azetidine, pyrrolidine, morpholine or piperazine; wherein each of the aforementioned non-H moieties is optionally One or more unsubstituted substituents selected from the group consisting of CH ₃ , C ₂ H ₅ , OH, OCH ₃ , OC ₂ H ₅ , CH ₂ COOH, C ₂ H ₄ COOH, C ₃ H ₆ COOH, N(Me)(Me), N(Me)(Et), N(Et)(Et), tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine and pyrrolidone; R ^2a , R ^2c and R ^2d are each independently H or F; R ^2b is H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ or OC ₂ H ₅ ; R ^7a and R ^7b are each independently H or CH ₃ Or CH ₂ CH ₃ ; R ^7c and R ^7d are each independently H, CH ₃ or F; R ^8a and R ^8e are each independently H, F, Cl or CH ₃ ; R ^8b and R ^8d are each independently The ground is H, Cl, F, CH ₃ , OCH ₃ or CF ₃ ; R ^8c is H, Cl, CH ₃ or OCH ₃ ; and X is CH.

In other embodiments, R ^1a and R ^1b are each independently selected from the group consisting of H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentyl, cyclohexyl, oxetane, Tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, R ^1a and R ^1b are formed together , , or ; R ^2a , R ^2b , R ^2c and R ^2d are each selected from the group consisting of H, F, Cl, CH ₃ and OCH ₃ ; wherein: R ^2a , R ^2b , R ^2c and R ^2d are each H; R ^2a , R ^2c and R ^2d are each H and R ^2b is F; R ^2a , R ^2b and R ^2c are each H and R ^2d is F; R ^2a , R ^2c and R ^2d are each H, and R ^2b is OCH ₃ ; R ^2a , R ^2c and R ^2d are each H and R ^2b is CH ₃ ; R ^2a , R ^2c and R ^2d are each H and R ^2b is Cl; R ^2a , R ^2b and R ^2d Each is H, and R ^2c is F; R ^2a and R ^2b are each F, and R ^2c and R ^2d are each H; or R ^2a and R ^2c are each H, R ^2c is Cl, and R ^2d is F; R ^7a and R ^7b are each independently H or CH ₃ ; R ^7c and R ^7d are each independently H, CH ₃ or F; wherein: R ^7c and R ^7d are both H; R ^7c and R ^7d are CH ₃ ; or R ^7c and R ^7d are both F; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, F, Cl, CH ₃ , OCH ₃ and CF. ₃ wherein: R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each H; R ^8a , R ^8b , R ^8d and R ^8e are each H and R ^8c is Cl; R ^8a , R ^8b , R ^8d and R ^8e are each H, and R ^8c is CH ₃ ; R ^8a , R ^8b , R ^8d and R ^8e are each H and R ^8c is OCH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is Cl; R ^8a , R ^8c , R ^8d and R ^8e Each is H, and R ^8b is CF ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is CH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is OCH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is F; R ^8b , R ^8c , R ^8d and R ^8e are each H and R ^8a is Cl; R ^8b , R ^8c , R ^8d and R ^8e are each H and R ^8a is CH ₃ ; R ^8b , R ^8c and R ^8d are each H, R ^8a is F, and R ^8e is Cl; and R ^8a , R ^8d and R ^8e are each Is H, and R ^8b and R ^8c are each Cl; R ^8b , R ^8d and R ^8e are each H, and R ^8a and R ^8c are each Cl; or R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F.

In one embodiment, R ^1a and R ^1b are each H. In another embodiment, R ^1a and R ^1b are each independently H, CH ₃ , C ₂ H ₅ or C ₃ H ₇ .

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is

In one embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is cyclopentyl, cyclohexyl or .

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide Object or

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is phenyl, or .

In another embodiment, one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is 2-pyridyl, 3-pyridyl, 4-pyridyl.

In one embodiment, R ^1a and R ^1b are formed together , , or

In some embodiments: R ^1a and R ^1b are each independently H or CH ₃ ; R ^2a , R ^2c and R ^2d are each H; R ^2b is Cl; R ^7a and R ^7b are each H; W is CR ^7c R ^7d ; R ^7c and R ^7d are each H; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, F, Cl, CH ₃ , OCH ₃ and CF _{3 .} ; X is CH; and n is 2.

In some embodiments, the compound is a compound of Formula Ib, wherein: R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted naphthenic a heterocycloalkyl group, optionally substituted heteroaryl group; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _{1 -4} alkyl or CF ₃ ; R ³ are each independently H or optionally substituted alkyl; R ⁷ is each independently H, F or optionally substituted alkyl; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, optionally substituted alkyl or OR ⁴ ; or any two adjacent groups of R ^8a , R ^8b and R ^8c together form 4 to a substituted cycloalkyl ring or a 4- to 7-membered optionally substituted heterocycloalkyl ring; wherein R ⁴ is optionally substituted alkyl, optionally substituted cycloalkyl or, as appropriate Substituted heterocycloalkyl; and X is CH.

In some embodiments, the compound Ib compound of formula wherein: R ^1a and R ^1b are based are each independently ^{H; R 2a, R 2b,} R 2c and R ^2d line are each independently H or halo; R ³ lines each Independently H or optionally substituted alkyl; R ⁷ are each independently H, F or optionally substituted alkyl; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently Is H, F, Cl, optionally substituted alkyl or OC _1-4 alkyl optionally substituted by halogen; or any two adjacent groups of R ^8a , R ^8b and R ^8c together form 4 to 7 members Optionally substituted cycloalkyl ring or 4 to 7 member optionally substituted heterocycloalkyl ring; and X is CH.

In some embodiments, the compound of Formula I-a can be a compound as shown in Table 1, or a pharmaceutically acceptable salt thereof.

In Table 1 above, the IC ₅₀ data is expressed as follows: greater than or equal to 10 micromolar concentration designated as A; less than 10 micromolar concentration but greater than or equal to 1 micromolar concentration designated as B; less than 1 micromolar concentration But greater than or equal to 500 nanomolar concentrations are designated as C; less than 500 nanomolar concentrations but greater than or equal to 100 nanomolar concentrations are designated as D; less than 100 nanomolar concentrations are designated as E. The method for determining the IC ₅₀ data of Table 1 is provided in the description of Analysis 1 below.

In some embodiments, the compound of Formula Ia can include:

Or a pharmaceutically acceptable salt thereof.

In various embodiments, R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ , A substituted heteroaryl or optionally substituted heterocycloalkyl.

In other embodiments, R ³ is H, optionally substituted alkyl of, OR ^{4, halogen, SR 4, S (O)} 2 R 4, NR 5 R 6 or the optionally substituted heterocycloalkyl.

In other embodiments, R ³ is H, optionally substituted alkyl of, OR ^4, halogen, or ^{NR 5 R 6, SR 4,} S (O) 2 R 4 or the optionally substituted heterocycloalkyl; And R ⁷ is an alkyl group.

In some embodiments, R ³ is H, optionally substituted alkyl, OR ⁴ , halogen, NR ⁵ R ⁶ , SR ⁴ , S(O) ₂ R ⁴ or optionally substituted heterocycloalkyl; And R ⁷ is an alkyl group. In some such embodiments, R ³ is H, optionally substituted alkyl, halo, NR ⁵ R ⁶ , SR ⁴ , S(O) ₂ R ⁴ or optionally substituted heterocycloalkyl.

In one embodiment of this aspect, R ³ is H, optionally substituted alkyl, halo or NR ⁵ R ⁶ .

In another aspect, R ³ is H, optionally substituted alkyl, optionally substituted heteroaryl, OR ⁴ , halogen, NR ⁵ R ⁶ , SR ⁴ , S(O) ₂ R ⁴ or a heterocycloalkyl group optionally substituted; and R ⁷ is an alkyl group.

In one embodiment of this aspect, R ⁴ is optionally substituted alkyl or optionally substituted cycloalkyl.

In another embodiment, R ⁴ is alkyl, which is optionally substituted with halo, aryl, heteroaryl, heterocycloalkyl or cycloalkyl.

In another embodiment, R ⁴ is cycloalkyl, which is optionally substituted by halogen, alkyl, halo, aryl, heteroaryl, heterocycloalkyl or cycloalkyl.

In another embodiment, the R ⁴ is selected from the group consisting of: , ,

In another aspect of this embodiment, R ³ is the optionally substituted alkyl, optionally substituted aryl, the heteroaryl, NR ⁵ R ⁶ or the optionally substituted heterocycloalkyl.

In another embodiment, R ³ is an optionally substituted alkyl.

In one embodiment, R ³ is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl.

In another embodiment, R ³ is -CD ₃ .

In another embodiment of this aspect, R ³ is NR ⁵ R ⁶ , and wherein R ⁵ and R ⁶ are each independently an optionally substituted alkyl.

In another embodiment, R ³ is NR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are each independently methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl, They are each replaced by a halogen as appropriate.

In another embodiment, the R ³ is selected from the group consisting of: , ,

In one embodiment of this aspect, R ³ is optionally substituted heterocycloalkyl.

In another embodiment, R ³ is optionally substituted by a monocyclic heterocycloalkyl group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazine , tetrahydrofuranyl, each optionally substituted with halo, cyano, oxo, -CF _3, alkyl and cycloalkyl.

In another embodiment, the R ³ is selected from the group consisting of: ,

In another embodiment, R ³ is optionally substituted bicyclic heterocycloalkyl.

In another embodiment, the R ³ is selected from the group consisting of: , and .

In another aspect of this embodiment, R ³ is optionally substituted aryl of heteroaryl.

In another embodiment, R ³ is optionally substituted pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, furyl, phenylthio, and thiazolyl. In another embodiment, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, furyl, phenylthio and thiazolyl are optionally substituted by halogen.

In another embodiment, R ³ is .

In some embodiments, R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _1-7 cycloalkyl or C _1-6 aralkyl; wherein each of the foregoing non-H moieties is optionally One or more substituents selected from unsubstituted substituents of the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen.

In other embodiments, R ^1a and R ^1b are each independently H or C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally unsubstituted by one or more selected from the group consisting of Substituent substitution: C _1-3 alkyl, hydroxy and OC _1-3 alkyl.

In other embodiments, R ^1a and R ^1b are each independently H or unsubstituted C _1-3 alkyl. In other embodiments, R ^1a and R ^1b are each H.

In some embodiments, R ^2a , R ^2b , R ^{2c ,} and R ^2d are each independently H, halo, C _1-4 alkyl, OC _1-4 alkyl, or CF ₃ . In other embodiments, R ^2a , R ^2b , R ^{2c ,} and R ^2d are each independently F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H _{5 ,} or CF ₃ . In other embodiments, R ^2a , R ^2c and R ^2d are each independently H; and R ^2b is H, F or Cl. In some exemplary embodiments, R ^2a , R ^{2c ,} and R ^2d are each H; and R ^2b is Cl.

In some embodiments, R ³ is H, C _1-4 alkyl or halo; wherein the C _1-4 alkyl group is optionally substituted with one or more unsubstituted substituents selected from the group consisting of: C _1-3 alkyl, halogen, hydroxy, alkoxy, carboxyl and amine groups.

In other embodiments, R ³ is C _1-3 alkyl, F, Cl or Br; wherein the C _1-3 alkyl group is optionally subjected to one or more unsubstituted substituents selected from the group consisting of Substitution: C _1-2 alkyl, halogen, hydroxy, OC _1-3 alkyl, carboxyl and amine.

In other embodiments, R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, Cl, or Br; wherein the CH ₃ and the C ₂ H ₅ are each optionally substituted with one or more halogens.

In some exemplary embodiments, R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, Cl, or Br.

In some exemplary embodiments, R ³ is NR ⁵ R ⁶ , SR ⁴ , S(O) ₂ R ⁴ or optionally substituted heterocycloalkyl.

In some embodiments, R ⁷ is C _1-6 alkyl. In other embodiments, R ⁷ is C _1-4 alkyl. In other embodiments, R ⁷ is C _1-3 alkyl. In some exemplary embodiments, R ⁷ is CH ₃ or C ₂ H ₅ .

In some embodiments, R ^8a , R ^8b , R ^8c , R ^{8d ,} and R ^8e are each independently H, halo, C _1-4 alkyl, OC _1-4 alkyl, NR ⁵ R ⁶ , CF ₃ Or CN. In other embodiments, R ^8a , R ^8b , R ^8c , R ^{8d ,} and R ^8e are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H _{5 ,} or CN. In other embodiments, R ^8a and R ^8e are each independently H, F or Cl; R ^8b and R ^8d are each independently H, F, OCH ₃ or CN; and R ^8c is H, F or Cl . In some exemplary embodiments: R ^8a , R ^8c , R ^{8d ,} and R ^8e are each H, and R ^8b is CN; R ^8a , R ^8c , R ^{8d ,} and R ^8e are each H, and R ^8b is OCH ₃ R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F or Cl; R ^8b , R ^8d and R ^8e are each H, R ^8a is Cl, and R ^8c is F; ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is Cl.

In some embodiments, J is a bond or CH ₂ .

In some embodiments: R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _1-7 cycloalkyl or C _1-6 aralkyl; wherein each of the foregoing non-H moieties is optionally One or more substituents selected from unsubstituted substituents of the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, C _1-4 alkyl, halogen Or NR ⁵ R ⁶ ; wherein the C _1-4 alkyl group is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C _1-3 alkyl, halogen, hydroxy, alkoxy And a carboxyl group and an amine group R ⁷ are a C _1-6 alkyl group; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OC _1-4 Alkyl, NR ⁵ R ⁶ , CF ₃ or CN.

In other embodiments: R ^1a and R ^1b are each independently H or C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally unsubstituted by one or more selected from the group consisting of Substituent substitution: C _1-3 alkyl, hydroxy and OC _1-3 alkyl; R ^2a , R ^2b , R ^2c and R ^2d are each independently F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CF ₃ ; R ³ is C _1-3 alkyl, F, Cl or Br; wherein the C _1-3 alkyl group is optionally subjected to one or more selected from the group consisting of Substituted substituents substituted: C _1-2 alkyl, halogen, hydroxy, OC _1-3 alkyl, carboxy and amine; R ⁷ is C _1-4 alkyl; R ^8a , R ^8b , R ^8c , R ^8d And R ^8e are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CN; and J is a bond or CH ₂ .

In other embodiments: R ^1a and R ^1b are each independently H or unsubstituted C _1-3 alkyl; R ^2a , R ^2c and R ^2d are each independently H; R ^2b is H, F Or Cl; R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, Cl or Br; wherein the CH ₃ and the C ₂ H ₅ are each optionally substituted by one or more halogens; R ⁷ is C _{1 -3} alkyl; R ^8a and R ^8e are each independently H, F or Cl; R ^8b and R ^8d are each independently H, F, OCH ₃ or CN; and R ^8c is H, F or Cl.

In some exemplary embodiments: R ^1a and R ^1b are each H; R ^2a , R ^2c and R ^2d are each H; R ^2b is Cl; and R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, Cl or Br; R ⁷ is CH ₃ or C ₂ H ₅ ; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, CN, OCH ₃ , F and Cl, Wherein: R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is CN; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is OCH ₃ ; R ^8b , R ^8c And R ^8d are each H, and R ^8a and R ^8e are each F or Cl; R ^8b , R ^8d and R ^8e are each H, R ^8a is Cl, and R ^8c is F; or R ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is Cl.

In some embodiments, R ³ is OR ⁴ .

In some embodiments, R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _1-7 cycloalkyl or C _1-6 aralkyl; wherein each of the foregoing non-H moieties is optionally One or more substituents selected from unsubstituted substituents of the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen.

In other embodiments, R ^1a and R ^1b are each independently H or C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally unsubstituted by one or more selected from the group consisting of Substituent substitution: C _1-3 alkyl, hydroxy and OC _1-3 alkyl.

In other embodiments, R ^1a and R ^1b are each independently H or unsubstituted C _1-3 alkyl. In other embodiments, R ^1a and R ^1b are each H.

In some embodiments, R ^2a , R ^2b , R ^{2c ,} and R ^2d are each independently H, halo, C _1-4 alkyl, OC _1-3 alkyl, or CF ₃ . In other embodiments, R ^2a , R ^2b , R ^{2c ,} and R ^2d are each independently F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H _{5 ,} or CF ₃ . In other embodiments, R ^2a , R ^2c and R ^2d are each independently H; and R ^2b is H, F or Cl. In some exemplary embodiments, R ^2a , R ^{2c ,} and R ^2d are each H; and R ^2b is Cl.

In some embodiments, R ⁴ is C _1-5 alkyl; wherein the C _1-5 alkyl group is optionally substituted by one or more selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 alkyl An unsubstituted substituent of a group consisting of an oxy group, a cycloalkyl group, and a heterocycloalkyl group; or a substituted heterocycloalkyl group.

In other embodiments, R ⁴ is C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally substituted with one or more selected from the group consisting of Cl, F, C _1-2 alkyl, C _1- An unsubstituted substituent of a group consisting of ₂ alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetane and tetrahydrofuran; substituted oxetane; or substituted tetrahydrofuran.

In other embodiments, R ⁴ is C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally substituted with one or more selected from the group consisting of F, CH ₃ , OCH ₃ , cyclopropyl, cyclobutene An unsubstituted substituent of a group consisting of a oxetane or a substituted oxetane.

In some exemplary embodiments, R ⁴ is CH ₃ , C ₂ H ₅ , , ,

In some embodiments, R ⁷ is C _1-6 alkyl. In other embodiments, R ⁷ is C _1-4 alkyl. In other embodiments, R ⁷ is C _1-3 alkyl. In some exemplary embodiments, R ⁷ is CH ₃ or C ₂ H ₅ .

In some embodiments, R ^8a , R ^8b , R ^8c , R ^{8d ,} and R ^8e are each independently H, halo, C _1-4 alkyl, OC _1-4 alkyl, NR ⁵ R ⁶ , CF ₃ Or CN. In other embodiments, R ^8a , R ^8b , R ^8c , R ^{8d ,} and R ^8e are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H _{5 ,} or CN. In other embodiments, R ^8a and R ^8e are each independently H, F or Cl; R ^8b and R ^8d are each independently H, F, OCH ₃ or CN; and R ^8c is H, F or Cl . In some exemplary embodiments: R ^8a , R ^8c , R ^{8d ,} and R ^8e are each H, and R ^8b is CN; R ^8a , R ^8c , R ^{8d ,} and R ^8e are each H, and R ^8b is OCH ₃ R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F or Cl; R ^8b , R ^8d and R ^8e are each H, R ^8a is Cl, and R ^8c is F; ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is Cl.

In some embodiments, J is a bond. In other embodiments, J is a C _1-4 alkylene group.

In some embodiments: R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _1-7 cycloalkyl or C _1-6 aralkyl; wherein each of the foregoing non-H moieties is optionally One or more substituents selected from unsubstituted substituents of the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-3 alkyl or CF ₃ ; R ⁴ is C _1-5 alkyl; wherein C _{The 1-5} alkyl group is optionally substituted by one or more unsubstituted groups selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 alkoxy, cycloalkyl and heterocycloalkyl. a substituent; or a substituted heterocycloalkyl group; R ⁷ is a C _1-6 alkyl group; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkane a group, OC _1-4 alkyl, NR ⁵ R ⁶ , CF ₃ or CN; and J is a bond.

In other embodiments: R ^1a and R ^1b are each independently H or C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally unsubstituted by one or more selected from the group consisting of Substituent substitution: C _1-3 alkyl, hydroxy and OC _1-3 alkyl; R ^2a , R ^2b , R ^2c and R ^2d are each independently F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CF ₃ ; R ⁴ is C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally substituted by one or more selected from the group consisting of Cl, F, C _1-2 alkyl An unsubstituted substituent of the group consisting of C _1-2 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetane and tetrahydrofuran; substituted oxetane; Substituted tetrahydrofuran; R ⁷ is C _1-4 alkyl; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CN.

In other embodiments: R ^1a and R ^1b are each independently H or unsubstituted C _1-3 alkyl; R ^2a , R ^2c and R ^2d are each independently H; R ^2b is H, F Or Cl; R ⁴ is C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally substituted by one or more selected from the group consisting of F, CH ₃ , OCH ₃ , cyclopropyl, cyclobutyl and oxygen An unsubstituted substituent of a heterocyclic butane group; or a substituted oxetane; R ⁷ is a C _1-3 alkyl group; and R ^8a and R ^8e are each independently H, F or Cl R ^8b and R ^8d are each independently H, F, OCH ₃ or CN; and R ^8c is H, F or Cl.

In some exemplary embodiments: R ^1a and R ^1b are each H; R ^2a , R ^2c and R ^2d are each H; R ^2b is Cl; R ⁴ is CH ₃ , C ₂ H ₅ , , , , , , R ⁷ is CH ₃ or C ₂ H ₅ ; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, CN, OCH ₃ , F or Cl, wherein: R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is CN; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is OCH ₃ ; each of R ^8b , R ^8c and R ^8d Is H, and R ^8a and R ^8e are each F or Cl; R ^8b , R ^8d and R ^8e are each H, R ^8a is Cl, and R ^8c is F; or R ^8b and R ^8e are each H, R ^8a And R ^8d are each F, and R ^8c is Cl.

In some embodiments, the compound of Formula I is a compound as shown in Table 2, or a pharmaceutically acceptable salt thereof, and the compound of Formula Ib is a compound as shown in Table 3, or a pharmaceutically acceptable salt thereof, The compound of formula II is a compound shown in Tables 4 and 5 or a pharmaceutically acceptable salt thereof.

Or a pharmaceutically acceptable salt thereof.

Table 3. Exemplary embodiments of compounds of Formula I-b:

Or a pharmaceutically acceptable salt thereof.

In Table 2-5 above, the IC ₅₀ data is expressed as follows: greater than or equal to 10 micromolar concentration designated as A; less than 10 micromolar concentration but greater than or equal to 1 micromolar concentration designated as B; less than 1 micromolar Ear concentrations, but greater than or equal to 500 nanomolar concentrations, are designated as C; less than 500 nanomolar concentrations but greater than or equal to 100 nanomolar concentrations are designated as D; less than 100 nanomolar concentrations are designated as E. Methods for determining the IC ₅₀ data of Tables 2 through 5 are provided in the description of Analysis 1 below.

In some embodiments, a compound of Formula I or Formula II can include:

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, one or both of the R ³ or R ⁷ substituents contain at least one hydrazine.

In another embodiment of the compound of Formula II, each of the R ³ and R ⁷ substituents contains at least one hydrazine.

In some embodiments of the compound of Formula II, the R ⁷ substituent is alkyl, and wherein the alkyl group contains at least one hydrazine.

In other embodiments of the compound of formula II, R ^{7 is} a substituted methyl group, and wherein the methyl group comprises at least one deuterium.

In other embodiments of compounds of Formula II, R ⁷ substituent is -CD _3.

In some embodiments of the compound of Formula II, the R ³ substituent is an optionally substituted alkoxy group or an optionally substituted heterocycloalkyl group, and wherein the R ³ substituent contains at least one hydrazine.

In another embodiment of the compound of Formula II, the R ³ substituent is 2-methylpropoxy, 2,2-dimethylpropoxy, cyclopropylmethoxy, cyclobutylmethoxy, pyrrolidinyl. Or piperidinyl, and wherein the R ³ substituent contains at least one hydrazine.

In another embodiment of the compound of Formula II, the R ³ substituent is selected from:

In some embodiments of the compound of Formula II, the compound of Formula II is selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of Formula II, the compound is selected from the group consisting of: and Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound has Formula IIa:

Or a pharmaceutically acceptable salt thereof.

Formula IIa

In some embodiments of the compound of Formula IIa, the compound has Formula IIa ₁ :

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of Formula II, the compound is Compound 240:

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound has Formula IIb:

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of Formula II, the compound has Formula IIb ₁ :

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of Formula II, the compound is Compound 241:

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound has Formula IIc:

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of Formula II, the compound is Compound 242:

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound has Formula IId:

Or a pharmaceutically acceptable salt thereof.

In another embodiment of the compound of Formula II, the compound has Formula IId ₁ :

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound has Formula IIe: Formula IIe

Or a pharmaceutically acceptable salt thereof, wherein R ^7e is CH ₃ or CD ₃ .

In some embodiments of the compound of Formula II, the compound has Formula IIf:

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound has Formula IIg:

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound has Formula IIg ₁ :

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compounds of Formula II and Formula IIe, the compound is selected from the group consisting of:

Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula II, the compound is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof.

In some embodiments of Formula II, R ¹⁰ is NR ^1a R ^1b , R ³ is OR ⁴ or optionally substituted heterocycloalkyl, and R ⁷ is optionally substituted alkyl. In some embodiments of Formula II, R ¹⁰ is NR ^1a R ^1b , wherein NR ^1a R ^1b is NH ₂ , or wherein at least one R ^1a R ^1b is H and the other R ^1a R ^1b is an optionally substituted alkane And R ³ is optionally substituted heterocycloalkyl or OR ⁴ , wherein R ⁴ is optionally substituted alkyl or optionally substituted cycloalkyl, and R ⁷ is CH ₃ , CF ₃ or CD ₃ . In some embodiments, at least one position on R ³ and R ⁷ may have a germanium atom replacing the H atom. In some embodiments, R ³ is OR ⁴ , wherein R ⁴ is optionally substituted alkyl. In some embodiments, R ³ is OR ⁴ , wherein R ⁴ is optionally substituted cycloalkyl. In some embodiments, R ³ is optionally substituted heterocycloalkyl. In some embodiments, at least one position on R ³ and R ⁷ may have a germanium atom replacing the H atom. In some embodiments, R ³ is a deuterated heterocycloalkyl. In some embodiments, R ⁷ is CD ₃ .

In some embodiments of Formula II, when B is And when J is a C _1-4 alkylene group, R ^{10 is} not a hydroxyl group. In other embodiments of formula II, J is a bond and R ¹⁰ is NR ^1a R ^1b, or optionally substituted hydroxyl group of alkyl. In some embodiments of Formula II, B is And J is a bond or a C _1-4 alkyl group, and R ¹⁰ is NR ^1a R ^1b , a hydroxyl group or an optionally substituted alkyl group.

In some embodiments of Formula II, R ¹⁰ is NR ^1a R ^1b or hydroxy.

In some embodiments of Formula II, R ¹⁰ is OH. In other embodiments, R ¹⁰ is NR ^1a R ^1b . In other embodiments of Formula II, R ¹⁰ is NR ^1a R ^1b . In some embodiments, when bonded to a -(SO ₂ )- group, R ¹⁰ is hydroxy, amine or optionally substituted alkyl. In some embodiments, R ¹⁰ is NH ₂ .

In certain embodiments of formula II, R ^{7 is} a methyl group. In other embodiments, R ⁷ is ethyl. In other embodiments, R ⁷ is propyl. In other embodiments, R ⁷ is butyl.

In some embodiments of Formula II, R ^1a or R ^1b is N-methylazetidin-3-yl, 2-methoxy-2-methylpropyl, 2-hydroxy-2-methyl Propyl and 2-hydroxyethyl. In other embodiments, one of R ^1a or R ^1b is H and the other of R ^1a or R ^1b is N-methylazetidin-3-yl, 2-methoxy-2-methyl Propyl, 2-hydroxy-2-methylpropyl and 2-hydroxyethyl.

In some embodiments of Formula II, X ¹ is CH. In other embodiments, X ¹ is N. In some embodiments, X ² is CR ^2a . In other embodiments, X ² is N. In some embodiments, X ³ is CR ^2b . In other embodiments, X ³ is N. In some embodiments, X ⁴ is CR ^2d . In other embodiments, X ⁴ is N. In some embodiments, X ⁵ is O. In other embodiments, X ⁵ is S. In some embodiments of Formula II, X ⁶ is CR ^2b . In some embodiments, X ⁷ is CR ^2b .

In some embodiments of Formula II, R ⁴ is alkoxyalkyl, cycloalkylalkyl, haloalkyl, bicyclic cycloalkyl, heterocycloalkyl or cycloalkyl.

In some embodiments of Formula II, R ⁴ is 2-methoxyethyl, cyclopentylmethyl, 2-fluoropropyl, bicyclo[3.1.0]hexane-3-yl, tetrahydrofuran-3-yl , piperidin-4-yl, 2,2-dimethylpropyl or cyclobutyl.

In some embodiments of Formula II, R ³ is heteroaryl, haloaryl, alkylheteroaryl, monocyclic heterocycloalkyl, bicycloheterocycloalkyl, bridged bicyclic heterocycloalkyl, haloheterocycle Alkyl, haloalkylheterocycloalkyl, alkoxyheterocycloalkyl, alkylheterocycloalkyl, monocyclic cycloalkyl, bicyclocycloalkyl, (halo)(alkoxy)heterocycloalkyl Or a hydroxyheterocycloalkyl group.

In some embodiments of Formula II, R ³ is 4-fluoropyrazol-1-yl, 8-oxa-3-azabicyclo[3.2.1]oct-3-yl, 3-trifluoromethyl Azetidin-1-yl, 7-oxa-2-azabicyclo[3.1.1]heptan-2-yl, 4-chloropyrazol-1-yl, 2-oxa-6-nitrogen Heterospiro[3.3]heptane-6-yl, 3-fluoroazetidin-1-yl, 2,2-difluoropyrrolidin-1-yl, 2-oxa-5-azabicyclo[2.2 .1]heptane-5-yl, piperidin-1-yl, pyrrolidin-1-yl, pyrazol-1-yl, morpholin-3-one-1-yl, 3-methoxy nitrogen heterocycle Butan-1-yl, 3,3-difluoroazetidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 3-azabicyclo[3.1.0]hexane-3 -yl, 3-fluoro-4-methoxypyrrolidin-1-yl, 4-methylpyrazol-1-yl, 4-fluoropiperidin-1-yl, 2-azabicyclo[3.1.0] Hexane-2-yl, 2,6-dimethylmorpholin-1-yl, 4-methylpiperazin-1-yl, 4-hydroxypiperidin-1-yl, 4-fluoropiperidin-1- Base, 4,4-difluoropiperidin-1-yl, thiomorpholin-1-yl, piperid-4-yl or tetrahydrofuran-2-yl.

In another aspect, the invention includes a pharmaceutically acceptable salt of a compound of Formula I, Formula Ia, Formula Ib, Formula II, Formula II-k ₁ and Formula II-k ₂ , such as Tables 1, 2, The pharmaceutically acceptable salts of the compounds of Tables 3, 4 and 5.

Preparation, administration and use

In another aspect, the invention includes a compound comprising Formula I, Formula II, Formula II-k ₁ and Formula II-k _2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant Pharmaceutical composition of the agent. In some embodiments of this aspect, the invention includes a pharmaceutically acceptable salt of a compound of Table 1, Table 2, Table 3, Table 4, or Table 5. In some other embodiments of this aspect, the invention includes a compound comprising Table 1, Table 2, Table 3, Table 4 or Table 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier Or a pharmaceutical composition of an adjuvant.

The invention includes within its scope a pharmaceutically acceptable prodrug of a compound of the invention. "Pharmaceutically acceptable prodrug" means any pharmaceutically acceptable salt of a compound of the invention which, upon administration to a recipient, provides (directly or indirectly) a compound of the invention or an active metabolite or residue thereof, An ester, an ester salt, or other derivative. In some embodiments, prodrugs increase the bioavailability of such compounds when administered to a mammal, or they enhance the delivery of the parent compound to the bioregion relative to the parent material.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" means not destroying it A non-toxic carrier, adjuvant or vehicle for the pharmacological activity of a compound formulated together. Pharmaceutically acceptable carriers, adjuvants, and vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, Serum proteins (such as human serum albumin), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated plant fatty acids, water, salts or electrolytes (such as protamine sulfate ( Protamine sulfate)), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal cerium oxide, magnesium trisodium citrate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, carboxymethyl Cellulose sodium, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.

The pharmaceutically acceptable salts of the compounds of the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include ethyl hydrochloric acid, adipate, alginate, aspartate, benzoate, besylate, hydrogen sulfate, butyrate, citrate, camphorate, Camphorsulfonate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucose heptanoate, glycerol phosphate, Glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethane sulfonate, lactate, maleate, C Diacid salt, methane sulfonate, 2-naphthalene sulfonate, nicotinic acid salt, nitrate, oxalate, palmate, pectinate, persulphate, 3 -Phenylpropionate, phosphate, picrate, trimethylacetate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and Eleven acid salt. Other acids such as oxalic acid, while not in themselves pharmaceutically acceptable, are useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from suitable bases include alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts, and N ⁺ (C _1-4 alkyl) ₄ salts. The invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersible products can be obtained by this quaternization.

The compositions of the present invention can be administered orally, parenterally, by inhalation spray, in a superficial manner, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium.

For this purpose any bland fixed oil may be employed including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and their glyceride derivatives are suitable for the preparation of injectables, such as natural pharmaceutically acceptable oils of olive oil or castor oil, especially in their polyoxyethylated form. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersing agent, such as carboxymethylcellulose or a similar dispersing agent which is normally 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 commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can also be used The purpose of the deployment.

The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, troches, aqueous suspensions or solutions. In the case of a tablet for oral use, carriers which are usually used include lactose and corn starch. A lubricant such as magnesium stearate is also usually added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. When the aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. Add some sweetness if necessary Agent, flavoring or coloring agent.

Alternatively, the pharmaceutically acceptable compositions of the invention may be administered as a suppository for rectal administration. Such compositions may be prepared by mixing the medicament with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. These materials include cocoa butter, beeswax and polyethylene glycol.

The pharmaceutically acceptable compositions of the present invention may also be administered topically, especially when the therapeutic target includes areas or organs readily accessible by topical administration, including ocular, cutaneous or lower intestinal disorders. Suitable surface formulations for each of these areas or organs are readily prepared.

The topical application to the lower intestinal tract can be effected in the form of a rectal suppository formulation (see above) or in a suitable enema formulation. Surface transdermal patches can also be used.

For topical administration, a pharmaceutically acceptable composition may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyethylene oxide, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable composition may be formulated as a suitable lotion or cream in the form of a suspension or dispersion in the active ingredient 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-octyl-12 Alkanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable composition can be formulated as a micronized suspension in isotonic, pH adjusted sterile saline with or without a preservative such as benzalkonium chloride. A good solution is formulated in an isotonic, pH adjusted sterile saline solution. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition can be formulated in the form of an ointment such as a paraffin.

The pharmaceutically acceptable compositions of the invention may also be administered by nasal aerosol or inhalation Agents are given. These compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared in saline using benzyl alcohol or other suitable preservatives, bioavailable absorption enhancers, fluorocarbons, and/or other conventional solubilizing or dispersing agents. Solution.

In some exemplary embodiments, a pharmaceutically acceptable composition of the invention for oral administration is formulated.

The amount of a compound of the invention which may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated and the particular mode of administration. In some embodiments, the composition should be formulated such that a dosage of between about 0.01 to about 100 mg of the modulator per kilogram of body weight per day can be administered to a patient receiving such compositions.

It is also understood that the particular dosage and treatment regimen used for any particular patient will depend on a variety of factors, including the activity, age, weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, and treatment of the particular compound employed. The judgment of the physician and the severity of the particular disease being treated. The amount of the compound of the invention in the composition will also depend on the particular compound in the composition.

Other therapeutic agents that are normally administered to treat or prevent the condition may also be present in the compositions of the invention, depending on the particular condition or disease being treated or prevented. As used herein, other therapeutic agents that are normally administered to treat or prevent a particular disease or condition are referred to as "appropriate for the disease or condition being treated."

method

The compound of formula I, formula Ia, formula Ib, formula II, formula II-k ₁ and formula II-k ₂ or a pharmaceutically acceptable salt thereof inhibits the activity of the ROR-γ receptor. The compound of formula I, formula Ia, formula Ib, formula II, formula II-k ₁ and formula II-k ₂ or a pharmaceutically acceptable salt thereof inhibits the activity of the ROR-γ receptor in vitro. The compounds of Formula I, Formula Ia, Formula Ib or Formula II, Formula II-k ₁ and Formula II-k ₂ may also inhibit the activity of the ROR-γ receptor in vivo.

Accordingly, in one aspect, the present invention includes a method of the activity of inhibiting receptor ROR-γ, comprising contacting the receptor of Formula I, formulas Ia, Formula Ib, Formula II, Formula II-k _1, of formula II The -k ₂ compound or a pharmaceutically acceptable salt thereof is contacted. In one embodiment of this aspect, the compound of Formula I, Formula Ia, Formula Ib or Formula II, Formula II-k ₁ or Formula II-k ₂ or a pharmaceutically acceptable salt thereof inhibits ROR-γ in vitro Receptor activity. In another embodiment, a compound of Formula I, Formula Ia, Formula Ib, Formula II, or a pharmaceutically acceptable salt thereof, inhibits the activity of a ROR-gamma receptor in vivo. In some embodiments, the compound of Formula I, Formula Ia, Formula Ib, Formula II, Formula II-k ₁ , Formula II-k ₂ or a pharmaceutically acceptable salt thereof is a reverse agonist of the ROR-γ receptor Agent.

In another aspect, the invention comprises a method of treating a ROR-gamma receptor mediated disease in a patient or reducing the severity of a ROR-gamma receptor mediated disease in a patient, comprising administering to a patient in need thereof And a compound of formula I, formula Ia, formula Ib, formula II, formula II-k ₁ , formula II-k ₂ or a pharmaceutically acceptable salt thereof.

In another aspect, the invention includes a treatment or overexpression or upregulation of a "type 17" proinflammatory cytokine, including IL-17a, IL-17f, IL-22, IL-26, IL-21, and GMCSF. A related method of inflammatory disease.

In one embodiment, the ROR-gamma receptor mediated disease can include an autoimmune disease. In some embodiments, the autoimmune disease is selected from the group consisting of: articular adhesion stagnation, asthma, Bethel's disease, chronic obstructive pulmonary disease, Crohn's disease, type 1 diabetes, multiple sclerosis Symptoms, optic neuromyelitis, rheumatic polymyalgia, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Hugh's syndrome, systemic lupus erythematosus, systemic sclerosis, transplant rejection, inflammatory Enteropathy, ulcerative colitis and uveitis.

In another aspect, the invention comprises a method of modulating the activity of a ROR-gamma receptor with a reverse agonist comprising reacting the receptor with Formula I, Formula Ia, Formula Ib, Formula II, Formula II- Contacting k ₁ , a compound of formula II-k ₂ or a pharmaceutically acceptable salt thereof. In one embodiment of this aspect, the compound of Formula I, Formula Ia, Formula Ib, Formula II, Formula II-k ₁ , Formula II-k ₂ or a pharmaceutically acceptable salt thereof modulates ROR-γ in vitro Receptor activity. In another embodiment, the compound of Formula I, Formula Ia, Formula Ib, Formula II, or a pharmaceutically acceptable salt thereof, modulates the activity of the ROR-gamma receptor in vivo. In one embodiment, the compound of Formula I, Formula Ia, Formula Ib or Formula II is a reverse agonist of the ROR-gamma receptor.

Synthesis program

Compounds of Formula I, Formula Ia, Formula Ib or Formula II, Formula II-k ₁ , Formula II-k ₂ can be readily synthesized from commercially available starting materials using methods known in the art. Exemplary synthetic routes to produce compounds of Formula I, Formula Ia, Formula Ib, Formula II, Formula II-k ₁ or Formula II-k ₂ are provided in the following general schemes and examples. The following general procedures and examples are given to provide a better understanding of the synthetic procedures of the present invention and are not intended to be limiting in any way.

General Procedure I: Synthesis of a compound of formula I or formula II, at this time R ³ And R ⁷ Together, a 4- to 7-membered heterocyclic ring is optionally substituted.

Some of the compounds of formula I or formula II can be synthesized using the methods outlined in General Scheme I. Commercially available or synthetic bromine intermediates I.1 are first deuterated with various acid chlorides I.2 to form indoleamine I.3. The intermediate acid intermediate I.5 was obtained by treatment of I.3 with boric acid 1.4a under Suzuki coupling conditions. The carboxylic acid functional group in I.5 is further converted to an acid chloride which is subsequently reacted with a suitable amine based reagent I.6 to provide a compound of formula Ia. Alternatively, intermediate I.3 can be reacted directly with guanamine borate 1.4b under Suzuki coupling to give a compound of formula Ia wherein ^R1a and ^R1b are both hydrogen.

General Procedure II: Synthesis of a compound of formula I or formula II, at this time R ³ Is H, alkyl, substituted alkyl, halogen or NR ⁵ R ⁶ .

According to Scheme II the general synthesis of some compounds of formula I or formula II, wherein R ³ and R ⁷ are not joined together to form a fully saturated heterocyclic ring system. The general synthetic process is very similar to that described in general procedure I. As a first step, the amine-bromo intermediate II.1 is deuterated using acid chloride I.2 to yield a secondary guanamine II.2 . The guanamine nitrogen is further alkylated under basic conditions with a suitable halide to provide the intermediate II.3 . After treating the intermediate with boric acid I.4b under Suzuki coupling conditions, a compound of formula Ib wherein both R ^1a and R ^1b are hydrogen is obtained. When boric acid 1.4a is used, the Suzuki coupling reaction will result in the formation of an acid intermediate II.5 ; this acid is further converted to an acid chloride and reacted with various amines to provide a compound of formula Ib .

General Process III: Synthesis of a compound of formula I or formula II, at this time R ³ For OR ⁴ .

For some compounds of Formula I or Formula II, the synthetic routes described in General Scheme III can be applied. The arylamino-alcohol intermediate III.1 is deuterated at the amine group to provide the intermediate III.2. Any bismuthation by-product can be converted to the desired mono-chemical compound III.2 after simple hydrolysis with aqueous NaOH (1 N) at room temperature. The hydroxyl group in III.2 is then chemoselectively alkylated with a halide (R ⁴ X) or an electrophile (R ⁴ -lvg) having a suitable leaving group in place to form III.3. A compound of the formula Ic wherein R ^1a and R ^1b are hydrogen is synthesized from the intermediate III.3 under the conditions of Suzuki coupling using boric acid I.4b. Similar to the general procedures I and II, the intermediate III.3 can be converted to the acid intermediate III.5 after treatment with boric acid I.4a under Suzuki coupling conditions. The acid intermediate III.5 is further converted to an acid chloride which is subsequently reacted with a suitable amine to provide a compound of formula Ic.

Amidation of acid intermediates such as I.5 (general procedure I), II.5 (general procedure II), III.5 (general scheme III) can also be common in such as HOBt, amines and weak bases. Achieved under coupling conditions.

Instance

Example 1: Synthesis of 3-(1-(2-chloro-6-fluorobenzhydryl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- Fluorobenzamide

Step 1. 6-bromo at room temperature - are sequentially added to the stirred solution in 100mL CH ₂ Cl ₂ in the tetrahydroquinoline 1-A (5g, 23.7mmol), triethylamine (2.8g, 27.7mmol) and 2 -Chloro-6-fluorobenzhydrazinium chloride 1-B (4.6 g, 23.7 mmol). The reaction mixture was stirred for 3 hours and then diluted with H ₂ O (50mL). Dried organic phase was separated, washed with brine (50mL) dried over anhydrous Na ₂ SO _4, and concentrated in vacuo to give a pale gray solid of Amides 1-C (7.6g, 86% ). LC-MS: m/z = 368.0 [M+H] ⁺ .

Step 2. 1-C (150 mg, 0.41 mmol) and Pd(dppf)Cl ₂ (34 mg, 0.041 mmol) and K ₂ CO ₃ (170 mg, 1.23 mmol) obtained from the above step 1 in 5 mL of dioxane and 1 mL To the mixture in H ₂ O was added 5-aminemethylmercapto-2-fluorophenylboronic acid 1-D (90 mg, 0.49 mmol). The resulting mixture was heated under a nitrogen atmosphere at 90 ° C for 24 hours. After cooling, the mixture was diluted with H ₂ O (20mL), and extracted with EtOAc (20mL × 3). The combined organic extracts were washed with brine (20mL), dried over anhydrous Na ₂ SO ₄ dried and concentrated. The residue was purified by EtOAc EtOAc EtOAc EtOAc _{^{1 H NMR (300MHz, CD 3}} OD): δ 8.26-7.76 (m, 2H), 7.71-6.94 (m, 6H), 6.78-6.75 (m, 1H), 4.07-3.58 (m, 2H), 3.00- 2.90 (m, 2H), 2.21-1.96 (m, 2H). HPLC = 100% (214nm), 100 (254nm)%, t R = 6.14 min. LC-MS: m/z =427.1 [M+H] ⁺ .

Example 2: Synthesis of 3-(1-(2-chloro-6-fluorobenzylidenyl)-1,2,3,4-tetrahydroquinolin-6-yl)-benzamide

Add 3- from a mixture of 1-C (150 mg, 0.41 mmol) and Pd(dppf)Cl ₂ (34 mg, 0.041 mmol) and K ₂ CO ₃ (113 mg, 0.82 mmol) in 5 mL of DMF. Aminomethylmercapto-phenylboronic acid 2-A (69 mg, 0.45 mmol). The resulting mixture was heated at 100 ° C for 1 hour under microwave conditions. The solvent was removed in vacuo and EtOAc EtOAc m. ¹ H NMR (300 MHz, CD ₃ OD): δ 8.17 - 6.63 (m, 10H), 3.93 - 3.51 (m, 2H), 2.96 - 2.85 (m, 2H), 2.11-1.83 (m, 2H). HPLC = 100% (214nm), 100 (254nm)%, t R = 4.17 min. LC-MS: m/z = 409.1 [M+H] ⁺ .

Example 3: Synthesis of 5-(1-(2-chloro-6-fluorobenzylidenyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2-fluorobenzamide

Add 3- in a stirred mixture of intermediate 1-C (0.1 g, 0.28 mmol), Pd(dppf)Cl ₂ (0.024 g, 0.03 mmol) and K ₂ CO ₃ (0.082 mg, 0.59 mmol) in 5 mL DMF Aminomethylamido-4-fluorophenylboronic acid (0.054 mg, 0.28 mmol). The mixture was heated at 100 ° C overnight. The solvent was removed in vacuo <RTI ID=0.0> ¹ H NMR (300 MHz, CD ₃ OD): δ 8.06-6.92 (m, 9H), 3.97 - 3.48 (m, 2H), 2.89 - 2.80 (m, 2H), 2.08 - 1.93 (m, 2H). HPLC = 98.9% (214nm), 98.6 (254nm)%, t R = 6.49 min. LC-MS: m/z =427.1 [M+H] ⁺ .

Example 4: Synthesis of 3-(1-(2-chloro-6-fluorobenzylidenyl)-1,2,3,4-tetrahydroquinolin-6-yl)-2,4-difluorobenzamide amine

Step 1. Indoleamine 1-C (0.5 g, 1.4 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2 under nitrogen at 80 °C, 2'-bis(1,3,2-dioxaboron The mixture was stirred) (0.38g, 1.5mmol), Pd (dppf) Cl 2 (0.11g, 0.14mmol) and NaOAc (0.335g, 4.1mmol) in 10mL of dioxane and 2mL H ₂ O in the heated overnight. The mixture was diluted with H ₂ O, and extracted with EtOAc (20mL × 3). The combined extracts were washed with brine (20mL), dried over Na ₂ SO _4, then concentrated. The residue was purified by column chromatography eluting with EtOAc EtOAc (EtOAc: EtOAc LC-MS: m/z = 416.1 [M+H] ⁺ .

Step 2. Add 3 to a stirred mixture of boric acid ester 4-A (0.12 g, 0.29 mmol), Pd(dppf)Cl ₂ (47 mg, 0.06 mmol) and Na ₂ CO ₃ in 8 mL dioxane and 2 mL H 2 O -Bromo-2,4-difluorobenzoic acid 4-B (68 mg, 0.29 mmol). The mixture was heated overnight at 80 ° C under nitrogen. The solid was filtered and the filtrate was crystallised eluted with EtOAc EtOAc The combined organic layers were dried over anhydrous Na ₂ SO _4, and concentrated to provide the acid as a pale yellow solid 4-C (100mg, 78% ). LC-MS: m/z = 446.1 [M+H] ⁺ .

Step 3. A solution of acid 4-C (100mg, 0.22mmol) in 15mL anhydrous oxalyl acyl chloride _{(57mg, 0.45mmol) CH 2 Cl} 2 in the solution. The mixture was stirred for 2 hours at room temperature, followed by addition to _{NH 3 H 2 O (10mL)} . The reaction mixture was stirred for a further 2 hours and then concentrated. The residue was purified by EtOAc EtOAc EtOAc. _{^{1 H NMR (300MHz, CD 3}} OD): δ 8.09-6.65 (m, 8H), 4.02-3.48 (m, 2H), 2.88-2.78 (m, 2H), 2.09-1.91 (m, 2H); HPLC = 100 (214nm)%, 100 ( 254nm)%, t R = 6.26 min. LC-MS: m/z = 445.1 [M+H] ⁺ .

Example 5: Synthesis of 3-(1-(2-chloro-6-fluorobenzylidenyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4-methoxybenzimidamide

Borate 4-A (0.15 g, 0.36 mmol), 3-bromo-4-methoxybenzamide (0.091 g, 0.4 mmol), Pd(dppf)Cl ₂ (at P.sub. 0.029g, 0.036mmol) and _{K 2 CO 3 (0.335g, 4.1mmol} ) in 10mL DMF in the mixture was heated overnight. H ₂ O (20 mL) was added and the mixture was extracted with EtOAc EtOAc. The combined extracts were washed with brine (20mL), dried over anhydrous Na ₂ SO ₄ dried and concentrated. The residue was purified by EtOAcqqqqqq _{^{1 H NMR (300MHz, d 6}} -DMSO): δ 8.25-6.75 (m, 9H), 6.68-6.50 (m, 1H), 4.09-3.67 (m, 3H), 3.58-3.48 (m, 2H), 2.92 -2.73 (m, 2H), 2.06-1.92 (m, 2H). HPLC = 98.6% (214nm), 99.7 (254nm)%, t R = 4.12 min. LC-MS: m/z =439.0 [M+H] ⁺ .

Example 6: Synthesis of 3-(1-(2-chloro-6-fluorobenzylidenyl)-1,2,3,4-tetrahydroquinolin-6-yl)-4- Methyl benzamide

Follow the procedure of Example 5, by using 6-A (150mg) Alternatively bromo - benzoyl-amine 5-A, was obtained as a colorless solid of the title compound (40mg, 26%). ¹ H NMR (300 MHz, CD ₃ OD): δ 8.37-6.46 (m, 9H), 4.11-3.57 (m, 2H), 2.99-2.88 (m, 2H), 2.39-2.03 (m, 5H). HPLC = 99.8% (214nm), 99.8 (254nm)%, t R = 4.19 min. LC-MS: m/z =423.0 [M+H] ⁺ .

Example 7: Synthesis of 4-chloro-5-(1-(2-chloro-6-fluorobenzhydryl)-1,2,3,4-tetrahydroquinolin-6-yl)-2-fluorobenzoate Guanamine

Follow the procedure of Example 5, by using 7-A (130mg) Alternatively bromo - benzoyl-amine 5-A, was obtained as a colorless solid of the title compound (13mg, 10%). _{^{1 H NMR (300MHz, CD 3}} OD): δ 8.18-6.65 (m, 8H), 4.09-3.58 (m, 2H), 2.98-2.89 (m, 2H), 2.30-2.02 (m, 2H). HPLC = 100% (214nm), 100 (254nm)%, t R = 6.98 min. LC-MS: m/z = 461.1 [M+H] ⁺ .

Example 8: Synthesis of 4-chloro-3-(1-(2-chloro-6-fluorobenzhydryl)-1,2,3,4-tetrahydroquinolin-6-yl)benzamide

Step 1. NaNO ₂ (0.16 g) was added dropwise to a stirred mixture of amine 8-A (0.44 g, 1.59 mmol) and H ₂ SO ₄ (0.78 g, 7.96 mmol) in 20 mL of H ₂ O. , 2.34mmol) in 5mL H ₂ O solution in the. A solution of KI (0.8 g, 4.82 mmol) in H.sub.2 (5 mL) was added dropwise. The suspension was filtered and the filter cake was dissolved in EtOAc (20 mL). The organic solution was washed with brine (10mL), dried over anhydrous Na ₂ SO _4, and then concentrated. The residue was purified by column chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc _{^{1 H NMR (300MHz, CDCl 3}} ): δ 7.62-7.26 (m, 2H), 7.04-6.99 (m, 1H), 3.76-3.69 (m, 2H), 1.77-1.70 (m, 2H), 1.53-1.52 (m, 9H), 1.29 (d, J = 7.5 Hz, 6H).

Step 2. To a stirred solution of iodine intermediate 8-B (0.16 g, 0.41 mmol) in EtOAc (EtOAc) The progress of the reaction was monitored by TLC. Once the reaction is completed, i.e., by mixture was quenched with saturated aqueous NaHCO _3, and extracted with EtOAc (20mL × 3). The combined organic extracts were concentrated; the residue was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj . The mixture was stirred at room temperature for 2 hours, then diluted with EtOAc (20mL), washed with H ₂ O (10mL), brine (10 mL), dried over anhydrous Na ₂ SO _4. The solvent was removed to give the decylamine 8-C (0.15 g, 82%). _{^{1 H NMR (300MHz, CD 3}} OD): δ 7.99-6.33 (m, 6H), 4.18-3.53 (m, 2H), 1.96-1.82 (m, 2H), 1.38-1.31 (m, 6H).

Step 3. Following a procedure similar to that in Step 2 of Example 1, using Pd(dppf)Cl ₂ (56 mg, 0.07 mmol), 5-amine-methylmethyl-2-chlorophenylboronic acid 8-D (68 mg, 0.34 mmol) _{na 2 CO 3 (73mg, 0.68mmol} ) in 10mL of dioxane and 2mL H ₂ O in the iodine Amides intermediate 8-C (150mg, 0.34mmol) converted to the title compound (50mg, 31%, colorless solid). _{^{1 H NMR (300MHz, CD 3}} OD): δ 8.13-6.66 (m, 9H), 4.24-3.60 (m, 2H), 2.03-1.92 (m, 2H), 1.43-1.39 (m, 6H); HPLC = 100 (214nm)%, 100 ( 254nm)%, t R = 3.44 min. LC-MS: m/z = 471.1 [M+H] ⁺ .

Example 9: Synthesis of 4-chloro-3-(1-(2-chloro-6-fluorobenzylidenyl)-4,4-difluoro-1,2,3,4-tetrahydroquinolin-6-yl Benzoguanamine

Follow the procedure of Preparative Example 8, by using 1-Boc-4,4- difluoro-amino tetrahydroquinoline 9-A, was obtained as a colorless solid of the title compound. ¹ H NMR (300 MHz, CD ₃ OD): δ 8.41-6.76 (m, 9H), 4.35 (t, J = 5.9 Hz, 1H), 3.84 (t, J = 5.9 Hz, 1H), 2.75-2.51 (m) , 2H). HPLC = 100% (214nm), 100 (254nm)%, t R = 4.55 min. LC-MS: m/z = 479.1 [M+H] ⁺ .

Example 10: Synthesis of 4-chloro-3-(4-(2-chloro-6-fluorobenzhydryl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7 -yl)benzamide

Following the procedure described in Preparative Example 1, by using 7-bromo-3,4-dihydro- 2H -benzo[ b ][1,4]oxazine 10-A , the title was obtained as a colorless solid. Compound. _{^{1 H NMR (300MHz, CD 3}} OD): δ 8.43-7.74 (m, 3H), 7.65-7.36 (m, 3H), 7.32-7.22 (m, 1H), 7.17-7.01 (m, 2H), 6.66- 6.51 (m, 1H), 4.61-4.09 (m, 3H), 3.79-3.67 (m, 1H). HPLC = 100% (214nm), 100 (254nm)%, t R = 6.62 min. LC-MS: m/z = 445.0 [M+H] ⁺ .

Example 11: Synthesis of 4-chloro-3-(1-(2-chloro-6-fluorobenzylidenyl)porphyrin-5-yl)benzamide

Following the procedure described in Preparation Example 1, the title compound was obtained as a colorless solid, using 5-bromo-carboline 11-A . ¹ H NMR (300 MHz, CD ₃ OD): δ 8.29 - 5.88 (m, 9H), 4.35 - 3.87 (m, 2H), 3.26 - 2.31 (m, 2H). HPLC = 99.9% (214nm), 99.8 (254nm)%, t R = 7.38 min. LC-MS: m/z =429.1 [M+H] ⁺ .

Example 12: Synthesis of 4-chloro-3-(1-(2,6-difluorobenzylidinyl)porphyrin-5-yl)benzamide

Following the procedure described in Preparative Example 1, by using 5-bromo-porphyrin 11-A in Step 1 and 2,6-difluorobenzoic acid chloride in Step 2, a colorless solid was obtained. The title compound. ^{1 H NMR (300MHz, DMSO-} d6): δ 8.23 (d, J = 8.3,1H), 8.11 (br, s, 1H), 7.94-7.83 (m, 2H), 7.71-7.59 (m, 2H), 7.50-7.27 (m, 5H), 3.94 (t, J = 8.3, 2H), 3.23 (t, J = 8.3, 2H). LC-MS: m/z = 413.0 [M+H] ⁺ .

Example 13: Synthesis of 4-chloro-3-(1-(2-chloro-6-fluorobenzylidenyl)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzene Formamide

Step 1. (, 17mmol 2.5g) in 30mL CHCl ₃ was stirred in a solution of Br2 was added dropwise a solution of compound 13-A (5.4g, 17mmol) . The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and EtOAc EtOAc m. _{^{1 H NMR (300MHz, CD 3}} OD): δ 7.38 (m, 3H), 3.55-3.49 (m, 2H), 2.97-2.85 (m, 2H), 1.45-1.37 (m, 3H); LC-MS: m/z = 226.1 [M+H] ⁺ .

Step 2. Following the procedure described in Step 1 of Preparative Example 1, the bromo intermediate 13-B (1 g, 3.3 mmol) was converted to the decylamine 13-C (1.2 g, 95) after reaction with acid chloride 1-B. %).

Step 3. Following the procedure described in Preparation Example 3, the title compound (0.03 g, 21%) ). _{^{1 H NMR (300MHz, CD 3}} OD): δ 7.98-6.65 (m, 9H), 4.92-4.00 (m, 1H), 3.20-2.45 (m, 3H), 1.74-1.02 (m, 4H). HPLC = 99.6% (214nm), 99.6 (254nm)%, t R = 4.48 min. LC-MS: m/z = 457.1 [M+H] ⁺ .

Example 14: Synthesis of 4-chloro-3-(1-(2-chloro-6-fluorobenzhydryl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6- Benzomamide

Step 1. The stirred solution was added SOCl ₂ (3.2g, 27.2mmol) solution of 2,2-dimethyl-malonic acid 14-A (3.0g, 22.7mmol) in 40mL THF in. The mixture was heated under reflux for 2 hours and cooled in an ice bath. 4-bromoaniline (7.7 g, 45.4 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure. 50 mL of EtOAc was added and the mixture was extracted with EtOAc EtOAc. The combined aqueous extracts were acidified with EtOAc (EtOAc) The combined organic extracts were washed with EtOAc EtOAc m. ¹ H NMR (300 MHz, CD ₃ OD): δ 7.40 - 7.31 (m, 4H), 1.41 (s, 6H). LC-MS: m/z =286.1 [M+H] ⁺ .

Step 2. Intermediate 14-B (1.0 g, 3.5 mmol) was added to a stirred solution of P2O5 (0.3 g, 2.1 mmol) in 10 mL methanesulfonic acid. The mixture was heated overnight at 70 °C. After cooling to room temperature, the mixture was poured into ice water (50 mL). The organic extract was washed with EtOAc (EtOAc m. _{^{1 H NMR (300MHz, CD 3}} OD): δ 7.83 (d, J = 2.3Hz, 1H), 7.60-7.57 (m, 1H), 6.91 (d, J = 8.6Hz, 1H), 1.33 (s, 6H ). LC-MS: m/z =268.0 [M+H] ⁺ .

Step 3. A mixture of lithium aluminum hydride (0.142 g, 3.74 mmol) and aluminum chloride (0.54 g, 4.14 mmol) in 20 mL THF. A solution of intermediate 14-C (0.5 g, 1.87 mmol) in THF (10 mL) was slowly added to the above mixture over a period of 10 min. The mixture was stirred overnight at room temperature and then heated under reflux for 16 hours. After cooling to room temperature, the mixture was cooled in an ice bath while H ₂ O with carefully quenched. Stirring was continued for 10 minutes. A 1.0 M aqueous NaOH solution (8 mL) was added. The resulting aqueous mixture was extracted with EtOAc (30mL × 3), and the combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated to afford a yellow oil of 4,4-dimethyl-Bromo in vacuo Tetrahydroindole 14-D (0.11 g, 25%). LC-MS: m/z =240.1 [M+H] ⁺ .

Step 4. Following the procedure described in Step 1 of Preparative Example 1, bromo-4,4-dimethyl-tetrahydroindole 14-D (0.11 g, 0.46 mmol) was converted to the indoleamine 14 as a yellow oil. -E (0.2 g).

Step 5. Preparation of Follow the procedure of Example 3, making Amides Intermediate 14-E (0.2 g, 0.5mmol ) and the boronic acid 8-D were reacted to give a colorless solid of the title compound (20mg, 8.5%) . ¹ H NMR (300 MHz, CD ₃ OD): δ 8.34-6.69 (m, 9H), 4. 2-3.51 (m, 1H), 2.78-2.74 (m, 2H), 1.29-1.02 (m, 7H). HPLC = 99.6% (214nm), 99.2 (254nm)%, t R = 7.70 min. LC-MS: m/z = 471.1 [M+H] ⁺ .

Example 15: Synthesis of 4-chloro-3-(1-(2-chloro-6-fluorobenzhydryl)-2,3,4,5tetrahydro-1H-benzo[b]azepine-7-yl Benzoguanamine

Step 1. benzoate 15-A (5.0g, 30.27mmol) and triethylamine (4.59g, 45.41mmol) was added to 2-amino-4-chloro-in the solution of CH ₂ Cl ₂ 100mL 4- Ethyl acetobutanoate (5.48 g, 33.29 mmol). The mixture was stirred overnight at room temperature. Water (120 mL) was added. The aqueous mixture was extracted with CH ₂ Cl ₂ (100 mL×2). The combined organic extracts were dried over anhydrous Na ₂ SO _4, and concentrated to afford the intermediate as a yellow solid matter of 15-B (9.2g, 77% ) in vacuo. _{^{1 H NMR (300MHz, CDCl 3}} ): δ 11.19 (s, 1H), 8.85-8.55 (m, 1H), 8.04 (dd, J = 8.0,1.7Hz, 1H), 7.65-7.43 (m, 1H), 7.19-6.96 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.20-4.13 (m, 2H), 2.79-2.75 (m, 4H), 1.43 (t, J = 7.1 Hz, 3H) , 1.33-1.17 (m, 3H). LC-MS: m/z =294.2 [M+H] ⁺ .

Step 2. Intermediate 15-B (1.0 g, 3.4 mmol) and sodium acetate (0.42 g, 5.08 mmol) were dissolved in 20 mL of acetic acid. Bromine (2.0 g, 12.7 mmol) was added dropwise. The mixture was stirred overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (PE/EA = 10:/1, v/v) %). _{^{1 H NMR (300MHz, CDCl 3}} ): δ 11.11 (s, 1H), 8.62 (d, J = 9.0Hz, 1H), 8.14 (d, J = 2.3Hz, 1H), 7.60 (d, J = 9.0Hz , 1H), 4.39 (q, J = 7.2 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 2.75 (s, 4H), 1.43 (t, J = 7.1 Hz, 3H), 1.26 (t , J = 7.1 Hz, 3H). LC-MS: m / z = 372.0 [M + H] +.

Step 3. To a stirred solution of bromide 15-C (0.22 g, 9.18 mmol) in 30 mL EtOAc. The mixture was heated at 70 ° C for 2 hours, then cooled to room temperature and filtered. The solid collected by filtration was the desired intermediate 15-D (0.5 g, 57%). LC-MS: m/z =325.9 [M+H] ⁺ .

Step 4. Add 1 drop of water to a solution of intermediate 15-D (1.0 g, 3.1 mmol) in 10 mL DMF. The mixture was heated at 130 ° C for 10 minutes under microwave conditions. The solvent was removed under reduced pressure and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LC-MS: m/z =254.0 [M+H] ⁺ .

Step 5. A solution of the ketolide intermediate amide intermediate 15-E (0.6 g, 2.37 mmol) in 5 mL THF was added dropwise at room temperature to lithium aluminum hydride (0.5 g, 13.0 mmol) and aluminum chloride (2.1) g, 15.5 mmol) in a stirred mixture of 25 mL THF. The resulting mixture was heated at 65 ° C for 5 hours. After cooling, the precipitate was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj LC-MS: m/z =226.0 [M+H] ⁺ .

Step 6. Following the procedure described in Step 1 of Preparative Example 1, bromo-benzodiazepine 15-F (0.25 g) was converted to the decylamine 15-G (0.3 g, 71.4%). LC-MS: m/z = 382.0 [M+H] ⁺ .

The title compound (10 mg, 8.4%) was obtained from the title compound (10 mg, 8.4%). _{^{1 H NMR (300MHz, CD 3}} OD): δ 8.26-6.86 (m, 9H), 3.32-2.76 (m, 4H), 2.23-1.39 (m, 4H); HPLC = 100 (214nm)%, 100% ( 254 nm), t _R = 4.56 min. LC-MS: m/z = 457.1 [M+H] ⁺ .

Example 16: Synthesis of 4-chloro-3-(1-(2-chloro-6-fluorobenzylidenyl)-4-methyl-1,2,3,4, tetrahydroquinoxaline-6-yl) Benzylamine

Step 1. A solution of 4-bromo-2-fluoro-1-nitrobenzene 16-A (5.5 g, 25 mmol) in EtOAc (37.5 mL, 2M). The mixture was stirred at room temperature for 10 minutes, treated with saturated aqueous NH ₄ Cl (10 mL) and quenched. The aqueous mixture was extracted with EtOAc (30mL × 3), and the combined organic extracts were washed with brine (20mL), dried over anhydrous Na ₂ SO _4, concentrated to provide a yellow oil of the intermediate composition 16-B (5.6g, 97 %). LC-MS: m / z = 231.0 [M + H] +.

Step 2. To a 16-B (5.5g, 23.9mmol) in 50mL of dry THF was added K ₂ CO ₃ solution was stirred (6.6g, 47.8mmol) and 2-chloro-acetyl chloride (4.05g, 35.9mmol). The mixture was heated at 80 ° C for 2 hours. The mixture was diluted after cooling with EtOAc (50mL), washed with H ₂ O (20mL), brine (20 mL), dried over anhydrous Na ₂ SO _4, and concentrated to provide a yellow solid of Amides 16-C (7.3 g, 99%). LC-MS: m/z = 307.0 [M+H] ⁺ .

Step 3. A mixture of the decylamine 16-C (0.4 g, 1.30 mmol) in 10 mL of a 1.0 MB ₂ H ₆ /THF solution was stirred at room temperature for 48 hours. The reaction was quenched with 10 mL of methanol. The solvent was removed to afford the title compound 16-D (0.35 g, 92%). LC-MS: m/z =292.9 [M+H] ⁺ .

Step 4. Fe (0.33 g, 5.97 mmol) was added to a stirred mixture of intermediate 16-D (0.35 g, 5.97 mmol) in 10 mL ofEtOAc. The mixture was stirred at room temperature for 2 hours, basified with saturated aqueous NaHCO ₃ to pH 8, and then extracted with EtOAc (20mL × 3). The combined organic extracts were washed with brine (20mL), dried over anhydrous Na ₂ SO _4, and concentrated to give a yellow oil as a reduced product of 16-E (0.22g, 70% ) in vacuo.

Step 5. Heating a mixture of aniline 16-E (0.22 g, 0.84 mmol), K ₂ CO ₃ (0.35 g, 2.51 mmol) and KI (0.28 g, 1.67 mmol) in 10 mL of DMF with stirring at 80 ° C hour. The mixture was diluted with EtOAc (50mL), washed with _{H 2 O (20mL × 3)} , brine (20mL), and then dried over anhydrous Na ₂ SO _4. The solvent was removed to give the tetrahydroquinoxaline 16-F (0.19 g, 100%) as a yellow solid. LC-MS: m / z = 263.1 [M + H] +.

Step 6. Following the procedure described in Step 1 of Preparative Example 1, bromo-tetrahydroquinoxaline 16-F (0.19 g, 0.84 mmol) was converted to the decylamine 16-G (0.28 g, 88%). LC-MS: m/z = 383.0 [M+H] ⁺ .

Step 7. Following the procedure described in Step 2 of Preparative Example 1, bromo-tetrahydroquinoxaline decylamine 16-G (0.28 g) and 5-amine-mercapto-2-chlorophenylboronic acid 8-D The title compound (0.060 g, 18%) eluted. _{^{1 H NMR (300MHz, CD 3}} OD): δ 7.89-6.17 (m, 9H), 4.13-3.92 (m, 2H), 3.60-3.34 (m, 2H), 2.93 (s, 2H), 2.89 (s, 1H). HPLC = 98.7% (214nm), 99.1 (254nm)%, t R = 6.41 min. LC-MS: m/z =458.1 [M+H] ⁺ .

Example 17: Synthesis of 4-chloro-3-(1-(4-chlorobenzylidenyl)-1,2,3,4-tetrahydroquinolin-6-yl)benzamide

Step 1. To bromo - Add tetrahydroquinoline 1-A (5g, 23.7mmol) in 60mL THF was stirred in a solution of NaOH (1g, 25mmol) in a solution of (30mL) in H ₂ O. Di-tert-butyl dicarbonate (5.37 g, 25 mmol) was added. The mixture was stirred at room temperature for 12 hours. The solvent was removed in vacuo and aqueous mixture was extracted with EtOAc EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na ₂ SO _4, concentrated and purified by column chromatography to provide the compound with boc protection was a colorless solid was of 17-A (3g, 40.7% ). ^{1 H NMR (300MHz, CDCl3)} : δ 7.56-7.53 (m, 1H), 7.24-7.19 (m, 2H), 3.70-3.66 (m, 2H), 2.75-2.71 (m, 2H), 1.92-1.88 ( m, 2H), 1.52 (s, 9H).

Step 2. Add 5-Aminoformamido-2-chlorophenylboronic acid 8-D (0.7 g, 3.5 mmol) to 17-A (1.0 g, 3.2 mmol), Pd (dppf) Cl ₂ (0.26 g, 0.32) mmol) and K ₂ CO ₃ in the (0.88g, 6.4mmol) in DMF (40mL) was stirred mixture. The mixture was heated overnight at 100 °C. The solvent was removed under reduced pressure and the residue was purified mjjjjjjjjjjj _{^{1 H NMR (300MHz, CD 3}} OD): δ 7.87-7.21 (m, 6H), 3.91-3.51 (m, 2H), 2.84 (dd, J = 10.8,4.3Hz, 2H), 2.00-1.81 (m, 2H), 1.55 (s, 9H).

Step 3. Add intermediate 17-B (0.76 g, 19.1 mmol) synthesized from Step 2 above to 10 mL of 4N HCl in dioxane. The mixture was stirred at room temperature for 3 hr. ^{1 H NMR (300MHz, CD3OD)} : δ 7.92-7.37 (m, 6H), 3.62-3.56 (m, 2H), 3.04 (t, J = 6.2Hz, 2H), 2.34-2.09 (m, 2H). LC-MS: m/z =287.1 [M+H]+

Step 4. Following the procedure described in Step 1 of Preparative Example 1, intermediate 17-C (100 mg, 0.31 mmol) was reacted with 4-chlorobenzhydrin chloride (108.5 mg, 0.62 mmol) to give a colorless solid. The title product (20 mg, 15.2%). ¹ H NMR (300 MHz, CD ₃ OD): δ 7.85 - 6.83 (m, 10H), 3.94 - 3.89 (m, 2H), 2.96 - 2.92 (m, 2H), 2.14 - 2.03 (m, 2H). HPLC = 100% (214nm), 100 (254nm)%, t R = 6.94 min. LC-MS: m/z =427.0 [M+H] ⁺ .

Examples 18 to 31, 101. The following compounds of the invention listed in the Table were prepared following the procedure described in Example 1, Step 1, in which intermediate 17-C (available from Preparative Example 17) and suitable acid chloride were prepared. Compound reaction.

Example 32: Synthesis of 4-chloro-3-(1-(2-chloro-6-fluorobenzylidenyl)-1,2,3,4-tetrahydroquinolin-6-yl)-N-methylbenzene Formamide.

Step 1: Compound 1-C (1 g, 2.72 mmol) and 3-bromo-4-chlorobenzoic acid (2-C, 0.6 g, 3 mmol) obtained from Example 1 in 20 mL, Pd(dppf)Cl ₂ (0.4 g, 0.54 mmol) and sodium carbonate (0.57 g, 5.4 mmol) were sequentially added to a stirred mixture of dioxane and 5 mL of H ₂ O. The mixture was heated at 80 ° C for 16 hours. The 1,4-dioxane was removed in vacuo and aq. EtOAc (EtOAc) The organic extract was dried over anhydrous Na ₂ SO _4, concentrated and purified by column chromatography by using MeOH-CH ₂ Cl _2: fractions to provide a colorless solid of the acid 32-A (1 10, v / v) (0.5g, 41%). LC-MS m/z = 444.0 [M+H] ⁺ .

Step 2: Add methylamine hydrochloride (0.023 g, 0.34 mmol), HBTU (0.2 g, 0.53 mmol) to a solution of the acid 32-A (0.12 g, 0.27 mmol) from the above Step 1 in 5 mL DMF. And diisopropylethylamine (DIPEA, 0.1 g, 0.77 mmol). The mixture was stirred at room temperature for 4 hours and then concentrated in vacuo to remove most of the DMF solvent. The residue was diluted with 10 mL EtOAc and 10 mL H ₂ O and the phases were separated. The organic phase was washed with saturated _{NH 4 Cl (10mL × 1)} , saturated NaHCO ₃ (10mL), washed with brine (10mL), and dried over anhydrous Na ₂ SO _4. The solvent was removed and purified by EtOAc EtOAcjjjjjj ¹ H NMR (300 MHz, CD ₃ OD) δ : 8.05-6.60 (m, 9H), 3.95 - 4.45 (m, 2H), 2.83-2.77 (m, 5H), 2.07-1.918 (m, 2H). HPLC = 99.5% (214nm), 100 (254nm)%, t R = 4.53 min. LC-MS m/z = 457.0 [M+H] ⁺ .

Examples 33 to 71 and 100: Following the procedure described in Example 32, Step 2, or a slightly modified alternative procedure (Method B), the compounds of the invention listed in Table 7 were prepared by using the appropriate R ^1a R ^1b NH.

The general ester hydrolysis conditions of Examples 60, 61 and 62 in Table 5. For Examples 60, 61 and 62 where another acid hydrolysis step was required to produce the target compound, the following procedure was used: the corresponding ester precursor (1 molar equivalent) and 2N LiOH aqueous solution (2 molar equivalents) were stirred at room temperature. The mixture was stirred in THF (20 mL) EtOAc (EtOAc) The aqueous mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na ₂ SO _4, and concentrated in vacuo to give a crude material which was purified by preparative TLC to afford by Examples 60, 61 and 62.

Example 63: Synthesis of 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzimidamide)-[1,1'-biphenyl]-3-carboxamide

Step 1. To a stirred solution of 4-bromophenylmethylamine 63-A (0.098 mL, 0.78 mmol) in 5 mL CH ₂ Cl ₂ , triethylamine (0.217 mL, 1.55 mmol) and 2-chloro-6 -Fluoro-benzylidene chloride 1-B (0.116 mL, 0.881 mmol). The reaction mixture was stirred overnight at room temperature. Mixture was diluted with ethyl acetate, and then washed with saturated aqueous NaHCO _3, washed with H ₂ O and brine. Na ₂ SO ₄ organic layers were dried over anhydrous. The solvent was removed in vacuo <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI> LC-MS: m/z = 341.9 [M+H] ⁺ .

Step 2. Dissolve the indoleamine intermediate 63-B (270 mg, 0.7881 mmol) obtained in the above step 1 in a mixture of 1,4-dioxane (4 mL) and 2M aqueous Na ₂ CO ₃ (1 mL). in. Boric acid 8-D (143 mg, 0.717 mmol), Pd(dppf) ₂ Cl ₂ -CH ₂ Cl ₂ complex (70.2 mg, 0.086 mmol) was added to the above mixture. The reaction mixture was heated at 80 ° C for 30 minutes under microwave conditions. The mixture was diluted with EtOAc, washed subsequently with saturated aqueous NaHCO _3, H ₂ O and brine. The organic layer was dried over anhydrous Na ₂ SO _4, and concentrated to an oil in vacuo and the residue, which was purified by preparative HPLC to give a colorless solid of the title product of Example 63 (130.8mg, 44%). _{^{1 H NMR (300MHz, CD 3}} OD): δ7.83 (dd, J = 2.27,8.31Hz, 1H), 7.78 (d, J = 2.27Hz, 1H), 7.55-7.60 (m, 1H), 7.37- 7.42 (m, 3H), 7.24-7.34 (m, 1H), 7.15 (d, J = 8.31 Hz, 1H), 6.93-7.04 (m, 1H), 3.53-3.57 (m, 3H). LC-MS: m/z = 417.0 [M+H] ⁺ .

Examples 64 to 81. The following compounds of the invention listed in Table 8 were prepared following the procedures described in Example 63 by replacing the 63-A with an appropriately substituted aniline I or pyridylamine II. Several examples were prepared by further changing the acid chloride from 1-B to III.

Example 82: Synthesis of 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzimidamide)-[1,1'-biphenyl]-3-carboxamide

Step 1. successively added a solution of 2-amino-5- pyridin-bromophenol 82-A (400mg, 2.13mmol) was stirred in 14mL of the solution in CH ₂ Cl ₂ (0.189mL, 2.34mmol) and 2-chloro-6- Fluorine-benzylguanidinium chloride 1-B (0.309 mL, 2.34 mmol). The mixture was stirred at room temperature for 48 hours and diluted with EtOAc. The organic solution was washed with saturated aqueous NaHCO _3, H ₂ O and brine. Na ₂ SO ₄ organic layers were dried over anhydrous and concentrated to obtain an oily residue in vacuo. The crude product was purified by EtOAc EtOAc EtOAc EtOAc LC-MS: m/z = 343.8 [M+H] ⁺ .

Step 2. Compound 82-B (100 mg, 0.29 mmol) from Step 1 above was dissolved in DMF (2 mL). Potassium carbonate (60.2 mg, 0.435 mmol) and ethyl iodide (0.232 mL, 0.29 mmol) were added. The mixture was stirred overnight at room temperature. Add ethyl acetate. The organic solution was washed with saturated aqueous NaHCO _3, H ₂ O and brine. Na ₂ SO ₄ organic layers were dried over anhydrous and concentrated to obtain an oily residue in vacuo. The crude product was purified by EtOAc EtOAc EtOAc EtOAc EtOAc LC-MS: m/z =371.8 [M+H] ⁺ .

Step 3. To a solution of the second decylamine 82-C (96.4 mg, 0.26 mmol) in 1.78 mL of DMF was added sodium hydride (60% dispersion in mineral oil, 10.4 mg, 0.259 mmol). The mixture was stirred for 30 minutes and then iodomethane (0.032 mL, 0.517 mmol) was added dropwise. The reaction was continued overnight at room temperature. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO _3, H ₂ O and brine. Na ₂ SO ₄ organic layers were dried over anhydrous and concentrated to obtain an oily residue in vacuo. The crude product was purified by EtOAc EtOAc EtOAc (EtOAc) LC-MS: m/z = 385.8 [M+H] ⁺ .

Step 4. Following the procedure described in Step 2 of Preparative Example 63, the bromo-phenyl decylamine intermediate 82-D (100 mg, 0.259 mmol) from the above step 3 and boronic acid 8-D (57 mg, 0.2844 mmol). Reaction to give the title product Example 82 (68.7 mg, 58%). ^{1 H NMR (400MHz, DMSO-} d6): δ 8.04-8.17 (m, 1H), 7.01-8.00 (m, 9H), 6.85 (t, J = 6.27Hz, 1H), 3.94-4.25 (m, 2H) , 3.03-3.37 (m, 3H), 1.30-1.44 (m, 3H). LC-MS: m/z = 460.9 [M+H] ⁺ .

Examples 83 to 88. The compound is listed below in Table 9 in the present invention follows the procedure of Example 80 Step 2-4, to initiate the intermediate 82-B, be prepared by reaction with R ⁴ X more.

Example 89: Synthesis of N-(5-(5-aminomethylmethyl-2-chlorophenyl)-3-ethoxypyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzoate Guanamine

Step 1. To a stirred solution of 2-nitro-3-hydroxypyridine 89-A (5.0 g, 35.7 mmol) in 50 mL of DMF was added K ₂ CO ₃ (9.9 g, 71.4 mmol) and ethyl iodide (6.7). g, 42.8 mmol). The mixture was heated at 50 °C for 16 hours and diluted with 100 mL of EtOAC. The organic layer was washed with EtOAc (EtOAc m. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.07-8.06 (m, 1H), 7.54-7.49 (m, 2H), 4.21 (q, J = 6.8Hz, 2H), 1.47 (t, J = 6.8Hz, 3H). LC-MS: m/z = 169.1 [M+H] ⁺ .

Step 2. The nitro intermediate 89-B (6.0 g, 35.7 mmol) prepared in the above step 1 was dissolved in a mixture of 50 mL of EtOH and 2 mL of acetic acid. Fe powder (10.0 g, 178.5 mmol) and NH ₄ Cl (9.5 g, 178.5 mmol) were added. The resulting mixture was heated at 80 ° C for 1 hour with stirring. The mixture was filtered and the filtrate was concentrated in vacuo to give a crystallite. The organic solution was washed with H ₂ O (100mL × _2), dried and concentrated in vacuo to provide a yellow oil aminopyridine of 89-C (3.2g, 65% ). ^{1 H NMR (400MHz, CDCl3)} δ: 7.65 (d, J = 4.8Hz, 1H), 6.88 (d, J = 7.6Hz, 1H), 6.59 (dd, J = 4.8Hz, 7.6Hz, 1H), 4.68 (br s, 2H), 4.04 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H). LC-MS: m/z = 139.1 [M+H] ⁺ .

Step 3. To a stirred solution of the aminopyridine 89-C (3.2 g, 23.2 mmol) in 20 mL of EtOAc over EtOAc (EtOAc) The resulting mixture was stirred for 16 hours and concentrated under reduced pressure to give a residue. The crude product was washed with saturated aqueous NaHCO ₃ solution and extracted with EtOAc (30mL × 3) a mixture of an aqueous solution. The combined organic extracts were washed with brine (60 mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated to provide a yellow oil of the intermediate-bromo-89-D (3.6g, 72% ) in vacuum, which was used without Purification was used in the next step. LC-MS: m/z =21.7.1 [M+H] ⁺ .

Step 4. To a stirred solution of the bromine intermediate 89-D (0.6 g, 2.8 mmol) in 10 mL EtOAc EtOAc EtOAc. The reaction mixture was stirred at room temperature for 16 hours and concentrated. The residue was taken up in 20 mL EtOAc EtOAc. The residue was purified by reverse phase preparative _{HPLC (MeCN / H 2 O =} 5% to 95%) to give a yellow oil Amides of compound 89-E (0.27g, 26% ). LC-MS: m/z =373.1 [M+H] ⁺ .

Step 5. Sodium hydride (0.060 g, 1.46 mmol) and methyl iodide (0.125) were sequentially added to a solution of the decylamine 89-E (0.27 g, 0.73 mmol) in 3 mL of DMF. g, 0.88 mmol). The mixture was stirred at 0 ℃ 1 hour, followed directly by reverse-phase preparative _{HPLC (MeCN / H 2 O =} 5% to 95%) to give a colorless solid of Intermediate 89-F (0.25g, 89% ). ¹ H NMR (400 MHz, CDCl ₃ ): a mixture of constitutive isomers, δ 8.20 (s, 0.2 H), 7.84 (s, 0.8H), 7.24-7.22 (m, 1H), 7.14-7.08 (m, 1H), 6.99-6.97 (m, 1H), 6.84-6.29 (m, 1H), 4.11 (q, J = 6.8 Hz, 0.4H), 4.02 (q, J = 6.8 Hz, 1.6H), 3.45 (s) , 2.4H), 3.22 (s, 0.6 H), 1.46 (t, J = 6.8 Hz, 3H). LC-MS: m/z =378.2 [M+H] ⁺ .

Step 6. Heating the guanamine intermediate 89-F (0.25 g, 0.65 mmol), 3-bromo-4-chlorobenzoic acid (0.156 g, 0.78 mmol), Cs ₂ CO under a nitrogen atmosphere at 100 ° C under stirring. A mixture of ₃ (0.422 g, 1.3 mmol) and Pd (dppf) Cl ₂ (0.050 g, 0.06 mmol) in DMF-H ₂ O (2 mL, 3/1, v/v). The mixture was diluted with 3 mL MeOH and filtered. The filtrate by reverse phase preparative _{HPLC (MeCN / H 2 O =} 5% to 95%) to afford 89-G (0.12g, 40% ) acid intermediate. LC-MS: m/z = 463.1 [M+H] ⁺ .

Step 7. (, 0.26mmol 0.12g) in 2mL THF are added to a stirred solution of the acid _{89-G NH 4 Cl (0.070g} , 1.3mmol), HATU (0.198mg, 0.52mmol) and Et ₃ N (0.13g , 1.3 mmol). The resulting mixture was heated at <RTI ID=0.0></RTI></RTI><RTIgt_;</RTI><RTIgt_;</RTI><RTIgt_;</RTI><RTIgt_;</RTI><RTIgt_;</RTI><RTIgt_; ¹ H NMR (400 MHz, CDCl ₃ ): mixture of constitutive isomers, δ: 8.21-7.82 (m, 3H), 7.72-7.45 (m, 2.6H), 7.28-7.23 (m, 1.0H), 7.09 -6.94 (m, 1.4H), 4.25 (q, J = 6.8 Hz, 0.6H), 4.15 (q, J = 6.8 Hz, 1.4H), 3.49 (s, 2.1H), 3.28 (s, 0.9 H) , 1.47 (t, J = 6.8 Hz, 3H). LC-MS: m/z = 4621. [M+H] ⁺ .

Example 90: Synthesis of N-(5-(5-aminocarbamimido-2-chlorophenyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)-2-chloro- 6-fluoro-N-methylbenzamide

Step 1. Preparation of Example 89 following the similar procedure of the step 1, 3-trifluoromethyl-ethoxy-2-nitro and 89-A was prepared from CF ₃ CH ₂ OTf - pyridin-90-A (1.8g, 90 %). ¹ H NMR (400 MHz, CDCl 3 ) δ: 8.26 (dd, J = 2.0 Hz, 3.6 Hz, 1H), 7.62-7.60 (m, 2H), 4.53 (q, J = 8.0 Hz, 2H). LC-MS: m/z =223.0 [M+H] ⁺ .

Steps 2 to 7. Following the procedure described in Steps 2 to 7 of Preparation Example 89, Compound 90-A from Step 1 above was converted to the title product Example 90 as a pale yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): a mixture of constitutive isomers, δ 8.36 (d, J = 2.0 Hz, 0.3H), 8.02-7.83 (m, 3H), 7.72-7.51 (m, 2H) , 7.45-6.94 (m, 2.7H), 4.78-4.73 (m, 2H), 3.50 (s, 2.1 H), 3.30 (s, 0.9H). LC-MS: m/z = 516.2 [M+H] ⁺ .

Example 91: Synthesis of N-(5-(5-aminocarbamimido-2-chlorophenyl)-3-(cyclopropylmethoxy)pyridin-2-yl)-2-chloro-6-fluoro-N -methylbenzamide

Step 1. Following the procedure similar to that described in Step 1 of Preparative Example 89, 3-cyclopropylmethoxy-2-nitro-pyridine 91-A was prepared from 89-A and cyclopropylmethyl bromide.

Steps 2 to 7. Following the procedure described in Steps 2 to 7 of Preparation Example 89, Compound 91-A from Step 1 above was converted to the title product as a colorless solid. ¹ H NMR (400 MHz, CD ₃ OD): a mixture of constitutive isomers, δ 8.21-7.81 (m, 3H), 7.70-7.43 (m, 2.5H), 7.32-6.95 (m, 2.5H), 4.04 -3.94(m,2H), 3.52(s,2.2H), 3.29(s,0.8H),1.36-1.29(m,1H),0.69-0.63(m,2H),0.43-0.40(m,2H) . LC-MS: m/z = 448.1 [M+H] ⁺ .

Example 92: Synthesis of 6-chloro-4'-((2-chloro-6-fluoro-N-methylbenzylidinium)methyl)-3'-methyl-[1,1'-biphenyl] 3-methylamine

Step 1. To a solution of (4-bromo-2-methylphenyl)methanamine hydrochloride 92-A (160 mg, 0.68 mmol) and triethylamine (207 mg, 2.04 mmol) in 10 mL CH ₂ Cl ₂ Acid chloride 1-B (170 mg, 0.88 mmol) was added to the stirred mixture. The reaction was continued for 2 hours and the mixture was concentrated. The residue was purified by preparative EtOAc (EtOAc): _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.35-7.26 (m, 3H), 7.21 (d, J = 8.4Hz, 2H), 7.04 (t, J = 8.4Hz, 1H), 5.88 (br, 1H) , 4.61 (d, J = 5.6 Hz, 2H), 2.37 (s, 3H). LC-MS: m/z =356.0 [M+H] ⁺ .

Step 2. To a solution of the indole intermediate 92-B (115 mg, 0.32 mmol) in 3 mL DMF, EtOAc. Methyl iodide (92 mg, 0.64 mmol) was added. The mixture was stirred for 2 h and directly by reverse-phase preparative _{HPLC (CH 3 CN / H 2} O = 5% to 95%) to give a colorless solid of methyl Amides of 92-C (130mg, 86% ) . ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 7.36-7.35 (m, 1H), 7.34-7.32 (m, 1H), 7.32-7.28 (m, 1H), 7.26-7.23 ( m, 1H), 7.21-7.16 (m, 1H), 7.10-7.02 (m, 1H), 4.78 (AB, 1.5H), 4.33 (s, 0.5H), 3.04 (s, 0.75H), 2.75 (s) , 2.25H), 2.35 (s, 2.25H), 2.16 (s, 0.75H). LC-MS: m/z =370.0 [M+H] ⁺ .

Step 3. The obtained from the above step 2 to Amides 92-C (120mg, 0.32mmol) in 3mL DMF and in the 1mL H ₂ O mixture was added 3-borono-4-chlorobenzoic acid (78 mg, 0.39 mmol), cesium carbonate (212 mg, 0.65 mmol) and Pd(dppf)Cl ₂ (27 mg, 0.03 mmol). The resulting mixture was heated under a N ₂ atmosphere at 100 ° C for 16 hours with stirring. After cooling, the mixture was diluted with MeOH (3 mL) and filtered. The filtrate by reverse phase preparative _{HPLC (CH 3 CN / H 2} O = 5% to 95%) to afford the acid as a yellow solid intermediate 92-D (60mg, crude product). LC-MS: m/z = 446.1 [M+H] ⁺ .

Step 4. NH may be added to the acid from Step 3 above to obtain the 92-D (60mg, 0.14mmol) in a mixture of THF, 1mL of ₄ Cl (37mg, 0.70mmol) and HATU (103mg, 0.28mmol). The mixture was stirred at room temperature for 2 h, diluted with MeOH (2 mL) and filtered. The filtrate by _{(CH 3 CN / H 2 O} = 5% to 95%) was purified by reverse phase preparative HPLC to give the title product as a pale yellow solid (8mg, 13%). ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 7.89-7.81 (m, 2H), 7.60-7.58 (m, 1H), 7.51-7.47 (m, 1H), 7.43-7.31 (m, 3H), 7.28-7.24 (m, 2H), 4.92 (AB, 1.5H), 4.54 (s, 0.5H), 3.12 (s, 0.75H), 2.85 (s, 2.25H), 2.45 (s) , 2.25H), 2.23 (s, 0.75H). LC-MS: m/z = 445.1 [M+H] ⁺ .

Examples 93 to 97. The following compounds of the invention listed in Table 10 were prepared following the procedure described in Step 2 of Example 1, using a Suzuki coupling reaction to couple the bromo intermediate 1-C with a commercially available aryl boronic acid.

Example 98: Synthesis of 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzimidamide)-3'-(cyclopropylmethoxy)-[1,1'-linked Benzene]-3-carboxamide.

See Table 9 above.

Example 99: Synthesis of N-(5-(5-aminocarbamimido-2-chlorophenyl)-3-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)-2 -Chloro-6-fluoro-N-methylbenzamide.

See Table 11 below.

Example 103: Synthesis of 6-chloro-4'-(2-chloro-6-fluoro-N-methylbenzimidino)-3'-(2,2-difluoropropoxy)-[1,1 '-Biphenyl]-3-carbamamine.

Step 1. To 4-bromo-2-fluoro-1-nitro-benzene (208.2 mg, 0.946 mmol) and 2,2-difluoropropan-1-ol (100 mg, 1.041 mmol) in DMF (6 mL, 77.5 mmol To the stirred solution was added cesium carbonate (244 mg, 0.75 mmol). The reaction mixture was stirred at 40 ° C for 48 hours. The mixture was diluted with EtOAc, washed subsequently with saturated aqueous NaHCO _3, H ₂ O and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography using gradient elution (0 to 40%EtOAcEtOAc). The solvent was removed to give 168.3mg of yellow solid was intermediate 103-B (60%). LC-MS: m/z =295.9 [M+H] ⁺ .

Step 2. Raney nickel (1:9, nickel: water, 1.668 g, 2.842 mmol) was added to a stirred solution of 103-B (168.3 mg, 0.5684 mmol) in methanol (16 mL). The reaction mixture was stirred at room temperature for 2 hours, filtered and solvent was evaporated in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous NaHCO _3, H ₂ O and brine. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography eluting with EtOAc EtOAc (0 to 50%). The solvent was removed to give 64.6mg of a yellow oil 103-C (97.7%). LC-MS: m/z =265.9 [M+H] ⁺ .

Step 3. (, 0.367mmol 97.7mg) in CH stirring the ₂ Cl ₂ (2.4mL) was added the acid chloride 1-B (0.065mL, 0.492mmol) and pyridine (0.060 mL to 103-C, 0.742mmol ). The reaction mixture was stirred at room temperature for 48 hours, diluted with EtOAc, washed with saturated aqueous NaHCO _3, H ₂ O and brine. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by column chromatography eluting with EtOAc EtOAc (0 to 50%). The solvent was removed to give a colorless solid 148.5mg of 103-D (96%). LC-MS: m/z =421.8 [M+H] ⁺ .

Step 4. A solution of 10% sodium hydride in mineral oil (14.05 mg, 0.3514 mmol) was added to a solution of 103-D (148.5mg, 0.3514mmol) in DMF (2.4mL). The mixture was preactivated for 30 minutes at room temperature. Methyl iodide (0.044 mL, 0.703 mmol) was added dropwise to the obtained mixture at room temperature. The mixture was stirred overnight, added in EtOAc, washed with saturated aqueous NaHCO ₃ and then, H ₂ O, brine. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product was purified by column chromatography eluting with EtOAc /Heptane (0 to 30%). The solvent was removed to give a colorless oil 172.5mg of 103-E (100%). LC-MS: m/z =435.8 [M+H] ⁺ .

Step 5. Add boric acid 8-D (110.3 mg, 0.5531 mmol), 103-E (172.5 mg, 0.3950 mmol), PdCl ₂ (dppf) ₂ -CH ₂ Cl ₂ (1:1) complex (43 mg) to the microwave vial. , 0.053 mmol) and 2M aqueous Na ₂ CO ₃ (0.5926 mmol, 1.185 mmol). The reaction was carried out at 105 ° C for 35 minutes under microwave conditions (300 watts). The mixture was diluted with EtOAc after cooling, washed with _aqueous NaHCO, H ₂ O and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo tolu The crude product was purified by HPLC to provide a colorless solid of the title product of Example 103 (76.2mg, 38%). ^{1 H NMR (400MHz, DMSO-} d 6) δ 6.77-8.21 (m, 11H), 4.21-4.53 (m, 2H), 3.35 (d, J = 4.52Hz, 2H), 3.11 (s, 1H), 1.70 -1.87 (m, 3H). LC-MS: m/z = 511.1 [M+H] ⁺ . LC-MS: m/z = 511.1

Examples 98 and 115-126. The compound is listed below in Table 11 according to the present invention, the steps followed in the procedure described in Example 80 of 2 to 4, to the starting intermediate 89-A, be prepared by reaction with a variety of R ⁴ X .

Example 127: Synthesis of N- (5-(5-Aminomethylphenyl-2-chlorophenyl)-3-morpholinylpyridin-2-yl)-2-chloro-6-fluoro- N -methylbenzoate Guanamine

Step 1. Add morpholine (520 mg, 6 mmol), chlorine (X-Phos) to a solution of 3,5-dibromo-2-aminopyridine 127-A (1 g, 4 mmol) in 5 mL THF. [2-(2-Aminoethyl)phenyl]-palladium(II) (118 mg, 0.16 mmol) and EtOAc (10 mL, 10 mmol, 1.0M in THF). The mixture was heated under N ₂ at 65 ° C for 16 hours. After cooling to room temperature, 200mL EtOAc, the mixture was washed with brine (100mL × 3), dried over Na2SO4, and concentrated in vacuo to give a black oil which was purified by prep HPLC (MeCN: H ₂ O = Purification to give 127-B (300 mg, 29%) as a yellow solid. ^{1 H NMR (400MHz, DMSO- d} 6) δ: 7.74 (d, J = 2.0Hz, 1H), 7.25 (d, J = 2.0Hz, 1H), 5.89 (br s, 2H), 3.75-3.73 (m , 4H), 2.81-2.79 (m, 4H). LC-MS: m/z =258.0 [M+H] ⁺ .

Step 2. To a solution of 127-B (250 mg, 1 mmol) in 2 mL of EtOAc was added acid chloride 1-B (580mg, 3mmol). The reaction mixture was heated at 90 ° C for 2 hours with stirring and concentrated. The residue was dissolved in EtOAc (20 mL) and brine (EtOAc) The organic layer was concentrated in vacuo to give EtOAc m . LC-MS: m/z =570.1 [M+H] ⁺ .

Step 3. Heat at reflux for 127-C (220mg, crude material) and _{K 2 CO 3 (106mg, 0.8mmol} ) in a mixture of 20mL of methanol for 2 h and then concentrated. The residue was diluted with EtOAc (EtOAc) (EtOAc) The organic layer was dried and concentrated to afford 100mg of a yellow solid Amides 127-D (63%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.66 (br s, 1H), 7.55 (s, 1H), 7.40-7.35 (m, 2H), 7.25-7.24 (m, 1H), 7.11-7.05 (m, 1H), 3.88-3.87 (m, 4H), 2.97-2.95 (m, 4H). LC-MS: m/z = 414.0 [M+H] ⁺ .

Step 4. NaH (19 mg, 60% in mineral oil, 0.48 mmol) was added to a stirred solution of decylamine 127-D (100 mg, 0.24 mmol) in EtOAc. Methyl iodide (70 mg, 0.48 mmol) was added. After 1 hour, the mixture was quenched with saturated aqueous NH ₄ Cl (50mL) and extracted with EtOAc (50mL × 3). The combined organic extracts were washed with brine (100mL), dried over Na ₂ SO ₄ and concentrated to give 100mg Amides three 127-E (100%). LC-MS: m/z = 428.0 [M+H] ⁺ .

Step 5. Heating decyl 127-E (100 mg, 0.23 mmol), PdCl ₂ (dppf) ₂ (10 mg, 0.01 mmol), boric acid 8-D (92 mg, 0.46 mmol) and Na ₂ CO at 90 ° C under N _{2 . 3} (50 mg, 0.46 mmol) was stirred in 2 mL DMF for 16 h. The mixture was filtered and the filtrate was purified by prep _{HPLC (MeCN: H 2 O =} 3: 2) to give a yellow solid, 40mg of the title product of Example 127 (34%). HPLC: 100%. ¹ H NMR (400 MHz, CD ₃ OD) δ : 8.35 (s, 0.5H), 8.05-7.83 (m, 3H), 7.69-7.54 (m, 1.5H), 7.46-7.44 (m, 0.5H), 7.44 (s, 0.5H), 7.40-7.25 (m, 1H), 7.09-7.07 (m, 0.5H), 6.99-6.95 (m, 0.5H), 3.87-3.85 (m, 4H), 3.59 (s, 1.5) H), 3.32-3.31 (m, 1.5H), 2.93-2.87 (m, 4H). LC-MS: m/z = 503.1 [M+H] ⁺ .

Example 128: Synthesis of N- (5-(5-Aminomethylindol-2-chlorophenyl)-3-(propylthio)pyridin-2-yl)-2-chloro-6-fluoro- N -A Benzobenzamide

Step 1. successively added 3-hydroxy-2-nitro-pyridin-89-A (5g, 35.7mmol) in a solution of CH ₂ Cl ₂ 50mL triethylamine (10.7g, 107.1mmol) and trifluoromethanesulfonic anhydride ( 11.9 g, 42.8 mmol). The mixture was stirred at room temperature for 4 hours. The organic layer was washed with brine (100mL × 2) was washed and concentrated to give 6g of a yellow oil triflate Intermediate 128-A (62.5%) in vacuo. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.63 (dd, J = 1.2Hz, 4.4Hz, 1H), 7.97 (dd, J = 1.2Hz, 8.4Hz, 1H), 7.80 (dd, J = 4.8Hz, 8.4 Hz, 1H). LC-MS: m/z =273.0 [M+H] ⁺ .

Step 2. Triethylamine (6.8 g, 66.1 mmol) and propane-1-thiol (2.0 g, 26.4 mmol) were added to a solution of 128-A (6.0 g, 22.0 mmol) in 50 mL THF. The mixture was heated at 60 ° C for 20 hours and then concentrated. The residue was purified by column chromatography eluting with petroleum ether / EtOAc: 2.0g eluting to give the thioether as a yellow solid 128-B (46%) ( 5 1). ¹ H NMR (400 MHz, CDCl ₃ ) δ : 8.34 (dd, J = 1.6 Hz, 4.4 Hz, 1H), 7.78 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.54 (dd, J = 4.8 Hz, 8.4 Hz, 1H), 2.94 (t, J = 7.2 Hz, 2H), 1.80-1.75 (m, 2H), 1.10 (t, J = 7.6 Hz, 3H). LC-MS: m/z =199.0 [M+H] ⁺ .

Step 3. Heating nitrosyl ether 128-B (2.0 g, 10.1 mmol), Fe powder (2.8 g, 50.5 mmol), NH4Cl (2.7 g, 50.5 mmol) and HOAc (1 mL) in 20 mL of methanol at 80 °C. The mixture was stirred for 1 hour. The mixture was filtered, and the filtrate was evaporated mjjjjjjjj The organic solution was washed with water (100 mL x 2). Removal of the solvent gave 1.0 g of the aminopyridine intermediate 128-C (60%) as a yellow oil. LC-MS: m/z = 169.1 [M+H] ⁺ .

Step 4. To a stirred solution of 128-C (1.0 g, 5.9 mmol) in 10 mL of EtOAc over EtOAc (EtOAc) The resulting mixture was stirred at room temperature for 16 hr and concentrated in vacuo. The residue to pH 7 with saturated aqueous NaHCO ₃ solution and brine. The aqueous mixture was extracted with EtOAc (40 mL×3). The organic extracts were washed with brine (60mL), dried over Na ₂ SO _4, filtered and concentrated to give 1.0g of a yellow oil bromo-pyridin-128-D (70%). LC-MS: m/z =247.0 [M+H] ⁺ .

Step 5. Acid chloride 1-B (535 mg, 2.8 mmol) was added to a solution of 128-D (1.0 g, 2.8 mmol) in 4 mL EtOAc. The reaction mixture was stirred at room temperature for 16 hours and concentrated. The residue was dissolved in EtOAc (20 mL) and brine (EtOAc) The organic layer was concentrated in vacuo and the residue was by (MeCN / water = 5 to 95%) was purified by preparative HPLC to give 902mg of a yellow oil 128-E. LC-MS: m/z = 559.0 [M+H] ⁺ .

6. In Step 128-E with stirring under heating at 70 ℃ (902mg, 1.6mmol) and _{K 2 CO 3 (441mg, 2.4mmol} ) in a mixture of methanol and 5mL 3 hours. The mixture was filtered, and concentrated to give a residue, which was purified by reverse-phase preparative HPLC (MeCN / water = 5-95%) to afford 360mg of a yellow solid 128-F. LC-MS: m/z = 403.0 [M+H] ⁺ .

Step 7. NaH (71 mg, 60% in mineral oil, 1.79 mmol) was added to a stirred solution of 128-F (360 mg, 0.89 mmol Methyl iodide (151 mg, 1.06 mmol) was added. The mixture was stirred for 1 hour at 0 ℃, followed directly by reverse-phase preparative HPLC (MeCN / water = 5-95%) to afford 260mg of a white solid 128-G. LC-MS: m/z = 417.0 [M+H] ⁺ .

Step 8. Heating the guanamine 128-G (260 mg, 0.62 mmol), PdCl ₂ (dppf) ₂ (50 mg, 0.06 mmol), boric acid 8-D (150 mg, 0.75 mmol) and CS ₂ CO at 100 ° C under N _{2 . 3} (422 mg, 1.30 mmol) was stirred in a mixture of 2 mL DMF-H ₂ O (3:1) for 12 h. The mixture was diluted with methanol (3 mL) and filtered. The filtrate by reverse phase preparative _{HPLC (MeCN: H 2 O =} 3: 2) to give 153mg of a colorless solid of the title product of Example 128 (52%). HPLC: 100%. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 8.44 (s, 0.5H), 8.06 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.4 Hz, 0.5 H), 7.95 (dd, J = 2.4 Hz, 8.8 Hz, 0.5H), 7.89 (dd, J = 2.4 Hz, 8.8 Hz, 0.5H), 7.83 (d, J = 2.0 Hz, 1H), 7.71 (d) , J = 8.0 Hz, 0.5H), 7.63 (d, J = 8.0 Hz, 0.5H), 7.59-7.53 (m, 0.5H), 7.44 (d, J = 8.0 Hz, 0.5H), 7.31 (t, J = 8.4 Hz, 0.5 H), 7.28-7.23 (m, 0.5 H), 7.12 (d, J = 8.0 Hz, 0.5 H), 6.94 (t, J = 8.4 Hz, 0.5 H), 3.50 (s, 1.5) H), 3.27 (s, 1.5H), 3.05-3.00 (m, 2H), 1.76-1.71 (m, 2H), 1.07 (t, J = 7.6 Hz, 3H). LC-MS: m / z = 492.0 [M + H] +.

Example 129: Synthesis of N- (5-(5-Aminomethylindol-2-chlorophenyl)-3-(propylsulfonyl)pyridine- 2-yl)-2-chloro-6-fluoro- N -methylbenzamide

It was heated at 50 deg.] C Preparation of sulfide Example 128 (50mg, 0.1mmol) and _{H 2 O 2 (17mg, 0.5mmol} ) in a mixture of acetic acid 1mL of Example 128 in 6 hours. A 1.0 M aqueous Na2SO3 solution (10 mL) was added. The mixture was stirred for 30 min and extracted with EtOAc (10 mL×2). Dried and concentrated the organic extracts were combined, by reverse-phase preparative _{HPLC (MeCN / H 2 O =} 5 to 95%) to give 35mg of a colorless solid of the title sulfone product of Example 129 (66%). HPLC: 100%. ¹ H NMR (400 MHz, CDCl _{3 ,} ) δ : 8.96 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 2.4 Hz, 1H), 7.88-7.84 (m, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.45-7.39 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 8.0 Hz, 1H), 6.15 (br s, 1H), 5.67 ( Br s,1H),3.53-3.42(m,2H),3.35(s,3H),1.95-1.87(m,1H),1.81-1.72(m,1H),1.06(t, J =7.2Hz,3H ). LC-MS: m/z =524.0 [M+H] ⁺ .

Examples 130 to 136

The compound is listed below in Table 12 of the present invention following the procedure described in Example 82 steps of 2 to 4, to initiate the intermediate 82-B, be prepared by reaction with a variety of R ⁴ X. For compounds 130, 131 and 132 , the methyl iodide in step 3 of Example 82 was replaced with other R ⁷ X reagents.

Examples 163 , 165, 167, 168, and 171

Table-based compounds of the present invention listed below followed in Example 12 89 (steps 1 to 7) of the program, a plurality of R ⁴ X be prepared. For the compounds of Examples 163, 165 and 167, the step in the procedure of Example 895 using iodomethane in place of iodomethane -d _3.

Preparative Example 148 : N-(3-((1R,3r,5S)-bicyclo[3.1.0]hex-3-yloxy)-5-(5-aminecarboxamido-2-chlorophenyl) Pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide.

Step 1. To a solution of cis-bicyclo[3.1.0]hexan-3-ol (800 mg, 8.1 mmol, 1.5 eq.) in THF (3 mL) EtOAc (EtOAc) . The mixture was stirred at room temperature for 2 hours, then 3-fluoro-2-nitropyridine (760 mg, 5.4 mmol, 1.0 eq.). The mixture was stirred at 60 &lt;0&gt;C for 16 h then cooled to rt and diluted with EtOAc EtOAc. The mixture was washed with brine (2×20 mL) and concentrated. The residue was purified by flash chromatography on silica gel performed: purified (EtOAc petroleum ether = 1/5) to give a pale yellow oil of 148b (420mg, 35%). ESI-MS (M+H) ⁺ : 221.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.03 (dd, J = 1.2Hz, 4.4Hz, 1H), 7.46 (dd, J = 4.0Hz, 8.0Hz, 1H), 7.38 (dd, J = 1.2Hz, 8.0 Hz, 1H), 4.93-4.90 (m, 1H), 2.30-2.24 (m, 2H), 2.08-2.05 (m, 2H), 1.39-1.36 (m, 2H), 0.60-0.52 (m, 2H) .

Step 2. A mixture of 148b (420 mg, 1.9 mmol, 1.0 eq.), Fe powder (535 mg, 9.5 mmol, 5.0 eq.) and HOAc (1 mL) in EtOH (10 mL). The mixture was then filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (50mL) and the mixture was washed with aqueous NaHCO ₃ (2 × 50mL) and water (50mL). The organic phase was concentrated to give 148c (360 mg) as a yellow oil. The crude product was used in the next step without further purification. ESI-MS (M+H) ⁺ : 191.1.

Step 3. To a stirred solution of 148c (360 mg, 1.9 mmol, 1.0 EtOAc) (EtOAc) The resulting mixture was stirred at room temperature for 12 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (100mL) and treated with saturated aqueous NaHCO ₃ (100mL × 2), washed with brine (60 mL) and concentrated to give a yellow oil of 148d (330mg, 64% (two steps for purposes)) . ESI-MS (M+H) ⁺ : 269.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.67 (d, J = 2.4Hz, 1H), 6.86 (d, J = 2.0Hz, 1H), 4.76-4.73 (m, 1H), 4.63 (br s, 2H ), 2.30-2.24 (m, 2H), 2.05-2.01 (m, 2H), 1.39-1.36 (m, 2H), 0.57-0.41 (m, 2H).

Step 4. To a mixture of 148d (330 mg, 1.2 mmol, 1.0 eq.) in pyridine (5 mL) EtOAc . The reaction was stirred at 60 ° C for 12 hours and then concentrated in vacuo. The residue was taken up in EtOAc (20 mL)EtOAc. Crude 148e was used in the next step without further purification. ESI-MS (M+H) ⁺ : 581.1.

Step 5. Add the mixture of (710mg, 1.2mmol, 1.0 eq.) In MeOH (5mL) 148e of _{K 2 CO 3 (330mg, 2.4mmol} , 2.0 equiv). The reaction was stirred at 70 ° C for 2 hours and then concentrated in vacuo. The residue was taken up in EtOAc (20 mL)EtOAc. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc : ESI-MS (M+H) ⁺ : 425.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.08-8.02 (m, 1H), 7.34-7.32 (m, 1H), 7.23-7.05 (m, 3H), 4.83-4.79 (m, 1H), 2.33-2.20 (m, 2H), 2.08-2.01 (m, 2H), 1.41-1.40 (m, 2H), 0.59-0.39 (m, 2H).

Step 6. NaH (48 mg, 1.2 mmol, 2.0 eq.) and MeI (90 mg, 0.7 mmol, 1.2 eq.) were added sequentially to a solution of 148f (250 mg, 0.6 mmol, 1.0 eq) in DMF (3 mL). . The mixture was stirred at 0 °C for 1 h then quenched with MeOH (0.5 mL). The mixture was purified by EtOAc ( EtOAc EtOAc ) ESI-MS (M+H) ⁺ : 439.1.

Step 7. Stir 148 g (170 mg, 0.4 mmol, 1.0 eq.), (5-amine-mercapto-2-chlorophenyl)boronic acid (95 mg, 0.5 mmol, 1.2 eq.), Na ₂ at 100 ° C under N ₂ . a mixture of CO ₃ (85 mg, 0.8 mmol, 2.0 eq.) and Pd (dppf) Cl ₂ (32 mg, 0.04 mmol, 0.1 eq.) in DMF/H ₂ O (2.0 mL, 3/1, v/v) . The mixture was then diluted with MeOH (3.0 mL) and filtered. The filtrate by (MeCN / water = 5% -95%) purified by reverse phase HPLC to give a white solid of 148 (75mg, 37%). ESI-MS (M+H) ⁺ : 514.1, HPLC: 93.27%. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 8.11-7.29 (m, 5H), 7.25-6.79 (m, 3H), 6.32 (br s, 1H), 5.70 (br s, 1H), 4.83-4.80 (m, 1H), 3.30 (s, 2H), 3.28 (s, 1H), 2.30-2.12 (m, 2H), 2.10-2.07 (m, 2H), 1.39-1.34 (m, 2H), 0.64-0.57 (m, 2H).

Examples 140, 141, 142, 149, 150, 151, 152, 158, 160, 162, 166, and 170.

Listed below in Table 13 of the present invention follows based compound Example 148 (steps 1-7) of the program, a variety of alcohols R ₄ OH Alternatively cis- bicyclo [3.1.0] hexyl-3-ol be prepared. For the compounds of Examples 140 and 142, with methyl iodide in the step 6 of the procedure of Example 148 in the place of iodomethane -d _3.

Preparative Example 156 : 2-Chloro-N-(5-(2-chloro-5-((2-hydroxyethyl)aminemethanyl)phenyl)-3-(2,2,2-trifluoroethyl) Oxy)pyridin-2-yl)-6-fluoro-N-methylbenzamide

Step 1. Preparation of 156a by replacing the intermediate boronic acid 8-D with 3-dihydroxyboryl-4-chlorobenzoic acid as described in Example 90, Steps 1-7 . ESI-MS (M+H) ⁺ : 517.2.

Step 2. Add 4-chloro-3-[6-[(2-chloro-6-fluoro-benzylidenyl)-methyl-amino]-5-(2,2,2-trifluoro) to the vial -ethoxy)-pyridin-3-yl]-benzoic acid ( 156a , 50.1 mg, 0.0968 mmol), ethanolamine (16 mg, 0.26 mmol), hexafluorophosphate N,N,N',N'-tetramethyl- O-(7-azabenzotriazol-1-yl) (54 mg, 0.14 mmol) and N,N-dimethylformamide (1.2 mL, 16 mmol). N,N-Diisopropylethylamine (83 uL, 0.48 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. EtOAc was then added and the mixture was washed with NaHCO _3, water and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo. The crude product was purified by reverse phase HPLC. A second purification was carried out by flash column chromatography using a gradient of 0 to 100% ethyl acetate / heptane to afford 29.7 mg (55%) of 156 as a pale white solid powder. ¹ H NMR (400 MHz, dichloromethane-d ₂ ) δ 8.30 (br.s., 1H), 7.91 (s, 1H), 7.27-7.85 (m, 4H), 7.08-7.24 (m, 1H), 7.01 (d, J = 8.03 Hz, 1H), 6.85 (t, J = 8.53 Hz, 1H), 6.68 (br.s., 1H), 4.39-4.62 (m, 2H), 3.73-3.85 (m, 2H) , 3.57 (d, J = 4.77 Hz, 2H), 3.24 - 3.52 (m, 3H). LCMS m/z = 559.9 [M+H].

Examples 155, 154, 146, 145, 144, and 143.

The following compounds of the invention listed in Table 14 were prepared by coupling intermediate 156a with various amines (R ^1a NR ^1b ).

Preparative Example 190 : 6-Chloro-4'-(2-chloro-6-fluoro-N-methylbenzimidamide)-3'-(3-fluoroazetidin-1-yl)- [1,1'-biphenyl]-3-carboxamide.

Step 1. Add K ₂ CO to a solution of 190a (2.0 g, 9.0 mmol, 1.0 eq.) and 3-fluoroazetidine hydrochloride (1.0 g, 9.0 mmol, 1.0 eq.) in DMF (20 mL) ₃ (3.7 g, 27.0 mmol, 3.0 eq.). The mixture was stirred at 50 ° C for 20 hours and poured into water (100 mL). The mixture was extracted with EtOAc (100 mL×3). The combined organic layers (2 × 100mL) and washed with brine, dried over Na ₂ SO ₄ dried and concentrated to give a yellow solid of 190b (2.2g, 85%). ESI-MS (M+H) ⁺ : 275.0. ¹ H NMR (400 MHz, acetone - d ₆ ) δ : 7.76 (d, J = 9.2 Hz, 1H), 6.99-6.97 (m, 2H), 5.59 - 5.42 (m, 1H), 4.39 - 4.29 (m, 2H) ), 4.23-4.13 (m, 2H).

Step 2. Fe powder (2.2 g, 40.0 mmol, 5.0 eq.) was added to a solution of 190b (2.2 g, 8.0 mmol, 1.0 eq.) in AcOH (20 mL). The mixture was then stirred at 60 ° C for 2 hours. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc (150mL) and washed with _aqueous NaHCO (100mL × 2). The organic layer was dried, filtered and concentrated. The residue was performed by column chromatography (petroleum ether / EtOAc = 5: 1) was purified on silica gel to give a yellow oil of 190c (1.4g, 72%). ESI-MS (M+H) ⁺ : 245.0. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.92 (dd, J = 2.4Hz, 8.4Hz, 1H), 6.72 (d, J = 2.0Hz, 1H), 6.54 (d, J = 8.4Hz, 1H), 5.43-5.24 (m, 1H), 4.18-4.09 (m, 2H), 3.90-3.81 (m, 2H), 3.58 (br s, 2H).

Step 3. Stir a mixture of 190c (1.4g, 5.7mmol, 1.0 eq.) and 2-chloro-6-fluorobenzhydrin chloride (1.1g, 5.7mmol, 1.0 eq.) in pyridine (10mL). hour. The mixture was concentrated and EtOAc EtOAc m . ESI-MS (M+H) ⁺ : 401.0. ^{1 H NMR (400MHz, DMSO- d} 6) δ: 10.10 (s, 1H), 7.55-7.50 (m, 1H), 7.42 (d, J = 8.0Hz, 1H), 7.36 (t, J = 8.8Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H), 5.49-5.32 (m, 1H) , 4.30-4.21 (m, 2H), 4.05-3.97 (m, 2H).

Step 4. NaH (224 mg, 60% in minerals, 5.6 mmol, 1.2 eq.) and iodine were added sequentially to a stirred solution of 190d (1.9 g, 4.7 mmol, 1.0 eq.) in DMF (20 mL). Methane (674 mg, 4.7 mmol, 1.0 eq.). The resulting mixture was stirred at room temperature for 2 hours. And then extracted mixture was poured into H ₂ O (100mL) with in EtOAc (50mL × 3). The combined organic layers (100 mL) and washed with brine, dried over Na ₂ SO _4, and concentrated to give a yellow oil of 190e (2.0g, 85%), which was used without further purification in the next step. ESI-MS (M+H) ⁺ : 415.0.

Step 5. Stir 190e (100 mg, 0.24 mmol, 1.0 eq.), 5-amine-mercapto-2-chlorophenylboronic acid (48 mg, 0.24 mmol, 1.0 eq.), Pd (dppf) at 80 ° C under N ₂ . A mixture of Cl ₂ (39 mg, 0.04 mmol, 0.2 eq.) and Na ₂ CO ₃ (127 mg, 1.2 mmol, 5.0 eq.) in DMF / H ₂ O (3mL, 3:1, v/v). The mixture was filtered and the filtrate was directly purified by reverse phase HPLC (MeCN / water = 5% to 95%) by to afford a white solid of 190 (70mg, Y: 60% ) ESI-MS (M + H) +: 490.0. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 7.80-7.28 (m, 5H), 7.24-6.22 (m, 4H), 6.12 (br s, 1H), 5.50 (br s, 1H), 5.47-5.28 (m, 1H), 4.56-3.77 (m, 4H), 3.50 (s, 0.5H), 3.46 (s, 1H), 3.14 (s, 1.5H).

Preparative Example 188 : 6-Chloro-4'-(2-chloro-6-fluoro-N-methylbenzimidamide)-3'-(3-fluoroazetidin-1-yl)- N-(2-hydroxyethyl)-[1,1'-biphenyl]-3-carboxamide.

Step 1. Preparation of 188a was identical to that reported for 190 to afford 188a (1.18 g, 50%) as a white solid. ESI-MS (M+H) ⁺ : 491.0.

Step 2. To a solution of 188a (100 mg, 0.2 mmol, 1.0 eq.) in EtOAc (EtOAc) The mixture was stirred at room temperature for 30 minutes and 2-aminoethanol (18 mg, 0.3 mmol, 1.5 eq.) was added. The mixture was further stirred at room temperature for 1 hour. Water (20 ml) was added and the mixture was extracted with CH ₂ CH ₂ (20 mL). The organic layer was dried and concentrated. The residue (MeCN / water = 5% to 95%) was purified by reverse phase HPLC to give a white solid of 188 (32mg, 29%). ESI-MS (M+H) ⁺ : 534.1. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 7.77-7.27 (m, 4H), 7.23 - 6.25 (m, 5H), 5.46 - 5.30 (m, 1H), 4.57 - 3.88 ( m, 4H), 3.83-3.81 (m, 2H), 3.63-3.58 (m, 2H), 3.49 (s, 0.5H), 3.46 (s, 1H), 3.14 (s, 1.5H).

Examples 187, 186, 181, 177, 184, 180, 176, 185, 174, 178, 192, 182, 183, 175, 189, 173, 194, 172, 179 and 193.

The compound is listed below in Table 15 of the present invention following the Example 190 (Step 1-5), and 188 (Step 1 and 2) of the program, be prepared using a variety of R ₃ of the amine of Example 190 step 1. Examples of the compound of 181,185,178,183,175,189,173,174 and 179, the step 190 in the example of the Procedure 4 -d ₃ with iodomethane in place of iodomethane.

Preparative Example 200 : N-(5-(5-Aminomethylindol-2-chlorophenyl)-3-(3-fluoroazetidin-1-yl)pyridin-2-yl)-2- Chloro-6-fluoro-N-methylbenzamide.

Step 1. Hydrogen peroxide (30% in water, 5 mL) was added to sulfuric acid (10 mL) at 0 °C. The mixture was stirred at 15 ° C or less for 1.5 hours and then cooled to 0 ° C. Then a solution of 5-bromo-3-fluoro-pyridin-2-ylamine ( 200a , 1.3 g, 6.8 mmol, 1.0 eq.) in EtOAc (10 mL). The mixture was carefully poured into water (100 mL) and made basic with sodium carbonate (to pH = 9). The mixture was then extracted with EtOAc (100 mL×3). The organic layers were combined and the solvent removed in vacuo to give a yellow solid of 200b (430mg, 30%). ESI-MS (M+H) ⁺ : 221.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.48 (d, J = 1.2 Hz, 1H), 7.99 (dd, J = 1.6 Hz, 8.8 Hz, 1H).

Step 2. To a solution of 200b (450 mg, 2.0 mmol, 1.0 eq.) in DMF (5 mL), EtOAc (400 mg, 4.0 mmol, 2.0 eq.) and 3-fluoroazetidine (300 mg, 4.0 mmol, 2.0 equivalents). The mixture was stirred at 90 ° C under N ₂ for 2 h then diluted with EtOAc (200 mL). The mixture was washed with brine (3 × 100mL), dried over Na ₂ SO ₄ and concentrated to give a black oil, which _{(MeCN / H 2 O = 2} : 1) was purified by reverse phase HPLC to give a yellow oil of 200c (300mg, 53%). ESI-MS (M+H) ⁺ : 276.0.

Step 3. Preparation of 200d is the same as 190c (Example 190, Step 2) . ESI-MS (M+H) ⁺ : 246.0. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.55 (d, J = 2.0Hz, 1H), 6.85 (d, J = 2.0Hz, 1H), 5.56 (br s, 2H), 5.46-5.27 (m, 1H ), 4.20-4.11 (m, 2H), 3.90-3.81 (m, 2H).

Step 4. Preparation of 200e is the same as 190d (Example 190, Step 3) . ESI-MS (M+H) ⁺ : 558.0.

Step 5. Preparation of 200f is identical to 190e (Example 190, Step 4) . ESI-MS (M+H) ⁺ : 402.0.

Step 6. Preparation of 200g is the same as 190e (Example 190, Step 4) . ESI-MS (M+H) ⁺ : 416.0.

Step 190 7.200 Preparation of (Example 190, step 5) the same. ESI-MS (M+H) ⁺ : 491.1. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ: 8.09-6.87 (m, 8H), 5.50-5.33 (m, 1H), 4.41-3.86 (m, 4H), 3.53 (s) , 2H), 3.25-3.22 (m, 1H).

Examples 195, 197, 198, and 199 .

The following compounds of the invention listed in Table 16 were prepared following the procedure described in Example 200 .

Preparative Example 201: N- (5- (5- carbamoyl acyl-2-chlorophenyl) -3- (pyrrolidin--d ₈ -1- yl) pyridin-2-yl) -2-chloro-6 -Fluoro-N-(methyl-d ₃ )-benzamide.

Step 1. Slowly add trifluoromethanesulfonic anhydride to a solution of 201a (1.0 g, 4.6 mmol, 1.0 eq.) and TEA (926 mg, 9.2 mmol, 2.0 eq.) in dichloromethane (50 mL). 2.6 g, 9.2 mmol, 2.0 equivalents). Was stirred at -78 deg.] C under N ₂ for 2 h and then allowed to warm to room temperature and diluted with EtOAc (100mL). The mixture was washed with brine (3 × 50mL), dried over Na ₂ SO ₄ and concentrated to give a brown oil of 201b (1.6g, 100%). ESI-MS (M+H) ⁺ : 350.9. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.67 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H).

Step 2. To a solution of 201b (350 mg, 1.0 mmol, 1.0 eq.) in THF (5 mL), EtOAc ( EtOAc, EtOAc ( EtOAc ) 1.0 equivalent). The mixture was stirred at 70 &lt;0&gt;C for 1 h, cooled to rt then diluted with EtOAc (20 mL). The organic layer was washed with brine (2×20 mL) and concentrated to afford 201c . The crude product was used in the next step without further purification. ESI-MS (M+H) ⁺ : 280.0.

Step 3. A mixture of 201c (530 mg, 1.9 mmol, 1.0 eq.), Fe powder (535 mg, 9.5 mmol, 5.0 eq.) and HOAc (1 mL) in EtOH (10 mL). The mixture was then filtered and the filtrate was evaporated to give crystall The mixture was washed with aqueous NaHCO ₃ (2 × 50mL) and water (2 × 50mL). The organic phase was concentrated to give 201d (498 mg, 50% (for two steps) as a yellow solid. ESI-MS (M+H) ⁺ : 250.0. ¹ H NMR (400 MHz, CDCl ₃ ) δ : 7.76 (d, J = 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 4.65 (br s, 2H).

Step 4. To a mixture of 201d (299 mg, 1.2 mmol, 1.0 eq.) in EtOAc (5 mL) The reaction was stirred at 70 ° C for 12 hours and concentrated. The residue was dissolved in EtOAc (20mL), washed with brine (2 × 20mL), and concentrated to afford washed 201e. The residue was used in the next step without further purification. ESI-MS (M+H) ⁺ : 5621.

Step 5. to 201e (from the previous step, 1.2mmol, 1.0 eq) in of MeOH (5mL) was added a mixture of _{K 2 CO 3 (330mg, 2.4mmol} , 2.0 equiv). The reaction was stirred at 80 ° C for 2 hours and then concentrated. The residue was taken up in EtOAc (20 mL)EtOAc. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: ESI-MS (M+H) ⁺ : 406.0.

Step 6. NaH (30 mg, 0.8 mmol, 2.0 eq.) and MeI-d ₃ (116 mg, 0.8 mmol) were added sequentially to a solution of 201f (243 mg, 0.4 mmol, 1.0 eq) in DMF (3 mL). 2.0 equivalents). The mixture was stirred for 1 hour at room temperature and then with aqueous NH ₄ Cl (50mL) and quenched. The mixture was extracted with EtOAc (50 mL×2). The combined organic extracts were dried with EtOAc EtOAc m . ESI-MS (M+H) ⁺ : 423.0.

Step 7. Stir 201g (from the previous step, 0.4mmol , 1.0 eq.), 8D (1150114-35-4) (95mg, 0.5mmol, 1.2 eq.), Na ₂ CO ₃ (85mg) at 90 ° C under N ₂ atmosphere. , 0.8 mmol, 2.0 eq.) and a mixture of Pd(dppf)Cl ₂ (32 mg, 0.04 mmol, 0.1 eq.) in DMF / H ₂ O (2.0 mL, 3/1, v/v) for 6 hours. The mixture was then diluted with MeOH (3 mL) and filtered. The filtrate was purified by reverse phase HPLC (MeCN / water = 5% to 95%) by to afford a white solid of 201 (84mg, 34%). ESI-MS (M+H) ⁺ : 498.0. (400MHz, DMSO- d _6, mixture of isomers of ^{configuration) 1 H NMR δ: 8.12-8.08 (} m, 1H), 8.02-6.88 (m, 9H).

Examples 203, 206, 207, 214, 216, 219, 229, 202, 211, 217, 215, 218, 220, 221, 223, 224, 225, 226, 222, 205, 209, 227, 228, 230, 231 232. The following compounds of the invention listed in Table 17 were prepared following the procedure described in Example 201 .

Preparative Example 212 : N-(5-(5-Aminomethylindol-2-chlorophenyl)-3-(4-chloro-1H-pyrazol-1-yl)pyridin-2-yl)-2- Chloro-6-fluoro-N-methylbenzamide.

Step 1. 4-chloro--1H- pyrazole (340mg, 3.4mmol, 1.0 eq), CuI (32mg mixture to 212 (5mL) in the a (1g, 3.4mmol, 1.0 eq.) In DMF at room temperature , 0.17 mmol, 0.05 eq.), K ₂ CO ₃ (940 mg, 6.8 mmol, 2.0 eq.) and cyclohexane-1,2-diamine (78 mg, 0.68 mmol, 0.2 eq.). The mixture was stirred for 16 hours and then allowed to cool to room temperature and then diluted with EtOAc (300mL) under N ₂ at 130 ℃. The mixture was washed with brine (3 × 100mL), dried over Na ₂ SO ₄ and concentrated to give a dark oil, which by reverse phase HPLC _{(MeCN / H 2 O = 1} : 1) to give a yellow solid of 212b (500mg, 55%). ESI-MS (M+H) ⁺ : 273.0. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.11 (d, J = 2.0Hz, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.54 (d, J = 2.0Hz, 1H), 5.78 (br s, 2H).

Step 2. The preparation of 212c is the same as 200e (Example 200, Step 4) . ESI-MS (M+H) ⁺ : 584.9.

Step 3. The preparation of 212d is the same as 200f (Example 200, Step 5) . ESI-MS (M+H) ⁺ : 428.9.

Step 4. Preparation of 212e is the same as 133-1g (Example 200, Step 6) . ESI-MS (M+H) ⁺ : 442.9.

The preparation of step 5. 212 is the same as 200 (example 200, step 7) . ESI-MS (M+H) ⁺ : 518.0. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ: 8.70-6.78 (m, 10H), 6.61 (br s, 1H), 5.93 (br s, 1H), 3.29 (s, 3H) .

Example 210. The following compounds of the invention listed in Table 18 were prepared following the procedure described in Example 212 (Steps 1 to 5) by replacing 4-chloro-1H-pyrazole with 4-methyl-1H-pyrazole. .

Preparative Example 196 : N-(5-(5-Aminocarboxy-2-chlorophenyl)-3-(3-o-oxymorpholinyl)pyridin-2-yl)-2-chloro-6- Fluorine-N-methylbenzamide.

Step 1. Preparation of 196a was the same as for 200c , using sodium hydride instead of TEA as the base. ESI-MS (M+H) ⁺ : 302.1. ^{1 H NMR (400MHz, DMSO- d} 6) δ: 8.76 (d, J = 2.0Hz, 1H), 8.74 (d, J = 2.0Hz, 1H), 4.21 (s, 2H), 4.03-4.00 (m, 2H), 3.92-3.90 (m, 2H).

Step 2. The preparation of 196b is the same as that of 200d . ESI-MS (M+H) ⁺ : 272.0. ^{1 H NMR (400MHz, DMSO- d} 6) δ: 7.98 (d, J = 2.8Hz, 1H), 7.98 (d, J = 2.4Hz, 1H), 6.25 (br s, 2H), 4.16 (s, 2H ), 4.05-3.95 (m, 2H), 3.49-3.41 (m, 2H).

Step 3. Preparation of 196c is the same as 190d (Example 132-1, Step 3) . ESI-MS (M+H) ⁺ : 428.0.

Step 4. Preparation of 196d is identical to 190e (Example 132-1 , Step 4) . ESI-MS (M+H) ⁺ : 442.3.

Step 190 5.196 Preparation of (Example 132-1, in step 5) the same. ESI-MS (M+H) ⁺ : 517.1. ¹ H NMR (400 MHz, CD ₃ OD) δ : 8.70 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.96 ( Dd, J = 2.0 Hz, 8.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.59-7.53 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.33 (t, J = 8.8

Preparative Example 234 : N-(5-(5-Aminomethylindol-2-chlorophenyl)-3-(tetrahydrofuran-2-yl)pyridin-2-yl)-2-chloro-6-fluoro-N -methylbenzamide.

Step 1. Add [tBu ₃ PH]BF ₄ (145 mg) to a solution of 3-bromo-2-nitropyridine ( 163a , 1.0 g, 5.0 mmol, 1.0 eq.) in 1,4-dioxane (3 mL) , 0.5 mmol, 0.1 eq.), N-methyl-dicyclohexylamine (1.95 g, 10 mmol, 2.0 eq.), Pd ₂ (dba) ₃ (145 mg, 0.5 mmol, 0.1 eq.) and 2,3-dihydrofuran (700 mg, 10 mmol, 2.0 eq.). The mixture was stirred at 80 ° C for 2 hours and then allowed to cool to room temperature. The catalyst is removed by filtration and the filtrate was diluted with EtOAc (50mL), washed with brine (2 × 50mL) and concentrated to give a yellow oil of 234b in vacuo. This material was used in the next step without further purification. ESI-MS (M + H) +: 193.0, 1 H NMR (400MHz, CDCl 3) δ: 8.53 (dd, J = 2.0Hz, 8.8Hz, 1H), 8.19-8.16 (m, 1H), 7.68-7.64 (m, 1H), 6.51-6.49 (m, 1H), 6.02-5.97 (m, 1H), 5.00-4.97 (m, 1H), 3.45-3.38 (m, 1H), 2.51-2.45 (m, 1H) .

Step 2. Pd/C (100 mg, 10 wt%) was added to a solution of 234b (5.0 mmol, 1.0 eq. The mixture was hydrogenated at room temperature for 16 hours at room temperature. The catalyst was then removed by filtration and the filtrate was concentrated to afford 234c as a yellow oil. This material was used in the next step without further purification. ESI-MS (M + H) +: 165.0, 1 H NMR (400MHz, CD 3 OD) δ: 7.84 (dd, J = 1.2Hz, 4.8Hz, 1H), 7.50 (dd, J = 0.8Hz, 7.6Hz , 1H), 6.65 (dd, J = 0.8 Hz, 7.2 Hz, 1H), 4.80 (t, J = 7.2 Hz, 1H), 4.12-4.07 (m, 1H), 3.92-3.86 (m, 1H), 2.34 -2.29 (m, 1H), 2.08-2.01 (m, 2H), 1.92-1.90 (m, 1H).

Step 3. To a 234 c (from the previous step, 5.0mmol, 1.0 equiv) at room temperature in acetic acid (10 mL) was stirred in a solution of bromine (0.4mL, 7.5mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was neutralized with saturated aqueous NaHCO ₃ to pH = 7. The mixture was then extracted with EtOAc (4×30 mL). The combined organic extracts were washed with brine (60mL), dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was performed by column chromatography (petroleum ether / EtOAc = 3: 1) was purified on silica gel to give a yellow solid of 234d (691mg, 57%). ESI-MS (M+H) ⁺ : 243.0, ¹ H NMR (400 MHz, CD ₃ OD) δ : 7,89 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 4.78 (t, J = 7.2 Hz, 1H), 4.13-4.07 (m, 1H), 3.92-3.86 (m, 1H), 2.40-2.31 (m, 1H), 2.11-1.95 (m, 2H), 1.84- 1.75 (m, 1H).

Step 4. To a mixture of 234d (360 mg, 1.5 mmol, 1.0 eq.) in pyridine (2mL), 2-chloro-6-fluorobenzhydrin chloride (864 mg, 4.5 mmol, 3.0 eq.). The mixture was stirred at 70 ° C for 12 hours and then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL)EtOAc. The organic layer was concentrated in vacuo to afford crude 234e as yellow oil. ESI-MS (M+H) ⁺ : 555.0.

5. Step 234e was heated at reflux (from the previous step, 1.5mmol, 1.0 eq.) And a mixture of _{K 2 CO 3 (621mg, 4.5mmol} , 3.0 eq.) In MeOH (20mL) 2 h and then allowed to cool to room Warm and filter. The filtrate was concentrated and the residue was purified EtOAcjjjjjjjjj ESI-MS (M+H) ⁺ : 399.0, ¹ H NMR (400 MHz, CD ₃ OD) δ : 8.48 (s, 1H), 8.15 (s, 1H), 7.54 - 7.18 (m, 3H), 5.17 (t , J = 7.2 Hz, 1H), 4.17-4.11 (m, 1H), 3.93-3.88 (m, 1H), 2.58-2.53 (m, 1H), 2.04-2.02 (m, 2H), 1.78-1.73 (m , 1H).

Step 6. To a solution of 234f (200 mg, 0.5 mmol, 1.0 eq.) in EtOAc (3 mL) 1.0 mmol, 2.0 equivalents). The mixture was stirred for 1 hour and then with aqueous NH ₄ Cl (20mL) and quenched. With an aqueous solution of EtOAc (20mL × 2) and dried extracted, the combined organics were filtered and concentrated in vacuo to give a yellow oil of 234g. This material was used in the next step without further purification. ESI-MS (M+H) ⁺ : 413.0.

Step 7. Stir 234 g (from the previous step, 0.5 mmol, 1.0 eq.), PdCl ₂ (dppf) (40 mg, 0.05 mmol, 0.1 eq.), 5-amine-methyl hydrazino-2- chlorobenzene at 90 ° C under N ₂ phenylboronic acid (120mg, 0.6mmol, 1.2 eq) and _{Na 2 CO 3 (106mg, 1.0mmol} , 2.0 equiv) in _{DMF / H 2 O (2.0mL,} 3: 1) in the mixture for 6 hours. The mixture was cooled to room temperature, filtered and the filtrate was by reverse phase HPLC: purification _{(MeCN H 2 O = 5%} -95%) to afford a white solid of 234 (77mg, 32%). ESI-MS (M+H) ⁺ : 488.0. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 8.62-6.91 (m, 8H), 5.37-5.07 (m, 1H), 4.19-4.08 (m, 1H), 3.96-3.88 (m, 1H), 3.52 (s, 0.7H), 3.31 (s, 2.1H), 2.59-2.47 (m, 1H), 2.15 - 1.72 (m, 3H).

Preparative Example 235 : N-(5-(5-Aminocarboxy-2-chlorophenyl)-3-(tetrahydrofuran-3-yl)pyridin-2-yl)-2-chloro-6-fluoro-N -methylbenzamide.

Step 1 was stirred at 60 deg.] C 3-bromo-2-nitropyridine (235a, 1.03g, 5.08mmol) under N _2, 2- (2,5- dihydro-3-yl) -4,4 ,5,5-tetramethyl-1,3,2-dioxaboron (996 mg, 5.08 mmol, 1.0 eq.), S-phos (208 mg, 0.51 mmol, 0.1 eq.), Pd(OAc) ₂ (56 mg, 0.25 mmol, 0.05 eq.) and K ₃ PO ₄ (3.23 g, 15.2 mmol, 3.0 equiv.) in _{2 O (20mL, 9 THF /} H: mixture 1) for 3 hours. The mixture was then cooled to room temperature, diluted with EtOAc (150 mL) andEtOAc. Dry, filter and concentrate the organic layer in vacuo. The residue was performed by column chromatography (petroleum ether / EtOAc = 4: 1) was purified on silica gel to give a brown oil of 235b (890mg, 94%). ESI-MS (M+H) ⁺ : 193.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.46 (dd, J = 1.6Hz, 4.8Hz, 1H), 7.79 (dd, J = 1.6Hz, 8.0Hz, 1H), 7.57 (dd, J = 4.8Hz, 8.0 Hz, 1H), 6.13 - 6.11 (m, 1H), 4.92-4.83 (m, 4H).

Steps 2 through 7. Following the procedure described in steps 2 through 7 of Example 234 , intermediate 235b was converted to the final product of Example 235 . ESI-MS (M + H) +: 399.1, 1 H NMR (400MHz, CDCl 3, mixture of configuration isomers) δ: 8.52-7.31 (m, 7H ), 7.15-7.11 (m, 1H), 6.21 (br s,1H), 5.66(br s,1H),4.14-3.75(m,5H),3.52-3.35(m,3H),2.59-2.45(m,1H),2.15-1.90(m,1H) .

Preparative Example 233. The following compounds of the invention listed in Table 19 follow the procedure described in Example 235 (Steps 1 to 7) with 2-(3,6-dihydro-2H-pyran-4-yl) )-4,4,5,5-tetramethyl-1,3,2-dioxaboron Replace 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabor Prepared.

Preparative Examples 239 and 238 : N-(5-(5-Aminocarboxy-2-chlorophenyl)-3-((cyclopropylmethyl)sulfonyl)pyridin-2-yl)-2- Chloro-6-fluoro-N-methylbenzamide.

Step 1. Preparation of 239a Following the preparation of Step 2 (128-B) of Example 128, the propane thiol was replaced with p-methoxybenzyl mercaptan. ESI-MS (M+H) ⁺ : 277.0. ¹ H NMR (400 MHz, CD ₃ OD) δ : 8.34 (dd, J = 1.6 Hz, 4.4 Hz, 1H), 7.88 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 7.49 (dd, J = 4.4 Hz) , 8.0 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.16 (s, 2H), 3.80 (s, 3H).

Step 2. A solution of 239 a (3.0 g, 10.8 mmol, 1.0 eq.) in TFA (15 mL). The mixture was concentrated and the residue was purified EtOAcjjjjjjjjj ESI-MS (M+H) ⁺ : 157.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.53 (dd, J = 1.6Hz, 4.8Hz, 1H), 8.32 (dd, J = 1.6Hz, 8.4Hz, 1H), 7.62 (dd, J = 4.4Hz, 8.4 Hz, 1H).

Step 3. To a stirred solution of compound 239b (1.35 g, 8.6 mmol, 1.0 eq) in DMF (15 mL), NaH (0.52 g, 12.9 mmol, 1.5 eq.) and cyclopropylmethyl bromide (1.72 g) , 12.9 mmol, 1.5 equivalents). It was stirred at room temperature for 4 hours and then the reaction mixture was poured and extracted (50mL × 3) in EtOAc with ₂ O (50mL) H into. Combined organic layers were dried over Na ₂ SO ₄ and concentrated. The residue was performed by column chromatography (petroleum ether / EtOAc = 5: 1) was purified on silica gel to afford 1.36g (75%) of a yellow oil 239c. ESI-MS (M+H) ⁺ : 211.0. ^{1 H NMR (400MHz, DMSO- d} 6) δ: 8.37 (dd, J = 1.6Hz, 4.4Hz, 1H), 8.23 (dd, J = 1.6Hz, 8.4Hz, 1H), 7.76 (dd, J = 4.0 Hz, 8.0 Hz, 1H), 3.05 (d, J = 7.2 Hz, 2H), 1.03-0.96 (m, 1H), 0.58-0.54 (m, 2H), 0.31 - 0.21 (m, 2H).

Step 4. Preparation of 239d is the same as 128-C (Example 128, Step 3). ESI-MS (M+H) ⁺ : 181.0. ¹ H NMR (400 MHz, CD ₃ OD) δ : 7.73 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 7.56 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 6.47 (dd, J = 4.8 Hz) , 7.6 Hz, 1H), 2.56 (d, J = 7.6 Hz, 2H), 0.84-0.80 (m, 1H), 0.39-0.34 (m, 2H), 0.02-0.01 (m, 2H).

Step 5. Preparation of 239e is the same as 128-D (Example 128, Step 4). ESI-MS (M+H) ⁺ : 259.0.

Step 6. Preparation of 239f is identical to 128-E (Example 128, Step 5). ESI-MS (M+H) ⁺ : 571.0.

Step 7. Preparation of 239g is the same as 128-F (Example 128, Step 6). ESI-MS (M+H) ⁺ : 415.0.

Step 8. Preparation of 239h is identical to 128-G (Example 128, Step 7). ESI-MS (M+H) ⁺ : 429.1.

Step 9. 239 was prepared in the same manner as Example 128 (Step 8). ESI-MS (M+H) ⁺ : 504.0, HPLC: 100%. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 8.45 (d, J = 1.6 Hz, 0.5H), 8.08 (dd, J = 2.0 Hz, 10.4 Hz, 1H), 8.01- 7.86 (m, 2H), 7.82 (d, J = 1.6 Hz, 0.5 H), 7.70 (d, J = 8.4 Hz, 0.5 H), 7.62 (d, J = 8.4 Hz, 0.5 H), 7.51 - 7.53 ( m, 0.5H), 7.44 (d, J = 8.8 Hz, 0.5H), 7.33 - 7.22 (m, 1H), 7.11 (d, J = 8.0 Hz, 0.5H), 6.94 (t, J = 8.8 Hz, 0.5H), 3.53 (s, 1.5H), 3.29 (s, 1.5H), 3.11-2.97 (m, 2H), 1.13-1.106 (m, 1H), 0.65-0.60 (m, 2H), 0.34-0.31 (m, 2H).

Step 10. 238 was prepared in the same manner as in Example 129 . ESI-MS (M + H) +: 536.0, HPLC: 100%. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 9.04 (d, J = 1.6Hz, 1H), 8.69 (s, 1H), 8.06 (d, J = 1.6Hz, 1H), 8.01 (d, J = 8.4Hz , 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.59-7.55 (m, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.33-7.30 (m, 1H), 3.53-3.38 ( m, 2H), 3.31 (s, 3H), 1.15-1.09 (m, 1H), 0.66-0.64 (m, 1H), 0.48-0.44 (m, 1H), 0.42-0.25 (m, 2H).

Examples 237 and 236. The following compounds of the invention listed in Table 20 follow the procedure described in Examples 239 and 238 (Steps 1 to 10), replacing cyclopropylmethyl bromide with methyl iodide and ethyl iodide from the middle. Preparation 128-A.

Preparative Example 243 : 6-Chloro-4'-(2-chloro-6-fluoro-N-CD ₃ -benzimidamide)-N-(2-hydroxyethyl)-3'-(2,2 , 2-trifluoroethoxy)-[1,1'-biphenyl]-3-carboxamide.

Step 1: Stir 2-nitrophenol (1.39 g, 10 mmol), CF ₃ CH ₂ OTf (3.48 g, 15 mmol, 1.5 eq.) and Cs ₂ CO ₃ (6.5 g, 20 mmol, 2.0 eq. The mixture in DMF was 16 hours. The mixture was diluted with EtOAc (EtOAc) (EtOAc) Organics were dried and concentrated in vacuo to give a yellow solid of 243a (2.2g, 99%), which was used without further purification in the next step. ESI-MS (M+H) ⁺ : 2221. ¹ H NMR (400 MHz, CDCl ₃ ) δ : 7.89 (d, J = 8.4 Hz, 1H), 7.59-7.56 (m, 1H), 7.23-7.18 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 4.49 (q, J = 8.0 Hz, 2H).

Step 2: A mixture of 243a (2.2 g, 10 mmol), Fe powder (2.8 g, 50 mmol, 5.0 eq.) and HOAc (3.0 g, 50 mmol, 5.0 eq. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated to give a brown solid of 243b (1.9g, 100%), which was used without further purification in the next step. ESI-MS (M+H) ⁺ : 1921.

Step 3: (, 10mmol 1.9g) in 20mL HOAc was added in the Br ₂ (2.4g, 15mmol, 1.5 equiv) was added to 243b. The mixture was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in 100mL EtOAc and washed and treated with aqueous NaHCO ₃ (100mL × 3). Dry and concentrate the organics in vacuo. The residue was performed by column chromatography (petroleum ether / EtOAc = 4: 1) was purified on silica gel to give a pale yellow solid of 243c (1.6g, 60%). ESI-MS (M+H) ⁺ : 270.2. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 6.99 (dd, J = 1.6Hz, 8.4Hz, 1H), 6.89 (d, J = 1.6Hz, 1H), 6.62 (d, J = 8.0Hz, 1H), 4.34 (q, J = 8.0 Hz, 2H).

Step 4: Add 1-B (1.4g, 7.10mmol, 1.2 eq) of a solution of 243c (1.6g, 5.92mmol) in pyridine (10mL). The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was performed by column chromatography (petroleum ether / EtOAc = 6: 1) was purified on silica gel to give a yellow solid of 243d (1.8g, 70%). ESI-MS(M+H) ⁺ :426.1

Step 5: sequentially added to 243d (500mg, 1.17mmol) in 5mL DMF in the solution of NaH (94mg, 60% in mineral oil, 2.34mmol, 2.0 eq) and _{CD 3 I (203mg, 1.4mmol,} 1.2 equiv) . The reaction was stirred at room temperature for 1 h and quenched with water (50 mL). The mixture was extracted with EtOAc (50 mL×2). The combined organics were washed with water (50mL), brine (50mL), dried over Na ₂ SO ₄ and concentrated under vacuum to give a yellow solid of 243e (470mg, Y: 90% ), which was used without further purification The next step. ESI-MS (M+H) ⁺ : 443.1.

Step 6: A mixture of 243e (1.0g, 2.3mmol, 1.0 equiv), 3-borono-4-chlorobenzoic acid 2-C under a N ₂ atmosphere at 90 ℃ (550mg, 2.8mmol, 1.2 equiv), a mixture of Na ₂ CO ₃ (488 mg, 4.6 mmol, 2.0 eq.) and Pd(dppf)Cl ₂ (150 mg, 0.2 mmol, 0.1 eq.) in DMF/H ₂ O (12 mL, 3/1, v/v) hour. The mixture was diluted with MeOH (5 mL) and filtered. The filtrate was purified by EtOAc EtOAc ( EtOAc )

ESI-MS (M+H) ⁺ : 519.0. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 8.10-7.95 (m, 2H), 7.62-7.36 (m, 3H), 7.16-6.72 (m, 4H), 4.51-4.38 ( m, 2H).

Step 7: Stir 243f (104 mg, 0.2 mmol, 1.0 eq.), 2- aminoethanol (24 mg, 0.4 mmol, 2.0 eq.), HATU (152 mg, 0.4 mmol, 2.0 eq.) and TEA (40 mg, 0.4). A mixture of mmol, 2.0 eq. in DMF (3 mL) The mixture was purified by EtOAc (EtOAc EtOAc) ESI-MS (M+H) ⁺ : 5621. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 7.84-6.77 (m, 9H), 4.67-4.43 (m, 2H), 3.63-3.57 (m, 2H), 3.42-3.36 (m, 2H).

Preparative examples 244 to 270:

In some embodiments of the compound of Formula II, the compound has Formula IIf:

The following compounds of the invention listed in Table 21 were prepared following the procedures described in Examples 243, steps 1 through 7 . The 2-aminoethanol in step 7 is replaced with a plurality of amines to give the final product. For Examples 245, 247, 253, tert-butyl piperidin-4-ylaminocarbamate, tert-butyl azetidine-3-ylaminocarbamate, and tert-butyl piperazine-1-carboxylate ( The final product was obtained after removal of the BOC group in step 7 using dichloromethane containing trifluoroacetic acid at room temperature.

Preparative Examples 271 and 272 : 3-(6-chloro-4'-(2-chloro-6-fluoro-N-CD ₃ -benzimidamide)-3'-(2,2,2-trifluoro Ethoxy)-[1,1'-biphenyl]-3-ylcarboxylamido)propionic acid and N-(3-amino-3-oxopropyl)-6-chloro-4'- (2-Chloro-6-fluoro-N-CD ₃ -benzimidamide)-3'-(2,2,2-trifluoroethoxy)-[1,1'-biphenyl]-3- Formamide.

Step 1: Intermediate 243f (108 mg, 0.32 mmol, 1.0 eq.), ethyl 3-aminopropionate hydrochloride (100 mg, 0.65 mmol, 2.0 eq.), HATU (246 mg, 0.65 mmol, 2.0 Equivalent) and a mixture of TEA (65 mg, 0.38 mmol, 2.0 eq.) in DMF (3 mL) The mixture was purified by EtOAc EtOAc (EtOAc) ESI-MS (M+H) ⁺ : 618.2.

Step 2: (, 0.32mmol, 1.0 eq. 200 mg of) in the in MeOH (3mL) was added LiOH (39mg, 0.97mmol, 3.0 eq) and H ₂ O (0.5mL) to 271a. The reaction was stirred at 35 ° C for 2 hours. The mixture was acidified to pH = 6 with 1N HCl and concentrated in vacuo. The residue was purified by reverse phase HPLC (MeCN / water = 5% to 95%) by to afford a white solid of 271 (150mg, 79%). ESI-MS (M+H) ⁺ : 590.1.

Step 3: 271 (104 mg, 0.19 mmol, 1.0 eq.), ammonium chloride (21 mg, 0.39 mmol, 2.0 eq.), HATU (149 mg, 0.38 mmol, 2.0 eq.) and TEA (38 mg, 0.39 mmol, 2.0 equivalents of a mixture in DMF (3 mL) for 1 hour. The mixture was purified by EtOAc (EtOAc EtOAc) ESI-MS (M+H) ⁺ : 589.1. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 7.76-6.72 (m, 10H), 5.95-5.46 (m, 2H), 4.52-4.38 (m, 2H), 3.73-3.69 ( m, 2H), 2.57-2.54 (m, 2H).

Examples 273 to 277. The following compounds of the invention listed in Table 22 were prepared following the procedures described in Examples 271, Steps 1 and 2 .

Examples 278 to 281. The following compounds of the invention listed in Table 23 were prepared following the procedure described in Example 148 .

Table 23:

Preparative Examples 282-311

The following compounds of the invention listed in Table 24 were prepared following the procedures described in Examples 243, Steps 1 through 7 . The 2-aminoethanol in step 7 is replaced with a plurality of amines to give the final product. For compounds 447, 449 and 450, azetidine azet-3-yl(methyl)carbamate, tert-butyl (S)-pyrrolidin-3-ylcarbamate and (R) - Pyrrolidin-3-ylaminocarbamic acid tert-butyl ester was used in step 7 separately and the final product was isolated after removal of the BOC group with dichloromethane containing trifluoroacetic acid at room temperature.

Preparative Example 312. The following compounds of the invention listed in Table 25 were prepared following the procedures described in Examples 271, Steps 1 and 2 .

In some embodiments of the compound of Formula II, the compound has Formula IIg:

Examples 313 to 365.

The compound is listed in the following Table 26 according to the present invention following the Example 190 (Step 1-5), and 188 (Step 1 and 2) of the program, be prepared using a variety of R ₃ of the amine of Example 190 step 1. For the compounds of Examples 314, 319, 333, 334, 335, 341, 351, 352, 353, 354, 357, 358, 359, 360, 362, 364 , iodine was used in step 4 of the procedure described in Example 190 . Methane-d ₃ replaces methyl iodide.

Preparative examples: 366 to 372.

Preparative Example 366 : 4'-(2-Chloro-6-fluoro-N-methylbenzimidino)-3'-(3-fluoroazetidin-1-yl)-6-methyl -[1,1'-biphenyl]-3-carboxamide.

Step 1: A mixture of Intermediate 190e (4.0g, 9.6mmol, 1.0 _{eq), Pin 2 B 2 (3.0g} , 11.5mmol, 1.2 _{eq), Pd (dppf) Cl 2} (816mg under N ₂ at 80 ℃, 1.0 mmol, 0.2 eq.) and a mixture of EtOAc (EtOAc, EtOAc (EtOAc) The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc ( EtOAc:EtOAc ESI-MS (M+H) ⁺ : 463.2.

Step 2: A mixture of 366a (150mg, 0.3mmol, 1.0 eq), 366b (463mg, 0.3mmol, 1.0 _{eq), Pd (dppf) Cl 2} (24mg, 0.03mmol, 0.1 eq) under N ₂ at 80 deg.] C and A mixture of Na ₂ CO ₃ (160 mg, 1.5 mmol, 5.0 eq.) in DMF / H ₂ O (3 mL, 3:1, v/v) The mixture was then filtered and the filtrate was purified by EtOAc EtOAc EtOAc EtOAc ESI-MS (M+H) ⁺ : 471.1.

Et added to a stirred solution of the 366c (80mg, 0.17mmol, 1.0 eq), HATU (95mg, 0.25mmol, 1.5 eq) and _{NH 4 Cl (18mg, 0.34mmol,} 2.0 equiv) in DCM (5mL): Step 3 ₃ N (57 mg, 0.57 mmol, 3.0 eq.). The mixture was stirred at room temperature for 3 hours. The mixture was then filtered and the filtrate was concentrated in vacuo to remove solvent. Product was purified by reverse phase HPLC (MeCN / water = 5% to 95%) by to afford a white solid of 366 (70mg, 87%). ESI-MS (M+H) ⁺ : 470.2. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 7.68-6.14 (m, 9H), 5.39-5.19 (m, 1H), 4.33 - 3.64 (m, 4H), 3.39-3.37 (m, 1.8H), 3.06-3.04 (m, 1.2H), 2.25 (s, 1.2H), 2.00 (s, 1.8H).

Preparative Example 367 : 4'-(2-Chloro-6-fluoro-N-methylbenzimidamide)-3'-(3-fluoroazetidin-1-yl)-6-isopropyl Keto-[1,1'-biphenyl]-3-carboxamide

Compound 367 of the system following the procedure described in Example 366, and 366a by the intermediate was 3-bromo-4-isopropyl-benzoyl amine coupling be prepared to provide 60mg (80%) of 367 as a white solid. ESI-MS (M+H) ⁺ : 498.2. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 7.87-6.19 (m, 9H), 5.51-5.31 (m, 1H), 4.48-4.01 (m, 4H), 3.51-3.49 (m, 1.5H), 3.17-3.15 (m, 1.5H), 2.71-2.60 (m, 1H), 1.23-1.03 (m, 6H).

Preparative Example 368 : 2-Chloro-N-(2'-chloro-3-(3-fluoroazetidin-1-yl)-4'-aminesulfonyl-[1,1'-biphenyl ]-4-yl)-6-fluoro-N-methylbenzamide.

Compound 368 was prepared according to the procedure described in Example 366 , which was obtained by coupling of intermediate 366a with 4-bromo-3-chlorobenzenesulfonamide to afford 80 mg (58%) of 368 as white solid. ESI-MS (M+H) ⁺ : 526.1. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 8.03 - 6.34 (m, 9H), 5.53-5.31 (m, 1H), 4.50 - 3.84 (m, 4H), 3.50 - 3.48 (m, 1.6H), 3.17-3.15 (m, 1.4H).

Preparative Example 369 : 2-Chloro-N-(2'-chloro-3-(3-fluoroazetidin-1-yl)-5'-aminesulfonyl-[1,1'-biphenyl ]-4-yl)-6-fluoro-N-methylbenzamide.

Compound 369 of the system following the procedure described in Example 366, and 366a by the intermediate was 3-bromo-4-chlorophenyl sulfonamide Amides coupling be prepared to provide 120mg (50%) of 369 as a white solid. ESI-MS (M+H) ⁺ : 526.1. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 7.92-6.34 (m, 9H), 5.54-5.30 (m, 1H), 4.50-3.79 (m, 4H), 3.50-3.48 (m, 1.7H), 3.17-3.15 (m, 1.3H).

Preparative Example 370 : 2-Chloro-4'-(2-chloro-6-fluoro-N-methylbenzimidamide)-3'-(3-fluoroazetidin-1-yl)- [1,1'-biphenyl]-3-carboxamide.

Compound 370 of the system following the procedure of Example 366, 366a by the intermediate composition to provide 100mg (75%) of 370 as a white solid with 3-bromo-2-chlorobenzamide Amides coupling be prepared. ESI-MS (M+H) ⁺ : 490.1. ¹ H NMR (400 MHz, CD ₃ OD, mixture of configuration isomers) δ : 7.57-6.30 (m, 9H), 5.51-5.31 (m, 1H), 4.88-3.75 (m, 4H), 3.50-3.47 (m, 1.6H), 3.17-3.15 (m, 1.4H).

Preparative Example 371 : 4'-(2-chloro-6-fluoro-N-methylbenzimidamide)-3'-(3-fluoroazetidin-1-yl)-6-methoxy Base-[1,1'-biphenyl]-3-carboxamide.

Compound 371 of the system following the procedure described in Example 366, and 366a by the intermediate was 3-bromo-4-methoxybenzophenone Amides coupling be prepared to provide 65mg (73%) of 371 as a white solid. ESI-MS (M+H) ⁺ : 486.2. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 7.93-6.47 (m, 9H), 5.51-5.30 (m, 1H), 4.47-3.95 (m, 4H), 3.89 (s , 1.5H), 3.82 (s, 1.5H), 3.48-3.14 (m, 3H).

Preparative Example 372 : 4'-(2-Chloro-6-fluoro-N-methylbenzimidamide)-3'-(3-fluoroazetidin-1-yl)-6-(III Fluoromethyl)-[1,1'-biphenyl]-3-carboxamide.

Compound 372 of the system following the procedure of Example 366, 366a by the intermediate was reacted with 3-bromo-4- (trifluoromethyl) benzoyl amine coupling be prepared to provide 70mg (64%) of a white solid 372 . ESI-MS (M+H) ⁺ : 516.1. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 7.99-6.30 (m, 9H), 5.49-5.35 (m, 1H), 4.39-3.48 (m, 6H), 3.17-3.16 (m, 1H).

Preparative Example 373 : 4'-(2-Chloro-6-fluoro-N-methylbenzimidamide)-6-fluoro-3'-(3-fluoroazetidin-1-yl)- [1,1'-biphenyl]-3-carboxamide.

Compound 373 of the system following the procedure described in Example 366, 366a by the intermediate was 3-bromo-4-fluorophenyl and A Amides coupling be prepared to provide 80mg (67%) of 373 as a white solid. ESI-MS (M+H) ⁺ : 574.1. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 8.09-6.54 (m, 9H), 5.55-5.39 (m, 1H), 4.42-3.41 (m, 5.5H), 3.16- 3.01 (m, 1.5H).

Preparative Examples 374-380:

The present invention compounds of Table 27 listed the following Examples 190 to follow (Step 1-5), and 188 (Step 1 and 2) of the program, be prepared using a variety of R ₃ of the amine of Example 190 step 1. Examples 375,376,377,378,379,380 of the compound, the step in the example of the Procedure 190 4 -d ₃ with iodomethane in place of iodomethane.

Examples 382 through 399.

Step 1: Heating 381a (3.2 g, 12.7 mmol, 1.0 eq.), Boc ₂ O (5.5 g, 25.4 mmol, 2.0 eq.) and K ₂ CO ₃ (3.5 g, 25.4 mmol, 2.0 eq.) in THF. A mixture of -H ₂ O (1:1, 50 mL) was taken 16 h. The reaction mixture was cooled to room temperature then diluted with EtOAc (EtOAc). The mixture was washed with brine (3 × 50mL), dried over Na ₂ SO ₄ and concentrated to give a brown oil of 381b (3.8g, 85%). ESI-MS (M+H) ⁺ : 352.9.

Step 2: To the middle of 381b (3.6g, 10.2mmol, 1.0 equiv) in anhydrous DMF (10mL) solution under N ₂ at room temperature _{K 2 CO 3 (2.8g, 20.8mmol} , 2.0 eq.) And then MeI (1.7 g, 12.2 mmol, 1.2 eq.) was added. After stirring at room temperature for 16 hours, the mixture was diluted with an aqueous solution (50mL) ₄ Cl NH and extracted with EtOAc (50mL × 3). The combined organic layers (100 mL) and washed with brine, dried over Na ₂ SO ₄ dried and concentrated to give a yellow solid of 381c (3.7g, 99%). ESI-MS (M+H) ⁺ : 367.1.

Step 3: Stir 381c (3.7 g, 10 mmol, 1.0 eq.), Pd(dppf)Cl ₂ (40 mg, 0.5 mmol, 0.05 eq.), 5-amine-mercapto-2- chlorobenzene at 90 ° C under N ₂ acid (4.0g, 20mmol, 2.0 equiv) and Na (2.1g, 20mmol, 2.0 equiv) in _{DMF / H 2 O 2 CO 3} : a mixture of 16 hours (30mL, 3 1, v / v) in the. The mixture was then cooled to room temperature, filtered and the filtrate was concentrated in vacuo. The residue _{(MeCN / H 2 O = 3} : 2) was purified by reverse phase HPLC to give a yellow solid of 381d (4.3g, 96%), ESI-MS (M + H) +: 442.2.

Step 4: A solution of 381d (4.3 g, 9.8 mmol, 1.0 eq. The residue was reverse phase _{HPLC (MeCN / H 2 O =} 2: 1) to afford purified by a yellow solid of 381e (3.3g, 99%). ESI-MS (M+H) ⁺ : 342.1.

Step 5: This reaction step is carried out in parallel. Acid chloride (0.58 mmol, 2.0 eq.) was added to a mixture of 381e (100 mg, 0.29 mmol) and TEA (88 mg, 0.87 mmol, 3.0 eq.) in 3 mL DCM. The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by reverse phase HPLC (MeCN containing 0.05% ammonia and H ₂ O) by to afford the desired product.

Examples 382 to 399. The following compounds of the invention listed in Table 28 were prepared following the procedures described in steps 1 to 5 .

Preparative Example 400 : N-(3-(3-Azabicyclo[3.1.0]hex-3-yl)-5-(2-chloro-5-((2-(dimethylamino))ethyl) Aminomethyl)phenyl)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide.

The intermediate 400 of the present invention was prepared following the procedure described in steps 1 through 6 of Example 201 . 3-Azabicyclo[3.1.0]hexane hydrochloride replaces pyrrolidine- 2 , 2 , 3 , 3 , 4 , 4 , 5 , 5 - d ₈ for use in Step 1 .

Step 1: 400a (2.8g, 6.6mmol , 1.0 eq.), 913835-75-3 (2.0g, 9.9mmol , 1.5 eq.), Na ₂ CO ₃ (1.4g, 13.2) were stirred at 80 ° C under N ₂ atmosphere. Methanol, 2.0 eq.) and a mixture of Pd (dppf) Cl ₂ (0.5 g, 0.66 mmol, 0.1 eq.) in DMF / H ₂ O (15.0 mL, 3/1, v/v). The mixture was then cooled to room temperature, diluted with MeOH (30 mL) and then filtered. The filtrate was concentrated in vacuo and EtOAcqqqqqqqq ESI-MS (M+H) ⁺ : 500.1. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 8.05-6.93 (m, 8H), 3.78-3.32 (m, 5H), 3.31-2.87 (m, 2H), 1.68-1.66 (m, 2H), 0.72-0.44 (m, 2H).

Step 2: to 400b (100 mg, 0.2 mmol, 1.0 eq.), HATU (115 mg, 0.3 mmol, 1.5 eq.) and N1,N1-dimethylethane-1,2-diamine (35 mg, 0.4 mmol, 2.0 eq. Eth ₃ N (60 mg, 0.6 mmol, 3.0 eq.) was added to a stirred solution of DMF (3 mL). The mixture was stirred at room temperature for 2 hours. Mixture was directly purified by reverse phase HPLC (MeCN / water = 5% to 95%) by to afford 400 (60mg, 55%) of a yellow solid. ESI-MS (M+H) ⁺ : 570.2. ¹ H NMR (400 MHz, CD ₃ OD, mixture of configuration isomers) δ : 8.02-6.93 (m, 8H), 3.78-3.36 (m, 9H), 3.32-3.26 (m, 2H), 3.00-2.99 (m, 6H), 1.70-1.68 (m, 2H), 0.74-0.69 (m, 1H), 0.52-0.41 (m, 1H).

Examples 401 to 416. The following compounds of the invention listed in Table 29 were prepared following the procedure described in Example 400 .

Examples 417 to 422. The following compounds of the invention listed in Table 30 were prepared following the procedure described in Example 201.

Examples 423 and 424. The following compounds of the invention listed in Table 31 were prepared following the procedure described in Example 200 .

Examples 425 and 426. The following compounds of the invention listed in Table 32 were prepared following the procedure described in Example 212 .

Table 32:

Examples 427 and 428. The following compounds of the invention listed in Table 33 were prepared following the procedure described in Example 156 by coupling the intermediate 156a to the appropriate amine (R ^1a NR ^1b ).

Examples 429 to 434. The compounds of Examples 429, 431 and 435 of the present invention listed in Table 34 were prepared by coupling intermediate 156a with various amine esters as described in Step 271 of Example 271 . The compounds of Examples 430, 432 and 434 were prepared from 429, 431 and 455 , respectively, by hydrolysis of the methyl ester fraction using the procedure described in Step 2 , Example 271 .

Examples 435 and 436. The compounds of Examples 435 and 436 of the present invention listed in Table 35 were prepared by coupling the intermediate 156a with various amine esters followed by hydrolysis of the ester as described in Examples 271, Steps 1 and 2 .

Preparative Example 437 :

Step 1: 691872-15-8 (800 mg, 3.7 mmol, 1.0 eq.), bicyclol 109-0104 (490 mg, 3.9 mmol, 1.05 eq.) and PPh ₃ (1.45 g, 5.5) at 0 ° C under N ₂ atmosphere. DIAD (1.11 g, 5.5 mmol, 1.5 eq.) was added to a mixture of EtOAc (1 mL). The mixture was stirred at room temperature for 16 hours and then concentrated. The residue was taken up in EtOAc (30 mL)EtOAc. The residue was carried out by TLC on silica gel (EtOAc: petroleum ether = 1/10) to give a pale yellow oil of 437a (650mg, 54%). ESI-MS (M+H) ⁺ : 327.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.08 (d, J = 2.0Hz 1H), 7.53 (d, J = 2.0Hz, 1H), 5.26-5.22 (m, 1H), 2.51-2.50 (m, 2H ), 1.64-1.58 (m, 2H), 1.14-1.12 (m, 2H), 1.07 (s, 3H), 1.03 (s, 3H).

Step 2: A mixture of 437a (650 mg, 2.0 mmol, 1.0 eq.), Fe powder (560 mg, 10.0 mmol, 5.0 eq.) and HOAc (1 mL) in EtOH (10 mL). The mixture was filtered and the filtrate was evaporatedjjjjjjjjjj The mixture was washed with aqueous NaHCO ₃ (2 × 50mL) and water (50mL). The organic phase was dried and concentrated to give a yellow oil of 437b (540mg), which was used without further purification in the next step. ESI-MS (M+H) ⁺ : 297.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.62 (s, 1H), 6.89 (s, 1H), 4.99-4.92 (m, 1H), 4.66 (br s, 2H), 2.53-2.45 (m, 2H) , 1.55-1.50 (m, 2H), 1.12-1.10 (m, 2H), 1.08 (s, 3H), 1.03 (s, 3H).

Step 3: To 437b (540mg, 1.8mmol, 1.0 equiv) at room temperature in pyridine (5mL) was added in the mixture 79455-63-3 (695mg, 3.6mmol, 2.0 equiv). The reaction was stirred at 60 ° C for 2 hours and concentrated in vacuo. The residue was taken up in EtOAc (20 mL)EtOAc. Crude 437c was used in the next step without further purification. ESI-MS (M+H) ⁺ : 609.1.

Step 4: (, 1.8mmol, 1.0 eq. 1.1g) mixture (10 mL) in the in MeOH was added _{K 2 CO 3 (495mg, 3.6mmol} , 2.0 equiv) was added to 437c. The reaction was stirred at 70 ° C for 2 hours and concentrated. The residue was taken up in EtOAc (20 mL)EtOAc. The residue was purified by EtOAc EtOAc ( EtOAc:EtOAc : ESI-MS (M+H) ⁺ : 453.1.

Step 5: (420mg, 0.93mmol, 1.0 eq.) In of DMF (3mL) was added NaH to 437d sequentially at 0 ℃ (75mg, 1.86mmol, 2.0 eq) and _{CD 3 I (160mg, 1.12mmol,} 1.2 equivalent). The mixture was stirred for 1 hour at 0 ℃ and washed with H ₂ O (5mL) and quenched. The residue was taken up in EtOAc (20 mL)EtOAc. Crude 437e was used in the next step without further purification. ESI-MS (M+H) ⁺ : 470.1.

Step 6: Stir 437e (430 mg, 0.93 mmol, 1.0 eq.), 1150114-35-4 (220 mg, 1.12 mmol, 1.2 eq.), Na ₂ CO ₃ (200 mg, 1.86 mmol, 2.0) at 100 ° C under N ₂ atmosphere. the mixture equiv.) and _{Pd (dppf) Cl 2 (73mg} , 0.09mmol, 0.1 eq) in _{DMF / H 2 O (2.0mL,} 3/1, v / v) in the 16 hours. The mixture was diluted with MeOH (3.0 mL) and filtered. The filtrate was purified by EtOAc (EtOAc EtOAc (EtOAc) ESI-MS (M+H) ⁺ : 545.2. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 8.11-7.30 (m, 5H), 7.15-6.78 (m, 3H), 6.34 (br s, 1H), 5.78 (br s, 1H), 4.96-4.94 (m, 1H), 2.51-2.44 (m, 2H), 1.64-1.59 (m, 2H), 1.11-1.01 (m, 8H).

Preparative sample 438 : N-(5-(5-Aminomethylindol-2-chlorophenyl)-3-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1.0] hex-3-yl) oxy) pyridin-2-yl) -2-chloro-6-fluoro -N-CD ₃ - benzoyl amine.

Step 1: To 109-0104 (850mg, 6.7mmol, 1.2 eq) at 0 ℃ was added NaH (336mg, 8.4mmol, 1.5 equiv) in the (8 mL) solution in THF. The mixture was stirred at room temperature for 2 hours, then 3-fluoro-2-nitropyridine (800 mg, 5.6 mmol, 1.0 eq.). The mixture was stirred at 60 ° C for additional 16 h and diluted with EtOAc (20 mL). The mixture was washed with brine (2×20 mL) and concentrated in vacuo. The residue was carried out by TLC on silica gel (EtOAc: petroleum ether = 1/10) to give a yellow oil of 438a (820mg, 59%). ESI-MS (M+H) ⁺ : 249.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 8.05 (dd, J = 1.2Hz, 4.4Hz, 1H), 7.47 (dd, J = 4.8Hz, 8.4Hz, 1H), 7.37 (dd, J = 0.8Hz, 8.8 Hz, 1H), 4.72-4.69 (m, 1H), 2.08-2.07 (m, 4H), 1.33-1.32 (m, 2H), 1.01 (s, 3H), 0.88 (s, 3H).

Step 2: The synthesis of 438b was identical to Example 437b (crude product). ESI-MS (M+H) ⁺ : 219.1.

Step 3: To a stirred solution of 438b (EtOAc, EtOAc (EtOAc) The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with saturated aqueous NaHCO ₃ (100mL × 2), washed (60 mL) brine and concentrated. The residue was carried out by TLC on silica gel (EtOAc: petroleum ether = 1/10) to give a yellow oil of 438c (270mg, 27% (two steps for purposes)). ESI-MS (M+H) ⁺ : 297.1. _{^{1 H NMR (400MHz, CDCl 3}} ) δ: 7.66 (d, J = 1.6Hz1H), 6.86 (d, J = 1.6Hz, 1H), 4.80 (br s, 2H), 4.58-4.55 (m, 1H), 2.05-1.91 (m, 4H), 1.32-1.30 (m, 2H), 1.01 (s, 3H), 0.89 (s, 3H).

Step 4: The synthesis of 438d was identical to Example 437c (crude product). ESI-MS (M+H) ⁺ : 609.1.

Step 5: The synthesis of 438e was identical to 437d (220 mg, 53% (for two steps); yellow solid). ESI-MS (M+H) ⁺ : 453.0.

Step 6: The synthesis of 438f was identical to 437e (crude product, yellow solid). ESI-MS (M+H) ⁺ : 470.1.

The synthesis of Step 7: 438 was identical to 437 (80 mg, 30% (for two steps), white solid). ESI-MS (M+H) ⁺ : 545.2. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 8.11 - 7.52 (m, 4.7H), 7.11-6.82 (m, 3.3H), 6.37 (br s, 1H), 5.82 (br) s, 1H), 4.71-4.57 (m, 1H), 2.13 - 2.03 (m, 4H), 1.33 (s, 2H), 1.01 (s, 3H), 0.85 (s, 3H).

Preparative Example 439 : N-(5-(5-Aminocarboxy-2-trifluoromethylphenyl)-3-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1 .0]hex-3-yl)oxy)pyridin-2-yl)-2-chloro-6-fluoro-N-CD ₃ -benzimidamide

The compound of Example 439 was prepared using the procedure as described in Example 438 . In step 7 , boronic acid 8-D is replaced with (5-aminomethylindenyl-2-(trifluoromethyl)phenyl)boronic acid to provide 401 . ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 8.07-6.95 (m, 8H), 4.71-4.70 (m, 1H), 2.08-2.00 (m, 4H), 1.36-1.33 (m, 2H), 1.02-1.00 (m, 3H), 0.90-0.87 (m, 3H). ESI-MS (M+H) ⁺ : 579.2.

Preparative Example 440 : N-(5-(5-Aminocarboxy-2-trifluoromethylphenyl)-3-(((1R,3r,5S)-6,6-dimethylbicyclo[3.1 .0]hex-3-yl)oxy)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide

The compound of Example 440 was prepared using the procedure as described in Example 438 . In step 7 , boronic acid 8-D is replaced with (5-aminoformamido-2-(trifluoromethyl)phenyl)boronic acid to provide 440 . ¹ H NMR (400 MHz, CD ₃ OD) δ : 8.07-6.95 (m, 8H), 4.71-4.70 (m, 1H), 3.49 (s, 2.5H), 3.28 (s, 0.5H), 2.08-2.00 ( m, 4H), 1.36-1.33 (m, 2H), 1.02-1.00 (m, 3H), 0.90-0.87 (m, 3H). ESI-MS (M+H) ⁺ : 579.2.

Preparative Example 441 : 4-(3-(3-Azabicyclo[3.1.0]hex-3-yl)-4-(2-chloro-6-fluoro-N-CD ₃ -benzimidamide) Phenyl)-5-chloro-N,N-dimethylpyridinecarbamide.

Step 1: Stir 441a (5.0 g, 11.7 mmol, 1.0 eq.), Pin ₂ B ₂ (5.9 g, 23.5 mmol, 2.0 eq.), KOAc (2.3 g, 23.5 mmol, 2.0 eq.) at 80 ° C under N ₂ atmosphere. ) and _{Pd (dppf) Cl 2 (979mg} , 1.2mmol, 0.1 eq.) in dioxane (50 mL for 4 h) of the. The mixture was cooled to room temperature and concentrated in vacuo. The residue was performed by column chromatography (petroleum ether / EtOAc = 10/1) was purified on silica gel to give a white solid of the desired product 441b (5g, 90%). ESI-MS (M+H) ⁺ : 474.2.

Step 2: Stir 441b (900 mg, 1.9 mmol, 1.0 eq.), 1256822-21-5 (447 mg, 1.9 mmol, 1.0 eq.), Na ₂ CO ₃ (403 mg, 3.8 mmol, 2.0) at 90 ° C under N ₂ atmosphere. the mixture equiv.) and _{Pd (dppf) Cl 2 (163mg} , 0.2mmol, 0.1 equiv) in _{DMF / H 2 O (40mL,} 3/1, v / v) in the 16 hours. Concentrate the solvent. The residue was diluted with MeOH (20 mL) and filtered. The filtrate was purified by EtOAc ( EtOAc EtOAc ) ESI-MS (M+H) ⁺ : 503.1.

Step 3: Stir 441c (80 mg, 0.16 mmol, 1.0 eq.), dimethylamine (11 mg, 0.24 mmol, 1.5 eq.), HOBT (32 mg, 0.24 mmol, 1.5 eq.), EDCI (46 mg, 0.24 mmol). 1.5 eq.) and a mixture of DIPEA (31 mg, 0.24 mmol, 1.5 eq.) in DMF (3 mL) The mixture was purified by EtOAc (EtOAc EtOAc (EtOAc) ESI-MS (M+H) ⁺ : 530.1. ¹ H NMR (400 MHz, CDCl ₃ , mixture of constitutive isomers) δ : 8.62 - 6.58 (m, 8H), 3.87 - 3.22 (m, 4H), 3.16 - 3.10 (m, 6H), 1.60-1.58 ( m, 2H), 0.65-0.45 (m, 2H).

Examples 442 to 445. The compounds of Example 428 of the present invention listed in Table 36 were prepared by coupling intermediate 441c with various amines as described in Step 3 of Example 441 .

Preparative Example 446 : 5-Chloro-4-(4-(2-chloro-6-fluoro-N-CD ₃ -benzimidamide)-3-(2,2,2-trifluoroethoxy) Phenyl)-N,N-dimethylpyridinecarbamide.

Step 1: Stir 243e (1.8 g, 4.0 mmol, 1.0 eq.), Pin ₂ B ₂ (2.0 g, 8.0 mmol, 2.0 eq.), KOAc (785 mg, 8.0 mmol, 2.0 eq.) at 90 ° C under N ₂ atmosphere. and _{Pd (dppf) Cl 2 (326mg} , 0.4mmol, 0.1 eq.) in a mixture of dioxane (20mL) in the four hours. The mixture was cooled to room temperature and concentrated to give 446a . The crude product was used in the next step without further purification. ESI-MS (M+H) ⁺ : 491.1.

Step 2: Stir 446a (7.8 g, 16.0 mmol, 1.0 eq.), 4-bromo-5-chloropicolinic acid (3.7 g, 19.2 mmol, 1.2 eq.), Na ₂ CO ₃ (N ₂ CO ₃ ) at 100 ° C under N ₂ atmosphere. A mixture of 3.4 g, 32.0 mmol, 2.0 eq.) and Pd(dppf)Cl ₂ (1.3 g, 1.6 mmol, 0.1 eq.) in DMF / H ₂ O (20 mL, 3/1, v/v). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc:EtOAc ESI-MS (M+H) ⁺ : 520.0.

Step 3: 446b (80mg, 0.15mmol , 1.0 eq.), dimethylamine hydrochloride (25mg, 0.30mmol, 2.0 eq.), HATU (114mg, 0.30mmol, 2.0 eq.) and TEA (30mg, A mixture of 0.30 mmol, 2.0 eq. in THF (2 mL) The mixture was purified by EtOAc (EtOAc EtOAc (EtOAc) ESI-MS (M+H) ⁺ : 547.1. ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ : 8.73 - 8.66 (m, 1H), 7.74 - 6.85 (m, 7H), 4.79 - 4.58 (m, 2H), 3.16 - 3.08 (m, 6H).

Preparative Examples 447 to 456:

The following compounds of the invention listed in Table 37 were prepared following the procedure described in Example 446 (Steps 1 through 3) and in Step 3 using a variety of R ^1a R ^2a NH amines.

Preparative Example 466 : N-(5-(4-Aminomethyl-2-chlorophenyl)-3-(piperidin-1-yl)pyridin-2-yl)-2-chloro-6-fluoro- N-methylbenzamide.

To 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-benzamide (60 mg, 0.21 mmol) and N-(5'-bromo-3,4,5,6-tetrahydro-2H-[1,3']bipyridine-2'- 2-chloro-6-fluoro-N-methyl-benzamide (91 mg, 0.21 mmol) in N,N-dimethylformamide (3.0 mL) and water (0.30 mL, 17 mmol) a mixture of [1,1' bis(diphenylphosphino)ferrocene]dichloropalladium(II) and methylene chloride (1:1) (14 mg, 0.017 mmol) and cesium carbonate (208.3) Mg, 0.64 mmol). The reaction mixture was stirred at 95 ° C for 40 minutes in a microwave reactor. EtOAc and water were added and the two layers were separated. The organic layer was concentrated and flash chromatographed (0-20% MeOH of CH ₂ Cl ₂₎ on silica gel to give the title product. The sample was further purified by reverse-phase HPLC (30×50 mm, 10 m, water containing 10-90% CH ₃ CN, 10 ml/min flow rate) to N-(5-(4-aminecarbamido-2-chlorophenyl) TFA salt (51 mg) of 3-(piperidin-1-yl)pyridin-2-yl)-2-chloro-6-fluoro-N-methylbenzamide. ¹ H NMR (400 MHz, DMSO- d6 ): a mixture of constitutive isomers, δ 8.31-7.07 (m, 10H), 3.48 (m, 1.3H), 3.17 (m, 1.7H), 2.95 - 2.75 (m, 2.8H), 2.54 (m, 1.2H), 1.66 (m, 4H), 1.53 (m, 2H). ESI-MS (M+1) ⁺ : 501.1.

Preparative Example 467: 2-Chloro-4 '- (2-chloro-6-fluoro -N-CD ₃ - benzoyl amino) -3' - (2,2,2-trifluoroethoxy) - [1,1'-biphenyl]-4-carboxamide.

Stirring 2-chloro-4'-(2-chloro-6-fluoro-N-CD ₃ -benzimidamide)-3'-(2,2,2-trifluoroethoxy)- at room temperature [1,1'-biphenyl]-4-carboxylic acid (intermediate Y1, 0.5 mmol), NH ₄ Cl (56 mg, 1.0 mmol), HATU (380 mg, 1.0 mmol) and triethylamine (101 mg, 1.0 mmol) The mixture in DMF (3 mL) was 1 hour. The mixture is directly (CH ₃ CN / water = 5-95%) was purified by reverse phase HPLC to afford the title compound of white solid (95mg). ¹ H NMR (400 MHz, CD ₃ OD, mixture of constitutive isomers) δ 8.07-6.87 (m, 9H), 4.79-4.53 (m, 2H). ESI-MS (M+H) ⁺ : 518.0.

Preparative Examples 468 to 476:

The following analogs as shown in Table 38 were synthesized from the appropriate carboxylic acid intermediate Y and amine (or ammonium chloride) following procedures analogous to the procedure of Example 408 .

Preparation of intermediate Y1 : 2-chloro-4'-(2-chloro-6-fluoro-N-CD ₃ -benzimidamide)-3'-(2,2,2-trifluoroethoxy)- [1,1'-biphenyl]-4-carboxylic acid

Stirring N-(4-bromo-2-(2,2,2-trifluoroethoxy)phenyl)-2-chloro-6-fluoro-N-CD ₃ -benzene under N ₂ atmosphere at 100 ° C Formamide (220 mg, 0.5 mmol), 4-dihydroxyboryl-3-chlorobenzoic acid (120 mg, 0.6 mmol), Na ₂ CO ₃ (106 mg, 1.0 mmol) and Pd(dppf)Cl ₂ (73 mg, 0.1) mmol) in a mixture of _{DMF / H 2 O (4.0mL /} 1.3mL) 16 h. The mixture was diluted with MeOH (3 mL) and filtered. The filtrate was purified by EtOAc EtOAc EtOAc:EtOAc ESI-MS (M+H) ⁺ : 519.1.

Preparation of intermediate Y2-Y10:

The following intermediates as shown in Table 39 were synthesized following a procedure similar to that of the intermediate Y1 .

Preparative Examples 477 to 478 :

Example 477 can follow the procedure described in Example 190 (Steps 1 through 5) by using piperidine-d10 in Step 1 and (5-Aminomethylindenyl-2-(trifluoromethyl) in Step 5. Phenyl)boronic acid was prepared.

Example 478 can follow the procedure described in Example 190 (steps 11 through 5) by using piperidine-d10 in step 1, methyl iodide-d3 in step 4, and (5-amine in step 5) Mercapto-2-(trifluoromethyl)phenyl)boronic acid was prepared.

All of the compounds described herein can also be isolated in the form of a pharmaceutically acceptable salt. In some embodiments, each compound described herein can be isolated as a TFA salt.

Analysis example

Analysis 1: Biochemical GST-RORγ TR-FRET analysis

Analysis 1 is a method for measuring the disruption or activation of coactivator peptide/RORγ binding by quantifying the ability of a molecule to inhibit or enhance the activity of RORγ.

RORγ TR-FRET Analytical Reagent

RORγ TR-FRET assay buffer component

Equipment and materials:

Final conditions for RORγ FRET analysis: (20 μL compound + 5 μL detection mixture = 25 μL total assay volume): 20 mM Tris-HCl pH 7.0, 60 mM NaCl, 5 mM MgCl ₂ , 1 mM DTT, 0.1% BSA; 10 nM GST-ROR γ (LBD) 40 nM biotin-TRAP220; 50 nM SA-APC; 1.5 nM Eu-anti-GST IgG; 1.0% DMSO. Since the compounds exhibited more potent inhibitory activity, 2.5 nM instead of 10 nM GST-ROR gamma (LBD) was used to improve analytical sensitivity.

Analysis plan:

Compound dilutions (125 x final test concentration) were prepared by preparing a 2.5 mM dilution from 10 mM stock using 100% DMSO. A 9-point triple compound dilution (2.5, 0.83, 0.28, 0.093, 0031, 0.0102, 0.0034, 0.0011, 0.00038 mM) was then prepared starting at a starting concentration of 2.5 mM. For example, 6 μL of 10 mM compound was added to 18 μL of DMSO, and 10 μL of the resulting solution was titrated into 20 μL of DMSO. Subsequently, 1 μL of 100% DMSO containing 125× test compound was diluted into 99 μL of assay buffer in a compound buffer diluted greiner dish to give a final DMSO concentration of 1%.

An 8.3x solution containing the europium-labeled antibody and RORy LBD was prepared, followed by the addition of 3 [mu]L of this solution to each well on a 384 well plate, followed by the addition of 20 [mu]L of each compound previously diluted in assay buffer (described above). Analytical controls (0% inhibition and 100% inhibition control) were added to rows 1, 12, 13 and 24 of the 384 well dilution greiner disk. For the 0% inhibition control, 1 [mu]L of 100% DMSO was added to 99 [mu]L of assay buffer. For the 100% inhibition control, 1 μL of 3.125 mM T0901317 (125×, 25 μM final concentration) was added.

The plate was shaken for 1 minute, centrifuged at 1000 rpm for 10 seconds, followed by incubation at room temperature for 1 hour and then 2 μL of 12.5×TRAP220 peptide and streptavidin-APC were added and read on a disk reader.

For initial analysis of color development, use LJL Analyst. The LJL Analyst settings are as follows: ratio: acceptor/donor; acceptor: HRTF (Packard); excitation: 铕FRET 330 nm; emission: FRET acceptor 665 nm; donor: HRTF (Packard); excitation: 铕FRET 330 nm; emission: FRET chelate donor; flash number/hole: 100; integration time: 400 μs; interval: 1 x 10 ms flash; delay after flash: 50 μs.

For routine analytical screening, an Envision disc reader is used. Envision settings are as follows: excitation: 330 ± 75 nm, emission 1: 665 ± 7.5 nm, emission 2: 615 ± 8.5 nm; delay: 90 μs; window period: 300 μs; flash number: 100; time between flashes: 2000 μs.

date analyzing:

The ROR gamma FRET assay is an endpoint analysis with a receiver/donor x 1000 reading (emission ratio). Analytical dose response tests were performed at each concentration double focus with 10 dilutions per compound curve. Conversion of the raw data to activity % was performed using an analytical control in which 100% activity was represented by the mean DMSO control. The 0% activity is the average of the 25 [mu]M T0901317 compound control. IC curve fitting was performed using a graphpad prism and fitted to the following S-shaped dose-response (variable slope) equation: Y = bottom + (top-bottom) / (1 + 10^ ((Log _EC50 -X) ) × Hill slope)); where X is the logarithm of the concentration and Y is the reaction (Y starts at the bottom and reaches the top in the S shape, which is the same as the "four-parameter logic equation")

In the final assay disk setup, there are 16 compounds per 384 well plate. The DMSO control (0% inhibition) was in lines 1 and 13. 25 μM T0901317 control (100% inhibition) in lines 12 and 24. Compound titres are in lines 2-11, 14-23. N = 2 for each concentration to produce 10-point IC ₅₀ curve.

Analysis 2: RORγ Gal4 Cell Report Conductor Analysis of 293T Cells

Cell culture.

After thawing from liquid nitrogen, cells were used for transactivation analysis after 2 to 3 passages. The freezing medium is a medium supplemented with up to 10% DMSO. Conventional cultures include two passages per week. In the analysis, cells were discarded after 4-6 weeks. Cells were grown to subconfluence (80-90%) for the purpose of transactivation analysis.

Secondary culture of 293T cells. The cells were seeded in T75 cm ² flasks in 20 mL of medium by adding 50 mL of FBS, 5 mL of Glutamax, 5 mL of NEAA, 5 mL of sodium pyruvate and 5 mL of penicillin/streptomycin to a 500 mL MEM bottle (with phenol red). The cells were grown at 37 ° C in the presence of 5% CO ₂ until they reached secondary confluence (80-90%), at which time the medium was discarded. PBS (about 5 mL per flask) was added to the flask at room temperature, and the cells were detached by tapping the flask. Viable cells count, the desired number of cells were transferred to a new flask, and the new volume of the flask and fresh media package (final volume: 20mL in T75 cm ² flask). The flask was incubated at 37 ° C under 5% CO ₂ .

Conductor analysis was performed on RORγ Gal4 cells. On day 1, cells were seeded in 96 well plates in plating medium (phenol red free MEM, 10% CCDS). On day 2, the plating medium was removed and the cells were transfected. About 4-6 hours after transfection, assay medium (MEM without phenol red and serum) was added, and then the compound was added. On day 3, cells were lysed, luciferase buffer was added, and luminescence was measured using a dual flash procedure.

Inoculate the cells. For each assay point, 50,000 293T cells were used per well of a 96-well white-walled clear bottom assay disk. The cells were seeded in a plating medium by adding 50 mL of CCDS, 5 mL of Glutamax, 5 mL of NEAA, 5 mL of sodium pyruvate, and 5 mL of penicillin/streptomycin to a 500 mL MEM bottle (no phenol red). Trypsin treated cells were used for vaccination to ensure reproducibility of the method. After one washing step with about 10 mL of PBS, 1.5 mL of trypsin-EDTA solution (Sigma-Aldrich; T3924) was added. After 2 to 3 minutes, the flask was lightly tapped and 8 mL of medium was added. The cells were briefly centrifuged at 200 xg for 2 minutes, the supernatant was discarded, and the cells were resuspended in a small volume by pipetting the suspension up and down 10 times or more. Because cells tend to form clots, special care must be taken to separate the cells from each other. Cells were then counted and seeded at 50,000 cells per well in 100 [mu]L of plating medium. The 96-well assay dish was incubated overnight at 37 ° C under a humidified atmosphere at 5% CO ₂ .

Transfection. Transfection was performed using a PEI solution produced in Phenex with 71 ng of total DNA per well (each well containing 50 ng of nuclear receptor expressing plastid plus 20 ng of pFR-Luc reporter and 0.5 ng of pRL-CMV reporter). The ratio of DNA:PEI solution was 1:5 (μg: μL), wherein the PEI concentration was 0.45 μg/μL, and the DNA:PEI ratio was 1:2.25 (μg/μg).

The DNA solution was prepared by diluting the DNA in OptiMEM and gently vortexing. A solution sufficient for 15 μL of DNA mixture per well should be prepared. For the experiments described herein, an excess of 16% was used. For example, for one assay plate, 2.24 μg of firefly luciferase reporter plastid (pFR-Luc), 5.6 μg of NR expression vector (pCMV-BD-nuclear receptor) and 56 ng of Renilla luciferase were reported. Body mass. These DNA amounts were diluted in 1680 μL OptiMEM.

The PEI solution was prepared by diluting PEI in the same volume of OptiMEM. The amount of PEI solution was calculated using the formula: μg of DNA × 5. For the experiments described herein, an excess of 16% was used. For example, for one assay plate, 39.8 μL of PEI solution was diluted in 1640 μL OptiMEM.

The transfection mixture was produced by immediately adding the PEI solution to the plastid solution (the plastid solution was not added to the PEI solution), gently vortexing, and incubating the resulting solution for at least 20 minutes at room temperature.

The coating medium is removed from the cells by dumping the tray and drying on a paper towel.

Add the transfection mixture (PEI+DNA) to the adherent cells. The 96-well assay plate was incubated in a moisture-containing atmosphere at 37 ° C under 5% CO ₂ for 4-6 hours.

Compound treatment and enzyme activity measurement. The DMSO compound master was prepared by diluting the compound from the 10 mM stock in row 11 and then diluting to the 4th row at a 1:3 ratio across the disk. Line 3 contained only DMSO (high control) and line 2 contained 2.5 mM Tularik control (low). The compound is at 1000X.

132 μL of plating medium (with CCDS) was added to each well to a new 96-well plate. Next, transfer 1 μL from each well of the DMSO compound dish to the corresponding well of the new dilution dish. The DMSO concentration was 7.5% and the compound was 7.5X. The disk is covered and mixed on the disk oscillator. About 4-6 hours after the addition of the transfection solution, 100 μL of assay medium was added to the cells. An assay medium was prepared by adding 5 mL of Glutamax, 5 mL of NEAA, 5 mL of sodium pyruvate, and 5 mL of penicillin/streptomycin to a 500 ml MEM bottle (no phenol red). Just 20 μL of the compound from the new dilution dish was added to the cells in triplicate. Although all wells on the edge of the disc were excluded from the analysis due to edge effects, they should all contain the same final medium volume: 150 [mu]L (1.3% CCDS, 0.1% DMSO and 1X compound). The cells were incubated for 16 to 20 hours in a moisture-containing atmosphere at 37 ° C under 5% CO ₂ . After incubation, the medium was completely removed by dumping the pan and drying it on a paper towel. Just 20 μL of 1× Passive Dissolution Buffer (Promega) was added and the plates were incubated on a disk shaker for 10-15 minutes at room temperature.

Measurements were made using a BMG LUMIstar OPTIMA illuminating disc reader. First, 75 μL of firefly luciferase buffer per well was injected. 75 μL of Renilla Luciferase buffer per well was injected just 1.1 seconds after the start of the firefly buffer injection. The total measurement time is 2 seconds per well. For direct firefly measurements, an average of values 7-11 (0.6 to 1 second) is used. For direct sea kidney measurements, an average of values of 16-20 (1.5 to 1.9 seconds) was used.

Materials and equipment for conductor analysis of ROR Gal4 cells. All plasmids used to transfect 293T cells were prepared using QIAGEN Maxi, Giga or Mega kits and lysed and diluted with MilliQ water.

Firefly luciferase buffer

Renilla luciferase buffer

material.

device.

ROR-γ has been implicated in the development and function of lymphoid tissue-inducing cells, thymocytes, γδ T cells, natural killer cells, and both cytotoxic αβ T cells and helper αβ T cells. These cell types and the soluble factors produced by such cells (including the cytokines IL-17, IL-17F and IL-26) have been shown to contribute to autoimmune diseases in many animal disease models and have been implicated in The pathogenesis of human immune-mediated diseases. The reverse agonist of ROR-γ blocks the development of these pathogenic cell types and the pro-inflammatory cytokines produced by such pathogenic cell types. This effect provides a therapeutic benefit to the immune-mediated diseases in which the cells function.

The compound exhibits a reverse agonist ROR-γ activity on nuclear receptors. Most of the compounds of the present invention, IC ₅₀ values of less than 15μM, and other compounds of the invention IC ₅₀ values as low as 0.010 m, as measured by the biochemical GST-RORγ TR-FRET analysis. In RORγ Gal4 cells reported in the analyzer as described above, the compounds of the invention tested EC ₅₀ of this value is less than the majority of 15μM, and the other compounds of the invention EC ₅₀ values as low as 0.050μM.

Analysis 3: RORγ splenocyte IL-17

Reagents and buffers used in IL-17 analysis of RORγ splenocytes

Equipment and materials.

Analysis program.

Day 1. Round bottom 96-well plates (Corning, #3799) were coated with PBS containing 10 μg/mL anti-mCD3e (50 μL per well) and stored overnight at 4 °C.

Day 0. A primary compound dilution (1000 x final test concentration) was prepared in a 96-well polypropylene disk (Greiner Bio-one, #651201) by preparing a 5 mM dilution from 10 mM stock using 100% DMSO. Seven-point triplicate dilutions of compounds (5, 1.667, 0.556, 0.185, 0.062, 0.021, 0.007, and 0.002 mM) were then prepared starting at a starting concentration of 5 mM. For example, 10 μL of 10 mM compound was added to 10 μL of DMSO, of which 8 μL was titrated into 16 μL of DMSO. The tray is covered and stored in a fume hood at room temperature.

Spleen cells are then prepared. Spleens from 3 wild-type C57BL/6 mice were collected and then dissociated on a 50 mL tube using a syringe plunger with a 70 [mu]m cell strainer (BD Falcon, #REF 352350). The cells were rinsed through the filter using approximately 20 mL RPMI and then centrifuged for 5 minutes at 0.3 rcf (1300 rpm, Eppendorf, # Centrifuge 5702R, rotor number A-4-38). Discard the supernatant. The pellets were dispersed and appropriately resuspended by gently pipetting and adding 1 mL of lysis buffer per spleen to the granules. After incubation for 5 minutes at room temperature, the cells were centrifuged at 0.3 rcf for 5 minutes and the supernatant was discarded. The cells were resuspended in 5 mL RPMI and counted. The cell concentration was then adjusted to 5 x 10 ⁶ cells per ml. Anti-mCD3e was aspirated from each well, and 100 μL of cells per well was plated in a 96-well plate (Corning, #3799).

A mixture of cytokines and antibodies in RPMI (5% excess) was prepared: 1 ng/mL TGF-b, 10 ng/mL IL-6, 0.625 ng/mL IL-23, 5 μg/ml anti-mCD28. 90 μl of the cytokine antibody mixture was added to each well to produce a total volume of 190 μl per well.

Just 5 μL of the diluted compound was added to 245 μL of RPMI, the solution was mixed, and 10 μL was transferred to each well. The final volume of each well was 200 μL, resulting in a final concentration of each compound of 5, 1.667, 0.556, 0.185, 0.062, 0.021, 0.007, 0.002 μM. Control wells were prepared by adding 7 μl of 100% DMSO to 343 μl RPMI for DMSO high control and 2.5 μm T0901317 for low control (by adding 4 μL of 5 mM T0901317 stock to 4 μL of DMSO) The solution was mixed and prepared, and then 7 μL to 343 μl of RPMI was added). The cells were incubated for 2 days at 37 ° C in a CO ₂ incubator.

Day 2 The supernatant was collected and stored at -20 °C. The IL-17 cytokine content of the supernatant was then determined using a mouse IL-17 DuoSet ELISA color kit. Analytical dose response tests were performed at each concentration of three stresses, using 8 dilutions for each compound curve. Conversion of the raw data to activity % was performed using an analytical control in which 100% activity was represented by the mean DMSO control and 0% activity was the average of 2.5 μM T0901317 compound control. The EC ₅₀ curve fit was performed using a graphpad prism and fitted to the following sigmoidal dose-response (variable slope) equation: Y = bottom + (top - bottom) / (1 + 10 ^ ((LogEC50 - X)) × Hill slope)), where all variables are as previously described.

Analysis of the IL 17-RORγ of the splenocytes as described above, EC testing of the compounds of the present invention, ₅₀ values between 0.500μM and 12.000μM. The specific exemplary activities of the test compounds are shown below.

In the above, the EC ₅₀ data is expressed as follows: greater than or equal to 10 micromolar concentration designated as A; less than 10 micromolar concentration but greater than or equal to 1 micromolar concentration designated as B; less than 1 micromolar concentration but greater than Or equal to 500 nanomolar concentrations designated as C; less than 500 nanomolar concentrations but greater than or equal to 100 nanomolar concentrations designated as D; and less than 100 nanomolar concentrations designated as E.

Claims (167)

A compound of formula I: Or a pharmaceutically acceptable salt thereof, wherein: R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, Optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocycloalkyl-alkyl And optionally substituted cycloalkyl-alkyl, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring; R ^2a , R ^2b , R ^2c and R ^2d are each independently H , halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ , optionally substituted heteroaryl or optionally substituted heterocycloalkyl; R ⁴ , R ⁵ and R ⁶ are each independently substituted as appropriate Alkyl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form as appropriate 4 to 7 members Heterocycle; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN, or any of R ^8a , R ^8b , R ^8c , R ^8d and R ^8e The two adjacent substituents may together form a 4- to 7-membered cycloaliphatic ring or a 4- to 7-membered heterocyclic ring which may be optionally substituted; X is CH or N; and J is a bond or C _1-4 alkyl. The compound of claim 1, wherein: R ³ and R ⁷ together form a 4- to 7-membered heterocyclic ring which is optionally substituted, and J is a bond. The compound of claim 2, wherein the compound of formula I is of formula Ia: Wherein: W is CR ^7c R ^7d , O or NR ^7a ; R ^7a and R ^7b are each independently H or C _1-4 alkyl, and R ^7c and R ^7d are each independently H, C _1-4 alkane. Base or halogen; and n is 1, 2 or 3. The compound of claim 1 to 3, wherein: R ^1a and R ^1b are each independently H, C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxygen Heterocyclobutane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, diazetidine, piperazine, morpholine, thiocyclobutane, Tetrahydrothiophene, tetrahydrothiopyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiopyran dioxide, C _1-6 aralkyl, furyl-C _1-6 alkyl, phenylthio-C _1-6 alkyl, 2H-pyrrolyl-C _1-6 alkyl, pyrrolyl-C _1-6 alkyl, oxazolyl-C _1-6 alkyl, thiazolyl-C _{1- 6} alkyl, imidazolyl-C _1-6 alkyl, pyrazolyl-C _1-6 alkyl, isoxazolyl-C _1-6 alkyl, isothiazolyl-C _1-6 alkyl, 1, 3,4-thiadiazolyl-C _1-6 alkyl, 2H-piperidyl-C _1-6 alkyl, 4-H-piperidyl-C _1-6 alkyl, pyridyl-C _{1- 6} alkyl, pyridazinyl-C _1-6 alkyl, pyrimidinyl-C _1-6 alkyl, pyrazinyl-C _1-6 alkyl, 1,3,5-triazinyl-C _1-6 alkyl; or R ^1a and R ^1b together form an azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone Morpholine, diazetidine or piperazine; wherein each of the aforementioned non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycle Alkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen. A compound of formula II: In another aspect, the invention includes a compound of formula II: Or a pharmaceutically acceptable salt thereof, wherein: J is a bond or a C _1-4 alkylene group; or ; B is , , , , or ; the restriction is that when J is C _1-4 alkyl and B is When R ^{10 is} not a hydroxyl group; X ¹ is CH or N; X ² is CR ^2a or N; X ³ is CR ^2b or N; X ⁴ is CR ^2d or N; X ⁵ is S or O; Z ¹ and Z ² is independently H or an optionally substituted alkyl; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halo, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, SR ⁴ , S(O) ₂ R ⁴ , NR ⁵ R ⁶ , optionally substituted a heteroaryl or optionally substituted heterocycloalkyl; each R ⁴ is independently an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl or, as appropriate Substituted heterocycloalkyl; R ⁵ and R ⁶ are each independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl or, optionally substituted heterocycloalkyl; R ⁷ is C _1-4 alkyl, or R ³ and R ⁷ may together form an optionally substituted 5 to 7 membered heterocyclic ring; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen. , C _1-4 alkyl, OR ⁴ , NR ⁵ R ⁶ , CF ₃ or CN; R ⁹ is a bond, optionally substituted alkyl or a substituted cycloalkylene group; R ¹⁰ is NR ^1a R ^1b , a hydroxy group or an optionally substituted alkyl group; R ^12a and R ^12b are each independently an optionally substituted alkyl group, or R ^12a and R ^12b may together form an optionally substituted 4 to 7 membered heterocyclic ring; and R ^1a and R ^1b are each independently H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted Cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroaralkyl, optionally substituted heterocyclic An alkyl-alkyl group, optionally substituted cycloalkyl-alkyl group, or R ^1a and R ^1b together form an optionally substituted 4 to 7 membered heterocyclic ring. The compound of any one of claims 1 to 5, wherein: R ^1a and R ^1b are each independently H, C _1-4 alkyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane , tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, tetrahydrothiophene dioxide, C _1-4 aralkyl, pyrrolyl-C _1-4 alkyl, imidazolyl-C _{1 -4} alkyl, pyrazolyl-C _1-4 alkyl, pyridyl-C _1-4 alkyl, pyridazinyl-C _1-4 alkyl, pyrimidinyl-C _1-4 alkyl, pyrazinyl -C _1-4 alkyl; or R ^1a and R ^1b together form azetidine, pyrrolidine, piperidine, morpholine, diazetidine or piperazine; wherein each of the aforementioned non-H moieties is optionally One or more unsubstituted substituents selected from the group consisting of C _1-4 alkyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine , pyrrolidone, piperidone, diazetidine, piperazine, morpholine, thiocyclobutane, tetrahydrothiophene, tetrahydrothiopyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide , tetrahydrothiopyran dioxide, hydroxyl, OC _1-4 alkyl, C _1-4 carboxyl and N(C _1-4 alkyl) ( C _1-4 alkyl). The compound of any one of claims 1 to 6, wherein: R ^1a and R ^1b are each independently H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentyl, cyclohexyl, oxyheterocycle Butane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl or pyridyl; or R ^1a and R ^1b together form azetidine, pyrrolidine, morpholine or piperazine; Each of the aforementioned non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH ₃ , C ₂ H ₅ , OH, OCH ₃ , OC ₂ H ₅ , CH ₂ COOH, C ₂ H ₄ COOH, C ₃ H ₆ COOH, N(Me)(Me), N(Me)(Et), N(Et)(Et), tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine and pyrrolidine ketone. The compound according to any one of claims 1 to 7, wherein at least one of R ^1a and R ^1b is an unsubstituted non-H moiety; or R ^1a and R ^1b together form an unsubstituted heterocyclic ring. The compound according to any one of claims 1 to 7, wherein at least one of R ^1a and R ^1b is a substituted non-H moiety; or R ^1a and R ^1b together form a substituted heterocyclic ring. The compound of any one of claims 1 to 9, wherein R ^1a and R ^1b are each independently selected from the group consisting of H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentyl, ring Hexyl, oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, , , R ^1a and R ^1b are formed together: , , , The compound of any one of claims 1 to 9, wherein R ^1a and R ^1b are each independently selected from the group consisting of H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentyl, ring Hexyl, oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , and Or R ^1a and R ^1b together , , or . The compound of claim 11, wherein each of R ^1a and R ^1b is H. The compound of claim 11, wherein R ^1a and R ^1b are each independently H, CH ₃ , C ₂ H ₅ or C ₃ H ₇ . The compound of claim 11, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is , , , , , The compound of claim 11, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is , , , , or The compound of claim 11, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is cyclopentyl, cyclohexyl or . The compound of claim 11, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene Oxide or . The compound of claim 11, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is phenyl, or . The compound of claim 11, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is 2-pyridyl, 3-pyridyl or 4-pyridyl. The compound of claim 11, wherein R ^1a and R ^1b are formed together , , The compound of any one of claims 1 to 20, wherein R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ . The compound of any one of claims 1 to 21, wherein R ^2a , R ^2b , R ^2c and R ^2d are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CF ₃ . The compound of any one of claims 1 to 22, wherein: R ^2a , R ^2c and R ^2d are each independently H or F; and R ^2b is H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ or OC ₂ H ₅ . The compound of any one of claims 1 to 23, wherein: R ^2a , R ^2b , R ^2c and R ^2d are each H; R ^2a , R ^2c and R ^2d are each H, and R ^2b is F; R ^2a R ^2b and R ^2c are each H and R ^2d is F; R ^2a , R ^2c and R ^2d are each H, and R ^2b is OCH ₃ ; R ^2a , R ^2c and R ^2d are each H, and R ^2b Is CH ₃ ; R ^2a , R ^2c and R ^2d are each H and R ^2b is Cl; R ^2a , R ^2b and R ^2d are each H and R ^2c is F; R ^2a and R ^2b are each F, and R ^2c and R ^2d are each H; or R ^2a and R ^2c are each H, R ^2c is Cl, and R ^2d is F. The compound of any one of claims 1 to 24, wherein R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, C _1-4 alkyl, OC _1-4 Alkyl, NR ⁵ R ⁶ , CF ₃ or CN. The compound of any one of claims 1 to 25, wherein R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently F, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ or CF ₃ . The compound of any one of claims 1 to 26, wherein: R ^8a and R ^8e are each independently H, F, Cl or CH ₃ ; and R ^8b and R ^8d are each independently H, Cl, F, CH ₃ , OCH ₃ or CF ₃ ; and R ^8c is H, Cl, CH ₃ or OCH ₃ . The compound of any one of claims 1 to 27, wherein: R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each H; and R ^8a , R ^8b , R ^8d and R ^8e are each H, and R ^8c is Cl; R ^8a , R ^8b , R ^8d and R ^8e are each H, and R ^8c is CH ₃ ; R ^8a , R ^8b , R ^8d and R ^8e are each H, and R ^8c is OCH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is Cl; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is CF ₃ ; R ^8a , R ^8c , R ^8d and R ^{8e is} each H and R ^8b is CH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is OCH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is F; R ^8b , R ^8c , R ^8d and R ^8e are each H and R ^8a is Cl; R ^8b , R ^8c , R ^8d and R ^8e are each H, and R ^8a is CH ₃ ; R ^8b R ^8c and R ^8d are each H, R ^8a is F, and R ^8e is Cl; R ^8a , R ^8d and R ^8e are each H, and R ^8b and R ^8c are each Cl; R ^8b , R ^8d and R ^{8e is} each H, and R ^8a and R ^8c are each Cl; or R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F. The compound of any one of claims 1 to 28, wherein X is N. The compound of any one of claims 1 to 28, wherein X is CH. The compound of any one of claims 3 to 30, wherein R ^7a and R ^7b are each independently H or C _1-3 alkyl. The compound of any one of claims 3 to 31, wherein R ^7a and R ^7b are each independently H or CH ₃ or CH ₂ CH ₃ . The compound of any one of claims 3 to 32, wherein R ^7a and R ^7b are each independently H or CH ₃ . The compound of any one of claims 3 to 33, wherein: W is CR ^7c R ^7d ; and R ^7c and R ^7d are each independently H, C _1-3 alkyl or F. The compound of any one of claims 3 to 34, wherein W is CR ^7c R ^7d ; and R ^7c and R ^7d are each independently H, CH ₃ or F. The compound of any one of claims 3 to 35, wherein: W is CR ^7c R ^7d ; and R ^7c and R ^7d are both H; R ^7c and R ^7d are both CH ₃ ; or R ^7c and R ^7d are F. The compound of any one of claims 3 to 33, wherein W is O. The compound of any one of claims 3 to 33, wherein: W is NR ^7a ; and R ^7a is C _1-3 alkyl. The compound of any one of claims 3 to 33 or 38, wherein: W is NR ^7a ; and R ^7a is CH ₃ . The compound of any one of claims 3 to 39, wherein n is 1. The compound of claim 3 to 39, wherein n is 2. The compound of claim 3 to 39, wherein n is 3. The compound of claim 3, wherein: R ^1a and R ^1b are each independently: H, C _1-6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, oxa Cyclobutane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone, diazetidine, piperazine, morpholine, thiocyclobutane, tetra Hydrothiophene, tetrahydrothiopyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiopyran dioxide, C _1-6 aralkyl, furyl-C _1-6 alkyl, benzene Thio-C _1-6 alkyl, 2H-pyrrolyl-C _1-6 alkyl, pyrrolyl-C _1-6 alkyl, oxazolyl-C _1-6 alkyl, thiazolyl-C _1-6 Alkyl, imidazolyl-C _1-6 alkyl, pyrazolyl-C _1-6 alkyl, isoxazolyl-C _1-6 alkyl, isothiazolyl-C _1-6 alkyl, 1,3 , 4-thiadiazolyl-C _1-6 alkyl, 2H-piperidyl-C _1-6 alkyl, 4-H-piperidyl-C _1-6 alkyl, pyridyl-C _1-6 Alkyl, pyridazinyl-C _1-6 alkyl, pyrimidinyl-C _1-6 alkyl, pyrazinyl-C _1-6 alkyl, 1,3,5-triazinyl-C _1-6 alkane or together with R ^1a and R ^1b are azetidine, pyrrolidine, piperidine, pyrrolidone, piperidone; yl Morpholine, diazetidine or piperazine; wherein each of the aforementioned non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycle Alkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, C _1-4 alkyl, OC _1-4 alkyl, NR ⁵ R ⁶ , CF ₃ or CN. The compound of claim 3 or 43, wherein: R ^1a and R ^1b are each independently H, C _1-4 alkyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran, tetra Hydroperidine, azetidine, pyrrolidine, piperidine, tetrahydrothiophene dioxide; C _1-4 aralkyl, pyrrolyl-C _1-4 alkyl, imidazolyl-C _1-4 alkyl , pyrazolyl-C _1-4 alkyl, pyridyl-C _1-4 alkyl, pyridazinyl-C _1-4 alkyl, pyrimidinyl-C _1-4 alkyl, pyrazinyl-C _{1- 4} alkyl; or R ^1a and R ^1b together form azetidine, pyrrolidine, piperidine, morpholine, diazetidine or piperazine; wherein each of the aforementioned non-H moieties is optionally one or more Substituted by an unsubstituted substituent of the following group: C _1-4 alkyl, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine, piperidine, pyrrolidone , piperidone, diazetidine, piperazine, morpholine, thiocyclobutane, tetrahydrothiophene, tetrahydrothiopyran, thiocyclobutane dioxide, tetrahydrothiophene dioxide, tetrahydrothiophene thiopyran dioxide, hydroxy, OC _1-4 alkyl, C _1-4 carboxyl and N (C _1-4 alkyl) (C _1-4 alkyl ^{); R 2a, R 2b,} R 2c and R ^2d line are each independently _{H, F, Cl, CH 3} , C 2 H 5, OCH 3, OC 2 H 5 or CF _3; R ^7a and R ^7b lines each Independently H or C _1-3 alkyl; R ^7c and R ^7d are each independently H, C _1-3 alkyl or F; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each Independently F, Cl, CH ₃ , CH ₂ CH ₃ , OCH ₃ , OCH ₂ CH ₃ or CF ₃ . The compound of claim 3, wherein R ^1a and R ^1b are each independently: H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentyl, cyclohexyl, Oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl or pyridyl; or R ^1a and R ^1b together form azetidine, pyrrolidine, morpholine or piperidine a azine; wherein each of the aforementioned non-H moieties is optionally substituted with one or more unsubstituted substituents selected from the group consisting of CH ₃ , C ₂ H ₅ , OH, OCH ₃ , OC ₂ H ₅ , CH ₂ COOH, C ₂ H ₄ COOH, C ₃ H ₆ COOH, N(Me)(Me), N(Me)(Et), N(Et)(Et), tetrahydrofuran, tetrahydropyran, morpholine, pyrrolidine And pyrrolidone; R ^2a , R ^2c and R ^2d are each independently H or F; R ^2b is H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ or OC ₂ H ₅ ; R ^7a and R ^7b are each independently H or CH ₃ or CH ₂ CH ₃ ; R ^7c and R ^7d are each independently H, CH ₃ or F; R ^8a and R ^8e are each independently H, F, Cl or CH ₃ ; R ^8b and R ^8d are each independently H, Cl, F, CH ₃ , OCH ₃ or CF ₃ ; R ^8c is H, Cl, CH ₃ or OCH ₃ ; For CH. The compound of any one of claims 3 or 43 to 45, wherein: R ^1a and R ^1b are each independently selected from the group consisting of H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , cyclopentane Base, cyclohexyl, oxetane, tetrahydrofuran, tetrahydropyran, piperidine, tetrahydrothiophene dioxide, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, , , , , , , , and Or R ^1a and R ^1b together , , or ; R ^2a , R ^2b , R ^2c and R ^2d are each selected from the group consisting of H, F, Cl, CH ₃ and OCH ₃ ; wherein: R ^2a , R ^2b , R ^2c and R ^2d are each H; R ^2a , R ^2c and R ^2d are each H and R ^2b is F; R ^2a , R ^2b and R ^2c are each H and R ^2d is F; R ^2a , R ^2c and R ^2d are each H, and R ^2b is OCH ₃ ; R ^2a , R ^2c and R ^2d are each H and R ^2b is CH ₃ ; R ^2a , R ^2c and R ^2d are each H and R ^2b is Cl; R ^2a , R ^2b and R ^2d Each is H, and R ^2c is F; R ^2a and R ^2b are each F, and R ^2c and R ^2d are each H; or R ^2a and R ^2c are each H, R ^2c is Cl, and R ^2d is F; R ^7a and R ^7b are each independently H or CH ₃ ; R ^7c and R ^7d are each independently H, CH ₃ or F; wherein: R ^7c and R ^7d are both H; R ^7c and R ^7d are CH ₃ ; or R ^7c and R ^7d are both F; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, F, Cl, CH ₃ , OCH ₃ and CF. ₃ wherein: R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each H; R ^8a , R ^8b , R ^8d and R ^8e are each H and R ^8c is Cl; R ^8a , R ^8b , R ^8d and R ^8e are each H, and R ^8c is CH ₃ ; R ^8a , R ^8b , R ^8d and R ^8e are each H and R ^8c is OCH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is Cl; R ^8a , R ^8c , R ^8d and R ^{8e is} each H, and R ^8b is CF ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is CH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is OCH ₃ ; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is F; R ^8b , R ^8c , R ^8d and R ^8e are each H and R ^8a is Cl; R ^8b , R ^8c , R ^8d and R ^8e are each H and R ^8a is CH ₃ ; R ^8b , R ^8c and R ^8d are each H, R ^8a is F, and R ^8e is Cl; R ^8a , R ^8d and R ^8e Each is H, and R ^8b and R ^8c are each Cl; R ^8b , R ^8d and R ^8e are each H, and R ^8a and R ^8c are each Cl; or R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F. The compound of any one of claims 3 or 43 to 46, wherein R ^1a and R ^1b are each H. The compound of any one of claims 3 or 43 to 46, wherein R ^1a and R ^1b are each independently H, CH ₃ , C ₂ H ₅ or C ₃ H ₇ . The compound of any one of claims 3 or 43 to 46, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is , , , The compound of any one of claims 3 or 43 to 46, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is , , , The compound of any one of claims 3 or 43 to 46, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is cyclopentyl, cyclohexyl or . The compound of any one of claims 3 or 43 to 46, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is oxetane, tetrahydrofuran, tetrahydropyran , piperidine, tetrahydrothiophene dioxide or . The compound of any one of claims 3 or 43 to 46, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is phenyl, or . The compound of any one of claims 3 or 43 to 46, wherein one of R ^1a and R ^1b is H, and the other of R ^1a and R ^1b is 2-pyridyl, 3-pyridyl, 4- Pyridyl. The compound of any one of claims 3 or 43 to 46, wherein R ^1a and R ^1b are formed together The compound of any one of claims 3 or 43 to 46, wherein: R ^1a and R ^1b are each independently H or CH ₃ ; R ^2a , R ^2c and R ^2d are each H; R ^2b is Cl; ^7a and R ^7b are each H; W is CR ^7c R ^7d ; R ^7c and R ^7d are each H; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, F. , Cl, CH ₃ , OCH ₃ and CF ₃ ; X is CH; and n is 2. The compound of any one of claims 1 to 3, wherein the compound of formula I is selected from the group consisting of: Its pharmaceutically acceptable salt. The compound of any one of claims 1 to 3, wherein the compound of formula I is: or Or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 5, wherein: R ³ is H, optionally substituted alkyl, optionally substituted cycloalkyl, OR ⁴ , halogen, NR ⁵ R ⁶ , SR ⁴ , S(O) ₂ R ⁴ or optionally substituted heterocycloalkyl; and R ⁷ is alkyl. The compound of claim 59, wherein R ⁴ is optionally substituted alkyl or optionally substituted cycloalkyl. A compound according to claim 60, wherein R ⁴ is alkyl, which is optionally substituted by halogen, aryl, heteroaryl, heterocycloalkyl or cycloalkyl. The compound of claim 60, wherein R ⁴ is cycloalkyl, which is optionally substituted by halogen, alkyl, halo, aryl, heteroaryl, heterocycloalkyl or cycloalkyl. The compound of any one of claims 59 to 62, wherein R ⁴ is selected from the group consisting of: , , , and . The compound of claim 59, wherein R ³ is H, optionally substituted alkyl, halo or NR ⁵ R ⁶ . The compound of claim 5, wherein: R ³ is H, optionally substituted alkyl, optionally substituted heteroaryl, OR ⁴ , halogen, NR ⁵ R ⁶ , SR ⁴ , S(O) ₂ R ⁴ or a heterocycloalkyl group optionally substituted; and R ⁷ is an alkyl group. The compound of claim 65, wherein R ³ is optionally substituted alkyl, optionally substituted heteroaryl, NR ⁵ R ⁶ or optionally substituted heterocycloalkyl. The compound of claim 66, wherein R ³ is an optionally substituted alkyl group. The compound of claim 67, wherein R ³ is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl. The compound of claim 68, wherein R ³ is -CD ₃ . The compound of claim 66, wherein R ³ is NR ⁵ R ⁶ , and wherein R ⁵ and R ⁶ are each independently an optionally substituted alkyl. The compound of claim 70, wherein R ³ is NR ⁵ R ⁶ , and wherein R ⁵ and R ⁶ are each independently methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl Bases, each of which is optionally substituted by halogen. The compound of claim 71, wherein R ³ is selected from the group consisting of: , The compound of claim 66, wherein R ³ is optionally substituted heterocycloalkyl. The compound of claim 73, wherein R ³ is optionally substituted by a monocyclic heterocycloalkyl group selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, and piperidin piperazinyl, tetrahydrofuranyl, each optionally substituted with halo, cyano, oxo, -CF _3, alkyl and cycloalkyl. The compound of claim 74, wherein R ³ is selected from the group consisting of: The compound of claim 75, wherein R ³ is optionally substituted bicyclic heterocycloalkyl. The compound of claim 76, wherein R ³ is selected from the group consisting of: , The compound of claim 66, wherein R ³ is optionally substituted heteroaryl. The compound of claim 78, wherein R ³ is optionally substituted pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, furyl, phenylthio and thiazolyl. The compound of claim 79, wherein R ³ is . The compound of claim 59, wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _1-7 cycloalkyl or C _1-6 aralkyl; wherein each of said non-H moieties The case is substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen. The compound of claim 59 or 81, wherein R ^1a and R ^1b are each independently H or C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally one or more selected from the group consisting of Substituted unsubstituted substituents: C _1-3 alkyl, hydroxy and OC _1-3 alkyl. The compound of any one of claims 59 to 81, wherein R ^1a and R ^1b are each independently H or an unsubstituted C _1-3 alkyl group. The compound of any one of claims 59 to 82, wherein R ^1a and R ^1b are each H. The compound of claim 59 or 81, wherein R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ . The compound of any one of claims 59 to 85, wherein R ^2a , R ^2b , R ^2c and R ^2d are each independently F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CF ₃ . The compound of any one of claims 59 to 86, wherein: R ^2a , R ^2c and R ^2d are each independently H; and R ^2b is H, F or Cl. The compound of any one of claims 59 to 87, wherein: R ^2a , R ^2c and R ^2d are each H; and R ^2b is Cl. The compound of any one of claims 59 to 88, wherein R ³ is H, C _1-4 alkyl or halogen; wherein the C _1-4 alkyl group is optionally one or more selected from the group consisting of Substituted by an unsubstituted substituent: C _1-3 alkyl, halogen, hydroxy, alkoxy, carboxy and amine. The compound of any one of claims 59 to 89, wherein R ³ is C _1-3 alkyl, F, Cl or Br; wherein the C _1-3 alkyl group is optionally selected from one or more selected from the group consisting of Substituted unsubstituted substituents of the group: C _1-2 alkyl, halogen, hydroxy, OC _1-3 alkyl, carboxyl and amine. The compound of any one of claims 59 to 90, wherein R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, Cl or Br; wherein the CH ₃ and the C ₂ H ₅ are each optionally Or multiple halogen substitutions. The compound of any one of claims 59 to 91, wherein R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, Cl or Br. The compound of any one of claims 59 to 92, wherein R ⁷ is C _1-6 alkyl. The compound of any one of claims 59 to 93, wherein R ⁷ is C _1-4 alkyl. The compound of any one of claims 59 to 94, wherein R ⁷ is C _1-3 alkyl. The compound of any one of claims 59 to 95, wherein R ⁷ is CH ₃ or C ₂ H ₅ . The compound of any one of claims 59 to 96, wherein R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl , NR ⁵ R ⁶ , CF ₃ or CN. The compound of any one of claims 59 to 97, wherein R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CN. The compound of any one of claims 59 to 98, wherein: R ^8a and R ^8e are each independently H, F or Cl; and R ^8b and R ^8d are each independently H, F, OCH ₃ or CN; And R ^8c is H, F or Cl. The compound according to any one of claims 59 to 99, wherein: R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is CN; and R ^8a , R ^8c , R ^8d and R ^8e are each H And R ^8b is OCH ₃ ; R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F or Cl; R ^8b , R ^8d and R ^8e are each H and R ^8a is Cl, and R ^8c is F; or R ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is Cl. The compound of any one of claims 59 to 100, wherein J is a bond or CH ₂ . The compound of claim 59, wherein: R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _1-7 cycloalkyl or C _1-6 aralkyl; wherein each of said non-H moieties Optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine And halogen; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl or CF ₃ ; R ³ is H, C _1-4 alkane a group, a halogen or NR ⁵ R ⁶ ; wherein the C _1-4 alkyl group is optionally substituted with one or more unsubstituted substituents selected from the group consisting of C _1-3 alkyl, halogen, hydroxy, The alkoxy group, the carboxyl group and the amine group R ⁷ are a C _1-6 alkyl group; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl, NR ⁵ R ⁶ , CF ₃ or CN. The compound of claim 59 or 102, wherein: R ^1a and R ^1b are each independently H or C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally selected from one or more selected from the group consisting of Substituted unsubstituted substituents: C _1-3 alkyl, hydroxy and OC _1-3 alkyl; R ^2a , R ^2b , R ^2c and R ^2d are each independently F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CF ₃ ; R ³ is C _1-3 alkyl, F, Cl or Br; wherein the C _1-3 alkyl group optionally consists of one or more selected from the group consisting of Substituted unsubstituted substituents of the group: C _1-2 alkyl, halogen, hydroxy, OC _1-3 alkyl, carboxy and amine; R ⁷ is C _1-4 alkyl; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CN; and J is a bond or CH ₂ . The compound of any one of claims 59 or 102 to 103, wherein: R ^1a and R ^1b are each independently H or an unsubstituted C _1-3 alkyl group; each of R ^2a , R ^2c and R ^2d is Independently H; R ^2b is H, F or Cl; R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, Cl or Br; wherein the CH ₃ and the C ₂ H ₅ are each optionally Or a plurality of halogen substitutions; R ⁷ is C _1-3 alkyl; R ^8a and R ^8e are each independently H, F or Cl; and R ^8b and R ^8d are each independently H, F, OCH ₃ or CN And R ^8c is H, F or Cl. The compound of any one of claims 59 or 102 to 104, wherein: R ^1a and R ^1b are each H; R ^2a , R ^2c and R ^2d are each H; R ^2b is Cl; and R ³ is CH ₃ , C ₂ H ₅ , CF ₃ , F, Cl or Br; R ⁷ is CH ₃ or C ₂ H ₅ ; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of: H, CN, OCH ₃ , F and Cl, wherein: R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is CN; R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b Is OCH ₃ ; R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F or Cl; R ^8b , R ^8d and R ^8e are each H, R ^8a is Cl, and R ^8c is F Or R ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is Cl. The compound of claim 1 or 59, wherein the compound of formula I is selected from the group consisting of: Its pharmaceutically acceptable salt. The compound of claim 59, wherein R ³ is OR ⁴ . The compound of claim 107, wherein R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _1-7 cycloalkyl or C _1-6 aralkyl; wherein each of said non-H moieties The case is substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine and halogen. The compound of any one of claims 107 to 108, wherein R ^1a and R ^1b are each independently H or C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally selected from one or more Substituted unsubstituted substituents of the group consisting of C _1-3 alkyl, hydroxy and OC _1-3 alkyl. The compound of any one of claims 107 to 109, wherein R ^1a and R ^1b are each independently H or an unsubstituted C _1-3 alkyl group. The compound of any one of claims 107 to 110, wherein R ^1a and R ^1b are each H. The compound of any one of claims 107 to 111, wherein R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-3 alkyl or CF ₃ . The compound of any one of claims 107 to 112, wherein R ^2a , R ^2b , R ^2c and R ^2d are each independently F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CF ₃ . The compound of any one of claims 107 to 113, wherein: R ^2a , R ^2c and R ^2d are each independently H; and R ^2b is H, F or Cl. The compound of any one of claims 107 to 114, wherein: R ^2a , R ^2c and R ^2d are each H; and R ^2b is Cl. The compound of any one of claims 107 to 115, wherein R ⁴ is C _1-5 alkyl; wherein the C _1-5 alkyl group is optionally substituted by one or more selected from the group consisting of halogen, C _1-4 An unsubstituted substituent of a group consisting of an alkyl group, a C _1-4 alkoxy group, a cycloalkyl group, and a heterocycloalkyl group; or a substituted heterocycloalkyl group. The compound of any one of claims 107 to 116, wherein R ⁴ is C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally substituted by one or more selected from the group consisting of Cl, F, C ₁ Unsubstituted substituent of a group consisting of _-2 alkyl, C _1-2 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetane and tetrahydrofuran; substituted oxetane An alkane; or a substituted tetrahydrofuran. The compound of any one of claims 107 to 117, wherein R ⁴ is C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally substituted by one or more selected from the group consisting of F, CH ₃ , OCH _3, cyclopropyl, without the group consisting of cyclobutyl and substituted oxetane substituent group; or substituted oxetane of. The compound of any one of claims 107 to 118, wherein R ⁴ is CH ₃ , C ₂ H ₅ , The compound of any one of claims 107 to 119, wherein R ⁷ is C _1-6 alkyl. The compound of any one of claims 107 to 120, wherein R ⁷ is C _1-4 alkyl. The compound of any one of claims 107 to 121, wherein R ⁷ is C _1-3 alkyl. The compound of any one of claims 107 to 122, wherein R ⁷ is CH ₃ or C ₂ H ₅ . The compound of any one of claims 107 to 123, wherein R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _1-4 alkyl, OC _1-4 alkyl , NR ⁵ R ⁶ , CF ₃ or CN. The compound of any one of claims 107 to 124, wherein R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CN. The compound of any one of claims 107 to 125, wherein: R ^8a and R ^8e are each independently H, F or Cl; and R ^8b and R ^8d are each independently H, F, OCH ₃ or CN; And R ^8c is H, F or Cl. The compound of any one of claims 59 or 107 to 126, wherein: R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is CN; each of R ^8a , R ^8c , R ^8d and R ^8e Is H, and R ^8b is OCH ₃ ; R ^8b , R ^8c and R ^8d are each H, and R ^8a and R ^8e are each F or Cl; R ^8b , R ^8d and R ^8e are each H, and R ^8a is Cl And R ^8c is F; or R ^8b and R ^8e are each H, R ^8a and R ^8d are each F, and R ^8c is Cl. The compound of any one of claims 107 to 127, wherein J is a bond. The compound of claim 107, wherein: R ^1a and R ^1b are each independently H, C _1-6 alkyl, C _1-7 cycloalkyl or C _1-6 aralkyl; wherein each of said non-H moieties Optionally substituted with one or more unsubstituted substituents selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, hydroxy, alkoxy, carboxy, amine And halogen; R ^2a , R ^2b , R ^2c and R ^2d are each independently H, halogen, C _1-4 alkyl, OC _1-3 alkyl or CF ₃ ; R ⁴ is C _1-5 alkyl; Wherein the C _1-5 alkyl group is optionally substituted by one or more selected from the group consisting of halogen, C _1-4 alkyl, C _1-4 alkoxy, cycloalkyl and heterocycloalkyl. Substituted substituent; or substituted heterocycloalkyl; R ⁷ is C _1-6 alkyl; R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, halogen, C _{1 -4} alkyl, OC _1-4 alkyl, NR ⁵ R ⁶ , CF ₃ or CN; and J is a bond. The compound of claim 107 or 129, wherein: R ^1a and R ^1b are each independently H or C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally selected from one or more selected from the group consisting of Substituted unsubstituted substituents: C _1-3 alkyl, hydroxy and OC _1-3 alkyl; R ^2a , R ^2b , R ^2c and R ^2d are each independently F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CF ₃ ; R ⁴ is C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally substituted by one or more selected from the group consisting of Cl, F, C Unsubstituted substituent of a group consisting of _1-2 alkyl, C _1-2 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, oxetane and tetrahydrofuran; substituted oxygen heterocycle Butane; or substituted tetrahydrofuran; R ⁷ is C _1-4 alkyl; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each independently H, F, Cl, CH ₃ , C ₂ H ₅ , OCH ₃ , OC ₂ H ₅ or CN. The compound of any one of claims 107 or 129 to 130, wherein: R ^1a and R ^1b are each independently H or an unsubstituted C _1-3 alkyl group; each of R ^2a , R ^2c and R ^2d is Independently H; R ^2b is H, F or Cl; R ⁴ is C _1-4 alkyl; wherein the C _1-4 alkyl group is optionally substituted by one or more selected from the group consisting of F, CH ₃ , OCH _3, without the group consisting of cyclopropyl, cyclobutyl, and substituted oxetane substituent group; or substituted the oxetane; ^{R. 7} is C _1-3 alkyl; R and ^{R. 8A 8e} are each independently H, F or Cl; R ^8b and R ^8d are each independently H, F, OCH ₃ or CN; and R ^8c is H, F or Cl. The compound according to any one of claims 107 or 129 to 131, wherein: R ^1a and R ^1b are each H; R ^2a , R ^2c and R ^2d are each H; R ^2b is Cl; and R ⁴ is CH ₃ , C ₂ H ₅ , , , , , , R ⁷ is CH ₃ or C ₂ H ₅ ; and R ^8a , R ^8b , R ^8c , R ^8d and R ^8e are each selected from the group consisting of H, CN, OCH ₃ , F or Cl, wherein: R ^8a , R ^8c , R ^8d and R ^8e are each H and R ^8b is CN; R ^8a , R ^8c , R ^8d and R ^8e are each H, and R ^8b is OCH ₃ ; each of R ^8b , R ^8c and R ^8d Is H, and R ^8a and R ^8e are each F or Cl; R ^8b , R ^8d and R ^8e are each H, R ^8a is Cl, and R ^8c is F; or R ^8b and R ^8e are each H, R ^8a And R ^8d are each F, and R ^8c is Cl. The compound of claim 1 or 107, wherein the compound of formula I is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. The compound of any one of claims 1, 107 or 133, wherein the compound of formula I is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound of formula I is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein one or both of the R ³ or R ⁷ substituents contain at least one hydrazine. The compound of claim 136, wherein each of the R ³ and R ⁷ substituents each contains at least one hydrazine. The compound of any one of claims 136 to 137, wherein the R ⁷ substituent is an alkyl group, and wherein the alkyl group contains at least one hydrazine. The compound of any one of claims 136 to 138, wherein the R ⁷ substituent is methyl, and wherein the methyl group contains at least one hydrazine. The compound of any one of claims 136 to 139, wherein the R ⁷ substituent is -CD ₃ . The compound of any one of claims 136 to 140, wherein the R ³ substituent is an optionally substituted alkoxy group or an optionally substituted heterocycloalkyl group, and wherein the R ³ substituent contains at least one hydrazine . The compound of any one of claims 136 to 141, wherein the R ³ substituent is 2-methylpropoxy, 2,2-dimethylpropoxy, cyclopropylmethoxy, cyclobutylmethoxy Or pyrrolidinyl or piperidinyl, and wherein the R ³ substituent contains at least one hydrazine. The compound of any one of claims 136 to 142, wherein the R ³ substituent is selected from the group consisting of: The compound of claim 5, wherein the compound of formula II is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. The compound of claim 144, wherein the compound is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound has the formula IIa: Or a pharmaceutically acceptable salt thereof. The compound of claim 146, wherein the compound has the formula IIa ₁ : Or a pharmaceutically acceptable salt thereof. The compound of claim 146, wherein the compound is compound 240: Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound has the formula IIb: Or a pharmaceutically acceptable salt thereof. The compound of claim 149, wherein the compound has the formula IIb ₁ : Or a pharmaceutically acceptable salt thereof. The compound of claim 150, wherein the compound is compound 241: Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound has the formula IIc: Or a pharmaceutically acceptable salt thereof. The compound of claim 152, wherein the compound is compound 242: Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound has the formula IId: Or a pharmaceutically acceptable salt thereof. The compound of claim 154, wherein the compound has the formula IId ₁ : Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound has the formula IIe: Or a pharmaceutically acceptable salt thereof, wherein R ^7e is CH ₃ or CD ₃ . The compound of claim 5, wherein the compound has the formula IIf: Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound has the formula IIg: Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound has the formula IIg ₁ : Or a pharmaceutically acceptable salt thereof. The compound of claim 156, wherein the compound is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. The compound of claim 5, wherein the compound is selected from the group consisting of: Or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 161, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant. A method of modulating the activity of a ROR-gamma receptor in vitro, which comprises ligating the receptor with a compound of any one of claims 1 to 161 or a pharmaceutically acceptable salt thereof touch. A method of modulating the activity of a ROR-gamma receptor in vivo, comprising contacting the receptor with a compound of any one of claims 1 to 161, or a pharmaceutically acceptable salt thereof. The method of claim 163 or 164, wherein the compound of any one of claims 1 to 161, or a pharmaceutically acceptable salt thereof, is a reverse agonist of the ROR-γ receptor. A method of treating a ROR-γ receptor mediated disease in a patient or reducing the severity of a ROR-γ receptor mediated disease in a patient, comprising administering to a patient in need thereof, as in any one of claims 1 to 161 A compound or a pharmaceutically acceptable salt thereof. The method of claim 166, wherein the disease is selected from the group consisting of: articular adhesion vertebrate, asthma, Behcet's disease, chronic obstructive pulmonary disease, Crohn's disease, Type 1 diabetes, multiple sclerosis, neuromyelitis optica, rheumatic polymyalgia, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, Sjögren's syndrome, Systemic lupus erythematosus, systemic sclerosis, transplant rejection, inflammatory bowel disease, ulcerative colitis, and uveitis.