HK1227037B - Compounds as modulators of ror gamma - Google Patents

Description

Compounds as RORγ modulators

Background of the Invention

1. Technical Field

The present invention relates to novel compounds that modulate RORγ activity and their use as pharmaceutical agents.

2. Background Information

RORγ (retinoic acid receptor-related orphan receptor gamma) (also known as "RORγt") is a transcription factor belonging to the steroid hormone receptor superfamily (reviewed by Jetten 2006. Adv. Dev Biol. 16:313-355). RORγ has been identified as a transcription factor required for T cell differentiation and secretion of interleukin-17 (IL-17) by a group of T cells called _Th17 cells (Ivanov, Cell 2006, 126, 1121-1133). The rationale for the use of RORγ-targeted therapies for chronic inflammatory diseases is based on emerging evidence that _Th17 cells and the cytokine IL-17 contribute to the initiation and progression of several autoimmune diseases, including psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, and Crohn's disease (reviewed in Miossec, Nature Drug Discovery 2012, 11, 763-776; see also Khan et al., Bioorganic & Medicinal Chemistry Letters 23 (2013), 532-536). Results from current clinical trials in psoriasis using neutralizing antibodies to IL-17 and its receptor, IL-17RA (Leonardi 2012, New England Journal of Medicine, 366, 1190-1199; Papp 2012, New England Journal of Medicine, 366, 1181-1189) emphasize the role of IL-17 in the pathogenesis of this disease. Therefore, reducing IL-17 secretion from activated _Th17 T cells by inhibiting RORγ may provide similar therapeutic benefits.

SUMMARY OF THE INVENTION

The present invention comprises a novel class of heteroaromatic compounds having the general structure of Formula (I) wherein the substituents are as defined herein:

These compounds can be used to treat autoimmune and allergic diseases, where they exhibit a better regulatory effect on RORγ.

Detailed Description of the Invention

Definitions and conventions used

Terms not expressly defined herein have the meanings understood by one skilled in the art based on the entire disclosure and the context as a whole.

As used herein, unless otherwise indicated, the following definitions apply:

The use of the prefix _Cxy , wherein x and y each represent a natural number, indicates that the chain or ring structure specified and mentioned in direct connection or the combination of chain and ring structure as a whole can consist of a maximum of y and a minimum of x number of carbon atoms.

In general, for groups that include two or more subgroups, unless otherwise indicated, the last named subgroup is the point of attachment of the group, e.g., the substituent "aryl- _{Ci_3} -alkyl" means an aryl group that is linked to a _{Ci_3} -alkyl group, which is linked to the core or group to which the substituent is attached. However, if a bond is described immediately before the first named subgroup, the first named subgroup is the point of attachment of the group, e.g., the substituent _" -S(O) _{nCi_6alkyl} " means a _{Ci_6} -alkyl group that is linked to a S(O) _n group, which is linked to the core or group to which the substituent is attached.

Alkyl represents a monovalent, saturated hydrocarbon chain which can exist in both straight (unbranched) and branched form. If the alkyl group is substituted, the substitutions may occur independently of one another (in each case monosubstituted or polysubstituted) on all hydrogen-carrying carbon atoms.

For example, the term "C _1-5 alkyl" includes, for example, H ₃ C-, H ₃ C-CH ₂ -, H ₃ C-CH ₂ -CH ₂ -, H ₃ C-CH(CH ₃ )-, H ₃ C-CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ -CH(CH ₃ )-, H ₃ C-CH(CH ₃ )-CH ₂ -, H ₃ CC(CH ₃ ) ₂ -, H ₃ C-CH ₂ -CH ₂ -CH ₂ -CH ₂ -, H ₃ C-CH ₂ -CH ₂ -CH(CH ₃ )-, H ₃ C-CH ₂ -CH(CH ₃ )-CH ₂ -, H ₃ C-CH(CH ₃ )-CH ₂ -CH ₂ -, H ₃ C-CH ₂ -C(CH ₃ ) ₂ -, H ₃ CC(CH ₃ ) ₂ -CH ₂ -, H ₃ C-CH(CH ₃ )-CH(CH ₃ )- and H ₃ C-CH ₂ -CH(CH ₂ CH ₃ )-.

Other examples of alkyl _groups are methyl (Me; _-CH3 ), ethyl (Et; _-CH2CH3 ), 1-propyl (n-propyl; n-Pr; _-CH2CH2CH3 ), 2-propyl ₍ i-Pr; isopropyl; -CH( _{CH3 ) 2} ), 1-butyl (n-butyl; _n -Bu; _{-CH2CH2CH2CH3} ) _, 2-methyl _- 1-propyl (isobutyl; i-Bu; _-CH2CH ( _CH3 ) ₂ ), 2-butyl (sec _- butyl; sec-Bu; -CH( _CH3 ) _CH2CH3 ), 2-methyl-2-propyl (tert-butyl; t-Bu; -C( _CH3 ) ₃ ), 1 _- pentyl ( _n -pentyl; _{-CH2CH2CH2CH2CH3} ) _, 2-pentyl (-CH( _CH3 ) _{CH2CH2CH3 ) , 3} ), 3-pentyl (—CH(CH ₂ CH ₃ ) ₂ ), 3-methyl-1-butyl (isopentyl; —CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-2-butyl (—C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (—CH(CH ₃ )CH(CH ₃ ) ₂ ), 2,2-dimethyl-1-propyl (neopentyl; —CH ₂ C(CH ₃ ) ₃ ), 2-methyl-1-butyl (—CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (n-hexyl; —CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (—CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (—CH(CH ₂ CH ₃ )(CH _{2 CH 2} CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), 2,3-dimethyl-1-butyl (-CH ₂ CH(CH ₃ )CH(CH ₃ )CH ₃ ), 2,2-dimethyl-1-butyl (-CH ₂ C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3,3-dimethyl-1-butyl (-CH ₂ CH ₂ C(CH ₃ ) ₃ ), 2-methyl-1-pentyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-methyl-1-pentyl (-CH _{2 CH} (CH ₃ )CH ₂ CH ₃ ), 1-heptyl (n-heptyl), 2-methyl-1-hexyl, 3-methyl-1-hexyl, 2,2-dimethyl-1-pentyl, 2,3-dimethyl-1-pentyl, 2,4-dimethyl-1-pentyl, 3,3-dimethyl-1-pentyl, 2,2,3-trimethyl-1-butyl, 3-ethyl-1-pentyl, 1-octyl (n-octyl), 1-nonyl (n-nonyl), 1-decyl (n-decyl), etc.

The terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., without any other definition, mean saturated hydrocarbon radicals having the corresponding number of carbon atoms, including all isomeric forms.

If alkyl is part of another (combined) group, such as for example C _x.-y alkylamino or C _x.- y alkoxy, the above definition of alkyl also applies.

Unlike alkyl groups, alkenyl groups (when used alone or in combination) consist of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C double bond and the carbon atoms may only be part of a C-C double bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form a second bond, the corresponding alkenyl group is formed.

The alkenyl group may optionally be present in a cis or trans or E or Z orientation about the double bond.

Unlike alkyl groups, alkynyl groups (when used alone or in combination) consist of at least two carbon atoms, wherein at least two adjacent carbon atoms are linked together by a C-C triple bond. If, in an alkyl group having at least two carbon atoms as defined above, two hydrogen atoms on adjacent carbon atoms are formally removed and the free valencies are saturated to form two additional bonds, the corresponding alkynyl group is formed.

A haloalkyl (haloalkenyl, haloalkynyl) group (when used alone or in combination) is derived from an alkyl (alkenyl, alkynyl) group as defined above by replacing one or more hydrogen atoms of the hydrocarbon chain independently by a halogen atom (which may be the same or different). If a haloalkyl (haloalkenyl, haloalkynyl) group is further substituted, the substitutions may occur independently (in each case as mono- or polysubstituted) on all hydrogen-bearing carbon atoms.

Examples of haloalkyl (haloalkenyl, haloalkynyl) are _-CF3 , -CHF2, _{-CH2F , -CF2CF3} , _-CHFCF3 , _{-CH2CF3 , -CF2CH3} , _-CHFCH3 , -CF2CF2CF3, _{-CF2CH2CH3 ,} -CF _{= CF2} , -CCl= _CH2 , _-CBr = _{CH2 , -C≡C} - _CF3 , _-CHFCH2CH3 , _{-CHFCH2CF3 , and the like} .

Halogen refers to fluorine, chlorine, bromine and/or iodine atoms.

The term "cycloalkyl" (when used alone or in combination) refers to a non-aromatic 3-12 membered (but preferably 3-6 membered) monocyclic carbocyclyl or a non-aromatic 6-10 membered fused bicyclic, bridged bicyclic, propellane, or spirocyclic carbocyclyl. The _C3-12 cycloalkyl group may be saturated or partially saturated, and the carbocyclic ring may be attached through any atom of the ring to produce a stable structure. Non-limiting examples of 3-10 membered monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclohexanone. Non-limiting examples of 6-10 membered fused bicyclic carbocyclyls include bicyclo[1.1.1]pentane, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, and bicyclo[4.4.0]decyl (decahydronaphthyl). Non-limiting examples of 6- to 10-membered bridged bicyclic carbocyclyls include bicyclo[2.2.2]heptyl, bicyclo[2.2.2]octyl, and bicyclo[3.2.1]octyl. Non-limiting examples of 6- to 10-membered propellerane carbocyclyls include, but are not limited to, [1.1.1.]propellerane, [3.3.3]propellerane, and [3.3.1]propellerane. Non-limiting examples of 6- to 10-membered spirocyclic carbocyclyls include, but are not limited to, spiro[3,3]heptyl, spiro[3,4]octyl, and spiro[4,4]heptyl.

The term "heterocyclyl" (when used alone or in combination) refers to a heterocyclic ring system containing 2 to 10 carbon atoms and 1 to 4 heteroatom ring atoms selected from NH, NR', oxygen, and sulfur (wherein R' is C _1-6 alkyl) and including a stable non-aromatic 4- to 8-membered monocyclic heterocyclyl or a stable non-aromatic 6- to 11-membered fused bicyclic, bridged bicyclic, or spirocyclic heterocyclyl. The heterocyclic ring may be fully saturated or partially saturated. In one embodiment, the heterocyclic ring is a C _3-6 heterocyclic ring, i.e., it contains 3 to 6 ring carbon atoms. Non-limiting examples of non-aromatic monocyclic heterocyclyls include tetrahydrofuranyl, azetidinyl, pyrrolidinyl, pyranyl, tetrahydropyranyl, dioxanyl, thiomorpholinyl, 1,1-dioxo-1,λ ₆ -thiomorpholinyl, morpholinyl, piperidinyl, piperazinyl, and azepinyl. Non-limiting examples of non-aromatic 6- to 11-membered fused bicyclic radicals include octahydroindolyl, octahydrobenzofuranyl, and octahydrobenzothienyl. Non-limiting examples of non-aromatic 6- to 11-membered bridged bicyclic radicals include 2-azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.2.1]octanyl. Non-limiting examples of non-aromatic 6- to 11-membered spirocyclic heterocyclic radicals include 7-aza-spiro[3,3]heptanyl, 7-spiro[3,4]octanyl, and 7-aza-spiro[3,4]octanyl. Sulfur and nitrogen may optionally be present in all possible oxidation stages (sulfur → sulfoxide -SO-, sulfone _-SO2- ; nitrogen → N-oxide).

The term "aryl" (when used alone or in combination) refers to an aromatic hydrocarbon ring containing from six to fourteen carbon ring atoms (e.g., _C6-14 aryl, preferably _C6-10 aryl). The term _C6-14 aryl includes monocyclic, fused, and bicyclic rings, wherein at least one of the rings is aromatic. Non-limiting examples of _C6-14 aryl groups include phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, benzocycloheptyl, and benzocycloheptenyl.

As used herein, the term "heteroaryl" (when used alone or in combination) refers to a heteroaryl ring system containing 2 to 10 carbon atoms and 1 to 4 heteroatom ring atoms selected from N, NH, NR', O, and S (wherein R' is C _1-6 alkyl), and includes aromatic 5- to 6-membered monocyclic heteroaryl groups and aromatic 7- to 11-membered heteroaryl bicyclic or fused rings wherein at least one of the rings is aromatic. Non-limiting examples of 5- to 6-membered monocyclic heteroaryl rings include furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyranyl, thiazolyl, pyrazolyl, pyrrolyl, imidazolyl, tetrazolyl, triazolyl, thienyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, and purinyl. Non-limiting examples of 7- to 11-membered heteroaryl bicyclic or fused rings include benzimidazolyl, 1,3-dihydrobenzimidazol-2-one, quinolinyl, dihydro-2H-quinolinyl, isoquinolinyl, quinazolinyl, indazolyl, thieno[2,3-d]pyrimidinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzopyranyl, benzodioxolyl, benzoxazolyl, benzothiazolyl, pyrrolo[2,3-b]pyridinyl, and imidazo[4,5-b]pyridinyl. Sulfur and nitrogen may optionally be present in all possible oxidation stages (sulfur → sulfoxide -SO-, sulfone _-SO2- ; nitrogen → N-oxide).

The compounds of the present invention are only those compounds known to those skilled in the art that are considered to be chemically stable. For example, compounds with "dangling valences" or carbanions are not compounds encompassed by the methods of the present invention disclosed herein.

Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or name is intended to encompass tautomers and all stereo, optical, and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.), and racemates thereof, as well as mixtures of individual enantiomers, diastereomers, or any of the foregoing in varying proportions, where such isomers and enantiomers and salts (including pharmaceutically acceptable salts thereof) exist, and their corresponding unsolvated forms and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

The compounds of the present invention also include their isotope-labeled forms. The isotope-labeled form of the activating agent of the present invention combination is identical to the activating agent, but in fact, one or more atoms of the activating agent have been replaced by one or more atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom usually found in nature. Examples of isotopes that can be easily purchased and incorporated into the activating agent of the present invention combination according to well-established operations include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl. The activating agent, prodrug, or pharmaceutically acceptable salt of the present invention combination containing one or more of the above-mentioned isotopes and/or other isotopes of other atoms are also considered to be within the scope of the present invention.

As used herein, the phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and/or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and consistent with a reasonable benefit/risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfuric acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfuric acid, and benzenesulfonic acid. Other acids, such as oxalic acid, although not pharmaceutically acceptable in themselves, may be used to prepare salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts. Other pharmaceutically acceptable salts can be formed with cations derived from metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and the like (see also Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or base form of these compounds with a sufficient amount of a suitable base or acid in water or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile or a mixture thereof.

For purposes of this invention, a therapeutically effective amount means an amount of a substance that eliminates the symptoms of a disease or alleviates these symptoms, or prolongs the survival of the treated patient.

Modes for Carrying Out the Invention

A general embodiment of the present invention relates to a compound of the following formula (I) or a pharmaceutically acceptable salt thereof:

in:

^R1 is:

-CN;

-S(O) _n R ⁶ ;

-S(O) _n NR ⁷ R ⁸ ;

-S(O)(NR ⁹ )R ⁶ ;

-N(R ⁹ )C(O)R ⁶ ;

-N(R ⁹ )C(O)OR ⁶ ;

-N(R ⁹ )S(O) _n R ⁶ ;

-C(O)OR ⁹ ;

-C(O ⁾ _nR7R8 ; ^or

-C(O)R ⁹ ; or

R ⁶ , R ⁷ , R ⁸ or R ⁹ of R ¹ may be cyclized on W to form a ring; and

^R2 and ^R3 are each independently:

(A)-H;

(B) C _1-3 alkyl optionally substituted by one, two or three groups selected from the group consisting of:

a) C _3-6 cycloalkyl;

b) -OR ⁹ ;

c)-CN;

d) -CF ₃ ;

e) halogen;

f) -C(O)OR ⁹ ;

g) -C(O) _n (R ⁹ ) ₂ ;

h) -S(O) _n R ⁹ ; and

i) -S(O) _n NR ⁷ R ⁸ ; or

(C) C _3-6 cycloalkyl;

(D) C _3-6 heterocyclyl; or

^R2 and ^R3 together with the carbon atoms to which they are attached form a _C3-6 carbocyclic ring; or

^R2 and ^R3 together with the carbon atoms to which they are attached form a _C3-6 heterocyclic ring; or

R ² or R ³ may be cyclized on W to form a ring;

^R4 is:

(A) C _1-6 alkyl optionally substituted by one, two or three groups selected from the following:

a) C _3-6 cycloalkyl;

b) C _3-6 heterocyclic group;

c) -OR ⁹ ;

d)-CN;

e) -S(O) _n R ⁹ ;

f) halogen; and

g) -CF ₃ ; or

(B) a C _3-12 cycloalkyl group optionally substituted by one, two or three groups selected from the following:

a) C _1-6 alkyl;

b) -OR ⁹ ;

c)-CN;

d) -S(O) _n R ⁹ ;

e) halogen; and

f) -CF ₃ ; or

(C) aryl, heteroaryl or heterocyclic groups, each optionally substituted with one, two or three groups selected from the group consisting of:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -S(O) _n R ⁹ ;

f) halogen; and

g) -CF ₃ ;

R ⁵ is aryl, heteroaryl, heterocyclyl or C _3-12 cycloalkyl, each optionally substituted by one, two or three groups selected from the following:

(A) C _1-6 alkyl, C _3-6 cycloalkyl or C _3-6 heterocyclyl, each optionally substituted by one, two or three groups selected from the following:

a) C _3-6 cycloalkyl;

b) C _3-6 heterocyclic group;

c) -OR ⁹ ;

d)-CN;

e)-S( ^O ) _nNR7R8 ^;

f) -S(O) _n R ⁹ ;

g) halogen; and

h) -CF ₃ ; or

(B)-OR ⁹ ;

(C)-CN;

(D)-CF ₃ ;

(E)-halogen;

(F)-S(O) _n NR ⁷ R ⁸ ;

(G)-S(O) _nR9 ; ^and

(H)-NR ⁷ R ⁸ ;

W is aryl, heteroaryl, heterocyclyl, C _3-12 cycloalkyl or alkynyl, each optionally substituted with one or two groups selected from:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -CF ₃ ;

f) halogen;

g) -NR ⁷ R ⁸ ;

h) -C(O)OR ⁹ ; and

i) -C(O) _n (R ⁹ ) ₂ ;

^R6 is selected from:

(A)-OH;

(B) C _1-6 alkyl optionally substituted by one or two groups selected from the following:

a) C _3-6 cycloalkyl;

b) -OR ⁹ ;

c)-CN;

d) -CF ₃ ; and

e) halogen;

(C) C _3-6 cycloalkyl; and

(D)-CF ₃ ;

^R7 and ^R8 are independently selected from:

(A)-H;

(B) C _1-3 alkyl optionally substituted by one or two groups selected from the following:

a) C _3-6 cycloalkyl;

b) -OR ⁹ ;

c)-CN;

d) halogen; and

(C) C _3-6 cycloalkyl; or

R ⁷ and R ⁸ together with the nitrogen to which they are attached form a saturated ring having 3 to 6 carbon atoms, wherein one carbon atom in the saturated ring may be optionally replaced by -O-, -NR ⁹ - or -S(O) _n -;

R ⁹ is selected from:

(A)-H;

(B) C _1-3 alkyl optionally substituted by one or two groups selected from the following:

a) C _3-6 cycloalkyl;

b) -OR ⁹ ;

c)-CN;

d) -CF ₃ ; and

e) halogen; or

(C) C _3-6 cycloalkyl; and

n is 0, 1 or 2.

Other subembodiments within the definitions of various substituents include the following:

R ¹ group embodiment

(1) ^R1 is:

-CN;

-S(O) _n R ⁶ ;

-S(O) _n NR ⁷ R ⁸ ;

-N(H)S(O) _nR6 ; ^or

-S(O)(NH)R ⁶ ; and

in:

^R6 is:

(A) C _1-3 alkyl optionally substituted by one or two groups selected from the following:

a) C _3-6 cycloalkyl;

b)-OR ⁹ ; and

c) -CN; or

(B) C _3-6 cycloalkyl;

R ⁷ and R ⁸ are each independently:

(A)-H; or

(B) C _1-3 alkyl; and

R ⁹ is selected from:

(A)-H;

(B) C _1-3 alkyl; or

(C) C _3-6 cycloalkyl; and

n is 1 or 2.

(2) ^R1 is:

-S(O) _n R ⁶ ;

-S(O ^)nNR7R8 _; ^or

-S(O)(NH)R ⁶ ; and

in:

^R6 is:

(A) C _1-3 alkyl optionally substituted by one or two groups selected from the following:

a) C _3-6 cycloalkyl;

b)-OR ⁹ ; and

c) -CN; or

(B) C _3-6 cycloalkyl;

R ⁷ and R ⁸ are each independently:

(A)-H; or

(B) C _1-3 alkyl; and

R ⁹ is selected from:

(A)-H;

(B) C _1-3 alkyl; or

(C) C _3-6 cycloalkyl; and

n is 1 or 2.

(3) R ¹ is -S(O) _n R ⁶ , -S(O) _n NR ⁷ R ⁸ or -S(O)(NH)R ⁶ ; and

^R6 is _C1-3 alkyl; and

R ⁷ and R ⁸ are each independently:

(A)-H; or

(B) C _1-3 alkyl; and

n is 2.

^R2 and ^R3 group embodiments

(1) ^R2 and ^R3 are each independently selected from:

(A)-H;

(B) C _1-3 alkyl optionally substituted by one, two or three groups selected from the group consisting of:

a) C _3-6 cycloalkyl;

b) -OR ⁹ ; or

c) halogen; and

^R2 and ^R3 together with the carbon atoms to which they are attached form a _C3-6 carbocyclic ring; or

^R2 and ^R3 together with the carbon atoms to which they are attached form a _C3-6 heterocyclic ring; and

R ⁹ is selected from:

(A)-H; and

(B) C _1-3 alkyl.

(2) ^R2 and ^R3 are each independently selected from:

(A)-H; and

(B) C _1-3 alkyl;

(3) ^R2 and ^R3 are H.

^R4 group embodiment

(1) R ⁴ is:

(A) C _1-6 alkyl optionally substituted by one, two or three groups selected from the following:

a) C _3-6 cycloalkyl;

b) a 4-, 5- or 6-membered heterocyclic group;

c)-OR ₉ ;

d)-CN;

e) halogen; and

f) -CF ₃ ; or

(B) a C _3-6 cycloalkyl group optionally substituted by one, two or three groups selected from the following:

a) C _1-6 alkyl;

b) -OR ⁹ ;

c)-CN;

d) halogen; and

e) -CF ₃ ; and

wherein one carbon in the C _3-6 cycloalkyl group may be optionally replaced by -O-;

(C) phenyl; or

(D) a 4-, 5-, or 6-membered heterocyclic group; and

R ⁹ is selected from:

(A)-H; and

(B) C _1-3 alkyl.

(2) ^R4 is:

(A) C _1-6 alkyl optionally substituted by one or two groups selected from the following:

a) C _3-6 cycloalkyl;

b) a 4-, 5- or 6-membered heterocyclic group;

c)-OR ⁹ ;

d)-CN;

e) halogen; and

f) -CF ₃ ; or

(B) a C _3-6 cycloalkyl group optionally substituted by one, two or three groups selected from the following:

a) C _1-6 alkyl;

b) -OR ⁹ ;

c)-CN;

d) halogen; and

e) -CF ₃ ; or

(C) phenyl; or

(D) a 4-, 5-, or 6-membered heterocyclic group; and

R ⁹ is a C _1-3 alkyl group.

(3) R ⁴ is:

(A) C _1-6 alkyl optionally substituted with one or two groups selected from C _3-6 cycloalkyl, halogen, -CF ₃ and C _1-3 alkoxy; or

(B) C _3-6 cycloalkyl optionally substituted with one or two groups selected from C _1-6 alkyl, -CF ₃ and halogen; or

(C) a 5-membered heterocyclic group.

R ⁵ group embodiment

(1) R ⁵ is an aryl group, a heteroaryl group or a heterocyclic group, each of which is optionally substituted by one, two or three groups selected from the following:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -CF ₃ ;

f) halogen; and

g) -NR ⁷ R ⁸ ; and

R ⁷ , R ⁸ and R ⁹ are each independently selected from:

(A)-H; and

(B) C _1-3 alkyl.

(2) ^R5 is:

(A) phenyl optionally substituted with one, two or three groups selected from the group consisting of:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -CF ₃ ; and

f) halogen; or

(B) a 5- or 6-membered heteroaryl group optionally substituted with one, two or three groups selected from the group consisting of:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -CF ₃ ;

f) halogen; and

g) -NR ⁷ R ⁸ ; and

R ⁷ , R ⁸ and R ⁹ are each independently selected from:

(A)-H; and

(B) C _1-3 alkyl.

(3) R ⁵ is pyridyl or pyrimidinyl, each optionally substituted by one, two or three groups selected from the following:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d) -CF ₃ ; and

e) -NR ⁷ R ⁸ ; and

R ⁷ and R ⁸ are each independently selected from:

(A)-H;

(B) C _1-3 alkyl; and

R ⁹ is a C _1-3 alkyl group.

(4) R ⁵ is a pyrimidinyl group optionally substituted by one or two groups selected from the following:

a) C _1-3 alkyl;

b) C _3-5 cycloalkyl;

c) C _1-3 alkoxy; and

d) -CF ₃ .

W Group Implementation

(1) W is phenyl, pyridyl, pyrimidyl, piperidyl, piperazinyl, pyrazinyl or C _3-12 cycloalkyl, each optionally substituted by one or two groups selected from the following:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -CF ₃ ;

f) halogen;

g) -NR ⁷ R ⁸ ;

h) -C(O)OR ⁹ ; and

i) -C(O) _n (R ⁹ ) ₂ ;

R ⁷ , R ⁸ and R ⁹ are each selected from:

(A)-H; and

(B) C _1-3 alkyl.

(2) W is phenyl, pyridyl, pyrimidinyl or piperidinyl.

Other embodiments include any possible combination of the above subembodiments of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and W.

Other sub-embodiments of formula (I)

Other sub-embodiments of the compound of formula (I) above include:

(1) A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

^R1 is:

-S(O) _n R ⁶ ;

-S(O ^)nNR7R8 _; ^or

-S(O)(NH)R ⁶ ;

^R2 and ^R3 are each independently selected from:

(A)-H; and

(B) C _1-3 alkyl;

^R4 is:

(A) C _1-6 alkyl optionally substituted by one or two groups selected from the following:

a) C _3-6 cycloalkyl;

b) a 4-, 5- or 6-membered heterocyclic group;

c) -OR ⁹ ;

d)-CN;

e) halogen; and

f) -CF ₃ ;

(B) a C _3-6 cycloalkyl group optionally substituted by one, two or three groups selected from the following:

a) C _1-6 alkyl;

b) -OR ₉ ;

c)-CN;

d) halogen; and

e) -CF ₃ ;

(C) phenyl; or

(D) a 5- or 6-membered heterocyclic group;

^R5 is:

(A) phenyl optionally substituted with one or two groups selected from the group consisting of:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -CF ₃ ; and

f) halogen; or

(B) pyridyl or pyrimidinyl, each optionally substituted with one, two or three groups selected from:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -CF ₃ ;

f) halogen; and

g) -NR ⁷ R ⁸ ; and

W is phenyl, pyridyl, pyrimidyl, piperidyl or C _3-12 cycloalkyl, each optionally substituted by one or two groups selected from:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d)-CN;

e) -CF ₃ ;

f) halogen;

g) -NR ⁷ R ⁸ ;

h) -C(O)OR ⁹ ; and

i) -C(O) _n (R ⁹ ) ₂ ;

^R6 is:

(A) C _1-3 alkyl optionally substituted by one or two groups selected from the following:

a) C _3-6 cycloalkyl;

b)-OR ⁹ and

b) -CN; or

(B) C _3-6 cycloalkyl;

R ⁷ , R ⁸ and R ⁹ are each independently:

(A)-H; or

(B) C _1-3 alkyl; and

n is 2.

(2) A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is -S(O) _n R ⁶ or -S(O) _n NR ⁷ R ⁸ ; and

^R2 and ^R3 are H;

^R4 is:

(A) C _1-6 alkyl optionally substituted by one or two groups selected from C _3-6 cycloalkyl, -CF ₃ and C _1-3 alkoxy; or

(B) C _3-6 cycloalkyl optionally substituted with one or two groups selected from C _1-6 alkyl, -CN and halogen; or

(C) a 5-membered heterocyclic group;

R ⁵ is pyrimidinyl optionally substituted with one, two or three groups selected from:

a) C _1-6 alkyl;

b) C _3-6 cycloalkyl;

c) -OR ⁹ ;

d) -CF ₃ ; and

e) -NR ⁷ R ⁸ ;

W is phenyl, pyridyl, pyrimidinyl or piperidinyl;

^R6 is _C1-3 alkyl;

R ⁷ , R ⁸ , and R ⁹ are each independently:

(A)-H; or

(B) C _1-3 alkyl; and

n is 2.

(3) A compound of formula (I) as described immediately above in (2) or a pharmaceutically acceptable salt thereof, wherein:

R ⁵ is pyrimidinyl optionally substituted with one or two groups selected from:

a) C _1-3 alkyl;

b) C _3-5 cycloalkyl; and

c) C _1-3 alkoxy; and

W is phenyl, pyridyl, pyrimidinyl or piperidinyl.

Specific compounds within the scope of the present invention include the compounds in Table 1 below, or pharmaceutically acceptable salts thereof:

Table 1

Physicochemical data (ie, HPLC retention times and mass spectral data) for all prepared compounds are also provided in Table I. HPLC methods are defined in the Synthesis Examples section below.

The present invention further relates to pharmaceutically acceptable salts of the compounds of formula (I) with inorganic or organic acids or bases.

In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof as a medicament.

In another aspect, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating a patient.

In another aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of autoimmune diseases and allergic diseases.

In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a pharmaceutical composition for treating autoimmune diseases and allergic diseases.

In another aspect, the present invention relates to a method for treating autoimmune diseases and allergic diseases, comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a pharmaceutical composition containing as active substance one or more compounds of formula (I) or pharmaceutically acceptable salts thereof, optionally in combination with conventional excipients and/or carriers.

The compounds of formula (I) can be prepared using the general synthetic methods described hereinafter, which also form part of the present invention.

General synthetic methods

The compounds of the present invention can be prepared by synthetic methods, synthetic examples, methods known to those of ordinary skill in the art, and methods described in the chemical literature. In the synthetic methods and examples described below, substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ and W shall have the meanings defined in the detailed description of the compounds of Formula I hereinabove. The methods described herein are intended to illustrate and be used to practice the present invention and are not intended to limit the scope of the subject matter, claimed compounds, and examples. Where the preparation of the starting compound is not described, it may be commercially available, may be prepared similarly to the compounds or methods described herein, or is described in the chemical literature. Unless otherwise indicated, solvents, temperatures, pressures, and other reaction conditions can be readily selected by one of ordinary skill in the art.

Amine intermediates of formula R ¹ -WC(R ² )(R ³ )-NH ₂ are commercially available; or can be prepared according to the general procedures described in US 7,879,873 and WO 2011/049917 or references; or can be prepared by a person of ordinary skill using methods described in chemical literature.

The compound of formula (I) can be prepared from intermediate A' according to reaction scheme I.

Reaction Formula I

As shown in Reaction Scheme I, a suitable pyrimidine of Formula A' wherein G is _NH2 , X is a group suitable for palladium-mediated cross-coupling reactions (e.g., I, Br, Cl, or _OSO2CF3 ), and Y is a suitable leaving group (e.g., Cl) can be reacted with _a suitable amine of formula ^R4NH2 or an _ammonium salt (e.g., hydrochloride) such as isopropylamine in the presence of a suitable base (e.g., i- _Pr2EtN or _Et3N ) in a suitable solvent (e.g., n-butanol) and under suitable reaction conditions such as a suitable temperature (e.g., about 120°C) to provide a compound of Formula B'. Alternatively, the pyrimidine of formula A', wherein G is a suitable synthetic precursor of _NH2 (e.g., nitro), can be reacted with a suitable amine or ammonium salt (e.g., hydrochloride) _of formula ^R4NH2 , such as 1-methylcyclopropylamine, in the presence of a suitable reagent and solvent (e.g., i- _Pr2EtN and THF, respectively) under suitable reaction conditions, such as a suitable temperature (e.g., about -78°C to about 25°C), to provide an intermediate, which can be converted to a compound of formula B' after further reaction with a suitable reagent (e.g., the _NO2 group can be reduced using a suitable reagent such as _SnCl2 ). The selection of a suitable amine of formula ^R4NH2 and a pyrimidine of formula A' for the _above reaction by one skilled in the art can be based on criteria such as the steric and electronic properties of the amine and the pyrimidine. The diaminopyrimidine of formula B' can be reacted with a suitable reagent (e.g., ethyl chloro-oxo-acetate) in a suitable solvent (e.g., _acetone ) and in the presence of a suitable base (e.g., _K2CO3 ) to provide a compound of formula C'. Dicarbonyl compounds of formula C' can be reacted with a suitable dehydrochlorination reagent, such as oxalyl chloride, in the presence of a suitable additive, such as a catalytic amount of DMF, in _a suitable solvent, such as _CH2Cl2 , and under suitable reaction conditions, such as a suitable temperature (e.g., about ambient temperature), to provide compounds of formula D'. Chloro-pteridinones of formula D' can be reacted with a suitable amine or ammonium salt, such as 4-ethanesulfonylbenzylamine, of formula ^R1 -WC( ^R2 )( ^R3 ) _-NH2 , in the presence of a suitable base, such as _Et3N , in a suitable solvent, such as THF, and under suitable reaction conditions, such as a suitable temperature (e.g., about ambient temperature), to produce compounds of formula E'. Pyrimidines of formula E' can be _heated with a suitable cross-coupling partner (e.g., boronic acid) and a suitable base (e.g., _K3PO4 ) in a suitable solvent (e.g., 1,4-dioxane) in the presence of a suitable cross-coupling catalyst (e.g., Pd(dppf) _Cl2 ) under suitable reaction conditions such as a suitable atmosphere (e.g., argon) and a suitable temperature (e.g., about 100°C) to provide compounds of formula (I).

Synthesis Example

Non-limiting examples showing methods for preparing the compounds of the present invention are provided below. The most preferred reaction conditions and reaction times may vary depending on the specific reagents used. Unless otherwise stated, solvents, temperatures, pressures and other reaction conditions can be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthesis Examples section. Intermediates and products can be purified by chromatography on silica gel, recrystallization and/or reverse phase HPLC (RHPLC). Discrete enantiomers can be obtained by separating the racemic product using chiral HPLC. The RHPLC purification method uses 0-100% acetonitrile in water containing 0.1% formic acid or 0.1% TFA and uses one of the following columns:

a) Waters Sunfire OBD C18 5μM 30x150mm column

b) Waters XBridge OBD C18 5μM 30x150mm column

c) Waters ODB C8 5μM 19x150mm column

d) Waters Atlantis ODB C18 5μM 19x50mm column

e) Waters Atlantis T3OBD 5μM 30x100mm column

f) Phenomenex Gemini Axia C18 5μM 30x100mm column

HPLC method:

Analytical LC/MS Analysis Method A:

Column: Waters BEH 2.1x50mm C18 1.7um column

gradient:

Analytical LC/MS Method B:

Column: Waters BEH 2.1x50mm C18 1.7um column

gradient:

Time (min) 0.05% formic acid in water 0.05% formic acid in ACN Flow rate (mL/min) 0 90 10 0.8 4.45 0 100 0.8 4.58 0 100 0.8

List of abbreviations used in the synthetic examples:

Method 1:

Synthesis of intermediate A

To a stirred suspension of A-1 (3.00 g, 18.18 mmol) in n-butanol (10 mL) was added A-2 (10.80 g, 18.18 mmol), followed by DIEA (6.46 mL, 36.58 mmol). The mixture was stirred at 120° _C for 17 h. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous _NH4Cl solution. The reaction was then diluted with EtOAc. The organic layer was separated and washed with water, followed by brine. The organic layer was dried ( _Na2SO4 ), decanted, and concentrated. The resulting residue was purified by _SiO2 flash chromatography to produce A-3.

To a stirred suspension of A-3 (1.00 g, 5.00 mmol) in acetone (100 mL) was added ethyl oxalyl chloride (0.88 g, 6.43 mmol) followed by K ₂ CO ₃ (1.85 g, 13.39 mmol). The mixture was stirred at room temperature for 18 h and a solid precipitated to give A-4.

To a stirred suspension of A-4 (1.14 g, 5.00 mmol) in CH ₂ Cl ₂ (250 mL) was added oxalyl chloride (1 mL) followed by 5 drops of DMF. The mixture was stirred at room temperature for 5 h. The mixture was then concentrated under reduced pressure to give A-5.

To a stirred suspension of A-5 (0.1 g, 0.39 mmol) in THF (4 mL) was added TEA (0.16 mL, 1.16 mmol) (or DIEA) followed by AG (91 mg, 0.38 mmol). The reaction was allowed to stir at room temperature for 18 h. The reaction was quenched by the addition of saturated aqueous _NH4Cl solution and the organics were extracted with EtOAc. The organic layer was washed with water and brine, dried ( _Na2SO4 ), decanted, and concentrated under vacuum. The resulting residue was purified by _SiO2 flash chromatography to yield Intermediate A. _MS (ES+): m/z 423.0 [M+H] ⁺ .

Method 2:

Synthesis of intermediate B

To a stirred suspension of B-1 (1.80 g, 9.30 mmol) and B-2 (1.00 g, 9.30 mmol) in THF (10 mL) at -78°C was added DIEA (3.29 mL, 18.59 mmol) and the reaction was allowed to slowly warm to 25°C. The volatiles were removed under reduced pressure and the crude material was redissolved in EtOAc and washed with _H2O . The organic layer was separated and washed twice more with _H2O . The organic layer was washed with brine, dried ( _Na2SO4 ), decanted and concentrated. The resulting residue was purified by flash chromatography _{on SiO2} to give B-3.

To a solution of B-3 (1.78 g, 7.79 mmol) in EtOH (50 mL) was added _SnCl₂ (1.48 g, 7.79 mmol) and heated to reflux for 4 h. The reaction was allowed to cool to room temperature and then poured onto ice. The solution was treated with 1N NaOH _(aq) to bring the pH to ~9 and then filtered through a pad of Celite. The organic phase was separated and washed first with _{H₂O and} then with brine. The organic layer was dried ( _Na₂SO₄ ), decanted, and concentrated. The crude product was purified by _SiO₂ flash chromatography to yield B-4.

As an alternative procedure for reducing nitropyrimidines to the corresponding aminopyrimidines, the following general procedure has been used for similar intermediates: To a solution of nitropyrimidine in EtOH, the catalyst RaNi is added. The reaction vessel is evacuated and purified with _N2 (g), then evacuated and filled with _H2 (g). The reaction is maintained under an atmosphere of _H2 (g) for 15 h. The vessel is evacuated and purged with _N2 (g). The reaction is filtered through a pad of Celite to remove the Ni catalyst and the filtrate is concentrated. The resulting residue is purified by _SiO2 flash chromatography to provide the corresponding aminopyrimidine.

To a stirred solution of B-4 (0.40 g, 2.01 mmol) in acetone (10 mL) was added K ₂ CO ₃ (0.70 g, 5.06 mmol) followed by ethyl oxalyl chloride (0.27 mL, 2.43 mmol). The reaction was stirred at room temperature for 24 h. The reaction was then filtered, redissolved in H ₂ O, and extracted with EtOAc. The aqueous phase was separated and extracted twice more with EtOAc. The organic phases were combined, dried (Na ₂ SO ₄ ), decanted, and concentrated to yield B-5.

To a solution of B-5 (0.70 g, 2.77 mmol) in CH ₂ Cl ₂ (50 mL) was added oxalyl chloride (0.47 mL, 5.54 mmol), followed by 5 drops of DMF. The reaction was allowed to stir at room temperature for 18 h. The volatiles were removed in vacuo. The crude material was redissolved in DCM and poured into H ₂ O. The organic layer was separated, washed with brine, dried (Na ₂ SO ₄ ), decanted, and concentrated. The resulting residue was purified by SiO ₂ flash chromatography to yield B-6.

To a stirred solution of B-6 (0.83 g, 3.06 mmol) in THF (10 mL) was added DIEA (1.07 mL, 6.12 mmol) followed by AF (0.72 g, 3.06 mmol). The reaction was stirred at room temperature for ₁₈ h. The volatiles were removed in vacuo, and the crude residue was resuspended in DCM and poured into _H₂O . The aqueous phase was separated and extracted twice more with DCM. The organic layers were combined, washed with brine, dried ( _Na₂SO₄ ), decanted, and concentrated. The resulting residue was purified by _SiO₂ flash chromatography to yield Intermediate B. MS (ES+): m/z 434.1 [M+H] ^⁺ .

The following intermediates were prepared in a similar manner:

(Note: As described in Method 34, the ethyl oxalate intermediates produced from the reaction of A-3 (Method 1) and B-4 (Method 2) with ethyl oxalyl chloride can be isolated and heated with a suitable base (such as TEA) in a suitable solvent (such as EtOH) at a suitable temperature (e.g., 130°C) to provide the corresponding intermediates A-4 and B-5, respectively).

Method 3:

Synthesis of intermediate AB

To a solution of AB-1 (300 mg, 1.29 mmol) in anhydrous MeOH (15 mL) was added NaOMe (208 mg, 3.86 mmol). The mixture was stirred at room temperature for 1 h. The solution was filtered and concentrated. The residue was purified by _SiO2 flash chromatography to yield intermediate AB. MS (ES+): m/z 230.8 [M+H] ⁺ .

Method 4:

Synthesis of intermediate AC

To a solution of AC-1 (320 mg, 2.07 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborane (520 mg, 4.14 mmol) and aq Na ₂ CO ₃ (2 M, 3.1 mL, 6.21 mmol) in dioxane (10 mL) was added dichloropalladium 4-di-tert-butylphosphino-N,N-dimethylaniline (73 mg, 0.10 mmol). The mixture was heated to 130° C. in a microwave reactor for 40 min. The mixture was diluted with MeOH (5 mL), filtered and concentrated. The residue was purified by SiO ₂ flash chromatography to give AC-2.

To a solution of AC-2 (363 mg, 2.71 mmol) in EtOH (10 mL) was added Br ₂ (432 mg, 2.71 mmol) at -10°C. The reaction mixture was stirred at room temperature for 18 h. The solution was concentrated and the residue was purified by SiO ₂ flash chromatography to yield intermediate AC. MS (ES+): m/z 214.3 [M+H] ⁺ .

Method 5:

Synthesis of intermediate AD

A mixture of AD-1 (100.0 g, 0.70 mol), formamidine acetate (146 g, 1.4 mol) and NaOMe (266.0 g, 4.9 mol) in MeOH (2 L) was stirred at 16° C. for 2 days. The reaction mixture was neutralized to pH 7 with acetic acid and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by SiO ₂ flash chromatography to yield AD-2.

To a stirred solution of AD-2 (66.0 g, 0.48 mol) and TEA (145.1 g, 1.44 mol) in DCM (1.5 L) was added dropwise a solution of _Tf2O (164.2 g, 0.58 mol) in DCM (500 mL) at 0°C and stirred for 3 h. The reaction mixture was quenched by the addition of _H2O (200 mL) and extracted with DCM (3 x 500 mL). The combined organic phases were washed with saturated aq _NaHCO3 , dried _{( Na2SO4} ), decanted, and concentrated. The resulting residue was purified by _SiO2 flash chromatography to yield AD-3.

A mixture of AD- ₃ (17.0 g, 0.06 mol), vinylboronic acid pinacol ester (29.3 g, 0.09 mol), K ₂ CO ₃ (26.3 g, 0.19 mol), Ag ₂ O (1.7 g, 10 wt%), and Pd(dppf)Cl ₂ (1.7 g, 10 wt%) in anhydrous THF (400 mL) was stirred at reflux under N 2 atmosphere for 18 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by SiO ₂ flash chromatography to give AD-4.

A mixture of AD-4 (27.3 g, 0.28 mol) and RaNi (30.0 g, 10 wt%) in EtOH (500 mL) was stirred under _H₂ atmosphere for 16 h. The vessel was purged with _N₂ and the contents were filtered. The filtrate was concentrated under reduced pressure and the resulting AD-5 (19.6 g) was used directly.

To a stirred solution of AD-5 (19.6 g, 0.13 mol) in EtOH (300 mL) at -10°C was added _Br₂ (52.9 g, 0.33 mol). After addition, the mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition _of 10% _{Na₂S₂O₃ (aq)} solution and basified by the addition of 10% _{Na₂CO₃ (aq)} solution to adjust to approximately pH 8. The mixture was extracted with EtOAc (3 x 200 mL). The organic layers were combined, dried ( _Na₂SO₄ ), decanted, and concentrated. The resulting residue was purified by _SiO₂ flash chromatography to yield intermediate AD. _MS (ES+): m/z 228.9 [M+H] ^⁺ .

Method 6:

Synthesis of intermediate AE

To a solution of AC-1 (2.50 g, 16.17 mmol), cyclopropylboronic acid (4.17 g, 48.51 mmol), and Na ₂ CO ₃ (aq) (2 M, 24.26 mL, 48.51 mmol) in dioxane (30 mL) was added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (572.5 mg, 0.81 mmol). The vessel was sealed and heated to 130° C. for 2 h. The vessel was cooled to room temperature, diluted with MeOH, and filtered. The filtrate was concentrated and purified by SiO ₂ flash chromatography to yield AE-1.

To a solution of AE-1 (660 mg, 4.12 mmol) in EtOH (15 mL) was added Br ₂ (658 mg, 4.12 mmol) at -10°C. The reaction was stirred at room temperature for 3 h. NH ₃ in MeOH (2N, 1 mL) was added for neutralization. The mixture was concentrated and purified by SiO ₂ flash chromatography to yield intermediate AE. MS (ES+): m/z 240.9 [M+H] ⁺ .

Method 7:

Synthesis of intermediate AF

A mixture of AF-1 (100 g, 561 mmol), EtI (131 g, 842 mmol), and TBAB (18 g, 56 mmol) in H ₂ O (200 mL), acetone (150 mL), and toluene (150 mL) was stirred in a sealed vessel at 80° C. for 18 h. The mixture was partitioned between H ₂ O and EtOAc. The organic layer was dried and concentrated. The residue was purified by SiO ₂ flash chromatography to yield AF-2.

A mixture of AF-2 (200 g, 1.09 mol), NBS (425.02 g, 2.39 mol) and AIBN (17.82 g, 108.54 mmol) in CCl ₄ (1.40 L) was refluxed for 18 h. The mixture was partitioned between H ₂ O and DCM. The organic layer was dried (Na ₂ SO ₄ ), decanted and concentrated to give AF-3.

To a solution of AF-3 (333 g, 974 mmol) and DIEA (129 g, 1 mol) in ACN (500 mL) was added dropwise AF-4 (138 g, 1 mol) in ACN (150 mL) at 0°C. The mixture was stirred for 5 h and then concentrated. The resulting residue was crystallized from MeOH to yield AF-5.

A solution of AF-5 (50 g, 190 mmol) in MeOH (200 mL) was added to a solution of NH ₃ in MeOH (2N, 800 mL) at -78°C. The reaction mixture was stirred at room temperature for 18 h and then concentrated. The resulting residue was crystallized from EtOAc to provide AF-6.

A solution of AF-6 (50 g, 250 mmol) in HCl in MeOH (1 N, 250 mL) was stirred at room temperature for 12 h, then concentrated to yield intermediate AF as an HCl salt. MS (ES+): m/z 200.4 [M+H] ⁺ .

Method 8:

Synthesis of intermediate AG

A mixture of AG-1 (8.0 g, 43.96 mmol), K ₂ CO ₃ (7.88 g, 57.1 mmol) and sodium ethanethiolate (4.06 g, 48.3 mmol) in NMP (60.0 mL) was stirred at room temperature under N ₂ for 18 h. The reaction mixture was poured into H ₂ O and filtered. The solid was washed with H ₂ O and dried under vacuum to give AG-2.

To a suspension of AG-2 (6.0 g, 36.6 mmol) in AcOH (2.63 g, 43.8 mmol) was added dropwise a solution of _KMnO₄ (5.78 g, 36.6 mmol) in _H₂O (20.0 mL). The reaction mixture was stirred at room temperature for 15 h. The mixture was diluted with water and extracted with EtOAc. The organic layer _was dried ( _Na₂SO₄ ), decanted, and concentrated. The resulting residue was purified by _SiO₂ flash chromatography to yield AG-3.

A solution of AG-3 (3.3 g, 16.8 mmol) and Pd/C (500 mg, 10% on carbon catalyst) in MeOH (30 mL) was stirred under H ₂ (50 psi) at room temperature for 8 h. The vessel was purged with N ₂ , filtered, and the filtrate was concentrated to give AG-4.

To a stirred solution of AG-4 (2.5 g, 12.5 mmol) in EtOAc (30 mL) was added a solution of HCl in EtOAc (2N, 20.0 mL). The solution was stirred at room temperature for 5 h and then filtered to produce intermediate AG. MS (ES+): m/z 201.2 [M+H] ⁺ .

Method 9:

Synthesis of intermediate AH

A mixture of AH-1 (113 g, 0.62 mol), K ₂ CO ₃ (171 g, 1.24 mol) and sodium ethanethiolate (67 g, 0.80 mol) in DMF (2 L) was stirred at room temperature under N ₂ for 18 h. The mixture was diluted with H ₂ O and extracted with EtOAc. The organic layer was dried (Na ₂ SO ₄ ), decanted and concentrated. The resulting residue was purified by SiO ₂ flash chromatography to give AH-2.

A solution of AH-2 (20.0 g, 0.12 mol), RaNi (40 g), Boc ₂ O (31.7 g, 0.14 mol) and TEA (24.5 g, 0.24 mol) in THF (600 mL) was stirred under H ₂ (50 psi) at room temperature for 12 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by SiO ₂ flash chromatography to give AH-3.

To a suspension of AH-3 (65 g, 0.24 mol) in AcOH (200 mL) was added dropwise a solution of KMnO ₄ (45.8 g, 0.29 mL) in water (500 mL) at -10°C. After the addition was complete, the reaction mixture was stirred at room temperature for 30 min. The mixture was diluted with H ₂ O and basified to approximately pH 8 by addition of aqueous Na ₂ CO ₃ and extracted with EtOAc. The combined organic layers were dried (Na ₂ SO ₄ ), decanted, and concentrated. The resulting residue was purified by crystallization to yield AH-4.

To a stirred solution of compound AH-4 (46.5 g, 0.15 mol) in MeOH (300 mL) at room temperature was added 4 M HCl in MeOH (300 mL) and stirred for 15 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by crystallization to yield intermediate AH. MS (ES+): m/z 202.1 [M+H] ⁺ .

Method 10:

Synthesis of intermediate AI

A suspension of AC (2 g, 9.4 mmol), AI-1 (4.8 g, 18.8 mmol), KOAc (2.8 g, 28.2 mmol), and Pd(dppf) _Cl₂ (1.15 g, 0.15 mmol) in 1,4-dioxane (40 mL) was stirred at 100°C for 18 h. After cooling to room temperature, the mixture was diluted with water (10 mL) and extracted with EtOAc ( ₂ x 50 mL). The combined organic phases were dried ( _Na₂SO₄ ), decanted, and concentrated. The resulting residue was purified by _SiO₂ flash chromatography to yield AI. MS (ES+): m/z 262.2 [M+H] ^⁺ .

Method 11:

Synthesis of intermediate AJ

To a solution of QQ (509 mg, 1.1 mmol) in MeOH (4 mL) was added a solution of HCl in dioxane (4 N, 1.1 mL, 4.4 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether and filtered to produce intermediate AJ-1.

To a solution of AJ-1 (200 mg, 0.55 mmol) in DCM (3 mL) was added TEA (0.77 mL, 5.51 mmol), followed by AJ-2 (175 mg, 1.10 mmol). The reaction mixture was stirred at room temperature for 1 h, then diluted with water (5 mL) and extracted with EtOAc (20 mL). The organic layer was dried (Na ₂ SO ₄ ), decanted, and concentrated. The resulting residue was purified by SiO ₂ flash chromatography to yield intermediate AJ. MS (ES+): m/z 485.0 [M+H] ⁺ .

Method 12:

Synthesis of intermediate AK

To a solution of AK-1 (2.00 g, 13.1 mmol) in THF (25 mL) was added Boc ₂ O (3.45 mL, 15.0 mmol) and TEA (3.64 mL, 26.1 mmol). The reaction mixture was stirred at room temperature for 18 h and then diluted with H ₂ O and extracted with EtOAc. The organic layer was concentrated to give AK-2.

To a solution of AK-2 (3.3 g, 13.1 mmol) in AcOH (10 mL) was slowly added H ₂ O ₂ (1.37 mL, 13.7 mmol). The reaction mixture was stirred at room temperature for 3 h and then quenched with saturated Na ₂ SO _{3 (aq)} and neutralized with 1N NaOH _(aq) . The mixture was extracted with EtOAc and concentrated to give AK-3.

To a mixture of AK-3 (1.0 g, 3.7 mmol), MgO (600 mg, 14.9 mmol), trifluoroacetamide (839 mg, 7.4 mmol), and Rh(II) acetate dimer (115 mg, 0.26 mmol) in DCM (10 mL) was added (diacetoxyiodo)benzene (1.79 g, 5.6 mmol). The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue was dissolved in MeOH, filtered through a pad of Celite, and _K2CO3 (2.55 g, 18.6 _mmol ) was added. The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The resulting residue was purified by _SiO2 flash chromatography to yield AK-4.

To a stirred solution of compound AK-4 (585 mg, 2.1 mmol) in DCM (2 mL) was added a solution of HCl in dioxane (4 N, 2 mL). The reaction mixture was stirred at room temperature for 15 h and then concentrated under reduced pressure to produce intermediate AK. MS (ES+): m/z 185.0 [M+H] ⁺ .

Method 13:

Synthesis of intermediate AL

To a solution of AL-1 (500 mg, 2.18 mmol) in ACN (12 mL) was added DIEA (0.46 mL, 2.61 mmol), Boc ₂ O (1.02 g, 4.68 mmol), and then DMAP (13.3 mg, 0.11 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was concentrated and the residue was diluted with EtOAc and washed sequentially with H ₂ O and brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by SiO ₂ flash chromatography to yield AL-2.

A mixture of AL-2 (250 mg, 0.85 mmol), Pd ₂ (dba) ₃ (39 mg, 0.043 mmol), Xanphos (41 mg, 0.071 mmol), Josiphos (13 mg, 0.024 mmol), and TEA (0.83 mL, 0.97 mmol) in toluene (17 mL) was degassed and heated to 115° C. for 1 h. The reaction mixture was then cooled to room temperature and ethanethiol (0.076 mL, 1.02 mmol) was added. The reaction mixture was heated to 115° C. for 3 h. The reaction mixture was concentrated and the residue was purified by SiO ₂ flash chromatography to yield AL-3.

To a solution of AL-3 (200 mg, 0.71 mmol) in acetone (14 mL) was added a solution of potassium persulfate (961 mg, 1.56 mmol) in water (7 mL). The reaction mixture was stirred at room temperature for 18 h. The mixture was concentrated, then diluted with _H₂O and extracted twice with DCM. The organics were combined, washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated to yield AL-4.

To a solution of AL-4 (206 mg, 0.67 mmol) in DCM (4 mL) was added a solution of HCl in dioxane (4 N, 1.68 mL, 6.73 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to yield AL as the HCl salt. MS (ES+): m/z 207.1 [M+H] ⁺ .

Method 14:

Synthesis of intermediate AM

To a solution of AM-1 (1 g, 7.80 mmol) in THF (40 mL) at 0°C was added DIEA (4.08 mL, 23.40 mmol), followed by the dropwise addition of benzyl chloroformate (1.52 mL, 10.14 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was then concentrated, diluted with water, and then extracted with EtOAc. The organic layer was then washed with saturated aq _NaHCO₃ (2×), _H₂O (2×), and brine, dried over _MgSO₄ , filtered, and concentrated. The residue was purified by _SiO₂ flash chromatography to yield AM-2.

To a solution of AM-2 (1 g, 3.81 mmol) in THF (20 mL) was added _Br (0.30 mL, 5.91 mmol) dropwise at 0°C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water and then extracted with EtOAc. The organic layer was then washed with saturated aq NaHCO ( _2X ), water (2X), and brine, _dried over MgSO, filtered, and concentrated. The residue was purified by _SiO flash chromatography to yield AM-3.

AM-4 was synthesized in a similar manner to intermediate AL-3.

AM-5 was synthesized in a similar manner to intermediate AL-4.

To a solution of AM-5 (146 mg, 0.41 mmol) in EtOH (10 mL) was added 10% Pd/C (150 mg) and the mixture was stirred at room temperature under a _H atmosphere for 18 h. The reaction mixture was filtered through Celite and rinsed with EtOAc. The filtrate was concentrated, and HBr in acetic acid (1.5 mL, 33 wt%) was added. The mixture was stirred at room temperature for 2.5 h, then filtered to yield AM as the HCl salt. MS (ES+): m/z 221.1 [M+H] ⁺ .

Method 15:

Synthesis of intermediate AN

To a solution of AN-1 (6 g, 3.99 mmol) in EtOH (60 mL) was added N ₂ H ₄ hydrate (31.1 ml). The mixture was heated to reflux for 45 min. The mixture was allowed to cool to room temperature and then concentrated. The residue was dissolved in diethylene glycol (20 mL) and KOH (6.72 g, 120 mmol) was added. The mixture was stirred at 120 ° C for 18 h. The mixture was allowed to cool to room temperature, diluted with EtOAc and the pH was adjusted to pH <4 with 1N HCl. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by SiO ₂ flash chromatography to produce AN-2.

To a solution of AN-2 (1.3 g, 9.54 mmol) in DCM (20 mL) was added Br ₂ (1.53 g, 9.57 mmol) dropwise at 0°C. The mixture was stirred at room temperature for 12 h. The mixture was quenched with aq NaHSO ₃ and extracted twice with DCM. The organic layers were combined and washed with brine, dried over Na ₂ SO ₄ , and concentrated. The residue was purified by SiO ₂ flash chromatography to yield AN-3.

AN-4 was synthesized in a similar manner to intermediate AH-4.

To a solution of AN-4 (800 mg, 3.24 mmol) in NMP (10 mL) was added CuI (920 mg, 4.83 mmol) and CuCN (397 mg, 4.43 mmol). The microwave reaction was heated at 200°C for 3 h. The mixture was poured into _H2O and extracted with EtOAc. The organic layer was washed with brine, dried _{over Na2SO4} , and concentrated. The residue was purified by recrystallization to yield AN-5.

AN-6 was synthesized in a similar manner to intermediate AH-3.

AN was synthesized in a similar manner to Intermediate AH. MS (ES+): m/z 198.0 [M+H] ⁺ .

Method 16:

Synthesis of intermediate AO

To a solution of sodium 1-propanethiolate (12.8 g, 130 mmol) in ACN (150 mL) maintained below 20° C. was added AG-1 (19.8 g, 108 mmol) in portions. The mixture was then stirred at room temperature for 16 h, poured into water (300 mL) and extracted with EtOAc (300 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by SiO ₂ flash chromatography to yield AO-1.

To a stirred solution of AO-1 (16.5 g, 83.0 mmol) in AcOH (150 mL) maintained below 10° C. was added a solution of KMnO ₄ (14.5 g, 92.0 mmol) in H ₂ O (150 mL) dropwise. The reaction mixture was stirred for 30 min. The mixture was diluted with water, basified by adding saturated aq Na ₂ CO ₃ and extracted with EtOAc. The solution was concentrated and the residue was purified by SFC to yield AO-2.

A mixture of AO-2 (7.80 g, 37.0 mmol) and RaNi (8.00 g) in MeOH (100 mL) was stirred at room temperature for 18 h under H _2. After filtration and concentration, the residue was purified by MPLC to give AO-3.

To solid AO-3 (7.40 g, 35.0 mmol) was added ethyl acetate (2 mL) and HCl in EtOAc (100 mL). The solution was stirred at room temperature for 5 h and the solid was filtered to give intermediate AO.

Method 17:

Synthesis of intermediate AP

A mixture of AP-1 (12.8 g, 130 mmol), sodium cyclopropanesulfonate (53.1 g, 369 mmol), and CuI (23.3 g, 123 mmol) in DMSO (150 mL) was stirred at 110°C for 2 h. After cooling to room temperature, the solution was poured into water and extracted with EtOAc. _The combined organic phases were dried over _Na₂SO₄ , filtered, and concentrated. The resulting residue was purified by MPLC to yield AP-2.

A mixture of AP-2 (10.3 g, 49 mmol), RaNi (25.0 g), _Boc2O (16.2 g, 74 mmol) and TEA (10.0 g, 99 mmol) in MeOH (250 mL) was stirred at room temperature under _H2 atmosphere for 18 h. After filtration and concentration, the residue was purified by MPLC to give AP-3.

To a solution of AP-3 (6.90 g, 22 mmol) in MeOH (60 mL) was added HCl in EtOH (60 mL). The solution was stirred at room temperature for 3 h and concentrated and recrystallized to give intermediate AP.

Method 18:

Synthesis of intermediate AQ

To a solution of AG-1 (82.0 g, 448 mmol) in ACN (1.0 L) was added sodium tert-butoxide (64.5 g). The mixture was cooled to 0°C and sodium thiomethoxide (172.5 g, 20% in _H₂O ) was added _dropwise . The reaction mixture was then allowed to stir at room temperature for 16 h. Water (800 mL) was added and the mixture was extracted with DCM. _The combined organic phases were washed with brine, dried ( _Na₂SO₄ ), and concentrated. The residue was purified by SiO₂ flash chromatography to yield AQ-1.

To a suspension of AQ-1 (51.5 g, 343 mmol) in AcOH (500 mL) was added dropwise a solution of KMnO ₄ (59.7 g, 36.6 mmol) in H ₂ O (500.0 mL) at 5°C. The reaction mixture was then stirred at room temperature for 1 h. The mixture was extracted with EtOAc, washed with aq. NaHCO ₃ , dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified by recrystallization to yield AQ-2.

To a solution of AQ-2 (15.0 g, 82 mmol) in MeOH (200 mL) was added RaNi (10.0 g), TEA (34.4 mL) and _Boc2O (17.8 g). The mixture was stirred under _H2 (50 psi) for 12 h. The vessel was purged with _N2 , filtered and the filtrate was concentrated. The residue was purified by _SiO2 flash chromatography to yield AQ-3.

A solution of AQ-3 (30.0 g, 105 mmol) in HCl in MeOH (500 mL) was stirred at room temperature for 12 h. The mixture was concentrated and recrystallized to give intermediate AQ. MS (ES+): m/z 187 [M+H] ⁺ .

Intermediate AR and intermediate AS were synthesized in a similar manner to intermediate AQ (MS (ES+): m/z 202.1 [M+H] ⁺ ).

Method 19:

Synthesis of intermediate AT

To a mixture of AT-1 (10.0 g, 55 mmol), N,N-dimethylethane-1,2-diamine (0.96 g, 11 mmol), and copper(II) trifluoromethanesulfonate (1.98 g, 5 mmol) in DMSO (100 mL) was added AT-2 (8.27 g, 98 mmol) at room temperature. The mixture was then heated to 120° C. for 30 min, quenched with H ₂ O, and extracted with EtOAc. The organic layer was dried, concentrated, and purified by SiO ₂ flash chromatography to yield AT-3.

A mixture of AT-3 (32.3 g, 165 mmol) and Pd (3.50 g, 33 mmol) in _NH4OH (30 mL)/EtOH (200 mL) was stirred under _H2 (15 psi) at room temperature for 15 h. The mixture was filtered, concentrated and purified by _SiO2 flash chromatography to give AT-4.

To a stirred solution of AT-4 (17.5 g, 87 mmol) in EtOH (100 mL) was added HCl in EtOH (100 mL). The solution was stirred at room temperature for 3 h and then concentrated and recrystallized to produce intermediate AT. MS (ES+): m/z 201 [M+H] ⁺ .

Method 20:

Synthesis of intermediate AU

To a solution of AU-1 (7.15 g, 26.5 mmol) in THF (50 mL) was added Boc ₂ O (6.70 mL, 29.2 mmol) and TEA (7.40 mL, 53.1 mmol). The reaction was allowed to stir at room temperature for 72 h. The solution was concentrated to give AU-2.

A mixture of AU-2 (5.25 g, 15.8 mmol), sodium tert-butoxide (1.82 g, 18.9 mmol), Pd(OAc) ₂ (177 mg, 0.79 mmol), and 1,1'-bis(diisopropylphosphino)ferrocene (396 mg, 0.95 mmol) was added to a sealed container purged with argon. Dioxane (35 mL) was added and the mixture was stirred at room temperature for 1 h. Triisopropylsilanethiol (3.72 mL, 17.3 mmol) was added and the solution was heated to 100°C for 1 h. The reaction was then poured into EtOAc and water. The organic layer was concentrated and the residue was purified by _SiO2 flash chromatography to produce AU-3.

A solution of AU-3 (2.50 g, 6.32 mmol) in THF (25 mL) was cooled to 0°C and degassed with argon. Tetrabutylammonium bromide (2.12 g, 7.58 mmol) was then added and the solution was stirred at 0°C for 1 h. Bromoacetonitrile (660 uL, 9.48 mmol) was then added and the solution was stirred at 0°C for 5 min. The solution was concentrated and partitioned between ether and water. The organic layer was concentrated to yield AU-4, which was used without further treatment.

To a solution of AU-4 (1.80 g, 6.47 mmol) in ACN/H ₂ O (10 mL) was added sodium periodate (4.18 g, 19.5 mmol) followed by ruthenium(III) chloride (7.87 mg, 0.038 mmol). The reaction mixture was stirred at room temperature for 30 min and then concentrated. The residue was purified by SiO ₂ flash chromatography to yield AU-5.

To a stirred solution of AU-5 (470 mg, 1.51 mmol) in DCM (3 mL) was added a solution of HCl in dioxane (2.00 mL, 8.00 mmol). The solution was stirred at room temperature for 1 h and concentrated to give intermediate AU. MS (ES+): m/z 211.1 [M+H] ⁺ .

Method 21:

Synthesis of intermediate AV

To concentrated HCl (200 mL) at 0° C. was added AV-1 (20.0 g, 168 mmol), followed by the dropwise addition of aq NaNO ₂ (25.5 g in 25 mL H ₂ O), maintaining an internal temperature of <5° C. The solution was allowed to stir at 0° C. for 15 min and then slowly added to a mixture of SO ₂ (108 g) and CuCl (84 mg) in AcOH (200 mL, >5 equiv) at 5° C. The solution was stirred at 5° C. for 90 min. The reaction mixture was extracted with DCM (2×500 mL), dried (Na ₂ SO ₄ ), and the organic solution of AV-2 was used directly in the next step.

To a solution of AV-2 (20.0 g, 99 mmol) in DCM (200 mL) was added a solution of ammonia in MeOH (100 mL) at 0° C. and stirred at room temperature for 30 min. The mixture was concentrated to dryness and the resulting residue was purified by SiO ₂ flash chromatography to yield AV-3.

To a solution of AV-3 (15.0 g, 82 mmol) in MeOH (200 mL) was added RaNi (10.0 g), TEA (34.4 mL) and _Boc2O (17.8 g). The mixture was stirred at room temperature under _H2 (50 psi) for 12 h. The vessel was purged with _N2 , filtered and the filtrate concentrated. The residue was purified by _SiO2 flash chromatography to yield AV-4.

A solution of AV-4 (30.0 g, 105 mmol) in HCl in MeOH (500 mL) was stirred at room temperature for 12 h. The mixture was concentrated and recrystallized to give intermediate AV. MS (ES+): m/z 188.1 [M+H] ⁺ .

Intermediate AW was synthesized in a similar manner to intermediate AV.

Method 22:

Synthesis of intermediates (S)-AX and (R)-AX

To a solution of AG-3 (2.40 g, 12 mmol) in THF (30 mL) was added MeMgBr (30 mL) dropwise at -30°C. After addition, the mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by the addition of saturated aq _NH4Cl (100 mL) and extracted with EtOAc ( ₃ x 100 mL). The organic phase was washed with brine, dried over _Na2SO4 , and concentrated under reduced pressure. The residue was purified by _SiO2 flash chromatography to yield AX-1.

To a solution of AX-1 (200 mg, 1.0 mmol) in MeOH (2 mL) was added _NH₄OAc (723 mg) and _NaBH₃CN (41 mg) at 0°C. The mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure, water (50 mL) was added, and the mixture was adjusted to pH > 12 and then extracted with DCM (50 mL). The organic phase was dried _{over Na₂SO₄} and concentrated. The residue was purified by preparative TLC to yield AX-2.

AX-2 was separated by SFC to yield (S)-AX (67.9% ee) and (R)-AX (95.5% ee).

Method 23:

Synthesis of intermediate AY

To a solution of AY-1 (1.25 g, 5.49 mmol) in anhydrous MeOH (15 mL) was added NaOMe (2.37 g, 43.89 mmol). The mixture was stirred at room temperature for 1 h. The solution was filtered and concentrated. The residue was purified by _SiO2 flash chromatography to yield intermediate AY. MS (ES+): m/z 218.9 [M+H] ⁺ .

Method 24:

Synthesis of intermediate AZ

To a solution of sodium hydride (342 mg, (60%), 8.57 mmol) in DMF (10 mL) was added anhydrous isopropanol (360 uL, 4.71 mmol). The mixture was stirred at room temperature for 1 h. AB-1 (1.00 g, 4.28 mmol) was then added and the mixture was stirred for an additional 1 h before being poured onto ice. The mixture was then extracted with EtOAc and concentrated. The residue was purified by _SiO2 flash chromatography to yield intermediate AZ. MS (ES+): m/z 258.8 [M+H] ⁺ .

Method 25:

Synthesis of intermediate BA

A solution of BA-1 (1.00 g, 7.78 mmol) and Ni(dppe)Cl ₂ (82 mg, 0.16 mmol) in anhydrous Et ₂ O (5 mL) was cooled to -10°C. Then, n-propylmagnesium bromide was added dropwise and the mixture was stirred at -10°C for 2 h. The mixture was quenched with saturated NH ₄ Cl, extracted with DCM and concentrated. The crude BA-2 was used without further treatment.

To a solution of BA-2 (1.0 g, 7.34 mmol) in EtOH (10 mL) at 0°C was added Br ₂ (379 uL, 7.34 mmol). The reaction mixture was stirred at room temperature for 2 h. The solution was concentrated and the residue was purified by SiO ₂ flash chromatography to yield intermediate BA. MS (ES+): m/z 217.4 [M+H] ⁺ .

Method 26:

Synthesis of intermediate BC

A solution of BA-1 (1.00 g, 7.78 mmol) and Ni(dppe)Cl ₂ (82 mg, 0.16 mmol) in anhydrous Et ₂ O (5 mL) was cooled to -10°C. A solution of isopropylmagnesium bromide (3.22 mL, 9.33 mmol) was added dropwise and the mixture was stirred at -10°C for 1 h. The mixture was quenched with saturated NH ₄ Cl, extracted with DCM and concentrated. The crude BC-1 was used as is.

To a solution of BC-1 (1.0 g, 7.34 mmol) in EtOH (10 mL) at 0°C was added Br ₂ (378 uL, 7.34 mmol). The reaction mixture was stirred at room temperature for 2 h. The solution was concentrated and the residue was purified by SiO ₂ flash chromatography to yield intermediate BC. MS (ES+): m/z 216.4 [M+H] ⁺ .

Method 27:

Synthesis of intermediate BD

A solution of BA-1 (1.00 g, 7.78 mmol) and Ni(dppe)Cl ₂ (82 mg, 0.16 mmol) in anhydrous Et ₂ O (5 mL) was cooled to -10°C. A solution of cyclopropylmagnesium bromide (1.36 g, 8.56 mmol) was added dropwise and the mixture was stirred at -10°C for 2 h. The mixture was quenched with saturated aqueous NH ₄ Cl, extracted with DCM and concentrated. The crude BD-1 was used without further treatment.

To a solution of BD-1 (1.0 g, 6.74 mmol) in EtOH (10 mL) at 0°C was added _Br2 (347 uL, 6.74 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was concentrated and the residue was purified by _SiO2 flash chromatography to yield intermediate BD. MS (ES+): m/z 229.2 [M+H] ⁺ .

Method 28:

Synthesis of intermediate BE

To a solution of BE-1 (40.0 g, 244 mmol) in THF (800 mL) was added PPh ₃ (98.0 g) and NCS (160.0 g). The reaction mixture was stirred at 80° C. for 10 h. The mixture was then quenched with water and extracted with EtOAc. The solution was concentrated and the residue was purified by SiO ₂ flash chromatography to yield BE-2.

To a stirred solution of BE-2 (3.00 g, 14.79 mmol) in toluene and DMF was added Pd(PPh ₃ ) ₄ (600 mg), Pd(dppf)Cl ₂ (600 mg) and Na ₂ CO ₃ (6.27 g, 59.17 mmol). The mixture was stirred at 90° C. for 5 h. The mixture was quenched with water and extracted with EtOAc. The solution was concentrated and the residue was purified by SiO ₂ flash chromatography to give BE-3.

To a solution of BE-3 (860 mg, 5.0 mmol) in EtOH (5 mL) was added Br ₂ (347 uL, 6.74 mmol) at -10°C. The reaction mixture was stirred at room temperature for 18 h. The solution was concentrated and the residue was purified by SiO ₂ flash chromatography to yield intermediate BE. MS (ES+): m/z 267 [M+H] ⁺ .

Method 29:

Synthesis of intermediate BF

To a solution of AB (6.00 g, 26.2 mmol) and BF-1 (7.86 mL, 34.1 mmol) in toluene (60 mL) and THF (18 mL) was added n-butyllithium (12.6 mL, 31.4 mmol) dropwise over 30 min at -78°C. The solution was stirred at -78°C for 30 min and then slowly warmed to -20°C. The solution was quenched with 1N HCl (40 mL). The layers were then separated and the aqueous layer was adjusted to pH ~8 with 2M NaOH. A white solid began to precipitate and the mixture was cooled in a freezer for 1 h. The solid was filtered to produce intermediate BF. The aqueous layer was extracted with MeTHF and concentrated to produce more intermediate BF. MS (ES+): m/z 195.1 [M+H] ⁺ .

Intermediate BG was synthesized in a similar manner to intermediate BF.

A hexane solution of n-butyllithium (2.5 M, 12.2 mL, 30.5 mmol) was added dropwise over 40 minutes to a -78°C solution of AC (5.00 g, 23.5 mmol) and BF-1 (7.04 mL, 30.5 mmol) in a mixture of toluene (50 mL) and THF (12 mL). The reaction mixture was stirred at -78°C for 30 minutes, warmed to -20°C over 1 hour, and quenched with HCl (50 mL, 1 N). The resulting mixture was stirred at ambient temperature for 30 minutes, the phases separated, and the aqueous layer neutralized to pH ~7 with NaOH (4 M). The turbid mixture was cooled to 0°C, and the resulting precipitate was filtered to provide intermediate BG. MS (ES+): m/z 178.9 [M+H] ⁺ .

Method 30:

Synthesis of intermediate BH

To a mixture of 2-methylpropanal (5 g, 69.34 mmol) and NH ₄ Cl (7.42 g, 138.69 mmol) in water (50 mL) was added NaCN (4.08 g, 83.2 mmol). The mixture was stirred at room temperature for 18 h. The mixture was extracted with EtOAc (3x). The organics were combined, dried over Na ₂ SO ₄ , and concentrated to give the crude intermediate BH which was used without further treatment.

Method 31:

Synthesis of intermediate BI

To a mixture of BI-1 (20 mL, 104 mmol) and 2,2-dimethyloxirane (15 mL, 17 mmol) was added LiBr (1.86 g, 21.4 mmol) in one portion. The reaction mixture was stirred at room temperature for 16 h. Additional 2,2-dimethyloxirane (2.0 mL, 23 mmol) was added and the mixture was heated at 60°C for 2 h. The reaction mixture was quenched with water and then extracted twice with EtOAc. The organics were combined, washed with brine, dried _{over Na₂SO₄} , filtered, and concentrated to produce BI-2.

To a solution of BI-2 (2.0 g, 7.4 mmol) in DCM (20 mL) was added Deoxo-Fluor (1.51 mL, 8.17 mmol) at -21°C. After addition, the reaction mixture was stirred at -21°C for 5 min and then quenched with saturated aq NaHCO ₃ until pH ~8. The layers were separated and the aqueous layer was extracted with DCM. The combined organics were washed with saturated aq NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and concentrated to yield BI-3.

To a solution of BI-3 (1.5 g, 5.5 mmol) in toluene (30 mL) was added dropwise a solution of HCl in dioxane (4 N, 1.45 mL, 5.80 mmol). The reaction mixture was stirred at room temperature for 2 h and then filtered to give BI-4.

A mixture of BI-4 (500 mg, 1.62 mmol), 5% Pd/C (103 mg), and MeOH (3 mL) was hydrogenated on an Endeavor (60° C., 400 psi) for 5 h. The reaction mixture was filtered through Celite and rinsed with MeOH. The filtrate was concentrated to yield intermediate BI as the HCl salt. MS (ES+): m/z 92.3 [M+H] ⁺ .

Method 32:

Synthesis of intermediate BJ

To a solution of BJ-1 (7.40 mL, 99.0 mmol) in DCM (100 mL) was added (R)-2-methyl-2-propanesulfenamide (10.0 g, 82.5 mmol), MgSO ₄ (49.66 g, 412 mmol) and pyridinium p-toluenesulfonate (1.04 g, 4.13 mmol). The reaction mixture was allowed to stir at room temperature for 72 h. The reaction mixture was then filtered and the residue was purified by SiO ₂ flash chromatography to yield BJ-2.

To a solution of BJ-2 (9.72 g, 56.1 mmol) in THF (200 mL) was added tetramethylammonium fluoride (6.27 g, 67.3 mmol). The solution was degassed with argon and then cooled to -55°C. A solution of trifluoromethyltrimethylsilane (12.4 mL, 84.1 mmol) in THF (250 mL) was added dropwise using another funnel and the reaction was allowed to stir at -55°C for 2 h. The reaction mixture was then allowed to slowly warm to -10°C and quenched with saturated aqueous _NH4Cl . The aqueous layer was extracted with EtOAc and the combined organic layers were concentrated to yield BJ-3, which was used further without further treatment.

To a solution of BJ-3 (9.00 g, 37.0 mmol) in MeOH (30 mL) was added 4 M HCl in dioxane (18.5 mL, 74.0 mmol). The solution was allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated to half volume and diluted with ether until a white precipitate formed. The solid was then filtered to produce intermediate BJ.

Method 33:

Synthesis of intermediate BK

To a solution of BK-1 (9.47 g, 113 mmol) in DCM (100 mL) was added (R)-2-methyl-2-propanesulfenamide (10.5 g, 86.6 mmol), MgSO ₄ (52.1 g, 433 mmol), and pyridinium p-toluenesulfonate (1.09 g, 4.33 mmol). The reaction mixture was allowed to stir at room temperature for 18 h. The reaction mixture was then filtered and the residue was purified by SiO ₂ flash chromatography to yield BK-2.

To a solution of BK-2 (8.60 g, 45.9 mmol) in DCM (350 mL) at -50°C was added methylmagnesium bromide (36.0 mL, 108 mmol). The solution was stirred at -50°C for 3 h. The reaction was then allowed to warm to room temperature and stirred for 18 h. The solution was quenched with saturated aqueous _NH4Cl and extracted with EtOAc (2X). The organic layer was concentrated to yield BK-3, which was used without further treatment.

To a solution of BK-3 (5.00 g, 24.6 mmol) in MeOH (20 mL) was added 4 M HCl in dioxane (12.3 mL, 49.2 mmol). The solution was allowed to stir at room temperature for 1 h. The reaction mixture was then concentrated and the residue was purified by _SiO flash chromatography to yield intermediate BK.

Intermediate BL was synthesized in a similar manner to intermediate BK.

Intermediates BM, BN, BO, BP, BQ, BR, and BS were synthesized in a similar manner to intermediates AJ.

Method 34:

Synthesis of intermediate BT

To a stirred suspension of 2,4-dichloro-pyrimidin-5-ylamine (3.03 g, 18.1 mmol) in n-BuOH (40 mL) was added (1S,2S)-2-amino-cyclopentanol hydrochloride (2.50 g, 17.2 mmol) and DIEA (9.20 mL, 51.8 mmol). The mixture was stirred at 130° C. for 4 h. The reaction mixture was then concentrated under reduced pressure and the crude product was triturated to a solid in EtOAc and heptane and filtered to yield BT-1.

To a stirred solution of BT-1 (3.61 g, 15.5 mol) in acetone (200 mL) was added _{K₂CO₃ (} 5.34 g, 38.6 mmol) and ethyl chloro-oxoacetate (1.94 mL, 17.0 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude ketoester was dissolved in anhydrous EtOH (50 mL), placed in a pressure flask, and TEA (5.43 mL, 38.6 mmol) was added. This was heated to 130°C for 1 h. The reaction mixture was concentrated under reduced pressure and dissolved in EtOAc (100 mL). The organic layer was washed sequentially with water (2 x 20 mL) and brine (20 _mL ), dried ( _Na₂SO₄ ), decanted, and concentrated. The resulting residue was triturated to a solid in EtOAc and heptane to produce BT-2.

To a mixture of BT-2 (500 mg, 1.73 mmol) in DCM (100 mL) was added Dess-Martin periodinane (2.25 g, 5.20 mmol) and the mixture was stirred at room temperature for 96 h. The mixture was washed with saturated _NaHCO₃ (50 mL), and the organic layer was dried ( _Na₂SO₄ ) _and concentrated under reduced pressure. The solid residue was suspended twice in DCM (50 mL), sonicated, and filtered. The resulting solid was resuspended in EtOAc (20 mL) and sonicated. The solid product was filtered to yield BT-3.

To a mixture of BT-3 (124 mg, 0.442 mmol) in DCM (6 mL) was added oxalyl chloride (0.076 mL, 0.88 mmol) at room temperature, followed by the addition of anhydrous DMF (0.30 mL, 3.9 mmol) until the solid dissolved. The mixture was stirred at room temperature for 30 min, and LCMS indicated unreacted starting material. More oxalyl chloride (0.048 mL, 0.55 mmol) was added to the mixture and the mixture was stirred for an additional 10 min. Under a stream of nitrogen, the reaction was concentrated at 35 ° C for 1 h and the resulting residue, BT-4, was used directly.

To a stirred solution of BT-4 (132 mg, 0.442 mmol) and AG (105 mg, 0.442 mmol) in DMF (2 mL) at room temperature was added TEA (0.311 mL, 2.21 mmol), and the mixture was stirred at room temperature for 15 min. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried ( _Na₂SO₄ ), decanted, and concentrated. The resulting residue was purified by _SiO₂ flash chromatography to yield intermediate BT. _MS (ES+): m/z 463.1 [M+H] ^⁺ .

Method 35:

Synthesis of Example 9.

Intermediate AB (27 mg, 0.12 mmol), bis(pinacolato)diboron (30 mg, 0.12 mmol), potassium acetate (35 mg, 0.36 mmol), and [1,1'-bisdiphenylphosphinoferrocene]-palladium(II) dichloride (9 mg, 0.011 mmol) were combined in a degassed solution of toluene/DME/ethanol/water (3:2:2:1, 3 mL). The vessel was heated to 90°C in a microwave reactor for 20 min. In a separate vessel, Intermediate A (50 mg, 0.12 mmol), bis(pinacolato)diboron (30 mg, 0.12 mmol), KOAc (35 mg, 0.36 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (8 mg, 0.011 mmol) were combined in degassed 1,4-dioxane (3 mL). The reaction was heated to 90°C in a microwave reactor for 20 min. The contents of the two vessels were combined and _{Na2CO3 (aq)} (2M, 1 mL) was added. The reaction was heated to 120°C in a microwave reactor for 30 min. The vessel was cooled to room temperature and the contents were filtered and concentrated. The resulting residue was purified by _SiO2 flash chromatography to produce Example 9. MS (ES+): m/z 537.2 [M+H] ⁺ .

Synthesis of Example 11.

Intermediate AC (252 mg, 1.18 mmol), bis(pinacolato)diboron (600 mg, 2.36 mmol), potassium acetate (348 mg, 2.36 mmol), and [1,1'-bisdiphenylphosphinoferrocene]-dichloropalladium(II) (95 mg, 0.118 mmol) were combined in a degassed solution of toluene/DME/ethanol/water (3:2:2:1, 3 mL). The vessel was heated to 90°C in a microwave reactor for 20 min. In a separate vessel, Intermediate A (500 mg, 1.18 mmol), bis(pinacolato)diboron (600 mg, 2.36 mmol), potassium acetate (348 mg, 2.36 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (84 mg, 0.118 mmol) were combined in degassed 1,4-dioxane (3 mL). The reaction was heated to 90°C in a microwave reactor for 20 min. The contents of the two vessels were combined and _{Na2CO3 (aq)} (2M, 1 mL) was added. The reaction was heated to 120°C in a microwave reactor for 30 min. The vessel was cooled to room temperature and the contents were filtered and concentrated. The resulting residue was purified by _SiO2 flash chromatography to produce Example 11. MS (ES+): m/z 521.4 [M+H] ⁺ .

Synthesis of Example 15.

Intermediate AE (283 mg, 1.18 mmol), bis(pinacolato)diboron (600 mg, 2.36 mmol), potassium acetate (348 mg, 3.54 mmol), and [1,1'-bisdiphenylphosphinoferrocene]-palladium(II) dichloride (95 mg, 0.12 mmol) were combined in a degassed solution of toluene/DME/ethanol/water (3:2:2:1, 3 mL). The vessel was heated to 90°C in a microwave reactor for 20 min. In a separate vessel, Intermediate A (500 mg, 1.18 mmol), bis(pinacolato)diboron (600 mg, 2.36 mmol), potassium acetate (348 mg, 3.54 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (84 mg, 0.12 mmol) were combined in degassed 1,4-dioxane (3 mL). The reaction was heated to 90° C. in a microwave reactor for 20 min. The contents of the two vessels were combined and 2M sodium bicarbonate (1 mL) was added. The reaction was heated to 120° C. in a microwave reactor for 30 min. The vessel was allowed to cool to room temperature and the contents were filtered and concentrated. The resulting residue was purified by SiO ₂ flash chromatography to produce Example 15. MS (ES+): m/z 547.4 [M+H] ⁺ .

Synthesis of Example 17.

Intermediate AB (52 mg, 0.23 mmol), bis(pinacolato)diboron (58 mg, 0.23 mmol), KOAc (67 mg, 0.23 mmol), and [1,1'-bisdiphenylphosphinoferrocene]-palladium(II) dichloride (18 mg, 0.23 mmol) were combined in a degassed solution of toluene/DME/ethanol/water (3:2:2:1, 3 mL). The vessel was heated to 90°C in a microwave reactor for 20 min. In a separate vessel, Intermediate G (100 mg, 0.23 mmol), bis(pinacolato)diboron (58 mg, 0.23 mmol), KOAc (67 mg, 0.69 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (16 mg, 0.023 mmol) were combined in degassed 1,4-dioxane (3 mL). The reaction was heated to 90°C in a microwave reactor for 20 min. The contents of the two vessels were combined and _{Na2CO3 (aq)} (2M, 1 mL) was added. The reaction was heated to 120°C in a microwave reactor for 30 min. The vessel was cooled to room temperature and the contents were filtered and concentrated. The resulting residue was purified by _SiO2 flash chromatography to produce Example 17. MS (ES+): m/z 551.4 [M+H] ⁺ .

Synthesis of Example 63.

Intermediate AB (105 mg, 0.46 mmol), bis(pinacolato)diboron (175 mg, 0.69 mmol), potassium acetate (67 mg, 0.69 mmol), and [1,1'-bisdiphenylphosphinoferrocene]-dichloropalladium(II) (18 mg, 0.045 mmol) were combined in a degassed solution of toluene/DME/ethanol/water (3:2:2:1, 3 mL). The vessel was heated to 90°C in a microwave reactor for 20 min. In a separate vessel, Intermediate B (100 mg, 0.23 mmol), bis(pinacolato)diboron (175 mg, 0.69 mmol), KOAc (67 mg, 0.69 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (16 mg, 0.045 mmol) were combined in degassed 1,4-dioxane (3 mL). The reaction was heated to 90° C. in a microwave reactor for 20 min. The contents of the two vessels were combined and 2M sodium bicarbonate (1 mL) was added. The reaction was heated to 120° C. in a microwave reactor for 30 min. The vessel was cooled to room temperature and the contents were filtered and concentrated. The resulting residue was purified by SiO ₂ flash chromatography to produce Example 63. MS (ES+): m/z 548.0 [M+H] ⁺ .

Synthesis of Example 65.

Intermediate AC (174 mg, 0.820 mmol), bis(pinacolato)diboron (277 mg, 1.093 mmol), potassium acetate (161 mg, 1.64 mmol), and [1,1'-bisdiphenylphosphinoferrocene]-palladium(II) dichloride (43 mg, 0.055 mmol) were combined in a degassed solution of toluene/DME/ethanol/water (3:2:2:1, 3 mL). The vessel was heated to 90°C in a microwave reactor for 20 min. In a separate vessel, Intermediate X (247 mg, 0.547 mmol), bis(pinacolato)diboron (277 mg, 0.820 mmol), potassium acetate (161 mg, 1.64 mmol), and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (43 mg, 0.055 mmol) were combined in degassed 1,4-dioxane (3 mL). The reaction was heated to 90°C in a microwave reactor for 20 min. The contents of the two vessels were combined and _{Na2CO3 (aq)} (2M, 1 mL) was added. The reaction was heated to 120°C in a microwave reactor for 30 min. The vessel was cooled to room temperature and the contents were filtered and concentrated. The resulting residue was purified by _SiO2 flash chromatography to produce Example 65. MS (ES+): m/z 550.0 [M+H] ⁺ .

The following compounds were prepared in a similar manner:

Examples 1-8, 10, 12-14, 16, 18-62, 64, 66-92, 129.

Method 14:

Synthesis of Example 93.

A mixture of AJ (100 mg, 0.21 mmol), Intermediate AI (83.7 mg, 0.32 mmol), K ₃ PO ₄ (91 mg, 0.43 mmol), and Pd(dppf)Cl ₂ (26 mg, 0.03 mmol) in 1,4-dioxane (2 mL) was purged with argon, and then H ₂ O (0.25 mL) was added. The mixture was stirred at 100° C. for 18 h. After cooling to room temperature, the mixture was diluted with water (2 mL) and extracted with EtOAc (2×5 mL). The combined organic phases were dried (Na ₂ SO ₄ ), decanted, and concentrated. The resulting residue was purified by reverse phase HPLC to produce Example 93. MS (ES+): m/z 584.0 [M+H] ⁺ .

Synthesis of Example 136.

A mixture of NNN (3500 mg, 8.05 mmol), Intermediate BG (2149 mg, 12.07 mmol), K ₃ PO ₄ (3417 mg, 16.09 mmol), and Pd(dppf)Cl ₂ (986 mg, 1.21 mmol) in 1,4-dioxane (60 mL) was purged with argon, and then H ₂ O (6 mL) was added. The mixture was stirred at 100° C. for 18 h. After cooling to room temperature, the mixture was diluted with water (2 mL) and extracted with EtOAc (2×5 mL). The combined organic phases were dried (Na ₂ SO ₄ ), decanted, and concentrated. The resulting residue was purified by reverse phase HPLC to produce Example 136. MS (ES+): m/z 533.0 [M+H] ⁺ .

Synthesis of Example 158

A mixture of MMM (3360 mg, 7.49 mmol), Intermediate BG (2664 mg, 14.97 mmol), K ₃ PO ₄ (3177 mg, 14.97 mmol), and Pd(dppf)Cl ₂ (916 mg, 1.12 mmol) in 1,4-dioxane (60 mL) was purged with argon, and then H ₂ O (6 mL) was added. The mixture was stirred at 100° C. for 18 h. After cooling to room temperature, the mixture was diluted with water (2 mL) and extracted with EtOAc (2×5 mL). The combined organic phases were dried (Na ₂ SO ₄ ), decanted, and concentrated. The resulting residue was purified by reverse phase HPLC to produce Example 158. MS (ES+): m/z 539.3 [M+H] ⁺ .

The following compounds were prepared in a similar manner:

Examples 94-128, 130-132, 134, 137-144, 146-157, 159-199, 201-265.

Synthesis of Example 133:

A mixture of AC (5.39 g, 25.3 mmol), bis(pinacolato)diboron (10.4 g, 40.5 mmol), potassium acetate (3.98 g, 40.5 mmol), and Pd(dppf) _Cl2 DCM complex (0.83 g, 1.01 mmol) in DME/Tol/EtOH/ _H2O (10:6:3:1) was purged with argon, sealed, and stirred at 80°C for 30 min. This mixture was added to an argon-purged mixture of BU-1 (synthesized according to the procedures described in Steps 1 and 2 of Method 1) (2.70 g, 10.1 mmol) and Pd(amphos) _Cl2 (0.71 g, 1.01 mmol), and the sealed mixture was heated to 110°C for 2 h. The mixture was then concentrated, diluted with EtOAc, filtered, and concentrated again. The crude product was purified by flash chromatography on _SiO2 to yield BU-2.

To a solution of BU-2 (856 mg, 2.35 mmol) in DCM (15 ml) was added oxalyl chloride (596 mg, 4.70 mmol) followed by 5 drops of DMF. The reaction was allowed to stir for 18 h. The reaction was then concentrated and the residue yielded BU-3, which was used as is.

To a stirred solution of BU-3 (150 mg, 0.36 mmol) in DMF was added DIEA (196 uL, 1.41 mmol) at room temperature. 10 minutes later, BU-4 (84.1 mg, 0.42 mmol) was added and the reaction was stirred at room temperature for 10 minutes. The mixture was then concentrated and purified by reverse phase HPLC (NH ₄ CO ₃ ) to yield Example 133. MS (ES+): m/z 509.1 [M+H] ⁺ .

Examples 135 and 145 were synthesized in a manner similar to Example 133.

Method XX:

Synthesis of Example 200:

To a solution of 216 (100 mg, 0.195 mmol) in dioxane (2 mL)/water (1 mL) was added LiOH (28.0 mg, 1.17 mmol). The reaction was stirred at room temperature for 16 h. The mixture was concentrated and dissolved in water, acidified to pH ~5 with 1N HCl, filtered, washed with water, and dried in a vacuum oven to yield 200. MS (ES+): m/z 498.1 [M+H] ⁺ .

Biological activity

The compounds of the present invention have activity as RORγ (orphan receptor gamma related to retinoic acid receptor) modulators.

Reporter gene assay (RGA)

A nuclear receptor transactivation assay was performed to quantify the ability of the test compound to inhibit RORγ transactivation of the luciferase reporter. A similar assay is described in Khan et al., Bioorganic & Medicinal Chemistry Letters 23 (2013), 532-536. The system uses transiently transfected HEK 293 cells co-transfected with two plasmids (pGL4.3, luc2P/GAL4UAS/Hygro and pBIND, Gal4DBD hRORCLBD1-3). The positive control is transiently transfected with two plasmids, and the negative control contains the pGL4.3 promoter sequence. The assay was combined in a 384-well plate, where transiently transfected cells and test compounds were cultured at different concentrations for 20-24 hours. The next day, the assay plate was removed and equilibrated at room temperature for 20-30 minutes. Luciferase production was detected using the Bright-Glo ^™ Luciferase Assay System. After adding Bright GLO detection reagent, the plate was incubated at room temperature for 20 minutes. The plate was read on an Envision plate reader to measure the luminescence signal. The RLU signal was converted to a POC relative to the control wells and blank wells.

Cell seeding medium:

RPMI 1640-Invitrogen#11875135), 2.5% FBS-Invitrogen#26140, 1xPenicillin-Streptomycin-Gibco#15140

Compound Dilution Buffer:

1X HBSS - Invitrogen #14025126

Analysis disk: Greiner#781080-020

Bright Glo Luciferase Assay System: Promega #E2620

The lysis buffer provided in the kit was thawed and 100 mL of lysis buffer was added to the substrate powder.

The following table presents the results obtained when compounds of the invention were tested in the above assay, which demonstrate their activity as RORγ modulators:

Table II: Biological activity in reporter gene assays

Methods of therapeutic use

Based on the biological properties of the compounds of formula (I) of the present invention or their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and all the salts in the above-mentioned forms, they are suitable for the treatment of autoimmune and allergic diseases because they exhibit a good regulatory effect on RORγ.

The present invention therefore relates to compounds of formula (I) and pharmaceutically acceptable salts thereof and all tautomers, racemates, enantiomers, diastereomers, and mixtures thereof, which are useful in treating diseases and/or conditions in which the activity of RORγ modulators has therapeutic benefits, including (but not limited to) the treatment of autoimmune or allergic diseases.

Such diseases that can be treated by the compounds of the present invention include, for example, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, lupus nephritis, systemic sclerosis, vasculitis, scleroderma, asthma, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, type I diabetes, Crohn's disease, ulcerative colitis, graft-versus-host disease, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, atherosclerosis, uveitis, and non-radiographic spondyloarthropathies.

For the treatment of the above-mentioned diseases and conditions, a therapeutically effective dose will generally be in the range of about 0.01 mg to about 10 mg/kg body weight per dose of the compound of the invention; preferably about 0.1 mg to about 5 mg/kg body weight per dose. For example, when administered to a 70 kg human, the dosage range is about 0.7 mg to about 750 mg/dose of the compound of the invention, preferably about 7.0 mg to about 350 mg/dose. A certain degree of conventional dose optimization may be required to determine the most preferred dosing level and mode. The active ingredient may be administered 1 to 6 times daily.

General Administration and Pharmaceutical Compositions

When used as a drug, the compound of the present invention is usually administered in the form of a pharmaceutical composition. Such compositions can be prepared using operations well known in the medical field and usually include at least one compound of the present invention and at least one pharmaceutically acceptable carrier. The compound of the present invention can also be administered alone or in combination with an adjuvant having the following effects: enhancing the stability of the compound of the present invention, promoting the administration of a pharmaceutical composition containing the adjuvant in certain embodiments, providing enhanced solubility or dispersibility, enhanced antagonist activity, providing adjuvant therapy, etc. The compound of the present invention can be used alone or in combination with other active substances of the present invention, and optionally can also be combined with other pharmacologically active substances. In general, the compound of the present invention can be administered in a therapeutically effective amount or a pharmaceutically effective amount, but can also be administered in smaller amounts for diagnosis or other purposes.

Any one of the modes of administration of an acceptable pharmaceutical composition can be used to implement administration of the compound of the present invention in pure form or in the form of an appropriate pharmaceutical composition. Therefore, the administration can be, for example, oral, buccal (for example, sublingual), nasal, parenteral, topical, transdermal, vaginal or rectal, in the form of solid, semisolid, lyophilized powder or liquid dosage form, such as, for example, tablets, suppositories, pills, soft elastic gelatin capsules and hard gelatin capsules, powders, solutions, suspensions or mists, etc., preferably in a unit dosage form suitable for simple administration of precise doses. The pharmaceutical composition will generally include conventional pharmaceutical carriers or excipients and the compound of the present invention as an active agent, and may also include other medicaments, pharmaceutical reagents, carriers, adjuvants, diluents, vehicles or combinations thereof. Such pharmaceutically acceptable excipients, carriers or additives and methods for preparing pharmaceutical compositions for various modes or administration are known to those skilled in the art. The following documents demonstrate the current state of the art, for example: Remington: The Science and Practice of Pharmacy, 20th edition, A. Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook of Pharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995; Handbook of Pharmaceutical Excipients, A.H. Kibbe (ed.), American Pharmaceutical Ass'n, 2000; H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th edition, Lea & Febiger, 1990; each of which is incorporated herein by reference in its entirety to more appropriately describe the current state of the art. As will be appreciated by one skilled in the art, the form of the compound of the invention used in a particular pharmaceutical formulation will be selected (e.g., a salt) to have the appropriate physical characteristics (e.g., water solubility) required for the formulation to be effective.

All patent or non-patent documents or literature materials cited in this application are incorporated herein by reference in their entirety.

Claims (8)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: ^R1 is: -S(O) _n R ⁶ ， -S(O) _n NR ⁷ R ⁸ , or -S(O)(NH)R ⁶ ； ^R2 and ^R3 are each independently selected from: (A)-H; and (B)C _1-3 alkyl groups; ^R4 is: (A) _C1-6 alkyl groups optionally substituted with one or two groups selected from the following: a) _C3-6 cycloalkyl; b) 4, 5, or 6-membered heterocyclic groups; c)-OR ⁹ ; d)-CN; e)-halogens; and f)-CF ₃ ; (B) _C3-6 cycloalkyl groups optionally substituted with one, two, or three groups selected from the following: a) _C1-6 alkyl; b)-OR ₉ ; c)-CN; d)-halogens; and e)-CF ₃ ; (C) Phenyl; or (D) 5- or 6-membered heterocyclic group; ^R5 is: (A) A phenyl group optionally substituted with one or two groups selected from the following: a) _C1-6 alkyl; b) _C3-6 cycloalkyl; c)-OR ⁹ ; d)-CN; e)-CF ₃ ; and f)-halogen; or (B) Each of the following groups may be optionally substituted with one, two, or three pyridinyl or pyrimidinyl groups: a) _C1-6 alkyl; b) _C3-6 cycloalkyl; c)-OR ⁹ ; d)-CN; e)-CF ₃ ; f)-halogens; and g)-NR ⁷ R ⁸ ; and W is a phenyl, pyridyl, pyrimidinyl, piperidinyl, or _C3-12 cycloalkyl group, each optionally substituted with one or two of the following groups: a) _C1-6 alkyl; b) _C3-6 cycloalkyl; c)-OR ⁹ ; d)-CN; e)-CF ₃ ; f)-Halogen; g)-NR ⁷ R ⁸ ; h)-C(O)OR ⁹ ; and i)-C(O)N(R ⁹ ) ₂ ; R ⁶ is: (A) _C1-3 alkyl groups optionally substituted with one or two groups selected from the following: a) _C3-6 cycloalkyl; b)-OR ⁹ and c)-CN; or (B)C _3-6 cycloalkyl; ^R7 , ^R8 , and ^R9 are each independently: (A)-H; or (B)C _1-3 alkyl groups; and n is 2. 2. The compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein: ^R1 is -S(O) _nR6 or ^-S (O) _nNR7R8 ^{; and R2} and ^R3 are H; ^R4 is: (A) Any _C1-6 alkyl group substituted with one or two groups selected from _C3-6 cycloalkyl, _-CF3 and _C1-3 alkoxy groups; or (B) _C3-6 cycloalkyl groups optionally substituted with one or two groups selected from _C1-6 alkyl, -CN, and halogens; or (C) 5-membered heterocyclic group; R ⁵ is a pyrimidinyl group optionally substituted with one, two, or three groups selected from the following: a) _C1-6 alkyl; b) _C3-6 cycloalkyl; c)-OR ⁹ ; d)-CF ₃ ; and e)-NR ⁷ R ⁸ ; W is phenyl, pyridinyl, pyrimidinyl, or piperidinyl; ^R6 is a _C1-3 alkyl group; ^R7 , ^R8 , and ^R9 are each independently: (A)-H; or (B)C _1-3 alkyl groups; and n is 2. 3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following list: 4. A pharmaceutical composition comprising a compound as claimed in any of the preceding claims or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 5. The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, used as a pharmaceutical agent. 6. Use of the compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating patients with autoimmune diseases or allergic diseases. 7. The use as claimed in claim 6, wherein the autoimmune disease or allergic disease is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, lupus nephritis, scleroderma, asthma, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile idiopathic arthritis, type I diabetes, inflammatory bowel disease, graft-versus-host disease, psoriatic arthritis, reactive arthritis, adhesive capsulitis, Crohn's disease, ulcerative colitis, uveitis, and non-radiological spondyloarthritis. 8. The use as claimed in claim 6, wherein the autoimmune disease or allergic disease is selected from juvenile rheumatoid arthritis.