CN1976918A - 4,5-disubstituted-2-aryl pyrimidines - Google Patents

Abstract

4,5-disubstituted-2-arylpyrimidines of Formula (I) and Formula (II) are provided: wherein R1, R2, R3, R8, R9, A and Ar are defined herein. Such compounds are ligands of C5a receptors. Preferred compounds of Formula I and II bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse activity at C5a receptors. The present invention also relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds in treating a variety of inflammatory, cardiovascular, and immune system disorders. In addition, the present invention provides labeled 4,5-disubstituted-2-arylpyrimidines, which are useful as probes for the localization of C5a receptors.

Description

4,5-disubstituted-2-arylpyrimidine

technical field

The present invention generally relates to 4,5-disubstituted-2-arylpyrimidines as modulators of the mammalian complement C5a receptor, and to pharmaceutical formulations comprising said modulators. The present invention relates to the use of said modulators in the treatment of various inflammatory and immune system diseases and as probes for localizing the C5a receptor.

【Prior Technology】

C5a, a 74 amino acid peptide, is produced by cleaving the complement protein C5 by the complement C5 convertase enzyme in the complement cascade. C5a has anaphylatoxic (such as bronchoconstricting and spasmogenic) and chemotactic effects. Therefore, it is active in initiating inflammatory responses in either the vascular or cellular phase. Because it is a plasma protein, usually almost immediately available for provoking stimuli, it is the primary transmitter of a complex sequence of events resulting in an amplification or amplification of the initial inflammatory stimulus. The allergic toxicity and chemotactic effect of C5a peptide are believed to be caused by its interaction with C5a receptor (CD88 antigen), a 52kD cell membrane-linked G-protein coupled receptor (GPCR). C5a is a powerful chemoattractant for polymorphonuclear leukocytes, bringing neutrophils, basophils, eosinophils and monocytes to to sites of inflammation and/or cellular injury. C5a is one of the most potent chemotactic agents known for various inflammatory cell types. C5a also primes or primes neutrophils for antibacterial functions such as phagocytosis. In addition, C5a stimulates the release of inflammatory regulators such as histamine, TNF-α, IL-1, IL-6, IL-8, prostaglandins, and leukotriene and the release of lysosomal enzymes and other Cytotoxic components are released from granulocytes. Among other functions, C5a also promotes the production of reactive oxygen species and smooth muscle contraction.

Consideration of the experimental evidence implies that increased C5a content is associated with several autoimmune and inflammatory and related diseases. Agents that prevent C5a from binding to C5a receptors, including inverse agonists, can modulate signal transduction on C5a receptor interactions and can inhibit pathogenic events, including chemotaxis, on helpful Allergic Toxic Activity in Inflammatory and Autoimmune Symptoms. The present invention provides such formulations and has further related advantages.

【Content of invention】

In some aspects, the present invention provides a 4,5-disubstituted-2-arylpyrimidine compound represented by general formula I or a pharmaceutically acceptable salt thereof:

in

_R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted (cycloalkyl)alkoxy, or optionally substituted heterocycloalkyl;

R ₂ is selected from _-XRA , -(CR _A R _B )OR ₄ , -CR _A R _B NR ₄ R ₅ or -CR _A R _B Q;

_R is selected from optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy group, optionally substituted heterocycle, optionally substituted heterocycle-oxyl group, -O-(CR _A R _B )mY, -N(R _B )-(CR _A R _B )m- _XRA , or -N( _RB )-(CR _A R _B )mY, wherein the heterocyclic ring is saturated, unsaturated or aromatic and has 1 to 3 rings and each ring has 3 to 7 ring members;

_R4 is:

(i) C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₄ alkylamino) C ₂ -C ₄ alkyl, (3- to 7-membered heterocycloalkyl) C ₀ -C ₄ alkyl, aryl C ₀ -C ₄ alkyl, or ( Heteroaryl) C ₀ -C ₄ alkyl, each of which is optionally substituted; or

(ii) linking with R ₅ , and together with the nitrogen to which R ₄ and R ₅ are bonded, form a heterocyclic ring having 1 to 3 rings, each ring having 5 to 7 ring members, and the heterocyclic ring is selectively replaced;

_R5 is:

(i) hydrogen;

(ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, (C _3- C ₇ carbocycle) C ₀ -C ₄ alkyl, each of which is optionally substituted ;or

(iii) linking with _R to form an optionally substituted heterocycle;

Ar is mono-, di-, or trisubstituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl having 1 to 3 rings, each ring having 5 to 7 ring members;

R _A and R _B , being the same or different, are at each occurrence independently selected from:

(i) hydrogen or hydroxyl; or (ii) alkyl, cycloalkyl or (cycloalkyl)alkyl, each of which is optionally substituted with one or more substituents independently selected from Keto, hydroxyl, halogen, cyano, amino, C _1-6 alkoxy, -NH(C _1-6 alkyl), -N(C _1-6 alkyl)(C _1-6 alkyl), -NHC(=O)(C _1-6 alkyl), -N(C ₁ -C ₆ alkyl)C(=O)(C _1-6 alkyl), -NHS(O) _n (C _{1- 6} alkyl), -S(O) _n (C _1-6 alkyl), -S(O) _n NH(C _1-6 alkyl), -S(O) _n N(C _1-6 alkyl )(C _1-6 alkyl) or Z;

X at each occurrence is independently selected from, _-CHRB- , -O-, -C(=O)-, -C(=O)O-, -S(O) _n- , _-NRB- , - C(=O)NR _B -, -NR _B C(=O)-, or -NR _B S(O) _n -;

Y and Z are independently selected at each occurrence from 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated or aromatic and optionally substituted with one or more substituents , the substituents are independently selected from halogen, keto, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, mono or di(C _1-4 alkyl) amino, or -S(O) _n (alkyl);

Q is an optionally substituted carbocyclic or optionally substituted heterocyclic group which is saturated, unsaturated or aromatic and comprises 3 to 18 rings arranged in 1, 2 or 3 rings Atoms, the rings are fused, spiro or chemically bonded;

m is independently selected at each occurrence from an integer from 0 to 8; and

n is independently selected from 0, 1 or 2 at each occurrence.

In other aspects, the present invention provides a 4,5-disubstituted-2-arylpyrimidine compound represented by the general formula II or a pharmaceutically acceptable salt thereof:

in

Ar is mono-, di-, or trisubstituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl having 1 to 3 rings, each ring having 5 to 7 ring members ;

A is OR ₄ , NR ₄ R ₅ , or CR ₄ (XR _y ) ₂ ;

_R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted (cycloalkoxy)alkoxy, or optionally substituted heterocycloalkyl;

_R is selected from halogen, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkane Oxygen, optionally substituted cycloalkoxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy group, optionally substituted heterocycle, optionally substituted heterocycle-oxyl group, -E-(CR _C R _D )mZ, -E-(CR _C R _D ) _{m -XRA} , wherein the hetero the ring has 1 to 3 rings, each ring has between 3 and 7 ring members,

_R4 is:

(i) C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₄ alkylamino) C ₂ -C ₄ alkyl, (3- to 7-membered heterocycloalkyl) C ₀ -C ₄ alkyl, aryl C ₀ -C ₄ alkyl, or ( Heteroaryl) C ₀ -C ₄ alkyl, each of which is substituted by 0 to 4 substituents independently selected from R _x , C ₂ -C ₄ alkanoyl, mono- or di-(C ₁ -C ₄ alkyl) aminoC ₁ -C ₄ alkyl, mono- or di-(C ₁ -C ₄ alkyl) amino (C ₁ -C ₄ alkoxy), (3 to 7 membered ring heterocycle Alkyl) C ₀ -C ₄ alkyl or XR _y ; or

(ii) and R ₅ are linked, and together with the nitrogen to which R ₄ and R ₅ are bound, form a heterocyclic ring having 1 to 3 rings, each ring having 5 to 7 ring members, and wherein the heterocyclic ring is passed through Substituted by 0 to 4 substituents independently selected from R _x , keto and WZ;

_R5 is:

(i) hydrogen;

(ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, (C ₃ -C ₇ carbocycle) C ₀ -C ₄ alkyl, each of which is substituted by 0 to 3 Substituents are independently selected from halogen, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, methylamino, dimethylamino, trifluoromethyl or trifluoromethyl Fluoromethoxy; or

(iii) link with _R to form an optionally substituted heterocyclic ring;

R ₈ and R ₉ are independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkyl Amino or C ₃ -C ₇ cycloalkyl C ₀ -C ₄ alkyl;

E is a single covalent bond, oxygen or NRA;

X is a single covalent bond, -CR _A R _B -, -O-, -C(=O)-, -C(=O)O-, -S(O) _n- , or -NR _B- ; and R _y is:

(i) hydrogen; or

(ii) C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C ₃ -C ₁₀ carbocyclic C ₀ -C ₄ alkyl or (3 to 10-membered heterocycle) C ₀ - C ₄ alkyl, each of which is substituted by 0 to 6 substituents independently selected from R _x , keto, -NH(C ₁ -C ₆ alkanoyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkanoyl), -NHS(O _n )(C ₁ -C ₆ alkyl), -N(S(O _n )(C ₁ -C ₆ alkyl) ₂ , - S( _On )NH(C ₁ -C ₆ alkyl) or -S( _On )N(C ₁ -C ₆ alkyl)2;

W is a single covalent bond, -CR _A R _B -, -NR _B - or -O-;

Z at each occurrence is independently selected from 3- to 7-membered carbocyclic or heterocyclic rings, each of which is substituted with 0 to 4 substituents independently selected from halogen, keto, -COOH , hydroxy, amino, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono- or di-(C _1-6 alkyl ) amino, (C ₁ -C ₆ alkyl) (2-acetamide) amino or -S ( _On ) (C _1-6 alkyl);

R _A and R _B are independently selected at each occurrence from:

(i) hydrogen; or

(ii) C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, saturated or partially saturated (C ₃ -C ₁₀ carbocycle) C ₀ -C ₄ alkyl or saturated or partially saturated ( 3 to 10-membered heterocycle) C ₀ -C ₄ alkyl, each of which is substituted by 0 to 6 substituents independently selected from keto, hydroxyl, halogen, cyano, amino, C ₁ -C ₆ alkoxy, mono- or di-(C ₁ -C ₄ alkyl)amino, -COOH, -C(=O)NH ₂ , -NHC(=O)(C ₁ -C ₆ alkyl ), -N(C ₁ -C ₆ alkyl)C(=O)(C ₁ -C ₆ alkyl), -NHS(O _n )(C ₁ -C ₆ alkyl), SO ₃ H, -SO ₂ NH ₂ , -S(O _n )(C ₁ -C ₆ alkyl), -S(O _n )NH(C ₁ -C ₆ alkyl), -S(O _n )N(C ₁ -C ₆ Alkyl) (C ₁ -C ₆ alkyl) or Z;

R _C and R _D are independently selected from R _A , hydroxyl, C ₁ -C ₆ alkoxy, or keto;

Each occurrence of R _x is independently selected from halogen, hydroxy, amino, keto, nitro, -COOH, C(=O) _NH2 , _C1 - _C6 alkoxycarbonyl, -C(C=O) NH(C ₁ -C ₆ alkyl), -C(=O)NH(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl , mono- or di-(C ₁ -C ₆ alkyl)amino, C ₁ -C ₆ alkoxy, C ₁ -C ₂ hydroxyalkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy Group, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl or -S(O _n )(C ₁ -C ₆ alkyl);

m is independently selected at each occurrence from an integer from 0 to 8; and

n is independently selected from 0, 1 or 2 at each occurrence.

In other aspects, the present invention provides 4,5-disubstituted-2-arylpyrimidine compounds as shown in general formula IX:

in

Ar is mono-, di-, or tri-substituted phenyl, wherein phenyl is substituted by one to three substituents selected from the group consisting of hydroxyl, halogen, cyano, amino, nitro, -COOH, aminocarbonyl, - SO ₂ NH ₂ , C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 haloalkyl, C _1-6 aminoalkyl, C _1-6 hydroxyalkyl, C _1-6 carboxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 alkanoyl, C _1-6 alkanoyloxy, C _{3 -6} alkanone, C _1-6 alkyl ether, mono or di-(C _1-6 alkyl)-amino C _0-6 alkyl, NHC(=O)(C ₁ -C ₆ alkyl), N (C ₁ -C ₆ alkyl)C(=O)(C ₁ -C ₆ alkyl), NHS( _On )(C ₁ -C ₆ alkyl), (C ₁ -C ₆ alkyl)C( =O)NH ₂ , (C ₁ -C ₆ alkyl)C(=O)NH(C ₁ -C ₆ alkyl), (C ₁ -C ₆ alkyl)C(=O)NH(C ₁ - C ₆ alkyl)(C ₁ -C ₆ alkyl), -S-(O) _n -(C ₁ -C ₆ alkyl), -S-(O) _n NH-(C ₁ -C ₆ alkyl ), -S-(O) _n N-(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) or Z; or

q is 0, 1 or 2;

A is OR ₄ , NR ₄ R ₅ or CR ₄ R ₅ XR _y ;

_R is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, cycloalkoxy or (cycloalkyl)alkoxy, each of which is represented by 0 to 4 radicals Substituted by a group, the group is independently selected from the group wherein the phenyl is substituted by one to three of the following substituents, the substituents are independently selected from: hydroxyl, halogen, cyano, amino, nitro, -COOH , aminocarbonyl, -SO ₂ NH ₂ , C _{1-6 alkyl, C 1-6 alkenyl} , C _1-6 alkynyl, C _1-6 haloalkyl, C _1-6 aminoalkyl, C _1-6 Hydroxyalkyl, C _1-6 carboxyalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 alkylthio, C _1-6 alkanoyl, C _1-6 alkanoyl Oxygen, C _3-6 alkanone, C _1-6 alkyl ether, mono or di-(C _1-6 alkyl)-amino C _0-6 alkyl, NHC (=O) (C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl)C(=O)(C ₁ -C ₆ alkyl), NHS( _On )(C ₁ -C ₆ alkyl), (C ₁ -C ₆ Alkyl)C(=O)NH ₂ , (C ₁ -C ₆ alkyl)C(=O)NH(C ₁ -C ₆ alkyl), (C ₁ -C ₆ alkyl)C(=O) NH(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -S-(O) _n -(C1-C6 alkyl), -S-(O) _n NH-(C ₁ -C ₆ alkyl), -S-(O) _n N-(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or Z;

_R4 is:

(i) C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₄ alkylamino) C ₂ -C ₄ alkyl, (3- to 7-membered heterocycloalkyl) C ₀ -C ₄ alkyl, phenyl C ₀ -C ₄ alkyl, or ( Heteroaryl) C ₀ -C ₄ alkyl, each of which is substituted by 0 to 4 substituents independently selected from R _x , C ₂ -C ₄ alkanoyl, mono- or di-(C ₁ -C ₄ alkyl) amino C ₁ -C ₄ alkyl, mono- or di-(C ₁ -C ₄ alkoxy) amino C ₁ -C ₄ alkoxy, (3 to 7 membered cycloheterocycloalkane group) C ₀ -C ₄ alkyl or XRy; or (ii) linked with R ₅ and together with the nitrogen to which R ₄ and R ₅ are bonded form 1 to 3 rings, each ring has 5 to 7 rings ring-membered heterocycle, wherein the heterocycle is substituted by 0 to 4 substituents independently selected from _Rx , keto and WZ, the substituents are selected from _Rx , keto or WZ;

_R5 is:

(i) hydrogen;

(ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, (C ₃ -C ₇ carbocycle) C ₀ -C ₄ alkyl, each of which is optionally selected from 0 to 3 Substituents are substituted, and the substituents are independently selected from halogen, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy; or

(iii) link with _R to form an optionally substituted heterocycle;

R ₈ and R ₉ are independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkyl Amino or C ₃ -C ₇ cycloalkyl C ₀ -C ₄ alkyl;

R ₁₃ represents 0 to 3 substituents independently selected from the following:

(i) R _x ; or

(ii) phenyl or pyridyl; each of which is substituted by 0 to 4 substituents independently selected from halogen, hydroxyl, amino, cyano, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- or di-(C ₁ -C ₄ alkyl) amino;

X is a single covalent bond, -CR _A R _B -, -O-, -C(=O)-, -C(=O) ₀ -, -S(O)n- or -NR _B -;

Ry _is :

(i) hydrogen; or

(ii) C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C ₃ -C ₁₀ carbocyclic C ₀ -C ₄ alkyl or (3 to 10-membered heterocycle) C ₀ - C ₄ alkyl, each of which is substituted by 0 to 6 substituents independently selected from R _x , keto, -NH(C ₁ -C ₆ alkanoyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkanoyl), -NHS(O _n )(C ₁ -C ₆ alkyl), -N(S(O _n )C ₁ -C ₆ alkyl) ₂ , -S (O _n )NH(C ₁ -C ₆ alkyl) or -S(O _n )N(C ₁ -C ₆ alkyl) ₂ ;

W is a single covalent bond, -CR _A R _B -, -NR _B - or -O-;

Z is independently selected from 3- to 7-membered carbocyclic or heterocyclic rings, each of which is substituted by 0 to 4 substituents independently selected from halogen, keto, -COOH, hydroxyl, amino, Cyano, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono- or di-(C _1-6 alkyl) amino, or- S( _On )(C _1-6 alkyl);

R _A and R _B are independently selected at each occurrence from:

(i) hydrogen; or

(ii) C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, saturated or partially saturated (C ₃ -C ₁₀ carbocycle) C ₀ -C ₄ alkyl or saturated or Partially saturated (3 to 10 membered heterocycle) C ₀ -C ₄ alkyl, each of which is substituted by 0 to 6 substituents independently selected from keto, hydroxy, halogen, cyano, amino , C1-C ₆ alkoxy, mono- or di-(C ₁ -C ₄ alkyl) amino, -COOH, -C(=O)NH ₂ , -SO ₂ NH ₂ -, -NHC(=O) (C ₁ -C ₆ alkyl), N(C ₁ -C ₆ alkyl)C(=O)(C ₁ -C ₆ alkyl), -NHS(O _n )(C ₁ -C ₆ alkyl) , -S( _On )(C ₁ -C ₆ alkyl), -S(On ₎ NH(C ₁ -C ₆ alkyl), -S( _On )N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) or Z; R _C and R _D are independently selected from R ₄ , hydroxyl, C ₁ -C ₆ alkoxy or keto;

R _x at each occurrence is independently selected from halogen, hydroxy, amino, cyano, nitro, -COOH, C(=O) _NH2 , _C1 - _C6 alkoxycarbonyl, mono- or di-( C ₁ -C ₆ alkyl)aminocarbonyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, mono- or di-(C ₁ -C ₆ alkyl)amino , -C ₁ -C ₆ alkoxy, C ₁ -C ₂ hydroxyalkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ - C ₄ alkyl or -S(O _n )C ₁ -C ₆ alkyl;

T is CO ₂ H, CONH ₂ , C _1-6 alkoxycarbonyl, mono- or di-(C ₁ -C ₆ alkyl) aminocarbonyl, SO ₃ H or SO ₂ (C _1-6 alkyl); as well as

Each occurrence of n is an integer independently selected from 0, 1 or 2.

In some embodiments, the 4,5-disubstituted-2-arylpyrimidines herein provide high affinity for the C5a receptor (i.e., binding to the C5a receptor with an affinity constant of less than 1 micromolar) or for C5a Very high affinity for the receptor (ie, the affinity constant for binding to the C5a receptor is less than 100 nanomolar). In some embodiments, the modulator has a higher affinity for human C5a receptor than for rat C5a receptor, preferably at least 5 times higher, more preferably at least 10 times higher. Compound affinity for the C5a receptor is determined, for example, by radiolabeled ligand binding assays as provided in Example 23.

In some aspects, the modulator herein is a C5a receptor antagonist, such as an inverse agonist. Some of these compounds have an EC50 of 1 micromolar in a standard in vitro C5a receptor-mediated chemotaxis assay (such as the assay provided in Example 18) or a calcium flux assay (as described in Example 25) (micromolar) or lower, 500nM or lower, 100nM or lower or 25nM or lower.

In a further aspect, the C5a receptor antagonist must not have C5a receptor agonist activity (ie less than 5% agonist activity in the GTP binding assay as described in Example 24).

The invention further provides, in other aspects, a pharmaceutical composition comprising at least one C5a receptor modulator as described herein, and a physiologically acceptable carrier or excipient. Processes for preparing the pharmaceutical compositions are also provided. The compositions are particularly useful in C5a-induced inflammation, such as that associated with various inflammatory and immune system diseases.

In a further aspect, there is provided a method of inhibiting C5a receptor signaling in a cell comprising contacting a cell expressing a C5a receptor with at least one C5a receptor modulator described herein, thereby reducing C5a receptor signaling.

Further provided is a method of inhibiting the binding of C5a to a C5a receptor in vitro, comprising combining a C5a receptor with at least one C5a receptor modulator described herein, under conditions sufficient to detect that binding of C5a to a C5a receptor is inhibited, and Touch down.

The invention further provides a method of inhibiting the binding of C5a to a C5a receptor in a human patient comprising contacting a cell expressing a C5a receptor with at least one C5a receptor modulator described herein.

In a further aspect, the invention provides methods of treatment of patients in need of anti-inflammatory therapy or immunomodulatory therapy. Such methods generally comprise administering to a patient a therapeutically effective amount of a C5a receptor modulator described herein. The treatment of humans, household companion animals (pets), or livestock suffering from such conditions is contemplated by the present invention. In some aspects, a method of treating a patient with fibrocystic, rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma comprises administering to the patient a therapeutically effective amount of a C5a described herein Conditioner. In a further described aspect, the method of treating a patient suffering from stroke, myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury comprises administering to the patient a therapeutically effective amount of C5a modulators described herein.

The present invention further provides a method for inhibiting C5a receptor-mediated cell chemotaxis, preferably leukocyte (e.g., neutrophil) chemotaxis, comprising combining mammalian leukocyte cells with a therapeutically effective amount of at least one of the This describes the C5a receptor modulator contacts. In some embodiments, the white blood cells are primate white blood cells, such as human white blood cells.

In a further aspect, the invention provides methods of using the C5a receptor modulators described herein as receptor (particularly C5a receptor) localization probes. Said localization is performed by tissue sections (for example via autoradiography (autoradiography) or in vivo (for example via positron emssion tomography, PET) or single positron emssion computed tomography (singlepositron emssion computed tomography, SPECT), scanning and imaging). In some such aspects, the invention provides a method for localizing a C5a receptor in a tissue sample, comprising: (a) combining a tissue sample containing a C5a receptor with a detectable receptor as described herein. The ground-labeled compound is contacted under conditions that allow the compound to bind to the C5a receptor; and (b) detecting the binding compound. The methods optionally include the step of washing the contacted tissue sample before detection. Appropriate Useful side labels include, for example, radioactive 125I, tritium, 14C, 32P, or 99Tc.

The invention also provides a pharmaceutical formulation package comprising: (a) a pharmaceutical composition as described herein in a container; and (b) instructions for using the composition to treat a patient suffering from one or more symptoms associated with C5a receptor modulation , such a condition as rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, bronchial asthma, stroke, myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury.

In yet another aspect, the invention provides processes for the preparation of the compounds disclosed herein, including intermediates.

These and other aspects of the invention will become more apparent with reference to the following detailed description.

【Implementation】

As mentioned above, the present invention provides 4,5-disubstituted-2-arylpyrimidines, which can regulate the activation of C5a receptor and signal transduction mediated by C5a receptor. The compounds can be used in various settings in vitro or in vivo to modulate (preferably inhibit) C5a receptor activity.

Chemical Narratives and Terminology

The compounds provided herein are generally described using standard nomenclature. For compounds having asymmetric centers, it is understood that (unless otherwise indicated) all optical isomers and mixtures thereof are also included. Elements having two or more asymmetric elements may also exist as mixtures of diastereomers. In addition, compounds having a carbon-carbon double bond are Z- and E-forms, and the present invention includes all isomeric forms unless otherwise specified. When a compound has multiple tautomeric forms, reference to the compound is not limited to any one particular tautomeric form, but is meant to include all tautomeric forms. Reference to compounds is further meant to include compounds in which one or more atoms are substituted with isotopes (ie, having the same atomic number but different mass numbers). Typical examples, but not limited to, areotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11C, 13C or 14C.

Some of the compounds described herein have general formulas that include variables (eg, R, _R1 to _R6 , Ar). Unless otherwise defined, the formulas have each variable independently defined, and any variable that occurs more than one time in the formula is independently defined at each occurrence. Thus, for example, a group is shown that is substituted with 0 to 2 R*, may be unsubstituted or substituted with up to 2 R*, and each occurrence of R* is independently selected from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "4,5-disubstituted-2-arylpyrimidine" used herein refers to the compound represented by the general formula I, formula II or other general formulas provided herein, or a pharmaceutically acceptable salt thereof. Obviously such compounds may be further substituted as indicated (eg 4,5,6-trisubstituted-2-arylpyrimidines are included in the term "4,5-disubstituted-2-arylpyrimidines").

The term "pharmaceutically acceptable salt" as used herein refers to acidic or basic salts generally considered in the art to be suitable for use in human or animal tissue contact without undue toxicity or carcinogenicity, and preferably No irritation, allergic reactions or other problems or complications. Such salts include mineral or organic acid salts of basic residues, such as amines, and basic or organic salts of acidic residues, such as carboxylic acids. Certain pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, malic acid, glycolic acid, fumaric acid, sulfuric acid, sulfamic acid, sulfanilic acid , formic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, nitric acid, benzoic acid, 2-acetylbenzoic acid, citric acid, tartaric acid, lactic acid, stearic acid, Salicylic acid, glutamic acid, ascorbic acid, pamoic acid (pamoic), succinic acid, fumaric acid, maleic acid, propionic acid, hydroxymaleic acid, hydroiodic acid, phenylacetic acid, Alkanoic acid (alkanoic acid) such as acetic acid, HOOC-(CH2)n-COOH where n is 0 to 4, etc. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium or ammonium. Those skilled in the art will recognize pharmaceutically acceptable salts of the compounds provided herein, including those listed in Remington's Pahrmaceutical Sciences 17th Ed., Mack Publishing Company, Easton, PA, p. 1418 (1985). In general, pharmaceutically acceptable acid or base salts can be synthesized from the parent compound containing the acid or base moiety by conventional chemical methods. Briefly, these salts can be obtained by reacting the free acid or base forms of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent or a mixture of both; usually a non-aqueous medium such as ether is preferred , ethyl acetate, ethanol, isopropanol, or acetonitrile.

It is obvious that the compounds represented by general formula I or general formula II may, but not necessarily, be formulated as hydrates, solvates or non-covalent complexes. Furthermore, multiple crystalline forms or polymorphous are within the scope of the present invention, prodrugs of the compounds represented by general formula I or general formula II. "Prodrug" means that the compound may not fully conform to the structural requirements of the compounds provided herein but is modified in vivo, and after administration to a patient, it will produce the general formula I or general formula II or other compounds provided herein. Compounds shown in the formula. For example, a prodrug can be an acylated derivative of a compound provided herein. Prodrugs include the combination of the hydroxyl, amino or sulfhydryl groups of a compound with any group that, upon administration to a mammal, cleaves to yield a free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate derivatives of alcohol and amine functional groups of the compounds provided herein. Prodrugs of the compounds provided herein can be achieved by modifying functional groups in the compounds in which way the modifications are cleaved to the parent compound.

A "therapeutically effective amount" (or dosage) is that amount which, when administered to a patient, results in an identifiable patient benefit (eg, providing detectable relief from the symptom being treated). Such relief may be detected by using any suitable criteria, including alleviation of one or more symptoms. A therapeutically effective amount or dosage is typically tested in vitro and/or alters C5a receptor activity or activation as measured by in vitro calcium mobility assays in body fluids (e.g., blood, plasma, serum, CSF, joint lubricating fluid, lymphatic A concentration of a compound sufficient to inhibit leukocyte chemotaxis is formed in fluid, interstitial fluid, tears, or urine. Clearly, identifiable patient benefit may become evident upon a single administration, or upon repeated administration to a therapeutically effective amount according to a preformulated formulation, as indicated by the type of drug being administered.

"Substituent" as used herein refers to a moiety of a molecule that is covalently bonded to a related atom within the molecule. For example, a "ring substituent" can be a moiety such as a halogen, alkyl, haloalkyl, or other substituent described herein, which is covalently bonded to an atom (preferably a carbon or nitrogen atom) in a ring member. As used herein, the term "substituted" means that any one or more hydrogens on the indicated atom are replaced by substituents selected from the proposed substituents, providing that the normal valence of the indicated atom will not be exceeded, and that the result of the substitution is a stable compound (ie compounds can be isolated, characterized and tested for chemical activity). When a substituent is keto (ie, =O), two hydrogens on the atom are replaced. When the aromatic moiety is substituted by a keto group, the aromatic ring is replaced with a corresponding partially unsaturated ring. For example pyridyl is substituted by keto to become pyridone.

The phrase "optionally substituted" means that a group may be unsubstituted or substituted at one or more of any of the substitutable positions, typically 1, 2, 3, 4 or 5, by one or more Suitable substituents are disclosed for substitution. Optionally substituted may also be the phrase "substituted with 0 to X substituents", where X is the maximum number of substituents.

Suitable substituents include, for example, halogen, cyano, amino, hydroxy, nitro, azido, formylamino, -COOH, SO ₂ NH ₂ , alkyl (eg C ₁ -C ₈ alkyl), alkenyl (such as C ₂ -C ₈ alkenyl), alkynyl (such as C ₂ -C ₈ alkynyl), alkoxy (such as C ₁ -C ₈ alkoxy), alkyl ether (such as C ₂ -C ₈ alk base ether), alkylthio (such as C ₁ -C ₈ alkylthio), haloalkyl (such as C ₁ -C ₈ haloalkyl), hydroxyalkyl (such as C ₁ -C ₈ hydroxyalkyl), aminoalkyl (such as C ₁ -C ₈ aminoalkyl), haloalkoxy (such as C ₁ -C ₈ haloalkoxy), alkanoyl (such as C ₁ -C ₈ alkanoyl), alkanonyl (such as C ₁ -C ₈ alkanonyl), alkanoyloxy (such as C ₁ -C ₈ alkanoyloxy), alkoxycarbonyl (such as C ₁ -C ₈ alkoxycarbonyl), mono- or di-(C ₁ -C ₈ alkyl ) amino, mono- or di-(C ₁ -C ₈ alkyl) amino C ₁ -C ₈ alkyl, mono- or di-(C ₁ -C ₈ alkyl) carbamido, mono- or di- (C ₁ -C ₈ alkyl)aminosulfonylamido, alkylpyridine (such as C ₁ -C ₈ alkylpyrylene), alkylpyridine (such as C ₁ -C ₈ alkylpyridine ), aryl (such as phenyl), arylalkyl (such as (C ₆ -C ₁₈ aryl) C ₁ -C ₈ alkyl, such as benzyl and phenethyl), aryloxy (such as C ₆ - C ₁₈ aryloxy, such as phenoxy), aralkoxy (such as (C ₆ -C ₁₈ aryl) C ₁ -C ₈ alkoxy) and/or 3- to 8-membered heterocyclic groups such as , coumarinyl (coumarinyl), quinolinyl, pyridyl, pyrinyl, pyrimidyl, furyl, pyrrolyl, thiophene, thiazolyl, Azolyl, imidazolyl, indolyl, benzofuryl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, piperidinyl, morpholinyl or pyrrolidinyl. It is provided herein that said groups of said general formula are optionally substituted with 1 to 3, 1 to 4 or 1 to 5 independently selected substituents.

A dash ("-") not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, _-CONH2 is attached via a carbon atom.

As used herein, "alkyl" is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups, when specifically designated with a particular number of carbon atoms. Therefore, the term "C ₁ -C ₆ alkyl" (or C _1-6 alkyl) as used herein refers to an alkyl group having 1 to 6 carbon atoms. "C ₀ -C ₄ alkyl" refers to a single covalent bond (such as C ₀ alkyl) or C ₁ -C ₄ alkyl. Alkyl groups include groups having from 1 to 8 carbon atoms (C _1-8 alkyl), from 1 to 6 carbon atoms (C _1-6 alkyl) or from 1 to 4 carbon atoms (C _1-4 Alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, second-butyl, third-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl , 2-hexyl, 3-hexyl or 3-methylpentyl. In some embodiments, the preferred alkyl group is methyl, ethyl, propyl, butyl or 3-pentyl. "Aminoalkyl" is an alkyl group as defined herein substituted with one or more _-NH2 substituents. "Hydroxyalkyl" is an alkyl group as defined herein substituted with one or more -OH substituents. "Carboxyalkyl" is an alkyl group as defined herein substituted with one or more -COOH substituents.

"Alkylene" means a divalent alkyl group as defined above. C ₀ -C ₄ alkylene is a single covalent bond or an alkylene group having 1 to 4 carbon atoms.

"Alkenyl" refers to a straight or branched hydrocarbon chain having one or more unsaturated carbon-carbon bonds, such as vinyl or propenyl. Alkenyl groups include C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkenyl or C ₂ -C ₄ alkenyl groups (each having 2 to 8, 2 to 6 or 2 to 4 carbon atoms), such as Vinyl, allyl or isopropenyl.

"Alkynyl" refers to a straight or branched hydrocarbon chain having one or more carbon-carbon triple bonds. Alkynyl groups include C ₂ -C ₈ alkynyl, C ₂ -C ₆ alkynyl, or C ₂ -C ₄ alkynyl groups, each having 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of alkynyl groups include ethynyl or propynyl.

"Alkoxy" as used herein means that the above-mentioned alkyl group is bonded through an oxygen bridge. Alkoxy groups include C _1-6 alkoxy or C _1-4 alkoxy groups, each having 1 to 6 or 1 to 4 carbon atoms. Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, second butoxy, third butoxy, n-pentoxy, 2-pentyloxy, 3-pentyloxy , isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy or 3-methylpentyloxy are representative alkoxy groups. Similarly, "alkylthio" means that the above-mentioned alkyl group is bonded via a sulfur bridge.

The term "alkanoyl" means that the above-mentioned alkyl group is bonded via a carbonyl bridge. Alkanoyl groups include C _2-8 alkanoyl, C _2-6 alkanoyl, or C _2-4 alkanoyl, each having 2 to 8, 2 to 6, or 2 to 4 carbon atoms. "C ₁ alkanoyl" refers to -(C=O)-H, which (and C _2-8 alkanoyl) is included in "C _1-8 alkanoyl". Acetyl is _C2 alkanoyl.

"Alkanonyl" means that the above-mentioned alkyl group is substituted with a keto group at at least one position through having the specified number of carbon atoms. "C _3-8 alkanonyl", "C _3-6 alkanonyl" or "C _3-4 alkanonyl" means that the alkanonyl group has 3 to 8, to 6 or to 4 carbon atoms, respectively. For example, a C ₃ alkanonyl group has the structure -CH ₂ -(C=O)-CH ₃ .

Similarly, "alkyl ether" refers to a straight or branched chain ether via a carbon-carbon bond. Alkyl ethers include C _2-8 alkyl ethers, C _2-6 alkyl ethers, or C _2-4 alkyl ethers having 2 to 8, to 6, or to 4 carbon atoms, respectively. For example, a C ₂ alkyl ether has the structure -CH ₂ -O-CH ₃ .

As used herein, "alkoxycarbonyl" refers to the aforementioned alkoxy group bonded via a ketone (-(C=O)-) bridge (ie, having the general formula -(C=O)-O-alkyl). Alkoxycarbonyl groups include C _1-8 , C _1-6 or C _1-4 alkoxycarbonyl groups, each having 1 to 8, to 6 or to 4 carbon atoms (i.e. the carbon of the ketone bridge is not included in the number of carbons) specified number). "C ₁ alkoxycarbonyl" means -(C=O)-O-CH ₃ ; C ₃ alkoxycarbonyl means -(C=O)-O-(CH ₂ ) ₂ CH ₃ or -(C=O)- O—(CH)(CH ₃ ) ₂ .

"Alkanoyloxy" refers to an alkanoyl group bonded through an oxygen bridge (ie, having the general formula -O-(C=O)-alkyl). Alkanoyloxy groups include C ₁ -C ₈ , C ₁ -C ₆ , or C ₁ -C ₄ alkoxycarbonyl groups, each having 1 to 8, to 6, or to 4 carbon atoms in the alkyl portion.

"Alkylamino" refers to a secondary or tertiary amine having the general formula -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl group is the same or different. Such groups include, for example, mono- or di-(C _1-8 alkyl)amino groups, wherein each alkyl group may be the same or different and contain 1 to 8 carbon atoms, or mono- or di- (C ₁ -C ₆ alkyl)amino groups or mono- or di-(C ₁ -C ₄ alkyl)amino groups. "Mono- or di-(C ₁ -C ₄ alkylamino)C ₀ -C ₄ alkyl" means a mono- or di-(C ₁ -C ₄ alkyl)amino group via a single covalent bond (i.e. C ₀ alkyl) or C ₁ -C ₄ alkylene (that is, having the general formula -C ₀ -C ₄ alkyl-NH-alkyl or -C ₀ -C ₄ alkyl-N (alkyl) (alkyl) ), wherein each alkyl group is the same or different. Similarly, "alkylaminoalkoxy" means an alkylamino group attached via an alkoxy group.

The term "aminocarbonyl" or "carbonylamino" refers to an amido group (ie -(C=O) _CH2 ). "Mono- or di-(C ₁ -C ₆ alkyl)aminocarbonyl" means that one or two hydrogen atoms of the amido group are substituted by independently selected from C ₁ -C ₆ alkyl groups. Such groups may be referred to as "-C(=O)NHalkyl" or "-C(=O)N(alkyl)alkyl".

"(C ₁ -C ₆ alkyl)(2-acetylamino)amino" refers to an amino group with one hydrogen C ₁ -C ₆ alkyl substituted, and one hydrogen is replaced by 2-acetylamino.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

"Haloalkyl" is a branched or straight chain alkyl group substituted with one or more halogen atoms (i.e. "haloC ₁ -C ₈ alkyl" has 1 to 8 carbon atoms; "haloC ₁ -C ₆ alkane group" has 1 to 6 carbon atoms). Examples of haloalkyl include, but are not limited to, mono-, di-, or tri-fluoromethyl; mono-, di-, or tri-chloromethyl; mono-, di-, tri-, tetra-, or penta-fluoroethyl; or Mono-, di-, tri-, tetra- or penta-chloroethyl. Typical haloalkyl groups are trifluoromethyl and difluoromethyl. In some of the compounds provided herein, no more than 5 or 3 haloalkyl groups are present. "Haloalkoxy" means that the above-mentioned haloalkyl group is bonded through an oxygen bridge, and "haloC ₁ -C ₈ alkoxy" has 1 to 8 carbon atoms.

A "carbocycle" is a saturated, partially saturated or aromatic group having 1 or 2 fused, pendant or spiro rings with 3 to 8 ring members in each ring, all of which are carbon. "Carbocycle" includes aromatic groups such as phenyl or naphthyl, and groups containing aromatic or non-aromatic rings (such as tetrahydronaphthyl), and groups with saturated and partially saturated rings (such as cyclohexyl and cyclohexyl) alkenyl) groups. Where substitution is indicated, carbocycles may be substituted at any ring member and such substitutions result in stable compounds. The term "C ₃ -C ₁₀ carbocycle" means having 3 to 10 ring members. "C ₃ -C ₁₀ carbocycle C ₀ -C ₄ alkyl" refers to a C ₃ -C ₁₀ carbocycle bonded via a single covalent bond or a C ₁ -C ₄ alkylene bond.

Some carbocycles are "cycloalkyl" (ie saturated or partially saturated carbocycles). Such groups typically contain 3 to 8 ring carbon atoms; in some embodiments, such groups have 3 to 7 ring carbon atoms. Cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and modifications of said groups occur by one or more single or triple bonds (e.g. cyclohexynyl) or bridged Or a caged saturated ring such as orthobornane or adamantane. If substituted, any ring carbon atom may be bonded to any indicated substituent.

In the term "(cycloalkyl)alkyl", "cycloalkyl" and "alkyl" are as defined above and the point of attachment is on the alkyl group. This term includes, but is not limited to, cyclopropylmethyl, cyclohexylmethyl or cyclohexylethyl. "(C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl" refers to a 3- to 7-membered cycloalkyl ring bonded via a single covalent bond or a C ₁ -C ₄ alkylene bond.

Similarly, "(cycloalkyl)alkoxy" refers to a cycloalkyl group bonded through an alkoxy group (ie has the general formula O-alkyl-cycloalkyl).

"Cycloalkoxy" refers to a cycloalkyl group as described above bonded via an oxygen bridge (eg cyclopentyloxy or cyclohexyloxy).

Other carbocycles are "aryl" (ie, the carbocycle includes at least one aromatic ring). In addition to aromatic rings, additional non-aromatic rings may also be present in aryl groups. Representative aryl groups include phenyl, naphthyl (eg 1-naphthyl or 2-naphthyl), biphenyl, tetrahydronaphthyl and indenyl.

The term "aralkyl" refers to an aryl group bonded through an alkylene group. Some aralkyl groups are arylC ₀ -C ₂ alkyl, where the aryl is bonded via a single covalent bond or a methylidene or ethylidene moiety. Such groups include, for example, wherein phenyl or naphthyl is bonded via a single covalent bond or C ₁ -C ₂ alkylene, such as benzyl, 1-phenyl-ethyl or 2-phenyl-ethyl.

The term "aryloxy" refers to an aryl group bonded through an oxygen (ie, a group having the general structure -O-aryl). Phenoxy is representative of aryloxy.

The term "aralkoxy" refers to an aryl group bonded through an alkoxy group (ie, a group having the general structure -O-alkyl-aryl).

A "heteroatom" is an atom other than carbon, such as oxygen, sulfur or nitrogen.

The term "heterocycle" or "heterocyclyl" is used to denote a saturated, partially saturated or aromatic group having 1 or 2 fused, pendant or spiro rings with 3 to 8 ring members in each ring, And at least one ring has 1 to 4 heteroatoms independently selected from N, O or S, and the remaining atoms are carbon. Some heterocycles are 3- to 10-membered monocyclic or bicyclic rings; others are 4- to 6-membered monocyclic rings. Heterocyclic rings can be linked at heteroatoms or carbon atoms to form stable structures, and can be substituted at carbon and/or nitrogen atoms as long as the resulting compound is stable. Any nitrogen and/or sulfur heteroatoms are selectively oxidized and any nitrogen atoms are selectively quaternized.

Variations of the term "(heterocyclo)alkyl" refer to heterocyclic rings bonded via a single covalent bond or an alkylene bond. Such groups include, for example, (3 to 10 membered heterocyclic) C ₀ -C ₄ alkyl groups, where the heterocycle contains 3 to 10 ring members and is bonded via a single covalent bond or C ₁ -C ₄ alkylene . Unless otherwise specified, the heterocyclic portion of the group is saturated, partially saturated or aromatic. "(4-6 membered heterocycle) C ₀ -C ₄ alkyl" refers to a heterocyclic ring containing 4 to 6 ring members bonded by a single covalent bond or a C ₁ -C ₄ alkylene group.

唑基、喹啉基、吡咯基、吡唑基或5，6，7，8-四氢异喹啉基。Some heterocycles are "heteroaryl" (ie, contain at least one aromatic ring and have 1 to 4 heteroatoms). When the total number of S and O in the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other; preferably the total number of S and O in the heteroaryl does not exceed 1, 2 or 3, more preferably 1 or 2, and The best is no more than 1. Examples of heteroaryl groups include, pyridyl, furyl, indolyl, pyrimidinyl, pyridinyl, pyrinyl, imidazolyl, Azolyl, thienyl, thiazolyl, triazolyl, iso

Azolyl, quinolinyl, pyrrolyl, pyrazolyl or 5,6,7,8-tetrahydroisoquinolyl.

Other heterocycles referred to herein are "heterocycloalkyl" (ie, saturated or partially saturated heterocycles). A heterocycloalkyl has 1 to 2 rings, each ring has 3 to about 8 ring atoms, and more typically 5 to 7 ring atoms. Examples of heterocycloalkyl include morpholinyl, piperazyl, piperidinyl or pyrrolidinyl.

唑基、吗啉基、 啶基、八氢异喹啉基、 二唑基、1，2，3- 二唑基、1，2，4- 二唑基、1，2，5-

二唑基、1，3，4- 二唑基

唑啉基、

唑基、

唑啶基、嘧啶基、啡啶基、啡啉基、啡基、啡噻基、啡 噻基(phenoxathiinyl)、啡

基、酞基、哌基、哌啶基、喋啶基、嘌呤基、吡喃基、吡基、吡唑啶基、吡唑啉基、吡唑基、嗒基、吡啶并 唑、吡啶并嘧唑、吡啶并噻唑、嗒基、吡啶基、嘧啶基、吡咯啶基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹基、喹 啉基、

啶基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、6H-1，2，5-噻二基、1，2，3-噻二唑基、1，2，4-噻二唑基、1，2，5-噻二唑基、1，3，4-噻二唑基、噻嗯基(thianthrenyl)、噻唑基、噻吩基、噻吩并噻唑基、噻吩并

唑基、噻吩并咪唑基、噻吩基、三基、1，2，3-三唑基、1，2，4-三唑基、1，2，5-三唑基、1，3，4-三唑基或口山基(xanthenyl)。Examples of other heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothiofuryl, benzothiophenyl, benzo Azolyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benziso Azolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolyl, 2H, 6H -1,5,2-Dithianyl, dihydrofuro[2,3-b]tetrahydrofuran, furyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-ind Azolyl, indolenyl, indolinyl, indolyl, indolyl, 3H-indolyl, isobenzofuryl, isochromanyl, isoindazolyl, isoindoline base, isoindolyl, isoquinolyl, isothiazolyl, iso

Azolyl, morpholinyl, Pyridyl, octahydroisoquinolinyl, Oxadiazolyl, 1,2,3- Oxadiazolyl, 1,2,4- Oxadiazolyl, 1,2,5-

Oxadiazolyl, 1,3,4- Diazolyl

oxazolinyl,

Azolyl,

Azolidinyl, pyrimidinyl, phenanthridinyl, phenanthrinyl, phenanthyl, phenthionyl, phenanthyl Thioyl (phenoxathiinyl), morphine

yl, phthaloyl, piperazyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridyl, pyrido Azole, pyridopyrimazole, pyridothiazole, pyridyl, pyridyl, pyrimidyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolinyl base, quinol Linyl,

Pyridyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadioinyl, 1,2,3-thiadiazolyl, 1,2,4-thiazolinyl Diazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thieno

Azolyl, thienoimidazolyl, thienyl, trioxyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4 - triazolyl or xanthenyl.

"C5a receptor" is a G-protein coupled receptor that specifically binds to the C5a peptide. Some preferred C5a receptors are human, such as the protein product that yields the sequence of the human C5a receptor PCR product described by Gerard and Gerard (1991) in Nature 349:614-17. The human C5a receptor is also described by Boulay (1991) in Biochemistry 30(12):2993-99 (the nucleotide sequence encoding the receptor is available at GENBANK Accession No. M62505). Non-primate C5a receptors include rat C5a receptors (encoded by nucleotide sequence with GENBANK Accession No.X65862, Y09613 or ABOO3042), canine C5a receptors (encoded by nucleotide sequence with GENBANK Accession No.X65860 ) and guinea pig C5a receptor (encoded by the nucleotide sequence with GENBANK Accession No.U86103).

A "C5a receptor modulator" (also referred to herein as a "modulator") is any compound that modulates C5a receptor activation and/or activity (i.e., C5a receptor-mediated signaling, as provided herein C5a-mediated chemotaxis assays, radioligand binding assays, or calcium mobility assays are used). In some embodiments, the modulators can be present in a standard C5a receptor-radioligand binding assay with an affinity constant of less than 1 micromolar for binding to the C5a receptor; and/or at EC50 is less than 1 micromolar in C5a-mediated chemotaxis assay or calcium mobility assay. In other embodiments, a C5a receptor modulator can exhibit an affinity constant or EC50 of less than 500 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM, or 5 nM in such assays. A modulator may be a C5a receptor agonist or antagonist, although some modulators of interest described herein preferably inhibit C5a activity from C5a binding (ie, the modulator is an antagonist). Additionally, or alternatively, the modulator may act as an inverse agonist of the C5a receptor. In some embodiments, modulators herein provide for modulating the activation and/or activity of a primate C5a receptor, such as a human C5a receptor, which may be a replicated, recombinantly expressed receptor, or a naturally expressed receptor. For the treatment of any particular species of non-human animal, compounds that exhibit high affinity for the C5a receptor of that particular species are preferred.

Some C5a receptor modulators exhibit high activity in standard in vitro C5a receptor-mediated chemotaxis assays, as described in Example 18. Said compounds show an EC50 of 4 μM or less in said standard C5a-mediated chemotaxis assay, preferably 1 μM or less of said test EC50, more preferably 0.1 μM or less of said test EC50 , and even better EC50 in said assay is 10 nM or less.

An "inverse agonist" of the C5a receptor is a compound that reduces the activity of the C5a receptor below its essential activity without adding to the C5a receptor. Inverse agonists can also inhibit the activity of C5a at the C5a receptor, and/or can inhibit the binding of C5a to the C5a receptor. The ability of a compound to inhibit the binding of C5a to the C5a receptor can be determined by a binding assay, such as the radioligand binding assay described in Example 23. C5a receptor basal activity can be determined by GTP binding assay, such as the assay in Example 24. C5a receptor activity can be reduced by. GTP binding assay or calcium mobility assay as assayed in Example 25.

A "neutral antagonist" of the C5a receptor is a compound that inhibits the activity of the C5a receptor without significantly altering the basal activity of the C5a receptor. Neutral antagonists of C5a inhibit the binding of C5a to the C5a receptor.

"Partial agonists" of the C5a receptor increase the activity of the C5a receptor above the basal activity of the receptor in the absence of C5a, but do not increase the activity of the C5a receptor to the extent brought about by the saturation of the natural agonist (C5a) Degree. Some agonist compounds inhibit the binding of C5a to the C5a receptor. Partial agonists of the C5a receptor generally increase C5a receptor activity, producing an increase in the range of 5% to 90% of the level of activity brought about by receptor saturating concentrations of the natural agonist (C5a). 4,5-disubstituted-2-arylpyrimidine

As mentioned above, the present invention provides 4,5-disubstituted-2-aryl pyrimidines represented by general formula I, II or IX, which can be used in various environments to alter the activity of C5a receptors, including in the treatment of patients with Patients with diseases or disorders related to C5a receptor modulation, such as autoimmune diseases and inflammatory conditions. C5a receptor modulators can also be used in various in vitro assays (such as receptor activity assays), as probes for the detection and localization of C5a receptors, and as probes for ligand binding and C5a receptor-mediated signaling assays. Standard.

Some compounds represented by general formula II include wherein R ₁ is hydrogen, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkoxy or (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl. In some compounds, _R1 is other than hydrogen. Other compounds represented by general formula II include those wherein R ₁ is C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, or wherein R ₁ is methyl, ethyl or methoxy.

Compounds shown in other general formula II, including said compound wherein:

_R4 is:

(i) C ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, mono- or di- (C ₁ -C ₄ alkylamino) C ₂ -C ₄ alkyl, (3- to 7-membered heterocycloalkyl) C ₀ -C ₄ alkyl, phenyl C ₀ -C ₄ alkyl, pyridyl C ₀ -C ₄ alkyl, pyrimidinyl C ₀ -C ₄ alkyl _, thienyl C ₀ -C ₄ alkyl, imidazolyl C 0 -C 4 alkyl, pyrrolyl C _{0 -C 4} alkyl, pyrazole C ₀ -C ₄ alkyl, benzisothiazolyl or tetrahydronaphthyl, each of which is substituted by 0 to 4 substituents independently selected from R _x , C ₂ -C ₄ alkane Acyl, mono- or di-(C ₁ -C ₄ alkyl) amino C ₁ -C ₄ alkyl, mono- or di-(C ₁ -C ₄ alkyl) amino C ₁ -C ₄ alkoxy, ( 3 to 7 membered heterocycloalkyl) C ₀ -C ₄ alkyl or XR _y ; or

(ii) and R _and the nitrogen to which R and R are bonded to form a heterocyclic ring having from ₁ to ₃ rings each having 5 to 7 ring members, wherein the heterocyclic ring can be Substituted by 0 to 4 substituents independently selected from _Rx , keto, or WZ; and

_R5 is:

_R5 is:

(i) hydrogen;

(ii) C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl or (C ₃ -C ₇ carbocycle) C ₀ -C ₄ alkyl, each of which is selectively selected from 0 to 3 substituents are substituted, and the substituents are independently selected from halogen, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, methylamino, dimethylamino, trifluoromethane or trifluoromethoxy; or (iii) and R ₁ are linked to form an optionally substituted heterocyclic ring.

Some compounds of general formula II include those wherein A is NR ₄ R ₅ ; these compounds are designated herein as compounds of general formula II-a. Some compounds of general formula II-a include compounds wherein:

R ₄ is selected from (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl, phenyl C ₀ -C ₄ alkyl, pyridyl C ₀ -C ₄ alkyl, pyrimidyl C ₀ -C ₄ alkane base, thienyl C ₀ -C ₄ alkyl, imidazolyl C ₀ -C ₄ alkyl, pyrrolyl C ₀ -C ₄ alkyl, pyrazolyl C ₀ -C ₄ alkyl, indolyl C ₀ -C ₄ Alkyl, Indazolyl C ₀ -C ₄ Alkyl, Benzocycloalkenyl C ₀ -C ₄ Alkyl, Decalinyl C ₀ -C ₄ Alkyl, Benzisothiazolyl C ₀ -C ₄ Alkyl, tetrahydroquinolyl C ₀ -C ₄ alkyl or tetrahydronaphthyl C ₀ -C ₄ alkyl, each of which is substituted by 0 to 4 substituents independently selected from R _x , mono- or di-(C ₁ -C ₄ alkyl)amino C ₁ -C ₄ alkyl, mono- or di-(C ₁ -C ₄ alkyl) amino C ₁ -C ₄ alkoxy, ( 3 to 7 membered heterocycloalkyl) C ₀ -C ₄ alkyl, C ₂ -C ₄ alkanoyl or C ₂ -C ₄ alkanoyloxy; and

R ₅ is C _1-6 alkyl, C _2-6 alkenyl or (C ₃ -C ₇ carbocyclyl)C ₀ -C ₄ alkyl.

In other compounds represented by the general formula II-a provided herein, R ₄ and R ₅ combine to form a saturated or partially saturated heterocycle containing 1 to 2 fused or spiro rings; Substituted by 4 substituents, the substituents are independently selected from halogen, hydroxyl, amino, cyano, -COOH, CH ₂ COOH, -CO ₂ -C _1-6 alkyl, -CH ₂ CO ₂ -C _{1- 6} alkyl, -C(C=O)NH ₂ , C ₁ -C ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, mono- or di-(C ₁ -C ₆ alkyl) Amino, C ₁ -C ₆ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl or -S(On ) C ₁ -C ₆ alkyl, SO ₃ H or phenyl. In some of these compounds, R ₄ and R ₅ combine to form a saturated 4- to 7-membered heterocyclic ring, and the heterocyclic ring can be independently selected from halogen, hydroxyl, amino, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, -COOH, -CH ₂ COOH, -CO ₂ Substituents of -C _1-2 alkyl or -CH ₂ CO ₂ -C _1-2 alkyl. In some compounds shown in general formula II-a, R ₄ and R ₅ are combined to form a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is selected from the group consisting of azepanyl, morpholinyl, and homomorpholinyl (homonorpholingl), pyrrolidinyl, piperazinyl, homopiperonyl, piperidinyl or homopiperidinyl.

In some other compounds represented by general formula II-a, R ₄ and R ₅ combine to form a heterocyclic ring containing two rings, wherein each ring is substituted by 0 to 3 substituents independently selected from Halogen, hydroxy, amino, cyano, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy. In some compounds shown in general formula II-a, R ₄ and R ₅ are combined to form a heterocycle containing two rings, including wherein the heterocycle is tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinoline group, decahydroisoquinolinyl, indazolyl, indolinyl, phenylimidazolyl, pyridoxinyl or benzoxinyl, etc.

It is also provided that the compound shown in general formula II further meets general formula III:

in:

R ₁₃ represents 0 to 3 substituents independently selected from:

(i) R _x ; or

(ii) phenyl or pyridyl; each of which is substituted by 0 to 4 substituents independently selected from halogen, hydroxyl, amino, cyano, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, mono- or di-(C ₁ - C ₄ alkyl) amino; and G is CH ₂ , sulfur, oxygen or NRE; wherein RE is:

(i) hydrogen; or

(ii) C ₁ -C ₆ alkyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, phenyl or 5 to 6 membered heterocyclic ring, each of which is 0 to 3 independently Substituents selected from R _x are substituted;

and other variables are as defined in Formula II.

In some compounds of formula III, G is oxygen.

In some compounds shown in general formula III, _R represents 0 to 2 substituents independently selected from halogen, methyl, methoxy, ethyl, phenyl and phenoxy, wherein each phenyl or The phenoxy group is substituted with 0 to 3 substituents independently selected from _Rx .

Some compounds shown in general formula II-a further satisfy general formula IV:

in:

R ₁₀ and R ₁₁ are independently selected from hydrogen, C _1-6 alkyl, C _1-2 haloalkyl or C ₃ -C ₇ cycloalkyl (C _0-2 alkyl); and

R ₁₂ represents 0 to 3 substituents independently selected from R _x , mono- or di-(C ₁ -C ₄ alkyl)amino C ₁ -C ₄ alkyl, mono- or di-(C ₁ -C ₄ Alkyl) amino C ₁ -C ₄ alkoxy or YZ; Or two adjacent R ₁₂ groups are connected to form a condensed 5- to 7-membered carbocyclic or heterocyclic ring;

and other variables are as defined in general formula II-a.

The present invention further provides some compounds shown in general formula IV, wherein R ₁₂ represents 0 to 3 substituents independently selected from halogen, hydroxyl, amino, cyano, C ₁ -C ₄ alkyl, mono- or di-( C ₁ -C ₂ alkyl) amino, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or (C ₃ -C ₇ cycloalkyl)C _0-3 alkyl.

Compounds represented by other general formula IV include those compounds wherein:

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Haloalkoxy, or (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl;

R ₃ is selected from alkoxy, cycloalkoxy, phenyl, 4 to 7-membered heterocycle, -O(CH ₂ ) _n phenyl, -O(CH ₂ ) _n pyridyl, -E-(CR _C R _D ) _m -Q or Q, each of which is substituted by 0 to 3 substituents selected from the group consisting of halogen, cyano, hydroxyl, keto, (CR _A R _B ) and T, C _1-6 alkane Base, C _1-6 alkoxy, C _1-6 haloalkyl C _1-6 haloalkoxy, ((C _1-6 alkyl) (CRARB) jT) amino, mono- or di-(C _1-6 Alkyl) amino, benzyl, S(O) _n C _1-6 alkyl, α, ω-C _1-4 alkylene, α, ω-C _1-4 alkylene oxy, α, ω- C _1-4 alkylenedioxy, -E-(CH ₂ ) _m -Q or Q;

T is CO ₂ H, CONH ₂ , C _1-6 alkoxycarbonyl, mono- or di-(C ₁ -C ₆ alkyl) aminocarbonyl, SO ₃ H, SO ₂ NH ₂ , or SO ₂ (C _{1 -6} alkyl);

j is an integer from 0 to 6;

Q is a saturated heterocyclic ring containing 4 to 7 ring members, wherein the point of attachment is a carbon or nitrogen atom;

R ₈ and R ₉ are independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkenyl, (C ₃ to C ₆ cycloalkyl) C ₀ -C ₄ alkyl or C _{1 -6} alkoxy; and

Ar is phenyl, 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, Isoxazolyl, indazolyl, indolyl, pyrrolyl, furyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

Compounds shown in other general formula II-a include compounds shown in general formula V:

in:

R ₁₂ and R ₁₃ independently represent 0 to 3 substituents selected from R _x ;

R ₁₄ is hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-2 haloalkyl or (C _3-7 cycloalkyl) C _0-2 alkyl, COOH , CONH ₂ , CH ₂ COOH, CH ₂ CONH ₂ , C _1-6 alkoxycarbonyl, CH ₂ CO ₂ -C _1-6 alkyl, or SO ₃ H; x is an integer selected from 0 to 2 (in In some compounds x is 1);

and other variables are as defined in general formula II-a. .

Some compounds represented by general formula V include wherein R ₁₂ and R ₁₃ independently represent 0 to 2 substituents independently selected from halogen, methyl, methoxy or ethyl; and R ₁₄ is hydrogen, C _{1- 6} alkyl, C _2-6 alkenyl or (C _3-7 cycloalkyl) C _0-2 alkyl.

Compounds or salts represented by general formula V are also provided, wherein:

R ₁ is hydrogen, C ₁ -C ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ haloalkane Oxygen, or (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl;

R ₃ is selected from alkoxy, cycloalkoxy, phenyl, 4 to 7-membered heterocycle, -O(CH ₂ ) _n phenyl, -O(CH ₂ ) _n pyridyl, -E-(CR _C R _D ) _m -Q or Q, each of which is substituted by 0 to 3 substituents selected from the group consisting of halogen, cyano, hydroxyl, keto, (CR _A R _B ) and T, C _1-6 alkane Base, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono- or di-(C _1-6 alkyl) amino, benzyl, S(O) _n (C _1-6 alkyl), α, ω-C _1-4 alkylene, α, ω-C _1-4 alkylene oxy, α, ω-C _1-4 alkylene dioxy, -E -(CH ₂ ) _m -Q or Q;

R _C and R _D are the same or different, and each occurrence is independently selected from hydrogen, keto, C _1-4 alkyl, hydroxy, or C _1-4 alkoxy;

T is CO ₂ H, CONH ₂ , C _1-6 alkoxycarbonyl, mono- or di-(C ₁ -C ₆ alkyl) aminocarbonyl, SO ₃ H, SO ₂ NH ₂ , or SO ₂ (C _{1 -6} alkyl);

j is an integer from 0 to 6;

Q is a saturated heterocycle comprising 4 to 7 ring members, wherein the point of attachment is a carbon or nitrogen atom;

R ₈ and R ₉ are independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkenyl, (C ₃ to C ₆ cycloalkyl) C ₀ -C ₄ alkyl or C _{1 -6} alkoxy; and

Ar is mono-, di- or tri-substituted phenyl or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furyl, indolyl, indazolyl, or triazolyl, each of which is optionally mono-, di- or tri- replace.

Compounds shown in other general formula II-a include compounds shown in general formula VI:

in:

R ₁₂ and R ₁₃ independently represent 0 to 3 substituents independently selected from R _x ;

G is _CH2 , NH, sulfur or oxygen;

_G3 is N, CH or CRx;

x is an integer selected from 0 to 2 (in some compounds x is 1);

and other variables are as defined in general formula II-a.

Other compounds of general formula II-a provided herein include compounds conforming to general formula VII:

in:

R ₁₂ and R ₁₃ independently represent 0 to 3 substituents independently selected from R _x ;

G is _CH2 , NH or oxygen (in some compounds G is _CH2 );

x is an integer selected from 0 to 2 (in some compounds x is 1);

and other variables are as defined in general formula II-a.

In some compounds represented by general formula VI or general formula VII, R ₁₂ and R ₁₃ independently represent 0 to 3 substituents independently selected from halogen, hydroxyl, amino, cyano, C _1-4 alkyl, Mono- or di-(C ₁ -C ₂ alkyl) amino, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or (C ₃ -C ₇ cycloalkane base) C ₀ -C ₂ alkyl. Other compounds represented by general formula VI or general formula VII include compounds wherein R ₁₂ and R ₁₃ independently represent 0 to 2 substituents independently selected from halogen, C _1-2 alkyl or C ₁ -C ₂ alkoxy groups (such as halogen, methyl, methoxy and ethyl).

Other compounds represented by general formula VII include compounds wherein R ₅ is C _1-6 alkyl; and R ₁₂ and R ₁₃ independently represent 0 to 2 substituents independently selected from halogen, methyl, methoxy or ethyl.

Other compounds represented by general formula II provided herein include said compounds, which are defined herein as compounds represented by general formula II-b, wherein

A is OR ₄ ; and

R ₄ is C ₂ -C ₆ alkyl, C ₂ -C ₆ alkenyl, phenyl C ₀ -C ₄ alkyl, naphthyl C ₀ -C ₄ alkyl, pyridyl C ₀ -C ₄ alkyl, pyrimidine C ₀ -C ₄ alkyl, thienyl C ₀ -C ₄ alkyl, imidazolyl C ₀ -C ₄ alkyl or pyrrolyl C ₀ -C ₄ alkyl, each of which has 0 to 4 substituents Substituted, the substituents are independently selected from R _x , mono- or di-(C ₁ -C ₄ alkyl)aminoC ₁ -C ₄ alkyl, mono- or di-(C ₁ -C ₄ alkyl) Amino C ₁ -C ₄ alkoxy, (3- to 7-membered heterocycloalkyl) C ₀ -C ₄ alkyl, or C ₂ -C ₄ alkanoyl.

Some compounds of general formula II-b include those wherein R is phenyl, benzyl, or pyridylmethyl, each of which is substituted by 0 to 4 substituents independently _selected from from R _x , mono- or di-(C ₁ -C ₄ alkyl) amino C ₀ -C ₄ alkyl, mono- or di-(C ₁ -C ₄ alkyl) amino C ₁ -C ₄ alkoxy , (3- to 7-membered heterocycloalkyl)C ₀ -C ₄ alkyl or C ₂ -C ₄ alkanoyl.

Other compounds provided herein include compounds of general formula II-b further satisfying general formula VIII:

in:

D is CH or N;

R ₂₁ represents 0 to 3 substituents independently selected from R _x and LR _d ; or two adjacent R21 groups are bonded to form a condensed 5- to 7-membered carbocyclic or heterocyclic ring and the carbocyclic or heterocyclic ring Substituted by 0 to 3 substituents independently selected from Rx;

L is a single covalent bond or -CH ₂ -;

R _d is piperyl, morpholinyl, piperidinyl or pyrrolidinyl;

and other variables are as defined in general formula II-b.

Some compounds as shown in general formula VIII include those compounds wherein;

R ₂₁ represents 0 to 3 substituents independently selected from R _x or LR _d ;

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Haloalkoxy, or (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl;

R ₃ is selected from alkoxy, cycloalkoxy, phenyl, 4 to 7-membered heterocycle, -O(CH ₂ ) _n phenyl, -O(CH ₂ ) _n pyridyl, -E-(CR _C R _D ) _m -Q or Q, each of which is substituted by 0 to 3 substituents selected from the group consisting of halogen, cyano, hydroxyl, keto, (CR _A R _B ) and T, C _1-6 alkane Base, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono- or di-(C _1-6 alkyl) amino, (C _1-6 alkyl) (( CR _A R _B )jT) amino, benzyl, S(O) _n C _1-6 alkyl, α, ω-C _1-4 alkylene, α, ω-C _1-4 alkylene oxy, α, ω-C _1-4 alkylenedioxy, -E-(CH ₂ ) _m -Q or Q;

T is CO ₂ H, CONH ₂ , C _1-6 alkoxycarbonyl, mono- or di-(C ₁ -C ₆ alkyl) aminocarbonyl, SO ₃ H, SO ₂ NH ₂ , or SO ₂ (C _{1 -6} alkyl);

j is an integer from 0 to 6;

Q is a saturated heterocycle comprising 4 to 7 ring members, wherein the point of attachment is a carbon or nitrogen atom;

E is O, NRD or a single covalent bond;

R ₈ and R ₉ are independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkenyl, (C ₃ to C ₆ cycloalkyl) C0-C4 alkyl or C _1-6 alkoxy; and

Ar is mono-, di- or tri-substituted phenyl; or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazole Base, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furyl, indolyl, indazolyl, or triazolyl, each of which is selectively mono-, di- or Three - replace.

Other compounds of general formula VIII include those wherein the groups are designated as:

茂、苯并[1，4]二

烷基或苯并 唑基，其每一个一个经0至3个独立地选自Rx的取代基取代。selected from naphthyl, tetrahydronaphthyl, benzofuryl, benzodi benzodioxolyl (benzodioxolyl, also known as benzodioxolyl), hydrogenindenyl, indolyl, indazolyl, benzodioxolyl

Mao, benzo[1,4] di

Alkyl or Benzo Azolyl, each of which is substituted by 0 to 3 substituents independently selected from Rx.

Some compounds represented by general formula IX as described above:

Ar is phenyl, pyridyl or pyrimidinyl, each of which is substituted by 0 to 4 substituents independently selected from halogen, hydroxy, cyano, amino, nitro, C ₁ -C ₆ alkane Base, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₂ haloalkoxy;

q is 1; j is an integer from 0 to 3; A is OR ₄ ; R ₁ is hydrogen, methyl or ethyl;

R ₄ is (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, (3 to 7 membered heterocycloalkyl) C ₀ -C ₄ alkyl, phenyl C ₀ -C ₄ alkyl or ( Heteroaryl) C ₀ -C ₄ alkyl, each of which is substituted by 0 to 4 substituents independently selected from R _x ;

R ₈ and R ₉ are independently selected from hydrogen or C ₁ -C ₆ alkyl;

R ₁₃ represents 0 to 3 substituents independently selected from R _x

_RA and RB are independently selected at each occurrence from hydrogen, methyl or ethyl;

Each occurrence of _Rx is independently selected from halogen, hydroxy, amino, cyano, nitro, -COOH, C(=O) _NH2 , _C1 - _C6 alkoxycarbonyl, -C(C=O) NH(C ₁ -C ₆ alkyl), -C(C=O)N(C ₁ -C ₆ alkyl) ₂ , C ₁ -C ₆ alkyl, C _2-6 alkenyl, C _2-6 alkyne radical, mono- or di-(C ₁ -C ₆ alkyl)amino, C ₁ -C ₆ alkoxy, C ₁ -C ₂ hydroxyalkyl, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkane Oxygen, (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl or -S(On)C ₁ -C ₆ alkyl; and

T is CO ₂ H, CONH ₂ , C _1-6 alkoxycarbonyl, mono- or di-(C ₁ -C ₆ alkyl)aminocarbonyl, SO ₂ NH ₂ , (C=O)CH ₂ NH ₂ , or SO ₂ (C _1-6 alkyl).

Some compounds of general formula V provided herein further satisfy general formula X:

in:

R ₁₂ and R ₁₃ represent 0 to 3 substituents independently selected from R _x ;

R ₁₄ is hydrogen, C ₁ -C ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₂ haloalkyl or (C ₃ -C ₇ cycloalkyl) C ₀ -C ₂ Alkyl, COOH, CONH ₂ , CH ₂ COOH, CH ₂ CONH ₂ , alkoxycarbonyl or CH ₂ CO ₂ -C _1-6 alkyl; and X is 0, 1 or 2.

Other compounds of general formula II-b provided herein satisfy general formula XI:

in:

D is CH or N;

R ₁₃ represents 0 to 3 substituents independently selected from hydrogen, methyl or ethyl;

R ₂₁ represents 0 to 3 substituents independently selected from R _x or LRF; or two adjacent R ₂₁ groups are bonded to form a condensed 5- to 7-membered carbocycle or heterocycle and the carbocycle or heterocycle The ring is substituted by 0 to 3 substituents independently selected from _Rx ;

L is a single covalent bond or -CH ₂ -;

RF is piperoxyl, morpholinyl, piperidinyl or pyrrolidinyl;

and other variables as described in general formula II-b.

Others according to any one of the general formula II, II-a, II-b, III, IV, V, VI, VII, VIII, IX, X or XI include said compounds wherein:

R ₃ is selected from alkoxy, cycloalkoxy, phenyl, 4 to 7-membered heterocycle, -O(CH ₂ )n phenyl, -O(CH ₂ )n pyridyl, -E(CR _C R _D ) _m -Q or Q, each of which may be substituted by 0 to 3 substituents selected from halogen, cyano, hydroxyl, keto, (CR _A R _B ) jT, C _1-6 alkane Base, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono- or di-(C _1-6 alkyl) amino, benzyl, S(O) _n C _{1 -6} alkyl, α, ω-C _1-4 alkylene, α, ω-C _1-4 alkylene oxy, α, ω-C _1-4 alkylene dioxy, -E-( CH ₂ ) _m -Q or Q;

R _C and R _D are the same or different, and each occurrence is independently selected from hydrogen, keto, C _1-4 alkyl, hydroxy, or C _1-4 alkoxy;

T is CO ₂ H, CONH ₂ , C _1-6 alkoxycarbonyl, mono- or di-(C ₁ -C ₆ alkyl) aminocarbonyl, SO ₃ H, SO ₂ NH ₂ , or SO ₂ (C _{1 -6} alkyl);

j is an integer from 0 to 6;

Q is a saturated heterocyclic ring comprising 4 to 7 ring members, wherein the point of attachment is a carbon or nitrogen atom.

R ₈ and R ₉ are independently selected from hydrogen, halogen, hydroxyl, C _1-6 alkyl, C _1-6 alkenyl, (C ₃ to C ₆ cycloalkyl) C ₀ -C ₄ alkyl or C _{1 -6} alkoxy.

Among some of these compounds:

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ Haloalkoxy, or (C ₃ -C ₇ cycloalkyl)C ₀ -C ₄ alkyl; and

Ar is phenyl, 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, Isoxazolyl, indazolyl, indolyl, pyrrolyl, furyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.

Further in some compounds, _R is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrole base, furyl, triazolyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl (azetidinyl, also known as azetidinyl), azepanyl or diazepine Cycloalkyl, each of which is substituted by 0 to 3 substituents selected from the group consisting of halogen, cyano, hydroxyl, keto, (CR _A R _B )jT, C _1-6 alkyl, C _{1 -6} alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono- or di-(C _1-6 alkyl) amino, benzyl, S(O) _n C _1-6 alkyl , α, ω-C _1-4 alkylene, α, ω-C _1-4 alkylene oxy, α, ω-C _1-4 alkylene dioxy, -E-(CH ₂ )mQ or Q. Other compounds represented by general formula III include those wherein R ₃ is selected from C _1-6 alkoxy, C _3-8 haloalkoxy, carboxyl substituted C _1-4 alkoxy or -E-(CH ₂ )mQ , wherein E is absent, O, MH or N(C _1-6 alkyl) or Q is a saturated 4 to 7 membered heterocyclic ring, and the point of attachment is an oxygen or nitrogen atom.

Any compound shown in some general formulas II, II-a, II-b, III, IV, V, VI, VII, VIII, IX, X or XI includes said compounds wherein:

R ₃ is a C _1-6 alkoxy group, a C _1-6 alkoxy group substituted by a carboxylic acid, a C _3-7 cycloalkoxy group, or a residue of the following formula:

in:

E is O, NRD or a single covalent bond;

m is an integer from 0 to 4;

p and q are integers independently selected from 0 to 5, such that 2≤p+q≤5;

G ₁ is CH, CR ₁₀ or N;

G ₂ is CH, CR ₁₀ , NH, _NRE , O or S;

R ₁₀ represents one or two substituents selected from the group consisting of halogen, cyano, hydroxyl, keto, (CH ₂ )jT, N(methyl)(CH ₂ )jT, methyl, ethyl, methoxy ethoxy, monofluoromethyl, difluoromethyl, trifluoromethyl, monofluoromethoxy, difluoromethoxy or trifluoromethoxy;

_RE is selected from R _D , T or CH ₂ T;

T is CO ₂ H, CONH ₂ , C _1-6 alkoxycarbonyl, mono- or di-(C ₁ -C ₆ alkyl) aminocarbonyl, SO ₃ H, SO ₂ NH ₂ or SO ₂ (C _{1- 6} alkyl); and

j is an integer of 0 to 6.

Some other compounds of any of the general formulas II, II-a, II-b, III, IV, V, VI, VII, VIII, IX, X or XI include those wherein _R has the residue of the formula base;

Where T is CO ₂ H, CONH ₂ , C _1-6 alkoxycarbonyl, mono- or di-(C _1-6 alkyl) aminocarbonyl, SO ₃ H, SO ₂ NH ₂ , or SO ₂ (C _{1 -6} alkyl);

G ₁ is N or CH; and

j is 0, 1, 2 or 3.

Compounds represented by other general formula III include those compounds wherein:

_R is selected from phenyl, phenoxy, benzyloxy, each of which is substituted by 0 to 2 groups selected from halogen, cyano, hydroxyl, COOH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 haloalkoxy, α, ω-C _1-3 alkenyldioxy, C _1-4 alkylthio, -SO(C _{1 -4} alkyl) or -SO ₂ (C _1-4 alkyl); or

R ₃ is selected from -E-(CH ₂ ) _m -Q, wherein E is absent, O, NH or N(C _1-6 alkyl) and Q is a saturated 4 to 7 membered heterocycle and wherein the point of attachment is carbon or nitrogen atoms.

Other compounds of the present invention include compounds shown in general formula XII:

in:

_R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally Substituted alkoxy, optionally substituted cycloalkoxy or optionally substituted (cycloalkyl)alkoxy;

_R is selected from optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heterocycle, Optionally substituted heterocycle-oxyl, -O-(CR _A R _B ) _m -Y, -N(R _B )-(CR _A R _B ) _m -XRA or -N(R _B )-(CR _A R _B ) _m -Y, wherein the heterocyclic residue is saturated, unsaturated or aromatic and has 1 to 3 rings, each ring has 3 to 7 ring members;

R _{and R} are independently selected from: (i) hydrogen or hydroxyl; or (ii) alkyl, cycloalkyl or (cycloalkyl)alkyl containing 1 to 8 carbon atoms, each of which is optionally substituted and optionally contain one or more double or triple bonds;

Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl;

R _A and R _B are the same or different, and at each occurrence are independently selected from:

(i) hydrogen or hydroxyl; or (ii) alkyl, cycloalkyl or (cycloalkyl)alkyl, each of which is optionally substituted with one or more substituents independently selected from keto , hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl ), -NHC(=O)(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)C(=O)(C ₁ -C ₆ alkyl), -NHS(O) _n (C ₁ -C ₆ alkyl), -S(O) _n (C ₁ -C ₆ alkyl), -S(O) _n NH(C ₁ -C ₆ alkyl), -S(O) _n N (C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl) or Z;

X at each occurrence is independently selected from -CHRB-, -O-, -C(=O)-, -C(=O)O-, -S(O) _n- , _-NRB- , -C (=O)NR _B -, -S(O)nNR _B -, -OC(=S)S-, -NR _B C(=O)-, -OSiHn(C _1-4 alkyl) 2-n- or -NR _B S(O)n-;

Y and Z are independently selected at each occurrence from 3- to 7-membered saturated, unsaturated or aromatic carbocyclic or heterocyclic groups, each of which is optionally substituted with one or more substituents, said The substituents are independently selected from halogen, keto, hydroxyl, amino, cyano, C _1-4 alkyl, C _1-4 alkoxy, -mono- or di(C _1-4 alkyl)amino or -S (O) _n (alkyl), the 3- to 7-membered heterocyclic group contains one or more heteroatoms independently selected from N, O or S, and the point of attachment is carbon or nitrogen;

m is independently selected at each occurrence from an integer from 0 to 8; and

n is independently selected from 0, 1 or 2 at each occurrence.

Some compounds represented by general formula XII include the compound wherein R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl, C _1-6 alkoxy, halogen, C ₁ -C ₆ halooxy, C ₁ -C ₆ haloalkoxy or (C ₃ -C ₈ epoxy)C ₁ -C ₆ alkyl.

Other compounds represented by general formula XII include the compound wherein R3 is phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxa Azolyl, isoxazolyl, pyrrolyl, furyl, triazolyl, piperidinyl, piperazinyl, pyrrolidinyl, azetidinyl, azetidinyl, diazetidinyl base, -O(CH ₂ ) _n phenyl, -O(CH ₂ ) _n pyridyl, -E-(CH ₂ ) _m -Q or Q, each of which may be substituted by 0 to 3 substituents, said The substituent is selected from halogen, cyano, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, mono- or di-(C _{1- 6} alkyl) amino, benzyl, S(O) _n C _1-6 alkyl, α, ω-C _1-4 alkylene, α, ω-C _1-4 alkylene oxy, α, ω -C _1-4 alkylenedioxy, -E-(CH ₂ ) _m -Q or Q; wherein Q is a saturated heterocyclic ring with 4 to 7 ring members, and its connection point is a nitrogen or carbon atom.

Some compounds shown in general formula XII include said compound further satisfying general formula XIII:

in:

Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl;

_R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally Substituted alkoxy, optionally substituted cycloalkoxy or optionally substituted (cycloalkyl)alkoxy;

_R and _R are independently selected from: (i) hydrogen or hydroxyl; or (ii) alkyl, cycloalkyl or (cycloalkyl)alkyl containing 1 to 8 carbon atoms, each of which optionally contains one or multiple double bonds or triple bonds, each of which is optionally substituted by one or more substituents independently selected from keto, hydroxyl, halogen, cyano, amino, C ₁ -C ₆ alkane Oxygen, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -NHC(=O)(C ₁ -C ₆ alkyl ), -N(C ₁ -C ₆ alkyl)C(=O)(C ₁ -C ₆ alkyl), -NHS(O) _n (C ₁ -C ₆ alkyl), -S(O) _n (C ₁ -C ₆ alkyl), -S (O) _n NH (C ₁ -C ₆ alkyl), -S (O) _n N (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl Base) or Z;

E is oxygen, NH, or N(C ₁ -C ₆ alkyl);

_G1 is oxygen, sulfur, nitrogen or carbon;

G ₂ is nitrogen or carbon, wherein at least one of G ₁ and G ₂ is not carbon;

p is 0, 1 or 2;

q is 0, 1 or 2, where the sum of p and q is at least 1;

_R at each occurrence is independently selected from hydrogen, halogen, hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ fluoroalkane Oxygen, -COOH, C(O)NH ₂ , -CH ₂ COOH or -CH ₂ C(O)NH ₂ ;

k is an integer from 0 to 3; and

m is an integer of 0 to 4.

为经0至2个R₆取代的哌基或哌啶环基。Some compounds shown in general formula XIII include the residues of the compound

is a piperyl or piperidine ring group substituted by 0 to 2 R ₆ .

Compounds shown in other general formula XII include said compounds shown in general formula XIV:

in:

Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl;

_R is selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally Substituted alkoxy, optionally substituted cycloalkoxy or optionally substituted (cycloalkyl)alkoxy;

_R and _R are independently selected from: (i) hydrogen or hydroxyl; or (ii) alkyl, cycloalkyl or (cycloalkyl)alkyl containing 1 to 8 carbon atoms, each of which optionally contains one or multiple double bonds or triple bonds, each of which is optionally substituted by one or more substituents independently selected from keto, hydroxyl, halogen, cyano, amino, C ₁ -C ₆ Alkoxy, -NH(C ₁ -C ₆ alkyl), -N(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -NHC(=O)(C ₁ -C ₆ alkyl base), -N(C ₁ -C ₆ alkyl)C(=O)(C ₁ -C ₆ alkyl), -NHS(O) _n (C ₁ -C ₆ alkyl), -S(O) n(C ₁ -C ₆ alkyl), -S(O) _n NH(C ₁ -C ₆ alkyl), -S(O) _n N(C ₁ -C ₆ alkyl) (C ₁ -C ₆ Alkyl) or Z;

E is a single covalent bond, O, NH or N(C ₁ -C ₆ alkyl);

G ₂ is nitrogen, CH or CR ₆ ;

_R at each occurrence is independently selected from hydrogen, halogen, hydroxy, cyano, COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 fluoroalkyl, C _1-4 fluoro Alkoxy, C _1-4 alkylthio, -SO (C _1-4 alkyl) or -SO ₂ (C _1-4 alkyl);

k is an integer from 0 to 3; and

m is an integer of 0 to 4.

In some compounds of formula I, II, IX or other formulas above, the "optionally substituted" residues are substituted with 0 to 4 substituents independently selected from keto, hydroxy, Halogen, cyano, amino, nitro, -COOH, aminocarbonyl, -SO ₂ NH ₂ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, C ₁ -C ₆ alkynyl, C ₁ -C ₆ haloalkyl, C _1-6 aminoalkyl, C 1-6 hydroxyalkyl, C _1-6 carboxyalkyl, C _1-6 alkoxy, _{C 1-6 haloalkoxy} , C ₁ -C ₆ alkane Thio, C ₁ -C ₆ alkanoyl, C ₁ -C ₆ alkanoyloxy, C ₃ -C ₆ alkanoyl ketone, C ₁ -C ₆ alkyl ether, C ₁ , mono- or di-(C ₁ -C ₆ alkyl)aminoC ₁ -C ₆ alkyl, -NHC(=O)(C ₁ -C ₆ alkyl), -N(C _1-6 alkyl)C(=O)(C _{1 -6} alkyl), -NHS(O) _n (C _1-6 alkyl), -(C ₁ -C ₆ alkyl)C(=O)NH ₂ , -(C ₁ -C ₆ alkyl)C (=O)NH(C ₁ -C ₆ alkyl), -(C ₁ -C ₆ alkyl)C(=O)NH(C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl), -S (O) _n (C ₁ -C ₆ alkyl), -S (O) _n NH (C ₁ -C ₆ alkyl), -S (O) _n N (C ₁ -C ₆ alkyl) ( C ₁ -C ₆ alkyl) or Z; wherein Z is as described above. In other compounds represented by general formula I or other above-mentioned general formulas, the "selectively substituted" residues are substituted with 0 to 4 substituents independently selected from hydroxyl, halogen, cyano, amino , -COOH, aminocarbonyl, -SO ₂ NH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₇ haloalkoxy, mono- or Di-(C ₁ -C ₄ alkyl)aminoC ₀ -C ₄ alkyl. Similarly, in some compounds, "mono-, di- or tri-substituted" residues are substituted with 1, 2 or 3 substituents independently selected from the above.

Some of the compounds of the general formulas provided herein have two or more stereocenters with at least more than 50% diastereomerism. For example, the compounds may have a diastereomer excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some of these compounds have a diastereomeric excess of at least 99%.

Some of the compounds of the general formulas provided herein have two or more stereocenters with at least more than 50% enantiomer. For example, the compounds may have an enantiomer excess of at least 60%, 70%, 80%, 85%, 90%, 95%, or 98%. Some of these compounds have an enantiomer excess of at least 99%. It is evident that single enantiomers (optical active forms) can be synthesized via asymmetric synthesis, resolved from optically pure compounds or racemates. Resolution of the racemic acid salt can be accomplished by, for example, known methods, crystallization in the presence of a resolving agent or chromatography using eg a chiral HPLC column.

The 4,5-disubstituted-2-arylpyrimidines provided herein detectably alter (modulate) C5a receptor activity and/or ligand attachment, as measured in standard in vitro C5a receptor-mediated chemotaxis assays ( As described in Example 18), radioligand binding (as described in Example 23), or C5a receptor-mediated calcium mobility assay (as described in Example 25). Preferred compounds exhibit an EC50 of about 500 nM or less in the C5a receptor-mediated chemotaxis, radioligand binding and/or calcium mobility assays, preferably an EC50 of about 250 nM or more in these assays Low, yet more preferably an EC50 of about 200, 150, 100, 50, 25, 10 or 5 nM or lower in such assays.

Initial characterization of compounds can conveniently be performed using C5a receptor binding assays or functional assays, such as those set forth in the Examples, and can be performed rapidly by performing such assays in a high throughput screening setting. Additional assays suitable for determining the effects of small molecule compounds on C5a receptor binding and receptor modulating activity, as well as assays suitable for use in measuring the effects of C5a-induced neutropenia in vivo, can be found in the open literature See, for example, in US Pat. No. 5,807,824, Examples 6 to 9 of columns 19 to 23 of which are incorporated herein by reference, as well as a discussion of complement and inflammation in columns 1 to 2 thereof. Those of ordinary skill in the relevant art will recognize such tests suitable for use on animal cells or different types of cells as deemed appropriate.

In some embodiments, preferred compounds have favorable pharmaceutical properties, including oral bioavailability (sub-lethal or preferably a pharmaceutically acceptable oral dose, preferably less than 2 grams, more preferably Preferably less than or equal to 1 gram, can provide in vivo detectable effects such as reduction of neutropenia induced by C5a), inhibition of leukocyte chemotaxis at nanomolar concentrations and preferably at sub nanomolar concentrations, Low toxicity (preferred compounds are non-toxic when administered to a subject in a therapeutically effective amount), minimized side effects (preferred compounds produce side effects comparable to placebo when administered to a subject in a therapeutically effective amount), low Serum protein binding and suitable in vitro and in vivo half-lives (preferred compound half-life in vitro and in vivo are equal, allowing Q.I.D doses, preferably T.I.D. doses, preferably B.I.D. doses, and more preferably once-a-day doses) . Distribution in the body is also desirable for complement activity (eg, compounds used to treat CNS diseases preferably cross the blood-brain barrier, while low brain concentrations are often preferred when compounds are used to treat peripheral diseases).

Pathway testing is well known in the art to test these properties, and to identify superior compounds for a particular use. For example, tests used in predicting bioavailability include transport across human intestinal cell monolayers, such as Caco-2 cell monolayers. Penetration of the human blood-brain barrier of a compound can be predicted from the brain compound concentration (eg, intravenously) of laboratory animals administered the compound. Serum protein binding assays can be predicted from albumin binding assays as described by Oravcová et al. (1996), Journal of Chromatography B 677: 1-27. Compound half-life is inversely proportional to the frequency of dosage of the compound to achieve a therapeutically effective amount. Compound half-lives in vitro can be predicted from microsomal half-life assays as described in Kuhnz and Gieschen (1998) Drug Metabolism and Disposition 26: 1120-27.

As noted previously, compounds provided herein are preferably non-toxic. In general, the term "non-toxic" should be understood as a related concept and intended to refer to any substance that has been approved by the United States Food and Drug Administration (FDA) for administration to mammals, preferably humans. , or as guidelines are established, will be FDA-approved for administration to mammals, preferably humans. In addition, highly preferred non-toxic compounds generally meet one or more of the following criteria: (1) do not substantially inhibit cellular ATP production; (2) do not significantly prolong the cardiac QT interval; (3) do not cause substantial hepatic enlargement; and (4) Does not promote the release of substantial liver enzymes.

As used herein, a compound that "does not substantially inhibit cellular ATP production" is a compound that meets the criteria set forth in Example 27 herein. In other words, cells treated with 100 [mu]M of the compound as in Example 27 had an ATP concentration at least 50% of that detected in untreated cells. In a more highly preferred embodiment, said cells have an ATP concentration of not less than 80% of the detectable ATP concentration of untreated cells.

A compound that "does not significantly prolong the cardiac QT interval" is one that does not cause a statistically significant cardiac QT interval (measured by electrocardiography) in guinea pigs, minipigs, or dogs at twice the minimum dose that produces therapeutically effective concentrations in vivo. measurement) extended. In some embodiments, doses up to 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 40, or 50 mg/kg administered parenterally or orally do not result in a statistically significant prolongation of the cardiac QT interval. "Statistically significant" means that the difference between the result obtained by using a standard parameter test of statistical significance such as the student's T test and the control group is at the level of p<0.1, or preferably at the level of p<0.05.

Compounds "without causing substantial hepatic enlargement" are those that, when administered daily for 5 to 10 days to laboratory rodents (such as mice or rats) at twice the minimum dose that produces therapeutically effective concentrations in vivo, cause hepatic The proportional increase in body weight will not exceed 100% compared to the control group. In a more highly preferred embodiment, said iso-doses do not cause liver enlargement greater than 75% or 50% of the control group. If non-rodent animals (such as dogs) are used, the dose should not cause an increase in liver to body weight ratio of no more than 50%, preferably no more than 25%, and more preferably no more than 10%. Preferred doses tested here include 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 40 or 50 mg/kg.

Similarly, "does not promote substantial release of liver enzymes" is a dose that does not raise serum ALT, LDH, or AST concentrations in laboratory rodents compared to controls if given at twice the minimum dose that yields therapeutically effective concentrations in vivo Sham-treated controls were greater than 100% compared to the control group. In more highly preferred embodiments, said dosage does not increase said serum concentrations by more than 75% or 50% compared to a control. In addition, a compound that "does not cause substantial release of liver enzymes" is effective in an in vivo hepatocyte assay if the concentration (in culture media or other such solutions that are in contact with and cultured with hepatocytes in vitro) is equal to that of the compound Twice the minimum therapeutically effective concentration in vivo did not cause any detectable release of the hepatic enzymes into the culture-mediated baseline concentration above that mediated in control sham-treated control cells. In a highly preferred embodiment, when the concentration of the compound is 5 times, preferably 10 times, the minimum therapeutically effective concentration of the compound in vivo, it does not cause any detectable release of the liver enzymes into the Culture media to concentrations above baseline.

In other specific examples, the preferred compounds will not inhibit or trigger microsomal cytochrome P450 enzyme activity, such as CYP1A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity, or CYP3A4 activity.

These preferred compounds will not cause chromosome breakage (clastogenic) or mutation (mutagenic) when the concentration is equal to the concentration of the minimum therapeutically effective amount in vivo (such as using such as Chinese hamster ovary cell in vitro micronucleus assay (micronuleus assay), Mouse lymphoma test, human lymphocyte chromosomal variation test, rodent bone marrow micronucleus test, Ames test (Ames test) and other standard tests). In other embodiments, the preferred compounds do not induce sister chromatid exchange (as in the Chinese hamster ovary assay) at the stated concentrations.

In such embodiments, preferred compounds exert their receptor-modulating effects with high efficiency. This means that it only binds to, activates or inhibits said receptors other than C5a receptors with an affinity constant greater than 100 nanomolar, preferably greater than 1 micromolar, and more preferably greater than 4 micromolar . Also provided herein are highly specific C5a receptor modulating compounds that exist with an affinity for the C5a receptor that is 200 times greater than the affinity for other cell receptors. Such receptors include neurotransmitter receptors such as α- or β-adrenergic receptors, muscarinic receptors (especially m1, m2 or m3 receptors), dopamine receptors or metabotropic receptors. Glutamate receptors (metabotropic glutamate receptors); and histamine receptors and cytokine receptors (eg, interleukin receptors, especially IL-8 receptors). Such receptors may include GABAA receptors, bioactive peptide receptors (different from C5a receptors and C3a receptors, including NPY or VIP receptors), neurohormone receptors, bradykinin receptors or Hormone receptors (eg, CRF receptors, thyrotropin-releasing hormone receptors, or melanin-concentrating hormone receptors). Highly specific compounds generally have fewer undesired side effects.

In some embodiments, provided herein are modulators that do not detectably bind with high or even moderate affinity to receptors that do not mediate inflammation, such as GABA receptors, MCH receptors, NPY receptors, body, dopamine receptors, serotonin receptors, or VR1 receptors. Additionally, or alternatively, some preferred C5a receptor modulators exhibit a substantially higher affinity for the C5a receptor (e.g., at least 5-fold higher, at least 10-fold higher, or at least 100-fold higher) than receptors that do not mediate an inflammatory response high). Assays for assessing receptor binding that does not mediate an inflammatory response include, for example, those described in US Pat. Application 10/152,189, incorporated herein by reference, discloses the MCH receptor binding assay in Example 2, pages 104-105; US Patent 6,362,186, incorporated herein by reference, in Example 19, columns 45-46 Discloses CRF1 and NPY receptor assays; US Patent 6,355,644, incorporated herein by reference, discloses dopamine receptor binding assays at column 10; and in US Patent 6,482,611, incorporated herein by reference, in Examples 4 to 5, Column 14 discloses the VR1 receptor binding assay. Notably, the C5a receptor modulators provided herein may, but need not, bind to one or more other receptors known to mediate inflammation, such as C3a receptors and/or A3 receptors.

Certain preferred compounds are C5a receptor antagonists that do not exhibit significant (eg, greater than 5%) agonist activity in any of the C5a receptor-mediated functional assays discussed herein. Specifically, this unwanted agonist activity can be assessed, for example, in the GTP binding assay in Example 24, by testing small molecules that mediate GTP binding in the absence of the natural agonist C5a. Similarly, small molecule compounds can be directly tested for their ability to stimulate calcium concentrations in the absence of a natural agonist (C5a) in a calcium flux assay (eg, Example 25). Preferred ranges for the compounds provided herein to exhibit C5a agonist activity are less than 10%, 5% or 2% of that in response to the natural agonist (C5a).

Also preferably, in some embodiments, C5a receptor modulators inhibit the occurrence of C5a-triggered oxidative burst (oxidative burst, OB) in inflammatory cells (such as neutrophils), which conveniently uses neutrophils in vitro Cell OB test assay.

For detection purposes, the compounds provided herein can be isotopically or radiolabeled. Thus, a compound of Formula I or Formula II (or any other formula specified herein) may have one or more atoms consisting of atoms of the same element having an atomic mass or atomic number different from that which occurs in nature. replace. Examples of isotopes that may occur in compounds provided herein include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, or chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, or 36Cl. In addition, substitution with heavier isotopes such as deuterium (ie, 2H) may afford certain therapeutic advantages, as greater metabolic stability, including, for example, increased half-life in vivo, or reduced dosage requirements, may therefore be preferable in some circumstances.

Pharmaceutical composition

The present invention also provides pharmaceutical compositions comprising one or more C5a receptor modulators provided herein, and at least one physiologically acceptable carrier or excipient. Pharmaceutical compositions include, for example, one or more of water, buffers (such as neutral buffered saline or phosphate buffered saline), ethanol, mineral oil, vegetable oil, dimethylsulfoxide, hydrocarbons (such as glucose , mannose, sucrose or dextran), mannitol, proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as EDTA or glutathione and/or preservatives. As noted above, other active ingredients can, but need not, be included in the pharmaceutical compositions provided herein.

The pharmaceutical compositions may be formulated for any suitable administration including, for example, topical (eg, dermal patches or ophthalmic), oral, nasal, or parenteral administration. Herein the term parenteral includes subcutaneous, intradermal, intravascular (e.g. intravenous), intramuscular, spinal, intracranial, intracerebrospinal or intraperitoneal injection, and any similar injection or infusion method. In some embodiments, the composition is preferably administered in oral form. Such forms include, for example, troches, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. In other embodiments, the compositions provided herein may be formulated as lyophilizates. Topical formulations may be preferable in certain conditions (eg, for the treatment of skin conditions such as burning or itching).

Compositions for oral administration may further include one or more ingredients such as sweetening, flavoring, coloring and/or preservative agents to provide an appealing and pleasurable preparation. Tablets contain the active ingredient in admixture with physiologically acceptable excipients which are used in the manufacture of tablets. Such excipients include, for example, inert agents (such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating or disintegrating agents (such as cornstarch or alginic acid), binding agents (such as starch, gelatin or gum arabic) or lubricants (eg, magnesium stearate, stearic acid, or talc). Tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a longer duration of action. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral administration may also be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent (such as calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules, in which the active ingredient is mixed with water or an oily medium (such as peanut oil, liquid paraffin or olive oil).

Aqueous suspensions contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents (such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth or acacia); and Dispersing or wetting agents (such as naturally occurring phospholipids such as lecithin, condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, condensation products of ethylidene oxides with long-chain fatty alcohols such as heptadecane Ethylideneoxycetyl alcohol, condensation products of ethylidene oxides with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitan monooleate, or ethylidene oxides with partial esters derived from fatty acids and condensation products of partial esters of hexitol anhydrides such as polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more Various sweeteners such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, palm oil, sesame oil or cocoa butter, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents as previously mentioned, and/or flavoring agents may be added to provide a pleasant oral preparation. Such suspensions can be preserved by the addition of antioxidants such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified above. Additional excipients, for example sweetening, flavoring or coloring agents, may also be present.

The pharmaceutical composition may also be in the form of an oil in water emulsion. The oily phase may be a vegetable oil such as palm oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers include naturally occurring gums such as acacia or tragacanth, naturally occurring phospholipids such as soy lecithin and esters or partial esters derived from fatty acids and hexitols, acid anhydrides such as sorbitan mono-oil acid esters) or condensation products derived from partial esters of fatty acids and hexitols with ethylidene oxides (e.g. polyoxyethylene sorbitan monooleate). The emulsion may also include one or more sweetening and/or flavoring agents.

Syrups and excipients may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also include one or more emollients, preservatives, flavoring and/or coloring agents.

The compounds may be formulated for oral or topical administration, such as topically to the skin or mucous membranes such as in the eye. Formulations for topical administration generally comprise a topical carrier in combination with the active agent, with or without additional ingredients. Suitable topical vehicles or additional ingredients are well known in the art, and it will be apparent that the choice of vehicle and the particular physical form and mode of delivery are a function of it. Topical carriers include water; organic solvents such as alcohols (such as ethanol or isopropanol) or glycerin; dihydric alcohols (such as butylene glycol, isoprene glycol, or propylene glycol); fatty alcohols (such as lanolin); water and organic solvents Mixtures and mixtures of organic solvents such as alcohols and glycerol; lipid-based materials such as fatty acids, acylglycerols (including oils such as mineral oil, and fats of natural or synthetic origin), glycerophospholipids, sphingolipids, or waxes; protein-based materials such as collagen or gelatin; silicone base materials (both non-volatile and volatile); and hydrocarbon compound base materials such as microsponges or polymer matrices. The composition includes one or more ingredients used to enhance the stability or effect of the application formulation, such as stabilizers, suspending agents, emulsifiers, viscosity regulators, gelling agents, preservatives, antioxidants, skin penetration enhancers, Emollients or sustained release materials. Examples of such ingredients are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, Lodon 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may include microcapsules, such as hydroxymethylcellulose or gelatin microcapsules, liposomes, albumin microcapsules, microemulsions, nanoparticles or nanocapsules.

Topical formulations can be prepared in a variety of physical forms including solids, ointments, creams, foams, emulsions, colloids, powders, aqueous liquids, emulsions, sprays or skin patches. The physical appearance and viscosity of the forms can be controlled by the presence and amount of emulsifiers and viscosity modifiers present in the formulation. Solids are usually firm and non-flowing, and are usually formulated as short sticks or sticks, or special forms; solids can be opaque or transparent, and optionally contain solvents, emulsifiers, wetting agents, softeners, fragrances, dyes/ Colorants, preservatives and other active ingredients are used to increase or enhance the effect of the final product. Creams and lotions are generally similar, differing primarily in viscosity; lotions and creams can be opaque, translucent, or clear and often contain emulsifiers, solvents, or viscosity modifiers, as well as humectants, emollients, fragrances, dyes/ Colorants, preservatives or other active ingredients are used to increase or enhance the effect of the final product. Colloids can be prepared in a range of viscosities, from viscous or high viscosity to thin or low concentration. These formulations, similar to lotions or creams, may also contain solvents, emulsifiers, humectants, emollients, fragrances, dyes/colorants, preservatives or other active ingredients to increase or enhance the effect of the final product. Liquids are thinner than creams, lotions, or gels and usually contain no emulsifiers. Liquid topical products often contain solvents, emulsifiers, humectants, emollients, fragrances, dyes/colorants, preservatives or other active ingredients to increase or enhance the effect of the final product.

Emulsifiers suitable for use in topical formulations include, but are not limited to, ionic emulsifiers, cetyl alcohol, nonionic emulsifiers such as polyoxyethylene oleyl ether, PEG-40 stearate, cetearyl Ether-20 (ceteareth-20), cetearyl ether-30, cetearyl ether alcohol, PEG-100 stearyl ether, or glyceryl stearate. Suitable viscosity modifiers include, but are not limited to, protective colloids or nonionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin or cetyl palmitate wax esters. The colloidal composition can be made by adding a gelling agent, such as chitosan, methylcellulose, ethylcellulose, polyvinyl alcohol, polyquaternium (polyquaternium), hydroxyethyl Cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or aminated glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic or anionic active agents. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauryl Amide DEA, cocamide DEA or cocamide MEA, oleyl betaine, cocamidopropylphosphatidyl PG-dimonium chloride or ammonium lauryl sulfate may be used in topical formulations. Suitable preservatives include, but are not limited to, antimicrobial agents such as methylparaben, propylparaben, sorbic acid, benzoic acid or formaldehyde, and physical stabilizers and antioxidants such as vitamin E , Sodium Ascorbate/Ascorbic Acid or Propyl Gallate. Suitable humectants include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol or butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate or mineral oil. Suitable flavoring and coloring agents include, but are not limited to, FD&C Red No. 40 or FD&C Yellow No. 5. Other suitable additional ingredients that may be included in topical formulations include, but are not limited to abrasives, absorbents, anti-caking agents, anti-foaming agents, antistatic agents, astringents (such as witch hazel, alcohol or herbal extracts such as chamomile extract), adhesives/excipients, buffers, chelating agents, film formers, adaptants, propellants, opacifying agents, pH regulators or protectants.

Examples of colloid formulations of suitable topical carriers are: hydroxypropyl cellulose (21%); 70/30 isopropanol/water (90.9%); propylene glycol (5.1%); and polysorbate 80 (1.9%) . Examples of foam formulations for suitable topical carriers are: Cetyl Alcohol (1.1%); Stearyl Alcohol (0.5%); Quaternium 52 (1.0%); Propylene Glycol (2.0%); Ethanol 95PGF3 (61.05%); Deionized water (30.05%); P75 hydrocarbon propellant (4.30%). All ratios are by weight.

Typical modes of delivery for topical formulations include application using the fingers; application using a physical applicator such as a cloth, tissue, gauze, cotton swab, or brush; spray (e.g., mist, aerosol, or foam spray); drop application ; spraying; dipping; and rinsing. Release controlling vehicles may also be used, and the compositions may be formulated for intradermal administration as a skin patch.

Pharmaceutical compositions can be prepared as sterile injectable aqueous or oleaginous suspensions. Regulators, depending on the carrier and the concentration used, can be suspended or dissolved in the carrier. Such compositions may be formulated according to known techniques using suitable dispersing, wetting and/or suspending agents, such as those mentioned above. Among the acceptable vehicles and solvents that can be employed are water, 1,3 butanediol, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the composition of spray formulations for injection, and adjuvants such as local anesthetics, preservatives and/or buffers can be dissolved in the carrier.

The C5a modulators described herein can be formulated as inhale formulations, including sprays, aerosols or aerosols. Such formulations are particularly useful in the treatment of asthma or other respiratory conditions. For use in inhalation formulations, the compounds provided herein may be delivered by inhalation methods known in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or physiologically and environmentally acceptable propellants. Other suitable devices are breath controlled inhalers, multiple dose dry powder inhalers and aerosol nebulizers. Aerosol formulations for use in targeted methods typically include propellants, surfactants and co-solvents and can be filled in conventional aerosol containers sealed with appropriate dosage valves.

Inhalation compositions may include liquid or powder compositions containing the active ingredient and suitable for nebulizer or intrabronchial use, or aerosol compositions for discrete metered dose administration via an aerosol unit. Suitable liquid compositions include the active ingredient in aqueous solutions, medically acceptable inhalation solvents such as isotonic saline or bacteriostatic water. The solution is administered by a pump or squeeze-actuated spray with a spray dispenser, or by any other conventional means for causing or enabling the desired dose of the liquid composition to be drawn into the patient's lungs. Suitable formulations, wherein the carrier is a liquid, for administration as, for example, nasal spray or nasal drops, comprise an aqueous or oily formulation of the active ingredient.

Suitable formulations for nasal administration, wherein the carrier is a solid, include a powder having a particle size in the range of, for example, 20 to 500 microns (microns), which may be primarily snuff, i.e. rapid inhalation of the powder through the nasal passages from a close nasal container ) way of administration. Suitable powder compositions include, according to the method described, a powder formulation of the active ingredient uniformly mixed with lactose or other inert powder suitable for intrabronchial administration. Powder formulations can be administered via an aerosol dispenser, or via disintegrable capsules that the patient inserts into a device that pierces the capsule and blows the powder out into a steady stream of air suitable for inhalation.

Modulators may also be prepared in the form of suppositories (eg, for rectal administration). Such compositions can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the agent. Suitable excipients include, for example, cocoa butter or polyethylene glycols.

Pharmaceutical compositions may be formulated as extended release formulations (ie, formulations such as capsules that result in slow release of the modulator upon administration). Such formulations may generally be prepared using known techniques and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. The carrier used in such formulations is biocompatible and may also be biodegradable; preferably a formulation that provides a relatively stable release concentration of the modulator. The amount of modulator in the extended release formulation depends, for example, on the site of implantation, the rate and desired time of release and the nature of the condition to be prevented or treated.

In addition to or in combination with the above-described modes of administration, modulators may be conveniently added to food or drinking water (eg, for administration to non-human animals including pets (eg, dogs and cats) or livestock). Animal feeding and drinking water compositions can be formulated so that the animals can consume the appropriate amount of the composition in their diet. The composition can be conveniently premixed into feed or drinking water.

Modulators are generally administered in a therapeutically effective amount. A preferred systemic dosage ranges from about 0.1 mg to about 140 mg per kilogram body weight per day (about 0.5 mg to 7 g per patient per day), and oral dosage is usually about 5 to 20 times higher than intravenous administration. The amount of active ingredient which may be combined with the carrier materials to produce a single dosage form will vary with the subject being treated and the particular form of administration. Dosage unit forms will generally contain from about 1 mg to 500 mg of active ingredient.

Also provided herein are packaged pharmaceutical compositions comprising a therapeutically effective amount of at least one C5a receptor antagonist in a container (preferably sealed), and instructions for using the C5a receptor antagonist to treat C5a receptor antagonists corresponding to Body regulating symptoms (eg, rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, bronchial asthma, chronic obstructive pulmonary disease (COPD), fibrocystic, Alzheimer's disease, stroke, myocardial infarction , atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury). The active ingredients can be formulated into a single pharmaceutical composition (eg in the same pharmaceutical composition). Alternatively, each active ingredient may be formulated in different compositions, by the same or different routes of administration. In a packaged pharmaceutical composition package, a medically effective amount may be packaged as a single dosage unit; alternatively, multiple agents may be conveniently packaged together. The C5a receptor modulator may be presented in any suitable container, including, but not limited to, plastic, paper, metal or glass packaging such as ampoule, bottle, vial, blister package, Infusion bag, syringe, inhaler, or tube. For example, a packaged pharmaceutical composition for oral administration of an active ingredient may be a blister pack containing an array of tablets. Instructions may be a label appearing on the container or on the inner packaging, or may be a package insert.

Instructions

The C5a modulators provided herein may also act as agonists or (preferably) antagonists, such as inverse agonists, in a variety of situations, in vitro or in vivo. In some aspects, a C5a antagonist can be used to inhibit the binding of a C5a receptor ligand (eg, C5a) to the C5a receptor in vitro or in vivo. Generally, the methods involve combining a C5a receptor with a sufficient concentration of one or more of the C5a receptor ligands in an aqueous solution and under other appropriate conditions for said ligand to bind to the C5a receptor. This provides the steps for contacting the receptor modulator. C5a receptors may be present in suspension (eg, in isolated cell membranes or cell preparations) or in cultured or isolated cells. In some embodiments, the C5a receptor is expressed on cells of the patient, and the aqueous solution is a body fluid. Typically, the concentration of a C5a receptor modulator contacted with the receptor should be sufficient to inhibit the binding of C5a to the C5a receptor in vitro, eg, to provide a calcium mobility assay or a chemotaxis assay herein.

Also provided are methods of modulating, preferably inhibiting, C5a receptor signaling activity. Such modulation can be achieved by contacting the C5a receptor (in vitro or in vivo) with a therapeutically effective amount of one or more C5a receptor modulators provided herein under conditions suitable for binding of the modulator to the receptor. C5a receptors can be present in suspension or in cultured or isolated cells or in patients. Modulation of signaling activity can be detected by detecting calcium ion conductivity (also known as calcium mobility or flux) or by detecting the effect of C5a receptor-induced chemotaxis on cells. C5a receptor modulators provided herein are preferably administered orally or topically to a patient (eg, a human) and, when modulating C5a receptor signaling activity, are present in at least one animal body fluid.

The present invention further provides methods of treating patients suffering from symptoms associated with C5a receptor modulation. As used herein, "treatment" includes disease-modifying treatment and symptomatic treatment, either of which can be prophylactic (i.e., to prevent, delay, or reduce the severity of symptoms before symptoms begin) or therapeutic (i.e. later, in order to reduce the severity and/or duration of symptoms). The condition "C5a receptor modulated response" is when modulation of C5a receptor activity results in a reduction of the condition or its symptoms. Patients may include primates (especially humans), domesticated pets (eg, dogs, cats, horses) or domestic animals (eg, cattle, pigs, sheep) at the doses described herein.

Symptoms corresponding to C5a receptor modulation include the following:

Autoimmune diseases - eg rheumatoid arthritis, lupus erythematosus (and related glomerulonephritis), psoriasis, Crohn's disease, irritable bowel syndrome, dermatomyosopathy, multiple sclerosis, bronchial asthma, Pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolysis and platelet status, Goodpasture's syndrome (or associated glomerulonephritis and pulmonary hemorrhage) , tissue transplant rejection, or hyperacute rejection of organ transplantation.

For the treatment of asthma, the C5a receptor antagonists provided herein can be used to prevent or reduce the severity of the early acute state of an asthma attack and the severity of the late state response after, for example, an asthma attack.

Inflammatory diseases and related conditions—such as neutropenia, sepsis, septic shock, Alzheimer's disease, stroke, severe burns associated with inflammation, lung injury and ischemia-reperfusion injury, osteoarthritis, and acute ( Adult) respiratory distress syndrome (ARDS), chronic pulmonary obstructive disease (COPD), systemic inflammatory response syndrome (SIRS), neonatal-onset multiple inflammatory disease (NOIMD), Muckle-Wells syndrome ), lichen planus, hereditary cold autoinflammatory syndrome (familial cold autoinflammatory syndrome, FCAS), inflammatory bowel disease (IBD), colitis, fibrous cyst, ruptured abdominal aortic aneurysm (ruptured abdominal aorticaneyrtsm) and multiple organ handicap syndrome (MODS). Also includes insulin-dependent diabetes mellitus (including diabetic retinopathy), lupus nephritis, Heyman nephritis, membranous nephritis and other forms of glomerulonephritis, contact sensitivity response, and blood and can cause Associated pathological sequelae of inflammation associated with contact with artificial surfaces of complement activation, such as resulting, for example, from extracorporeal blood circulation (eg, hemodialysis via a heart-lung machine, eg, in vascular-associated procedures, coronary artery bypass implantation or heart valve replacement) such as in vitro Dialysis syndrome or with other artificial blood vessels or container surfaces (such as ventricular assist devices, artificial heart machines, transfusion vessels, blood storage bags, plasma separation, platelet separation, etc.).

Cardiovascular and cerebrovascular diseases - such as myocardial infarction, coronary thrombosis, vascular occlusion, postoperative vascular reocclusion, atherosclerosis, traumatic central nervous system injury or ischemic heart disease. For example, a therapeutically effective amount of a compound provided herein can be administered to a patient at risk for myocardial infarction or thrombosis (i.e., a patient with one or more identifiable risk factors for myocardial infarction or thrombosis, such as, but not limited to, obesity , smoking, high blood pressure, high cholesterol, prior or genetic history of heart attack or blood clot) to reduce the risk of heart attack or blood clot.

Eye disorders - eg, vascular retinopathy, eye inflammation, age-related macular degeneration, retinal hyperplasia, Behcet's disease, vernalkeratoconjunctivitis, retinal microvascular occlusion, retinal hemorrhage, during IF-a therapy Prevent eye complications, or uveitis.

Vasculitis - eg, immune vasculitis, microscopic polyangiitis, Churg-Strauss syndrome, Kawasaki syndrome, Wegener's granulomatosis or urticarial vasculitis.

HIV Infection and AIDS - Provided herein are C5a receptor modulators that can be used to inhibit HIV infection, delay the progression of AIDS or reduce the severity of symptoms of HIV infection and AIDS.

In a further aspect, a C5a receptor modulator can be used to infuse a donated organ prior to transplanting the donated organ into a recipient patient. The perfusion is preferably performed using a solution (eg, a pharmaceutical composition) comprising a concentration of the modulator sufficient to inhibit the priming effect of the C5a receptor in vitro or in vivo. The infusion preferably reduces the severity of one or more inflammatory conditions following organ transplantation as compared to a transplant treatment control group (including, without limitation, historical control) receiving a transplanted donated organ without infusion or frequency.

In a further aspect, the C5a antagonists provided herein can be used to treat Alzheimer's disease, multiple sclerosis (multiple sclerosis), and cognitive degeneration associated with cardiopulmonary bypass surgery and related processes. The methods include administering to a patient suffering from, or considered at risk of developing, one or more of the above symptoms a therapeutically effective amount of a C5a antagonist provided herein.

In a further aspect, the C5a receptor modulators of the present invention can be used in the treatment and related diseases of pregnancy including antiphospholipid syndrome.

Suitable patients include those suffering from a disease or condition as defined herein. Typical patients treated herein include mammals, particularly primates, and specifically humans. Other suitable patients include domesticated pets such as dogs, cats, horses, or livestock such as cows, pigs, sheep.

In general, the methods of treatment provided herein comprise administering to a patient a therapeutically effective amount of one or more compounds provided herein. The method of treatment will vary depending on the compound being used and the particular condition being treated; for the treatment of most symptoms, the frequency of administration four times a day or less is preferred. In general, twice-a-day administration is preferred, and once-a-day administration is especially preferred. It will be appreciated that the particular dosage strength and regimen for any particular patient will vary depending on a number of factors including the activity of the particular compound employed, the patient's age, weight, general health, sex and diet, time and route of administration , frequency of excretion, co-administered drugs, or severity of specific disease, with the discretion of the medical practitioner prescribing the drug. It is generally preferred to use the lowest medically effective dose. Patients are generally observed for treatment effectiveness according to pharmaceutical or veterinary guidelines appropriate for the treatment or prophylaxis of the disease.

The methods of treatment provided herein further comprise administering to a patient one or more compounds provided herein or a form thereof in combination with at least one anti-inflammatory or immunomodulatory pharmaceutical agent.

As noted above, some of the compounds or compositions provided herein act as inhibitors of C5a receptor-induced chemotaxis (eg, as a standard for such chemotaxis assays). Accordingly, provided herein are methods for inhibiting C5a receptor-induced chemotaxis of cells, preferably leukocytes (eg, neutrophils). Such methods comprise contacting a leukocyte, particularly a primate leukocyte, particularly a human leukocyte, with one or more compounds provided herein. Preferred are those to which a compound provided herein is added at a concentration sufficient to inhibit leukocyte chemotaxis in an in vitro chemotaxis assay such that the chemotaxis concentration observed in the control group is significantly higher (as previously described).

Dosage concentrations on the order of about 0.1 mg to 140 mg per kg body weight per day are useful for treating or preventing symptoms of diseases caused by C5a activity (about 0.5 mg to 7 g per human patient per day). The amount of active ingredient which may be combined with carrier materials to produce a single dosage form may vary depending upon the host treated and the particular mode of administration, dosage unit forms generally containing from about 1 mg to about 500 mg of active ingredient. For compounds administered orally, percutaneously, intravascularly or subcutaneously, it is preferably administered in a sufficient amount so that the serum concentration reaches 5 ng (nanogram, nanogram)/ml to 10 μg (microgram, microgram)/ml serum, preferably should be Administer until a sufficient amount of C5a receptor modulator reaches a serum concentration of 20 ng to 1 μg/ml serum, and optimally should be administered until a sufficient amount of C5a receptor modulator reaches a serum concentration of 50 ng to 200 ng/ml serum. Injections of sufficient C5a receptor modulators directly into the joint fluid (used in the treatment of arthritis) should be administered to achieve a local concentration of approximately 1 micromolar.

In various aspects, the invention provides various non-pharmaceutical in vitro or in vivo uses of the compounds of the invention. For example, the compounds can be labeled and used as probes for the detection and localization of the C5a receptor in samples such as cell preparations, tissue sections, preparations or fragments thereof. Compounds can be used as positive controls for C5a receptor testing, as a standard for determining the ability of candidate agents to bind to C5a, or as positron emission tomography (PET) or single photon emission computerized tomography (single photon emission computerized) tomography, SPECT) radiotracers (radiotracers). The method can be used to characterize the C5a receptor in an organism. For example, a C5a receptor modulator can be labeled using any known method (e.g., radioactively labeled with a radioactive proton such as tritium, as described herein), and incubated with the sample at an appropriate time (e.g., by first assay binding to generate time). measurement) culture. After incubation, unbound compounds are removed (e.g., washed), and bound compounds are detected using any detection labeling method (e.g., radiographic or scintillation techniques for radiolabeled compounds; detection of luminophores and fluorophores). spectroscopic method). As a control group, paired samples containing a labeled compound and a larger amount (eg, 10-fold or more) of a non-labeled compound can be treated in the same manner. More detectable labels remained in the test sample than in the control group, indicating that the C5a receptor was present in the sample. Detection assays, including receptor radiographs (receptor mapping) for C5a receptors in cultured cells or tissue samples can be as described in Kuhar, Sections 8.1.1 to 8.1.9, Current Protocols in Pharmacology (1998), John Wiley & Sons, New York, description proceeds.

The modulators provided herein can also be used in a variety of known cell isolation methods. Examples include modulators that can be attached to the surface of tissue culture plates or other supports, affinity ligands for immobilization and thereby isolation, C5a receptors in vitro (eg, isolation of receptor expressing cells). In a preferred embodiment, the modulator is linked to a fluorescent marker, such as fluorescein, and the cells are contacted, which are then analyzed by fluorescence activated cell sorting (FACS).

compound preparation

Representative methods for the preparation of 4,5-disubstituted-2-arylpyrimidines are shown in Schemes 1 to 7. Those skilled in the art will judge that the reagents used in the following reaction schemes are commensurate with the synthesis and can be readily modified to produce compounds shown other than Formula I or II. When protecting groups are desired, selective deprotection steps can be used. Suitable protecting groups and methods of protection and deprotection are known as those described in Protecting Groups in Organic Synthesis by T. Greene. Compounds requiring protection and deprotection and intermediates are known.

The abbreviations used in the following reaction formulas and examples are as follows: n-BuLi n-tertiary butyllithium LiOMe lithium methoxide CDCl3 deuterated chloroform MeOH Methanol DCM Dichloromethane MHz megahertz DIBAL-H Diisobutylaluminum hydride Min minute DMA N,N-Dimethylacetamide MS mass spectrometry DMF N,N-Dimethylformamide (M+1) Mass number +1 DPPF 1,1-bis(diphenylphosphino)ferrocene NaOMe sodium methoxide Et Ethyl δ chemical shift EtOH ethanol Pd(PPh)4 Tetrakis(phenylphosphine)palladium(0) EtOAc ethyl acetate Ph Phenyl Eq. equivalent POCl3 Oxychlorophosphorus h Hour Rt Lag time HOAc Acetic acid sat. saturation HPLC HPLC TFA Trifluoroacetate 1H NMR Proton NMR THF Tetrahydrofuran Hz hertz TLC TLC KO Potassium tert-butoxide TMSCN Trimethylsilyl cyanide LAH lithium aluminum hydride 18-C-6 18-crown-6 LC/MS Liquid Chromatography/Mass Spectrometry

Reaction Scheme 1: Preparation of compounds represented by general formula II wherein A is OR ₄ or NR ₄ R ₅

烷、水；f.)6N的盐酸、加热；g.)POCl₃；h.)亲核基、碱或R₃B(OH)₂、Pd(PPh₃)₄。a.) C ₂ HO, base; b.) POCl ₃ ; c.) R ₄ R ₅ NH or R ₄ OH/base; d.) NaOMe, MeOH; e.) arylboronic acid, K ₃ PO ₄ , Pd (PPh ₃ ) ₄ , two

alkane, water; f.) 6N hydrochloric acid, heating; g.) POCl ₃ ; h.) nucleophilic group, base or R ₃ B(OH) ₂ , Pd(PPh ₃ ) ₄ .

Scheme 1 depicts a route for the preparation of compounds of general formula II, wherein A is OR ₄ or NR ₄ R ₅ . In step 1, the appropriate 6-substituted-1H-pyrimidin-2,4-one 1 is reacted with formaldehyde in the presence of sodium hydride to obtain the corresponding 5-hydroxymethyl-6-substituted-1H-pyrimidine-2,4- diketone2. In step 2, 5-hydroxymethyl-6-substituted-1H-pyrimidine-2,4-dione 2 is treated with phosphorous chloride in the presence of tri-n-butylamine to yield 2,4-dichloro-5-chloro Methyl-6-substituted-pyrimidine 3. Step 3 is defined as the reaction of an amine, phenol, or alcohol with 2,4-dichloro-5-chloromethyl-6-substituted-pyrimidine 3 to obtain 2,4-di Chloropyrimidine 4. Reaction of 2,4-dichloropyrimidine 4 with NaOMe in step 4 affords 2-chloro-4methoxypyrimidine 5 as a separable mixture with the corresponding isomer 4-chloro2-methoxypyrimidine . In step 5, a Suzuki coupling reaction of 5 with various aryl or heteroaryl boronic acids affords 2-aryl-4methoxypyrimidines 6. In step 6, 2-aryl-4-methoxypyrimidine 6 was treated with hydrochloric acid to obtain 2-aryl-4-hydroxypyrimidine 7. 7 was treated with phosphorus oxychloride to obtain 2-aryl-4-chloropyrimidine 8. 2- Aryl-4-chloropyrimidine 8 is used as a labile electrophile to react with various amines, alkoxy compounds and other nucleophiles to produce compound (9) represented by general formula II. Alternatively, 2-aryl-4chloropyrimidines 8 can be reacted with various boronic acids in the presence of a suitable palladium catalyst (such as Pd(Ph ₃ ) ₄ ) to obtain compounds of general formula II, wherein R3 via carbon-carbon bonded to the pyrimidine ring.

Reaction Scheme 2: Preparation of compounds represented by general formula II wherein A is OR ₄ or NR ₄ R ₅

a.) nucleophilic group; b.) aryl boronic acid, K ₃ PO ₄ , Pd(Ph ₃ ) ₄ .

Reaction scheme 2 depicts a different switching sequence in which _R3 is introduced before Ar. Step 1 is defined as the reaction of 2,4-dichloropyrimidine 4 with a nucleophilic group such as an amine or alkoxylate to provide 2-chloropyrimidine 10. Suzuki coupling of 10 in step 2 provides compounds (9) of general formula II. Usually additional synthetic transformations are required for _R3 of compounds 10 and 9 to obtain additional compounds of general formula II.

Reaction Scheme 3: Preparation of compounds represented by general formula II wherein A is OR ₄ or NR ₄ R ₅

a.) (i) ether, 0 to 5°C; (ii) 25% triethylamine aqueous solution, heating; b.) POCl ₃ , PhNEt2;

c.) nucleophilic group; d.) arylboronic acid, K3PO4, Pd(PPh3)4; e.) DIBAL-H; f.) _SOCl2 ;

g.) R ₄ R ₅ NH or R ₄ OH/base.

Scheme 3 depicts another route to prepare compounds of general formula II, wherein A is OR ₄ or NR ₄ R ₅ . Step 1 involves the reaction of commercially available ethoxycarbonyl isocyanate 11 with the appropriate ethyl 3-aminoacrylate 12 to give 6-substituted-5(ethoxycarbonyl)-1H-pyrimidine-2,4-dione 13. In step 2, 6-substituted-5(ethoxycarbonyl)-1H-pyrimidine-2,4-dione 13 is converted to the corresponding ethyl 2,4-dichloro-6-substituted-pyrimidine-5carboxylate 14 . Step 3 defines the reaction of ethyl 2,4-dichloro-6-substituted-pyrimidine-5 carboxylate 14 with a nucleophile to give 2-chloropyrimidine ester 15. In step 3, various content of isomeric substituent products can be obtained through nucleophilic 14-based 2-position reaction and double substitution, and are removed by silica gel chromatography. In step 4, 2-chloropyrimidine ester 15 is coupled with an appropriate metal aryl derivative with appropriate transition metal catalysis (such as the Suzuki reaction) to obtain 2-arylpyrimidine 16. Step 5 is limited to reduction of the ester group to form alcohol 17. Suitable reducing agents for use in step 5 include, but are not limited to, diisobutylaluminum hydride or LAH. Step 6 describes the conversion of alcohol 17 to the corresponding chloride 18. In step 7, chloride 18 reacts with various nucleophilic groups including amines and hydroxyaryls/heteroaryls in the presence of a base to produce various compounds (9) represented by general formula II.

Reaction scheme 4: Preparation wherein _RA and or _RB is not the compound shown in general formula I of hydrogen

a.) R _A MgX; b.) SOCl ₂ , pyrimidine; c.) H ₂ , Pd(C); d.) PDC; e.) RBMgX; f.) SOCl ₂ ; g.) R ₄ R ₅ NH Or R ₄ OH/base.

Reaction Scheme 4 depicts the manufacture of compound I wherein at least one of the substituents _RA or _RB is alkyl or aryl. In step 1, 2-arylpyrimidinate 16 is treated with a suitable organometallic reagent such as an organomagnesium compound to obtain mono-addition/reduction mixture product 19 and di-addition product 20. The addition/reduction product 19 dominated when organomagnesium reagents with hydrogen β to carbon-magnesium bonding were used. Compound 22 can be obtained from step 1 together with the di-addition product 20 when an arylmagnesium reagent is used. In step 2, the di-addition product 20 is dehydrated or reduced to provide compound (21) of general formula I. Suitable dehydration conditions include, but are not limited to, thionyl chloride in pyridine. Reduction of the dehydrated product can be via catalytic hydrogenation (eg hydrogen, Pd(C)). In step 2', compound 19 is oxidized to the corresponding ketone 22. Ketone 22 can be recycled to obtain more 20 by using the same conditions as step 1. Alternatively, in step 3', ketone 22 can be appropriately organometallic treated, dehydrated or hydrogenated to obtain a compound represented by general formula I, wherein RA and RB are different alkyl or aryl substituents (23). In a further variation of Reaction Scheme 4, compound 19 can be converted to the corresponding chloride 24 in step 2" and then reacted with an amine in step ₃ " to obtain compounds of general formula I wherein R is -CR _A R _B NR ₄ R ₅ or -CR _A R _B OR ₄ (25).

Reaction Scheme 5: Preparation of compounds represented by general formula I wherein _R is -NHR _A or -NR _A R _B

a.) Arylboronic acid, Pd(PPh3)4; b.) _H2 , Raney Ni; c.) Reductive amination.

Reaction Scheme 5 describes the preparation of compounds of formula I wherein _R2 is -NHRA or -NRARB. 2-Chloro-nitropyrimidine 26 can be prepared by methods in the literature (eg Journal Organic Chemistry 1983, 48, 60). In step 1, chloro-5-nitropyrimidine 26 can be coupled with an appropriate metal aryl derivative under a transition metal catalyst to obtain 2-aryl-5-nitropyrimidine 27. For example, this may limit the coupling of arylboronic acids via the Suzuki reaction (N. Miraura and A. Suzuki, Chemical Review 1994, 95, 2457) in the presence of palladium(0). In step 2, the nitro substituent in 27 is reduced to obtain 2-aryl-5-aminopyrimidine 28. This conversion can be accomplished by several steps known in the art, including hydrogen and transition metal catalysts and sodium bisulfite. In step 3, reductive amination reaction provides compound (29) represented by general formula I. Usually reductive amination is accomplished by reaction of 28 with various aldehydes in the presence of a reducing agent such as sodium triacetoxyborohydride. Those skilled in the art will appreciate that alkylation of 28 can also be achieved by acylation of the 5-amino substituent followed by reduction to obtain a mono-substitution. Suitable reducing agents for use in reducing acyl groups include diisobutylaluminum hydride in an inert solvent such as tetrahydrofuran. Alternatively, the acylation reaction can be followed by base and alkyl halide treatment and reduction to obtain asymmetric substitution of the 5-amino substituent. Suitable conditions for the foregoing alkylation reactions include treatment with a strong base comprising an alkali metal hydride, followed by treatment with an alkylating agent such as an alkyl halide of an alkyl bromide or iodide. Finally, 28 can also be directly alkylated by treatment with a strong base including an alkali metal hydride followed by an alkylating agent of an alkyl bromide or an alkyl halide of an alkyl iodide. Those skilled in the art will appreciate that the sequence of transformations in Scheme 4 can be modified. For example, step 2 can be performed at 26 to obtain the corresponding 5-amino-2-chloropyrimidine, followed by reductive amination as previously described in step 3 and coupling as described in step 1.

Reaction Scheme 6: Preparation of 3,5-disubstituted indazole 4-boronic acids

Scheme 6 depicts a pathway for the preparation of 3,5-disubstituted indazole-4-boronic acids. In step 1, substituted bromobenzene 29 was nitrated followed by reduction to afford brominated aniline 30, which was converted to the corresponding diazonium salt and cyclized to olindazole 31 in step 2 in the presence of a phase inversion catalyst. In step 3, indazole bromide 31 was converted to the corresponding indazole boronic acid 32. In Reaction Scheme 6, R ₁₂ and R ₁₃ are usually small alkyl groups such as methyl, ethyl, propyl or isopropyl.

Reaction Scheme 7: Preparation of 3-alkylindazole-4boronic acids

Scheme 7 depicts a pathway for the preparation of 3-alkylindazole-4boronic acids. In step 1, 3-bromofluorobenzene 33 was lithiate regioselectively and quenched with DMF to yield 2-bromo-6fluoro-benzaldehyde. Benzaldehyde is reacted with any of a variety of alkylGrignard reagents to obtain the corresponding secondary alcohol, which is ketone 34 via subsequent oxidation. Cyclocondensation with hydrazines yielded the corresponding 3-substituted-4-bromoindazoles, which were converted in step 2 to the corresponding boronic acids 35. In Reaction Scheme 7, _R12 is usually a small alkyl group such as methyl, ethyl, propyl or isopropyl.

Specific examples of the preparation of compounds of Formula I and II (and other formulas provided herein) described in the above schemes are provided in the Examples below. Unless otherwise noted, all starting materials and reagents were of standard commercial grade and were used without additional purification or had been prepared from the materials in the pathway methods. Those skilled in the art of organic synthesis will appreciate that starting materials and reaction conditions will vary depending on the desired final product.

Example

Example 1 Preparation of Certain Starting Materials

A. Synthesis of 2,6-diethylphenylboronic acid

2,6-Diethylbromobenzene was added dropwise to a THF (380 mL) solution of n-butyl lithium (2.0 M in cyclohexane, 99.1 mL, 198.2 mmol) through a funnel at -75 °C over 1 hour . After the addition, the reaction mixture was stirred at -75°C for 30 minutes; trimethyl borate (28.1 g, 270.3 mmol) was added slowly over 40 minutes. The reaction mixture was allowed to warm to room temperature overnight. 2N HCl (250 mL) was added slowly and the resulting mixture was stirred for 1 h. The organic layer was separated and the aqueous layer was extracted with ether (2 x 200 mL). The combined organic layers were dried using anhydrous _Na2SO4 , and the solvent was removed _in vacuo. Hexane (400 mL) was added to the residue, forming a white precipitate. Filtration and vacuum drying afforded 2,6-diethylphenylboronic acid as a white solid.

1H NMR: (CDCl3) 7.22(t, 1H), 7.04(s, 2H), 4.65(s, 2H), 2.64(q, 4H), 1.22(t, 6H).

B. Synthesis of 2,6-dimethyl-3-methoxyphenylboronic acid

Step 1. Preparation of aldehydes

A solution of 2-bromo-m-xylene (4.2 g, 23 mmol) in DCM (5 mL) was added dropwise to titanium tetrachloride (5.0 mL, 45 mmol) and dichloromethyl methyl ether (2.3 mL, 25 mmol) at -78°C ) in DCM (20 mL). After the addition was complete, the mixture was warmed to room temperature and stirred for a further 4 hours before being poured into ice water. The reaction was extracted with DCM. The organic portion was washed with water, dried over ( _Na2SO4 ), _and concentrated to give the aldehyde as a pale yellow solid, which was used in the next step without further purification.

1H NMR (CDCl ₃ ) 10.1 (s, 1H), 7.68 (d, 1H), 7.22 (d, 1H), 2.79 (s, 3H), 2.45 (s, 3H).

Step 2. Preparation of methyl ether

m-Chloroperbenzoic acid (68%, 8.4 g, 33 mmol) was added to a solution of the above aldehyde (4.7 g) in DCM (120 mL). The mixture was stirred at reflux overnight and concentrated in vacuo. The residue was dissolved in EtOAc and washed sequentially with sat NaHCO3 (3x), sat _NaHSO3 and water. The organic portion was _dehydrated ( _Na2SO4 ) and concentrated to give crude formate. The formate salt was treated with potassium carbonate (4 g) in EtOH (80 mL) for 20 min at room temperature, then filtered and concentrated to give the corresponding alcohol. The crude alcohol was dissolved in acetone (160 mL) and dimethyl sulfate (2.7 mL, 29 mmol), and potassium carbonate (8.0 g, 58 mmol) was added. The mixture was stirred at reflux for 5 hours. After cooling to room temperature, filtration, concentration and flash chromatography provided the desired methyl ether as a colorless oil.

1H NMR (CDCl3) 7.02 (d, 1H), 6.73 (d, 1H), 3.80 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H).

Step 3.2, Preparation of 6-dimethyl-3-methoxyphenylboronic acid

A solution of 2,4-dimethyl-3-bromoanisole (3.3 g, 15 mmol) in THF (15 mL) was added dropwise to n-butyllithium (11 mL of 1.6M in hexane, 17 mmol) at -78 °C in THF (35mL) solution. After 30 minutes, trimethyl borate (2.3 mL, 20 mmol) was added and the mixture was allowed to warm to room temperature overnight. The mixture was poured on 10% HCl and extracted with EtOAc. The organic portion was washed with saturated brine, dried (Na ₂ SO ₄ ), and concentrated to give the desired product as a brown oil.

1H NMR (CDCl ₃ ) 6.98 (d, 1H), 6.75 (d, 1H), 4.64 (br, s), 3.80 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H).

C. Synthesis of (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine

Ethyl chloroformate (7.74 g, 71.3 mmol) was added dropwise to (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K ₂ CO ₃ (18.8 g, 136 mmol) in a mixture of _CH3CN (100 mL). The resulting mixture was stirred overnight at room temperature. Water (100 mL) was added and the mixture was extracted with ether (2 x 100 mL). The combined extracts were washed with 1N HCl (2×10 mL), water, dried (Na ₂ SO ₄ ), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalene- 1-yl) ethyl carbamate.

Ethyl (1,2,3,4-tetrahydro-naphthalen-1-yl)carbamate (5.0 g, 22.8 mmol) was slowly added to a suspension of _LiAlH4 (2.6 g, 68 mmol) in THF (50 mL) under nitrogen in the liquid. The resulting mixture was stirred with heating at 75°C for 5 hours. Na ₂ SO ₄ ·10H ₂ O (15.0 g) and diethyl ether (100 mL) were added to the mixture under cooling. The resulting mixture was stirred at room temperature for 1 hour, filtered through celite, and concentrated in vacuo. 1N HCl (20 mL) and diethyl ether (20 mL) were added to the residue. Separate and discard the organic layer. The aqueous layer _was basified with 1N NaOH and extracted with _CH2Cl2 (2 x 25 mL). The combined extracts were washed with water (2x), dried (Na ₂ SO ₄ ), and concentrated to give (S)-methyl-(1,2,3,4-tetrahydro-naphthalene-1- base)-amine.

[α] RT = -10.6 (0.02, EtOH). 1H NMR (CDCl3) 7.30(m, 1H), 7.06-7.20(m, 3H), 3.66(t, 1H), 2.78(m, 2H), 2.50(s, 3H), 1.70-2.00(m, 4H) .

A similar procedure was followed to synthesize the following amines:

(R)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine;

(S)-Ethyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine;

(S)-Propyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine;

(S)-inden-1-yl-methyl-amine;

(±) methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine; or

(±) Inden-1-yl-methyl-amine.

D. Synthesis of 5-methylindole-4-boronic acid

Fuming nitric acid (>90% yellow fuming _HNO3 ) was added slowly to a solution of 2-bromo-m-xylene (20 g, 150 mmol) in HOAc (100 mL) cooled in an ice bath (above freezing point). The resulting mixture was allowed to warm to room temperature, stirred for 1 hour, and heated at 80° C. for 2 hours or analyzed by GC/MS followed by micro-scale base work-up until the reaction was complete. The reaction mixture was cooled to room temperature, poured into ice/water and stirred. The resulting yellow precipitate was collected by suction filtration and air-dried to obtain 2,6-dimethyl-3-nitrobromobenzene.

Bredereck's reagent (tert-butoxybis(dimethylamino))methane (16 g, 91 mmol) was added to 2,6-dimethyl-3-nitrobromobenzene (20 g, 87 mmol) in anhydrous DMF (120mL) solution. The resulting mixture was heated at 120 to 125 °C under N2 for 5 h or according to TLC until most of the starting material was consumed. The reaction mixture was cooled to room temperature, poured into water (300 mL), and extracted with DCM (100 mL x 3). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of enamines as a dark brown oil. This material was used in the next step without purification.

The crude mixture was dissolved in HOAc/water (250 mL, 4:1), cooled to 0 °C, and zinc powder (57 g, 870 mmol) was added slowly in portions to work up. After the addition was complete, the reaction mixture was heated at 110° C. for 4 hours. Zinc was removed by filtration through a pad of celite, and the filtrate was extracted with DCM (100 mL x 3). The combined filtrates were dried over anhydrous sodium sulfate, concentrated, and purified by flash chromatography on silica gel (EtOAc/Hexane 1:20) to afford 4-bromo-5-methylindole as a lilac oil Indole.

A solution of 4-bromo-5-methylindole (800 mg, 3.8 mmol) in anhydrous ether (8 mL) was added to potassium hydride (560 mg, 4.2 mmol, 30% dispersed in mineral oil) under argon at 0 °C with stirring. in anhydrous diethyl ether suspension. The resulting mixture was cooled to -78°C, and tert-butyllithium (4.9 mL of 1.7M in pentane, 8.4 mmol) was added slowly. The resulting cream colored mixture was stirred at -78°C for 1 hour before warming to room temperature. More anhydrous ether was added to aid stirring. After stirring for 24 hours, the resulting sticky mixture was diluted with ether and transferred in portions with stirring to a pre-cooled 1M phosphoric acid (50 mL) solution. After stirring for 30 minutes, the acidic mixture was extracted with diethyl ether (75 mL×3), and the combined extracts were extracted with 1N sodium hydroxide (20 mL×4). The combined basic extracts were cooled using an ice bath, acidified with 1M phosphoric acid, and extracted with EtOAc (20 mL x 3). The combined extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a beige residue. The residue was triturated with hexanes to obtain the desired 5-methylindole-4-boronic acid as a beige gum.

E. Synthesis of 6-isopropyl-2-methyl-3-nitrophenylboronic acid

6-Isopropyl-2-methylphenylboronic acid (8 g) was added portionwise to 90% HNO3 (50 mL) at -40°C over 1 hour, maintaining the internal temperature below -30°C. After the addition, the mixture was stirred at -40 to -30°C for 15 minutes, then poured onto ice and diluted with water. The solid was collected by filtration, washed with water and dried to give 6-isopropyl-2-methyl-3-nitrophenylboronic acid as a white solid.

1H NMR (DMSO-d6) 7.78 (d, 2H), 7.30 (d, 2H), 2.85 (m, 1H), 2.38 (s, 3H), 1.15 (s, 6H).

F. Synthesis of 4-hydroxy-piperidine-4-carboxamide

Step 1. Synthesis of 1-benzyl-4-hydroxy-piperidine-4-carboxamide

1-Benzyl-4-hydroxy-piperidine-4-carbonitrile (5 g, 23.12 mmol) was dissolved in _a mixture of _H2SO4 (18 mL) and _H2O (2 mL) at 0 °C. The mixture was allowed to warm to room temperature for 14 hours, transferred to cold 2N NaOH and adjusted to pH>8. The solid was filtered and washed with _H2O , and dried over sodium sulfate to give the crude product.

Step 2. Synthesis of 4-hydroxy-piperidine-4-carboxamide

Pd/C (150 mg) and HOAc (2 mL) were added to a MeOH solution of 1-benzyl-4-hydroxy-piperidine-4-carboxamide (2 g, 8.5 mmol). The mixture was shaken under _H2 (40 psi) for 14 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give the title product.

1H NMR (CD3OD) 2.96 (m, 4H), 2.05 (m, 2H), 1.49 (m, 2H).

G. Synthesis of 5-isopropyl-1H-indazole-4-boronic acid

Step 1. Preparation of 4-bromo-5-isopropyl-1H-indazole

Nitric acid (30 mL, fuming) was slowly added to an ice-cold solution of 2-isopropyl-6-methyl-bromobenzene (10 g, 213 mmol) in HOAc (60 mL). The mixture was heated at 90 °C for 1 hour and cooled to room temperature. _The reaction mixture was poured into 200 mL of ice water and extracted with _CH2Cl2 (3 x 60 mL). The combined extracts were washed with 1 N NaOH (3 x 40 mL), then water (40 mL), dried over (Na ₂ SO ₄ ), and concentrated to give crude 2-isopropyl-6-methyl-5- Nitro-bromobenzene, dissolved in HOAc (75 mL)/EtOH (75 mL). Fe powder (5.3 g, 95 mmol) was added thereto, and the mixture was refluxed for 2 hours. The mixture was cooled _to room temperature, diluted with water, and neutralized with solid _Na2CO3 . The mixture _was extracted with EtOAc, dried over ( _Na2SO4 ), and concentrated in vacuo. The residue was purified by flash chromatography (eluting with hexane/EtOH 4:1) to yield 3-bromo-4-isopropyl-2-methyl-aniline. A solution of NaNO ₂ (798 mg, 12 mmol) in H ₂ O (10 mL) was added dropwise to 3-bromo-4-isopropyl-2-methyl-aniline (2.4 g, 11 mmol) in HBF ₄ (15 mL) at 0° C. ) _-H2O (15 mL) slurry, and the mixture was stirred at 0 °C for 1 h. The resulting solid was filtered, washed with ice water, then Et2O, and dried under reduced pressure to yield the diazonium salt as a beige solid. A portion of the diazonium salt was added to a mixture of KOAc (1.5 g, 15 mmol) and 18-C-6 (98 mg, 0.37 mmol) in ethanol-free _CHCl3 (70 mL) at room temperature. The mixture was stirred for 1 hour and the resulting solid was removed by filtration. The filtrate was washed with _water , dried over ( _Na2SO4 ), and concentrated in vacuo. The residue was purified by flash chromatography (eluting with hexane/EtOAc 4:1) to yield 4-bromo-5-isopropyl-1H-indazole.

1H NMR (CDCl3) 8.03 (brs, 1H), 7.41 (d, 1H), 7.35 (d, 1H), 3.55 (m, 1H), 1.24 (d, 6H).

Step 2. Preparation of 5-isopropyl-1H-indazole-4-boronic acid

A solution of 4-bromo-5-isopropyl-1H-indazole (1.6 g, 6.9 mmol) in Et2O (4 mL) was slowly added to a solution of KH (1.0 g of 30% in mineral oil, 7.7 mmol) at 0 °C Et2O (20 mL) was suspended, and the mixture was stirred for 20 min. After cooling to -78°C, t-BuLi (8.9 mL of 1.7M in hexane, 15 mmol) was added and the resulting mixture was stirred at -78°C for 40 minutes. B(On-Bu)3 (5.6 mL, 21 mmol) was added thereto, and the mixture was stirred at room temperature for 24 hours. _The reaction mixture was quenched with 1N _H3PO4 and extracted with Et2O. The combined Et2O layers were back extracted with 1N NaOH (3 x 10 mL). The combined NaOH extracts were acidified with 1N H3PO4 and extracted with EtOAc. The EtOAc extract was washed with saturated brine, dried over (MgSO4), and concentrated to give 5-isopropyl-1H-indazole-4-boronic acid.

1H NMR (CDCl ₃ ) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (brs, 2H), 2.88 (m, 1H), 1.32 (d, 6H).

H. Synthesis of 3-isopropyl-1H-indazole-4-boronic acid

Step 1. 1-(2-Bromo-6-fluoro-phenyl)-2-methyl-propan-1-one

2,2,6,6-Tetramethylpiperidine (6.8 mL, 40 mmol) was added to a solution of n-BuLi (25 mL of a 1.6M solution in hexane, 40 mmol) in THF (100 mL) at -78 °C, and The mixture was stirred for 20 minutes. 3-Bromofluorobenzene (7.0 g, 40 mmol) was added thereto. After stirring at -78°C for 3 hours, DMF (15 mL, 200 mmol) was added and the mixture was warmed to room temperature and stirred for another 1 hour. The mixture was quenched with 1N HCl and extracted with EtOAc. The combined extracts were dried over ( _MgSO4 ) and concentrated in vacuo. The residue was purified by flash chromatography (eluting with hexane/EtOAc 10:1) to yield 2-bromo-6-fluoro-benzaldehyde.

1H NMR (CDCl ₃ ) 10.4 (s, 1H), 7.48-7.39 (m, 2H), 7.18-7.14 (m, 1H).

Isopropylmagnesium chloride (18 mL of 2M in Et2O, 35 mmol) was added to a solution of 2-bromo-6-fluoro-benzaldehyde (6.0 g, 30 mmol) in THF (40 mL) at -78 °C and heated at 0 °C The mixture was stirred for 1 hour. The mixture was poured into saturated _NH4Cl and extracted with EtOAc. The resulting crude alcohol was directly oxidized by Swern oxidation to give 1-(2-bromo-6-fluoro-phenyl)-2-methyl-propan-1-one.

1H NMR (CDCl ₃ ) 7.38 (d, 1H), 7.22 (m, 1H), 7.03 (t, 1H), 3.10 (m, 1H), 1.11 (d, 6H).

Step 2. Preparation of 3-isopropyl-1H-indazole-4-boronic acid

1-(2-Bromo-6-fluoro-phenyl)-2-methyl-propan-1-one (1.1 g, 4.5 mmol) was mixed with anhydrous hydrazine (0.17 mL, 5.4 mmol) in ethylene glycol ( 10 mL) and the mixture was heated at 160°C for 16 hours. Water was added, and _the mixture was extracted with _CH2Cl2 . The combined extracts were dried over ( _MgSO4 ) and concentrated in vacuo. The residue was purified by flash chromatography to yield 4-bromo-3-isopropyl-1H-indazole.

1H NMR (CDCl ₃ ) 10.1 (br s, 1H), 7.38 (d, 1H), 7.32 (d, 1H), 7.17 (t, 1H), 3.99 (m, 1H), 1.43 (d, 6H).

4-Bromo-3-isopropyl-1H-indazole was then converted to the corresponding boronic acid in a procedure similar to that provided in previous examples.

1H NMR (CD3OD) 7.44 (d, 1H), 7.32 (t, 1H), 7.05 (d, 1H), 3.56 (m, 1H), 1.38 (d, 6H). LCMS (m/z): 205.45 (MH)+.

Example 2.N-{[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2 , 3,4-Tetralin-1-amine

Step 1. Synthesis of 5-hydroxymethyl-6-methyl-pyrimidine-2,4-diol

NaOH (1.25N, 95 mL) was added to a flask containing 6-methyl-1H-pyrimidine-2,4-dione (10 g, 79.3 mmol), and the solution was stirred at room temperature for 10 minutes. Formaldehyde (37%, 19.60 mL) was added dropwise over 30 minutes. After 30 minutes, a thick white precipitate formed and the reaction was continued for another 150 minutes. Next, the suspension was filtered and the filter cake was transferred to an Erlenmeyer flask, and EtOH (neat, 200 mL) was added. The resulting white solid suspension was stirred for 30 minutes. The white solid was collected by filtration, washed with EtOH (50 mL), Et2O (100 mL), and dried in vacuo to give the desired 5-hydroxymethyl-6-methyl-pyrimidine-2,4-diol as a white solid. [MS estimated mass (156.14); observed mass (156.02)].

Step 2.2, Synthesis of 4-dichloro-5-chloromethyl-6-methyl-pyrimidine

Tri-n-butylamine (128.2 mL, 2 eq.) and POCl (100 mL) were added to a flask containing 5-hydroxymethyl-6-methyl-pyrimidine-2,4-diol (10 g, 64 mmol), and The solution was refluxed at 90°C for 7 hours. All _POCl3 was then removed using a rotovap and the residue was quenched with water (100 mL). The acidic aqueous solution was washed with Et2O (2 x 100 mL), then basified with NaOH (1 N), the product was extracted into EtOAc, washed with saturated NaHCO ₃ (100 mL), brine (100 mL), and washed with Na _{2 SO4} dehydration. The crude solution was filtered, concentrated, and purified by _SiO2 flash chromatography with hexanes: _Et2O (10:1) to afford 2,4-dichloro-5-chloromethyl- 6-Methyl-pyrimidine. [MS estimated mass (211.48); observed mass (211.05)].

Step 3. (1S)-(2,4-Dichloro-6-methyl-pyrimidin-5-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl) - Preparation of amines

K ₂ CO ₃ (70 mg, 1.0 eq., 0.51 mmol) was added to a solution containing 2,4-dichloro-5-chloromethyl-6-methyl-pyrimidine (107 mg, 0.51 mmol) in neat EtOH (10 mL) flask and cooled the reaction to 0 °C using an ice bath. A portion of (1S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (82 mg, 1.0 equiv, 0.51 mmol) in 1.0 mL of EtOH was added via syringe, and warmed up to room temperature over 3 hours. Water (50 mL) and EtOAc (50 mL) _were added, and the EtOAc layer was washed with water (100 mL) and brine (50 mL), and dried over _Na2SO4 . Concentration and vacuum drying afforded (1S)-(2,4-dichloro-6-methyl-pyrimidin-5-ylmethyl)-methyl-(1,2,3,4-tetrahydro -naphthalen-1-yl)-amine. [MS estimated mass (336.26); measured mass (336.30)]

Step 4. (1S)-(2-Chloro-4-methoxy-6-methyl-pyrimidin-5-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalene-1 -Preparation of -yl)-amine

MeOH (100 mL) was added to the solution containing (1S)-(2,4-dichloro-6-methyl-pyrimidin-5-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalene -1-yl)-amine (6.41 g, 19.06 mmol) in a flask and the solution was cooled to 0 °C using an ice bath. NaOMe (0.5M, 38 mL) was added via addition funnel over 20 minutes. Once the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature overnight. HOAc (2.0 mL) was added and the reaction mixture was stirred for 10 min, then concentrated under reduced pressure. The resulting oil was dissolved in EtOAc (100 mL), washed with saturated NaHCO3 ₍ 100 mL), brine (100 mL), and dried over _Na2SO4 . Flash chromatography on _SiO2 using _CHCl3 followed by 20:1 hexane:Et2O afforded the desired regioisomer (1S)-(2-chloro-4- Methoxy-6-methyl-pyrimidin-5-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. [MS estimated mass (331.84); observed mass (331.28)] Step 5. (1S)-N-{[2-(2,6-diethylphenyl)-4-methoxy-6-methyl Preparation of pyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalene-1-amine

Dioxane (10 mL), 2,6-diethylphenylboronic acid (3.65 g, 2.0 eq., 20.5 mmol) and K2CO3 (5.7 g, 4.0 eq., 41 mmol) were dissolved in 10 mL of water under nitrogen ) was added to containing (1S)-(2-chloro-4-methoxy-6-methyl-pyrimidin-5-ylmethyl)-methyl-(1,2,3,4-tetrahydro-naphthalene- 1-yl)-amine in a sealed test tube. Pd(PPh3)4 (5mol%, 590mg) was added, sealed and reacted at 95°C for 16 hours. After cooling to room temperature, EtOAc (100 mL) and water (100 mL) were added, and the organic layer was washed with saturated NaHCO ₃ (100 mL), brine (100 mL), and dried over Na ₂ SO ₄ . The crude sample was purified by SiO2 flash chromatography using hexane:Et2O 5:1 with 1.0% triethylamine to recover (1S)-N-{[2-(2,6-diethyl phenyl)-4-methoxy-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalene-1-amine. [estimated quality (429.60); measured quality (429.33)]

Example 3 1-[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalene-1- Synthesis of base]amino}methyl)pyrimidin-4-yl]piperidin-4-one

Step 1. 2-(2,6-Diethyl-phenyl)-6-methyl-5-{[methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl) Preparation of -amino]-methyl}-pyrimidin-4-ol

EtOH (50 mL) and HCl (12N, 50 mL) were added to the solution containing (1S)-N-{[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidine-5 -yl]methyl}-N-methyl-1,2,3,4-tetralin-1-amine (3.5 g, 8.15 mmol) in a flask, and the solution was heated at 90° C. for 16 hours. The solution was cooled to 0 °C and slowly basified with 5N NaOH followed by addition of EtOAc (100 mmol). The organic layer was washed with saturated NaHCO ₃ (100 mL), brine (100 mL), and dried over Na ₂ SO ₄ . Concentration and vacuum drying afforded 2-(2,6-diethyl-phenyl)-6-methyl-5-{[methyl-(1S)-(1,2,3,4 -tetrahydro-naphthalen-1-yl)-amino]-methyl}-pyrimidin-4-ol. [Estimated Quality (415.57); Measured Quality (415.33)]

Step 2. [4-Chloro-2-(2,6-diethyl-phenyl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3 , Preparation of 4-tetrahydro-naphthalen-1-yl)-amine

POCl3 (30 mL) was added to a solution containing 2-(2,6-diethyl-phenyl)-6-methyl-5-{[methyl-(1S)-(1,2,3,4-tetrahydro -naphthalen-1-yl)-amino]-methyl}-pyrimidin-4-ol (3.30 g, 7.94 mmol) in a flask and heated at 95° C. for 60 minutes. Once cooled, all POCl ₃ was removed under reduced pressure and saturated aqueous NaHCO 3 (100 mL) and EtOAc (100 mL) were added. The organic layer was washed with water ₍ 100 mL), brine (100 mL), and dried over _Na2SO4 . Filtration, concentration and vacuum drying afforded [4-chloro-2-(2,6-diethyl-phenyl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-( 1S)-(1,2,3,4-Tetrahydro-naphthalen-1-yl)-amine. [estimated quality (434.02); measured quality (434.28)]

Step 3. [2-(2,6-Diethyl-phenyl)-4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl)-6- Methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine

1,4-Dioxa-8aza-spiro(4,5)decane (1.0 mL of a 1.0 M solution in DMA, 5.0 eq.) was added to the solution containing [4-chloro-2-(2,6-di Bottle of ethyl-phenyl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine , the resulting solution was heated at 85°C with shaking for 12 hours. Once the reaction had cooled to room temperature, EtOAc (1.0 mL) and saturated NaHCO3 (1.0 mL) were added and the organic layer was coated directly onto a SiO2 preparative chromatography plate and eluted with hexane:Et2O 1:1 The product was obtained as [2-(2,6-diethyl-phenyl)-4-(1,4-dioxa-8-aza-spiro[4,5]dec-8-yl as a colorless oil. )-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine. [Estimated Mass (540.74); Measured Mass (540.43)].

Step 4. 1-[2-(2,6-Diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl] Preparation of amino}methyl)pyrimidin-4-yl]piperidin-4-one

HCl (3M, 20 mL) was added to a solution containing [2-(2,6-diethyl-phenyl)-4-(1,4-dioxa-8-aza-spiro[4,5]decane- 8-yl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (80mg, 0.148 mmol) in a flask and the reaction was heated at 60°C for 4 hours. Once cooled, the reaction was basified with NaOH (1 N, 100 mL) and EtOAc (100 mL) was added to extract the product. The organic layer was washed with water ₍ 100 mL), brine (100 mL), and dried over _Na2SO4 . Filtration, concentration and vacuum drying yielded 1-[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2, 3,4-Tetralin-1-yl]amino}methyl)pyrimidin-4-yl]piperidin-4-one. [Estimated Mass (496.69); Measured Mass (496.32)].

Example 4.4-(aminomethyl)-1-[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4 -Tetralin-1-yl]amino}methyl)pyrimidin-4-yl]piperidin-4-alcohol synthesis steps 1.1-(2-(2,6-diethyl-phenyl)-6-form Base-5-{[methyl-(1S)-(1,2,3,4-tetrahydronaphthalene-1-yl)-amino]-methyl}-pyrimidin-4-yl)-4-trimethyl Silyloxy-piperidine-4-carbonitrile

Anhydrous THF (5 mL) and TMSCN (0.213 mL, 1.2 eq., 1.60 mmol) were added sequentially to a flask containing LiOMe (2.55 mg, 0.05 eq., 0.067 mmol), and the reaction was degassed with nitrogen. Then add 1-[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydro Naphthalen-1-yl]amino}methyl)pyrimidin-4-yl]piperidin-4-one (0.66 g, 1.33 mmol) in THF (5 mL) and allowed to react for 1 hour. After the reaction was completed, aqueous NaHCO3 (10%, 50 mL) and EtOAc (50 mL) were added, _the organic layer was collected and washed with water (50 mL), brine (50 mL), and dried over _Na2SO4 . Filtration, concentration and vacuum drying yielded 1-(2-(2,6-diethyl-phenyl)-6-methyl-5-{[methyl-(1,2,3,4 -tetralin-1-yl)-amino]-methyl}-pyrimidin-4-yl)-4-trimethylsilyloxy-piperidine-4-carbonitrile. [estimated mass (595.89); measured mass (595.27)]

Step 2. 4-(aminomethyl)-1-[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4- Tetralin-1-yl]amino}methyl)pyrimidin-4-yl]piperidin-4-ol

1-(2-(2,6-Diethyl-phenyl)-6-methyl-5-{[methyl-(1,2,3,4-tetrahydro-naphthalene-1 -yl)-amino]-methyl}-pyrimidin-4-yl)-4-trimethylsilyloxy-piperidine-4-carbonitrile 12 (0.63 g, 1.06 mmol) in THF (5 mL) was added into a flask containing LAH (132 mg, 3.0 eq., 3.18 mmol) in anhydrous THF (20 mL). The reaction was refluxed overnight. It was then cooled to 0 °C, and water (0.132 mL), NaOH (15%, 0.132 mL) and water (0.396 mL) were added sequentially, followed by EtOAc (100 mL) and MgSO ₄ (100 mg). The suspension was filtered through celite and the celite layer was washed with 20:1 EtOAc:MeOH (2 x 100 mL). Concentration afforded 4-(aminomethyl)-1-[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2 , 3,4-tetrahydronaphthalen-1-yl]amino}methyl)pyrimidin-4-yl]piperidin-4-ol. [Estimated Mass (527.74); Measured Mass (527.27)].

Example 5. N-({1-[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetra Synthesis of Hydronaphthalen-1-yl]amino}methyl)pyrimidin-4-yl]-4-hydroxypiperidin-4-yl}methyl)acetamide

K2CO3 (33mg, 5.0eq., 0.24mmol) and acetic anhydride (0.023mL, 5.0eq., 0.24mmol) were added to 4-(aminomethyl)-1-[2-(2,6-diethyl Phenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetralin-1-yl]amino}methyl)pyrimidin-4-yl]piperidine- 4-Alcohol (25 mg, 0.047 mmol) in a vial of DMA (1.0 mL) and stirred at room temperature for 16 hours. Additional EtOAc (2.0 mL) and saturated NaHCO3 (2.0 mL) were then added and the organic layer was transferred directly to a _SiO2 plate and the product was eluted with 20:1 CHCl3:MeOH to afford N-({1- [2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}methyl yl)pyrimidin-4-yl]-4-hydroxypiperidin-4-yl}methyl)acetamide. [Estimated Mass (569.78); Measured Mass (569.30)].

Example 6.N-{[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalene- Synthesis of 1-yl]amino}methyl)pyrimidin-4-yl]-methyl}acetamide

Step 1. 2-(2,6-Diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}methanol Base) the preparation of pyrimidine-4-carbonitrile

KCN (780mg, 20.0eq., 12.0mmol) and DMA (5mL) were added to the solution containing [4-chloro-2-(2,6-diethyl-phenyl)-6-methyl-pyrimidin-5-yl In a sealed test tube of methyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine 9 (3.0 mL of 0.2M DMA solution, 0.6 mmol), the It was sealed and stirred at 130°C for 16 hours. Then EtOAc (50 mL) and saturated NaHCO3 (50 mL) were added, and _the organic layer was washed with water (100 mL), brine (100 mL), and dried over _Na2SO4 . The crude solution was filtered, concentrated and purified by _SiO2 flash chromatography with hexane:Et2O (5:1) to afford 2-(2,6-diethylphenyl)-6-methyl- 5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]amino}methyl)pyrimidine-4-carbonitrile. [Estimated Quality (424.58); Measured Quality (424.29)].

Step 2. (1S)-N-{[4-(aminomethyl)-2-(2,6-diethylphenyl)-6-methylpyrimidin-5-yl]methyl}-N-form Preparation of base-1,2,3,4-tetrahydronaphthalene-1-amine

Use an ice bath to dissolve 2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl A flask of ]amino}methyl)pyrimidine-4-carbonitrile (50 mg, 0.118 mmol) in toluene (5.0 mL) was cooled to 0°C. Then additional DIBAL (0.354 mL of a 1.5M solution in toluene, 3.0 eq., 0.53 mmol) was added and the reaction was allowed to proceed for 3 hours by warming to room temperature. HCl (1.0M, 1.0 mL) was added and stirred for 10 minutes, followed by basification with NaOH (5N). EtOAc (20 mL) was added, and _the organic layer was washed with NaHCO3 (10%, 100 mL), brine (100 mL), and dried over _Na2SO4 . Elution with 20:1 CHCl3:MeOH using _SiO2 plate chromatography afforded (1S)-N-{[4-(aminomethyl)-2-(2,6-bis) as a white foam Ethylphenyl)-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalene-1-amine. [Estimated Quality (428.61); Measured Quality (428.38)].

Step 3. N-{[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4-tetrahydronaphthalene-1 Preparation of -yl]amino}methyl)pyrimidin-4-yl]methyl}acetamide

Acetic anhydride (0.05mL, 25.0eq., 0.53mmol) was added to the solution containing (1S)-N-{[4-(aminomethyl)-2-(2,6-diethylphenyl)-6-methyl ylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalene-1-amine (9mg, 0.021mmol) in a bottle of CHCl3 (2.0mL), and make it Stir at room temperature for 2 hours. All solvent was then removed and excess acetic anhydride was azeotroped with toluene (3 x 2 mL). The sample was redissolved in CHCl3, and eluting through _SiO2 thiophene, washed with CHCl3. Concentration afforded N-{[2-(2,6-diethylphenyl)-6-methyl-5-({methyl[(1S)-1,2,3,4- Tetralin-1-yl]amino}methyl)pyrimidin-4-yl]methyl}acetamide. [Estimated Mass (470.65); Measured Mass (470.34)].

Example 7. (1S)-N-{[2-(2,6-diethylphenyl)-4-methyl-6-phenoxypyrimidin-5-yl]methyl}-N-methyl -Synthesis of 1,2,3,4-tetrahydronaphthalene-1-amine

Phenol (0.1 mL in 0.3M DMA, 0.03 mmol) and KOtBu (0.1 mL in 0.3M in 7:3 DMA:tBuOH, 0.03 mmol) were added to the solution containing [4-chloro-2-(2,6-di Ethyl-phenyl)-6-methyl-pyrimidin-5-ylmethyl]-methyl-(1S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine 9( 0.1 mL of 0.2M DMA solution, 0.02 mmol) in a vial and allowed to stir at 70°C for 16 hours. Then EtOAc (50 mL) and saturated NaHCO3 (50 mL) were added, and the organic layer was washed _with water (100 mL), brine (100 mL), and dried over _Na2SO4 . The crude solution was filtered, concentrated and purified by _SiO2 flash chromatography with hexane:Et2O (5:1) to afford (1S)-N-{[2-(2,6-diethyl phenyl)-4-methyl-6-phenoxypyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalene-1-amine. [Estimated Mass (491.67); Measured Mass (491.42)].

Example 8.2-(2,6-diethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methyl-6-piperone-1- Synthesis of pyrimidines

Step 1.2, Preparation of 4-dichloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine

KOtBu (42 mL of 1 M in THF, 42 mmol) was added dropwise to 2,4-dichloro-5-chloromethyl-6-methyl-pyrimidine (17.4 g, 82.7mmol) and carvacrol (6.21g, 41.4mmol) in DMA (166mL) solution. The resulting red-orange solution was slowly warmed to room temperature (-2 hours) and stirred for 18 hours. The reaction mixture was recooled to 0 °C and another portion of carvacrol (6.21 g, 41.4 mmol) was added followed by dropwise addition of KOtBu (42 mL of 1M in THF, 42 mmol). The reaction mixture was slowly warmed to room temperature (-2 hours) and stirred for 18 hours. The reaction mixture was partitioned between EtOAc (200 mL) and water (60 mL), the organic layer was separated, washed with water (60 mL x 3), brine (60 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain Orange oil. The crude product was dissolved in hexane (300 mL), rapidly extracted with Claisen's salkali (50 mL x 2), dried over sodium sulfate, filtered and evaporated to obtain an orange oil. Purification by chromatography on silica gel (10 EtOAc/hexanes) afforded 2,4-dichloro-5-(5-isopropyl-2-methyl-phenoxymethyl) as a colorless oil )-6-methyl-pyrimidine, which solidified on standing as a colorless oil.

LC/MS (Method 3), M+H=325.2, Rt=3.03min.; 1H NMR (CDCl3) δ=7.09(d, 1H), 6.82(d, 1H), 6.81(s, 1H), 5.17( s, 2H), 2.90 (m, 1H), 2.68 (s, 3H), 2.14, (s, 3H), 1.26 (d, 6H).

Step 2. 4-[2-Chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piper-1-carboxylic acid third Preparation of butyl ester

Add tert-butyl piper-1-carboxylate (560 mg, 3.01 mmol) and potassium carbonate (832 mg, 6.02 mmol) to 2,4-dichloro-5-(5-isopropyl-2-methyl- Phenoxymethyl)-6-methyl-pyrimidine (978 mg, 3.01 mmol) in DMA (4 mL). The resulting colorless suspension was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was partitioned between EtOAc (60 mL) and water (20 mL), the organic layer was separated, washed with water (20 mL×2), brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain Colorless oil consisting of ~2:1 mixture of isomeric addition products. Purification on a 30 g cartridge of silica gel (10 to 30% EtOAc/hexanes) afforded 4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxy) as a foam of colorless solid methyl)-6-methyl-pyrimidin-4-yl]-tert-butyl piper-1-carboxylate (lower Rf material).

1H NMR(CDCl3)δ=7.11(d, 1H), 6.83(d, 1H), 6.75(s, 1H), 4.84(s, 2H), 3.52(m, 8H), 2.90(m, 1H), 2.47 , (s, 3H), 2.16 (s, 3H), 1.45, (s, 9H), 1.27 (d, 6H).

Step 3.4-{2-(2,6-Diethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidin-4-yl} Preparation of tert-butyl piper-1-carboxylate

The third A mixture of butyl ester (700mg, 1.47mmol), 2,6-diethylphenylboronic acid (394mg, 2.21mmol), 2M aqueous sodium carbonate solution (2.21mL, 4.42mmol) and toluene (5mL) was blown with argon for 15 minutes to degas. Pd(PPh3)4 (87 mg, 5 mol%) was added, and the resulting yellow mixture was heated at 90°C under nitrogen with magnetic stirring for 40 hours. The reaction mixture was partitioned between EtOAc (50 mL) and water (15 mL), the organic layer was separated, washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a yellow liquid. Chromatography on a 30 g silica gel cartridge (10 to 30% EtOAc/hexanes) afforded 4-{2-(2,6-diethylphenyl)-5-[(5 -Isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidin-4-yl}piper-1-carboxylic acid tert-butyl ester (with recovered 4-[2-chloro-5 -(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piper-1-carboxylic acid tert-butyl ester).

LC/MS (Method 3), M+H=573.2, Rt=3.18min.; 1H NMR (CDCl3) δ=7.26(d, 1H), 7.12(d, 3H), 6.83(m, 2H), 4.99( s, 2H), 3.51(m, 4H), 2.90(s, 6H), 2.55, (s, 3H), 2.42(q, 4H), 2.24(s, 3H), 1.28(d, 6H), 1.10(t , 6H).

Step 4. 2-(2,6-Diethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methyl-6-piper-1-yl Preparation of pyrimidine

Trifluoroacetic acid (2 mL) was added to 4-{2-(2,6-diethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6- Methylpyrimidin-4-yl}piper-1-carboxylic acid tert-butyl ester (228 mg, 0.40 mmol). Gas emission then occurs and subsides rapidly. Toluene (10 mL) was added and removed under reduced pressure. The resulting residue was dissolved in EtOAc (25 mL) and extracted successively with saturated potassium carbonate (10 mL), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain 2-(2,6 -diethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methyl-6-piper-1-ylpyrimidine.

LC/MS (Method 3), M+H=473.2, Rt=2.35min.; 1H NMR (CDCl3) δ=7.26(d, 1H), 7.12(d, 3H), 6.83(m, 2H), 4.99( s, 2H), 3.49(m, 8H), 2.91(m, 1H), 2.56, (s, 3H), 2.42(q, 4H), 2.24(s, 3H), 1.42(s, 9H), 1.28(d , 6H), 1.13(t, 6H).

Example 9.2-(4-{2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidine- 4-yl}piper-1-yl)acetamide

Step 1. Preparation of 2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-4-methyl-6-piper-1-yl-pyrimidine trifluoroacetate

Trifluoroacetic acid (1 mL) was added to 4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piper -tert-butyl 1-carboxylate (500 mg, 1.05 mmol) in DCM (5 mL) with magnetic stirring. Gas emission was observed and persisted for ~20 min. The pale yellow solution was evaporated under reduced pressure, diluted with DCM (20 mL) and evaporated again. Place under high vacuum (~0.2 torr) for 20 minutes to obtain 2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-4-methyl-6-piper -1-yl-pyrimidine trifluoroacetate.

LC/MS (Method 2), M+H=432.1, Rt=1.46min.

Step 2. 2-{4-[2-Chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piper-1-yl Preparation of }-acetamide

2-Chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-4-methyl-6-piper-1-yl-pyrimidine trifluoroacetate (277 mg), A mixture of 2-bromoacetamide (290 mg, 2.11 mmol) and potassium carbonate (871 mg, 6.30 mmol) in DMA (10 mL) was stirred at room temperature for 3 hours. The reaction mixture was partitioned between EtOAc (30 mL) and water (10 mL), the organic layer was separated, washed with water (10 mL×2), brine (10 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain A yellow oil was produced. Purification by chromatography on silica gel afforded 2-{4-[2-chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6- Methyl-pyrimidin-4-yl]-piper-1-yl}-acetamide, the colorless oil solidifies on standing.

1H NMR(CDCl3)δ=7.10(d, 1H), 6.92(br s, 1H), 6.82(d, 1H), 6.74(s, 1H), 5.54(br s, 1H), 4.83(s, 2H) , 3.61, (m, 4H), 3.04 (s, 2H), 2.90 (m, 1H), 2.63 (m, 4H), 2.47 (s, 3H), 2.14 (s, 3H), 1.27 (d, 6H).

Step 3. 2-(4-{2-(2,6-Dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidine-4 Preparation of -yl}piper-1-yl)acetamide

2-{4-[2-Chloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidin-4-yl]-piper-1-yl }-acetamide (20mg, 0.05mmol), 2,6-diethylphenylboronic acid (21mg, 0.14mmol) and 2M sodium carbonate (0.14mL, 0.28mmol) in dioxane (1mL) Degassing was performed by blowing with argon for 20 minutes. Pd(PPh3)4 (2.9 mg, 5 mol%) was added, and the reaction mixture was heated at 100 °C under nitrogen with magnetic stirring. After 18 hours, the reaction mixture was partitioned between EtOAc (10 mL) and water (2 mL), the organic layer was separated, washed with brine (2 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain a dark oil. Purification on silica gel (3% MeOH/CH ₂ Cl ₂ /0.1% NH ₄ OH) afforded 2-(4-{2-(2,6-dimethylphenyl)-5-[ (5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidin-4-yl}piper-1-yl)acetamide.

LC/MS (Method 3), M+H=502.3, Rt=2.43min.; 1H NMR (CDCl3)δ=7.07-7.19(m, 4H), 6.82(m, 2H), 5.44(br s, 1H) , 4.97(s, 2H), 3.57(br s, 4H), 3.02(s, 2H), 2.91(m, 1H), 2.62(m, 4H), 2.56(s, 3H), 2.22(s, 3H), 2.16(s, 6H), 1.28(d, 6H).

Synthesis of Example 10.4-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]heptan-4-ol

Step 1. Preparation of 3-amino-2-ethoxycarbonylaminocarbonyl-but-2-enoic acid methyl ester

A solution of ethoxycarbonyl isocyanate (0.339 mol) in diethyl ether (40 mL) was added dropwise to methyl 3-aminocrotonate (39.0 g, 0.339 mol) at 0 to 5 °C under nitrogen with magnetic stirring in anhydrous diethyl ether (200 mL) solution. The resulting pale yellow suspension was stirred below 5°C for 4 hours. The solid was collected by suction filtration, rinsed with 50 mL of diethyl ether and dried under vacuum at room temperature for 30 hours to obtain methyl 3-amino-2-ethoxycarbonylaminocarbonyl-but-2-enoate as an off-white solid.

Preparation of step 2.5-carboxy-6-methyluracil methyl ester

A suspension of methyl 3-amino-2-ethoxycarbonylaminocarbonyl-but-2-enoate (59 g, 0.26 mol) in 25% aqueous trimethylamine (400 mL) was stirred at 50° C. for 18 hours. Another 100 mL portion of 25% trimethylamine in water was added and the reaction mixture was heated at 60 °C for 3 hours to form a homogeneous yellow solution. The reaction mixture was evaporated under reduced pressure to remove most of the trimethylamine, then acidified with HOAc. The resulting white solid was collected by suction filtration and dried under vacuum at 60 °C to afford 5-carboxy-6-methyluracil methyl ester.

1H NMR (CDCl3) δ = 3.92 (br s, 2H), 3.71 (s, 3H), 2.22 (s, 3H).

Step 3.2, Preparation of methyl 4-dichloro-6-methyl-pyrimidine-5-carboxylate

Tri-n-butylamine (70 mL) was slowly added to a suspension of 5-carboxy-6-methyluracil methyl ester (25.6 g, 139 mmol) in phosphorus oxychloride (250 mL) with magnetic stirring. The reaction mixture was heated at 95°C for 3 hours. The reaction mixture was cooled to room temperature, evaporated under reduced pressure and poured onto ice. The resulting residue was transferred to a separatory funnel and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with water (50 mL x 3) and brine (50 mL), dried over magnesium sulfate, filtered through a plug of silica gel and concentrated under reduced pressure to obtain a dark brown residue. Purification by chromatography on silica gel (1 :4 EtOAc/hexanes) afforded methyl 2,4-dichloro-6-methyl-pyrimidine-5-carboxylate.

1H NMR (CDCl3) δ = 4.00 (s, 3H), 2.59 (s, 3H).

Step 4. Preparation of methyl 2-chloro-4-methoxy-6-methyl-pyrimidine-5-carboxylate

Add 0.5M NaOMe in MeOH (139 mL, 69.6 mmol) dropwise to methyl 2,4-dichloro-6-methyl-pyrimidine-5-carboxylate at 0 °C under nitrogen with magnetic stirring over a period of 1 hour A solution of the ester (15.3 g, 69.6 mmol) in methanol (150 mL). HOAc (2 mL) was added and the reaction mixture was evaporated under reduced pressure. The resulting residue was treated with saturated NaHCO3 (100 mL) and extracted with EtOAc (120 mL x 3). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain a cream yellow solid. Purification by chromatography on silica gel (1:3 ether/hexane) afforded 2-chloro-4-methoxy as a white solid (the less polar one formed by the two isomeric addition products). Methyl-6-methyl-pyrimidine-5-carboxylate 1H NMR (CDCl3) δ = 4.03 (s, 3H), 3.92 (s, 3H), 2.48 (s, 3H). and methyl 4-chloro-2-methoxy-6-methyl-pyrimidine-5-carboxylate. 1H NMR (CDCl3) δ = 4.03(s, 3H), 3.95(s, 3H), 2.50(s, 3H).

Step 5. Preparation of 2-(2,6-diethyl-phenyl)-4-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester

Water (40 mL) containing potassium carbonate (10.5 g, 76 mmol, 4 eq) and 2,6-diethylphenylboronic acid (6.77 g, 38 mmol, 2 eq) were successively added to 2-chloro-4-methoxy-6 - Methyl-pyrimidine-5-carboxylate (4.1 g, 19.0 mmol) in DME (100 mL). The resulting mixture was degassed by blowing argon for 20 minutes. Pd(PPh3)4 (5 mol%) was added and the resulting yellow biphasic solution was heated at 95° C. with magnetic stirring for 18 hours in a sealed tube. The reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with EtOAc (75 mL×3). The combined organic layers were washed with brine (75 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting orange oil was purified by chromatography on silica gel (1:2 ether:hexane) to afford 2-(2,6-diethyl-phenyl)-4-methoxyl as a colorless oil. -6-Methyl-pyrimidine-5-carboxylic acid methyl ester.

1H NMR(CDCl3)δ=7.29(dd, 1H), 7.14(d, 2H), 4.00(s, 3H), 3.98(s, 3H), 2.55(s, 3H), 2.39(q, 4H), 1.10 (t, 6H).

Step 6. Preparation of 4-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]heptan-4-ol

Add n-propylmagnesium chloride (26mL, 2.0M, 0.05mol) dropwise to 2-(2,6-diethyl-phenyl)-4-methoxy -6-Methyl-pyrimidine-5-carboxylic acid methyl ester (3.3 g, 0.01 mol) in anhydrous THF (50 mL). The resulting reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with DCM (100 mL). The DCM layer was dried over magnesium sulfate, filtered and evaporated to obtain a residue. Purification by chromatography on silica gel eluting with 10% EtOAc-hexane afforded 4-[2-(2,6-diethylphenyl)-4-methoxy-6 as a colorless oil -methylpyrimidin-5-yl]heptan-4-ol and 1-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidine-5- Base] butan-1-ol. 4-[2-(2,6-Diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]heptan-4-ol. 1H NMR (300MHz, CDCl3): δ=7.23-7.29(m, 1H), 7.13(d, J=9Hz, 2H), 3.95(s, 3H), 2.72(s, 3H), 2.41(q, J= 7.5Hz, 4H), 2.18-2.30(m, 2H), 1.66-1.81(m, 2H), 1.42-1.54(m, 2H), 1.05-1.18(m, 8H), 0.91(t, J=7.2Hz, 6H); LC/MS found 371 (MH+). 1-[2-(2,6-Diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]butan-1-ol. NMR (300MHz, CDCl3): δ=7.23-7.28(m, 1H), 7.1(d, J=9Hz, 2H), 4.81-5.11(m, 1H), 4.01(s, 3H), 2.45(s, 3H ), 2.55(q, J=7.5Hz, 4H), 1.88-2.00(m, 1H), 1.30-1.81(m, 4H), 1.10(q, J=7.8, 4.8Hz, 6H), 0.91(t, J=7.2Hz, 6H); LC-MS found 328 (MH+).

Synthesis of Example 11.2-(2,6-diethylphenyl)-4-methoxy-6-methyl-5-(1-propylbutyl)pyrimidine

Step 1. Preparation of 2-(2,6-diethylphenyl)-4-methoxy-6-methyl-5-(1-propylbutenyl)pyrimidine

Add 1.5 _mL of SOCl dropwise to 4-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]heptan-4-ol under nitrogen (0.6g, 1.7mmol) in anhydrous pyridine (10mL). The reaction mixture was stirred at room temperature for 3 h, quenched with saturated aqueous NaHCO3, and extracted with DCM. _The organic layer was washed with water, brine, dried over _Na2SO4 and concentrated. The residue was purified by flash chromatography using 10% EtOAc-hexanes to provide 2-(2,6-diethylphenyl)-4-methoxy-6-methyl-5-( 1-Propylbutenyl)pyrimidine.

1H NMR (300MHz, CDCl3): δ=7.24-7.29(m, 1H), 7.13(d, J=9Hz, 2H), 5.39(t, J=7.5Hz, 1H), 3.91(s, 3H), 2.46 LC -MS found352(MH+).

Step 2. Preparation of 2-(2,6-diethylphenyl)-4-methoxy-6-methyl-5-(1-propylbutyl)pyrimidine

2-(2,6-Diethylphenyl)-4-methoxy-6-methyl-5-(1-propylbutenyl)pyrimidine (100 mg) was dissolved using Pd-C under a pressure of 50 psi The MeOH solution was hydrogenated for 18 hours. The catalyst was removed by filtration and the filtrate was concentrated to provide 2-(2,6-diethylphenyl)-4-methoxy-6-methyl-5-(1-propylbutyl)pyrimidine.

1H NMR (300MHz, CDCl3): δ=7.24-7.29(m, 1H), 7.13(d, J=8Hz, 2H), 3.91(s, 3H), 2.51(s, 3H), 2.41(q, J= 7.5Hz, 4H), 2.38-2.45(m, 8H), 1.58-1.82(m, 3H), 1.14-1.44(m, 2H), 1.08(q, J=7.5, 6.6Hz, 6H)0.89(t, J=7.5Hz, 6H); LC-MS found 355 (MH+).

Example 12.2-(2,6-diethylphenyl)-5-(1-ethoxybutyl)-4-methoxy-6-methylpyrimidine and 5-[1-(4-acetyl Synthesis of piper-1-yl)butyl]-2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidine

SOCl ₂ (7 mL, 0.015 mol) was added dropwise under nitrogen to 1-[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]butan- 1-alcohol (1 g, 3 mmol) [prepared as described in Example 10] in anhydrous DCM (20 mL). The solution was then stirred at room temperature for an additional 1 hour. The reaction mixture was concentrated and azeotroped twice with toluene to obtain 5-(1-chloro-butyl)-2-(2,6-diethyl-phenyl)-4-methoxy-6-methanol base-pyrimidines, which are used in standard nucleophilic displacement reactions to obtain a variety of compounds including:

2-(2,6-diethylphenyl)-5-(1-ethoxybutyl)-4-methoxy-6-methylpyrimidine; 1H NMR (300MHz, CDCl3) δ=7.27(t , J=7.0Hz, 1H), 7.12(d, J=7.5Hz, 2H), 4.86(t, J=5.7Hz, 1H), 3.93(s, 3H), 3.38(q, J=6.9, 6.0Hz , 2H), 2.62(s, 3H), 2.41(q, J=7.5, 7.5Hz, 4H), 1.12-2.12(m, 2H), 1.58-1.82(m, 3H), 1.08(q, J=7.5, 6.6Hz, 6H) 0.89 (t, J = 7.5Hz, 6H); LC-MS found 357 (MH+).

5-[1-(4-acetylpiper-1-yl)butyl]-2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidine; 1H NMR ( 300MHz, CDCl3) δ7.28(t, J=5.1Hz, 1H), 7.12(d, J=7.5Hz, 2H), 3.91(s, 3H), 3.40-3.80(m, 6H), 2.66(s, 3H), 2.42(q, J=7.5, 7.5Hz, 4H), 2.09(s, 3H), 2.02-2.24(m, 2H), 1.80-2.01(m, 2H), 1.40-1.71(m, 3H), 1.08 (q, J = 7.5, 6.6 Hz, 3H) 0.89 (t, J = 7.5 Hz, 6H); LC-MS found 439 (MH+).

Example 13.2-((2R)-4-{2-(2,6-Dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6- Synthesis of Methyl-4-Pyrimidinyl}-2-Methyl-1-Piperyl)Acetamide

Step 1. Preparation of 2-chloro-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methoxy-6-methylpyrimidine

~70% of 2,4-dichloro-5-(5-isopropyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine (2.64 g, ~5.68 mmol) was dissolved under nitrogen Cool to -5 °C while stirring magnetically. A solution of 0.5M NaOMe in MeOH (11.4 mL) was added dropwise rapidly. After 1 h, the reaction was complete (based on LC/MS analysis). The reaction mixture was evaporated under reduced pressure, diluted with DCM (15 mL), filtered and evaporated to obtain a pale yellow oil containing an isomeric mixture of mono-methoxy adducts. Purification on silica gel (10 to 60% EtOAc/hexanes) afforded a colorless oil containing the desired isomer (eluted first) plus impurities from the starting material.

1H NMR (400MHz, CDCl3) δ7.06(d, J=8Hz, 1H), 6.82(s, 1H), 6.78(d, J=8Hz, 1H), 5.05(s, 2H), 4.04(s, 3H ), 2.80(m, 1H), 2.55(s, 3H), 2.13(s, 3H), 1.26(d, J=6.8Hz, 6H); LC-MS found 321.1(MH+), rt=1.73min, Method 2.

Step 2. Preparation of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methoxy-6-methylpyrimidine

Using argon gas on the reaction containing 2-chloro-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methoxy-6-methylpyrimidine (~3.91 mol), 2, A mixture of 6-dimethylphenylboronic acid (1.17 g, 7.82 mmol), 1M aqueous sodium carbonate solution 15.6 mL, and dioxane (56 mL) was blown for 20 minutes for degassing. Pd(PPh3)4 (226mg, 0.05mol%) was added to the mixture. The resulting yellow mixture was heated and magnetically stirred at 90°C under nitrogen for 24 hours. An additional 450 mg of Pd(PPh3) was added and heating was continued for an additional 18 hours until the reaction was complete by LC/MS analysis. The reaction mixture was cooled to room temperature and partitioned between EtOAc (200 mL) and water (70 mL). The organic layer was separated, extracted with water (70 mL x 2), brine (70 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a yellow oil. Purification by chromatography on silica gel (5 to 50% EtOAc/hexanes) afforded the title compound as a colorless solid. LC-MS found value 391.4 (MH+), retention time = 1.93min.

Step 3. Preparation of 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl-6-methylpyrimidin-4-ol

Make 2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methoxy-6-methylpyrimidine (1.29 g, 3.30 mmol) and 6N HCl was heated at 100 °C for 3 h (until the starting material was consumed as determined by LC/MS analysis). The resulting mixture was adjusted to pH 6 using 10N NaOH, and extracted with EtOAc (100 mL x 3). The combined extracts were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to obtain a yellow gum. Purification by chromatography on silica gel (50 to 100% EtOAc/hexanes) afforded the title compound as a white solid.

1H NMR (400MHz, CDCl3) δ11.4(br s, 1H), 6.75-7.26(m, 6H), 5.00(s, 2H), 2.86(m, 1H), 2.51(s, 3H), 2.22(s , 6H), 2.19 (s, 3H), 1.24 (d, J=6.8Hz, 6H); LC-MS found 377.4 (MH+), rt=2.87min, Method 3.

Step 4. Preparation of 4-chloro-2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidine

2-(2,6-Dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidin-4-ol ( 760 mg, 2.0 mmol) and phosphorus oxychloride (5 mL) was heated at 80 °C with magnetic stirring for 2 h (until consumption of starting material as determined by LC/MS analysis). The reaction mixture was evaporated under reduced pressure, diluted with DCM (50 mL), extracted with saturated NaHCO3 (20 mL x 3), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a pale yellow oil. Purification by chromatography on silica gel (10 to 40% EtOAc/hexanes) afforded the title compound as a colorless oil.

1H NMR (400MHz, CDCl ₃ ) δ7.08-7.25(m, 4H), 6.88(s, 1H), 6.88(s, 1H), 6.82(d, J=9Hz, 1H), 5.28(s, 2H) , 2.91(m, 1H), 2.74(s, 3H), 2.21(s, 3H) 2.14(s, 6H), 1.28(d, J=6.8Hz, 6H); LC-MS found 395.4(MH+), rt =3.33min, Method 3.

Step 5. 2-(2,6-Dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methyl-6-[(3R)-3 Preparation of -Methylpiper-1-yl]pyrimidine

4-Chloro-2-(2,6-dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methylpyrimidine at 100°C (0.1 mmol in 0.5 mL DMA), (R)-2-methyl-piperone (40 mg) and sodium carbonate (85 mg) was stirred with heating for 18 hours. The reaction mixture was cooled and partitioned between EtOAc (6 mL) and water (2 mL). The organic layer was separated, washed with water (2 mL x 2), brine (2 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a colorless oil. Purification by chromatography on silica gel (2% MeOH/DCM/0.1% ammonia) afforded the title compound as a colorless oil.

1H NMR (300MHz, CDCl3) δ7.06-7.26(m, 4H), 6.79-6.82(m, 2H), 4.97(dd, 2H), 3.89-3.96(m, 2H), 2.87-3.05(m, 5H ), 2.62-2.69(m, 1H), 2.56(s, 3H), 2.23(s, 3H), 2.16(s, 6H), 1.27(d, J=6.8Hz, 6H), 0.93(d, J=6.6 Hz, 3H).

Step 6. 2-((2R)-4-{2-(2,6-Dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-6-methanol Preparation of yl-4-pyrimidinyl}-2-methyl-1-piperyl)acetamide

2-(2,6-Dimethylphenyl)-5-[(5-isopropyl-2-methylphenoxy)methyl]-4-methyl-6- A mixture of [(3R)-3-methylpiper-1-yl]pyrimidine (32 mg, 0.07 mmol), 2-bromoacetamide (29 mg, 0.21 mmol), sodium carbonate (44 mg) and DMA (1 mL) was heated and Stir magnetically for 18 hours. The reaction mixture was cooled and partitioned between EtOAc (8 mL) and water (2 mL). The organic layer was separated, washed with water (2 mL), brine (2 mL), dried over anhydrous sodium sulfate, filtered and evaporated to obtain a colorless oil. Purification by chromatography on silica gel (2% MeOH/DCM/0.1% ammonia) afforded the title compound as a colorless oil.

1H NMR (300MHz, CDCl3) δ7.06-7.26 (m, 5H), 6.81-6.83 (m, 2H), 5.58 (brd, J=6.3Hz, 1H), 4.97 (dd, 2H), 3.77-3.86 ( m, 2H), 3.25-3.33(m, 2H), 2.80-3.00(m, 4H), 2.45-2.62(m, 5H), 2.22(s, 3H), 2.16(s, 6H), 1.27(d, J=6.8Hz, 6H), 0.93 (d, J=6.6Hz, 3H).

Example 14.2-(4-(2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidine- 4-yl)-5,6-dihydropyridin-1(2H)-yl)acetamide

Step 1. 4-(2-(2,6-Diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidin-4-yl) - Preparation of 5,6-dihydropyridine-1 (2H) tertiary butyl carboxylate

K2CO3 (414 mg, 3 mmol) was added to 4-chloro-2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6 -Methylpyrimidine (423mg, 1mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine- In a solution of 1(2H)-tert-butylcarboxylate (Wustrow, DJ and Wise, LDSynthesis, 1991, 993) (371mg, 1.2mmol) in anhydrous DMF (5mL). The mixture was sparged with N2 for 15 min and PdCl2dppf (28 mg) was added. The mixture was then heated at 80° C. for an additional 16 hours under nitrogen. After cooling to room temperature, the mixture was diluted with ether, washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ , concentrated and purified by silica gel column chromatography to provide the title product. [Estimated mass (569.8); Measured mass (M+1: 570.6)].

Step 2. 2-(2,6-Diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-4-methyl-6-(1,2,3 , the preparation of 6-tetrahydropyridin-4-yl) pyrimidine

TFA (2 mL) was added to 4-(2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6 at 0 °C -Methylpyrimidin-4-yl)-5,6-dihydropyridine-1(2H)carboxylic acid tert-butyl ester (741 mg, 1.3 mmol) in anhydrous CH ₂ Cl ₂ (2 mL). The mixture was then stirred at room temperature for 16 hours. After removal of solvent and excess TFA under reduced pressure, the residue was neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The extract was dried over anhydrous MgSO ₄ , concentrated and purified by silica gel column chromatography to provide the desired product. [Estimated mass (469.7); Measured mass (M+1: 470.6)].

Step 3. 2-(4-(2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidine-4 Preparation of -yl)-5,6-dihydropyridin-1(2H)-yl)acetamide

This compound was obtained by using 2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-4-methyl-6-(1 , 2,3,6-tetrahydropyridin-4-yl)pyrimidine as starting material, prepared in a similar manner as described in Example 13. [Estimated mass (526.7); Measured mass (M+1: 527.4)].

Step 4. 2-(4-(2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methyl)-6-methylpyrimidine-4 Preparation of -yl)piperidin-1-yl)acetamide

Add 5% Pd/C (100 mg) to 2-(4-(2-(2,6-diethylphenyl)-5-((5-isopropyl-2-methylphenoxy)methanol (131 mg, 0.25 mmol) in EtOAc (5 mL). The reaction mixture was hydrogenated at room temperature and pressure for 16 hours. After filtration through celite, the solution was concentrated and purified by silica gel column chromatography to provide the product. [Estimated mass (528.7); Measured mass (M+1: 529.4)].

Example 15. Other 4,5-disubstituted-2-arylpyrimidines

The compounds shown in Tables I to V were prepared according to the procedures provided in the schemes above and further illustrated in the examples above. All compounds herein in Tables I to IV and in Examples 1 to 14 exhibited an IC50 of 2 micromolar or less in the calcium ion mobilization assay provided in Example 25.

LC/MS data are provided in tables with retention times in minutes and a number (1, 2 or 3) indicating the method used. For Table III, all LC/MS data were obtained by Method 1. The LC/MS method is as follows:

method 1:

Analytical HPLC/MS equipment: Waters 600 series pumps (Waters Corporation, Milford, MA), Waters 996 diode array detectors and Gilson 215 autosamplers (Gilson Inc., Middleton, Wl), Micromass ^(R) LCT time-of-flight electronics were used. Spray free mass analyzer for analysis. Data were acquired using MassLynx™ 4.0 software, processed with OpenLynx Global Server™, OpenLynx™, and AutoLynx™.

Analytical HPLC/MS conditions: 4.6×50mm, ChromolithTM SpeedROD RP-18e column (Merck K GaA, Darmstadt, Germany); UV 10 spectrum/second, total 220 to 340nm; flow rate 6.0mL/min; injection volume 1 μl;

Gradient conditions - mobile phase A was 95% water, 5% methanol with 0.05% TFA; mobile phase B was 95% methanol, 5% water with 0.025% TFA, and the gradient was 0 to 0.5 minutes 10 to 100% B, hold at 100% B for 1.2 minutes, return to 10% B for 1.21 minutes, injection-to-injection cycle time of 2.15 minutes.

Analytical MS conditions: capillary voltage 3.5kV; cone voltage 30V; resolution and light source temperature 350°C and 120°C, respectively; mass range 181 to 750 with a scan time of 0.22 seconds and an inter scan delay of 0.05 minutes.

Method 2:

HPLC equipment: Analysis was performed using a Waters 600 series pump (Waters Corporation, Milford, MA), a Waters 996 diode array detector, and a Gilson 215 autosampler (Gilson Inc., Middleton, Wl). Data were acquired using MassLynx 4.0 software processed with OpenLynxTM.

HPLC conditions: 4.6×50mm, ChromolithTM SpeedRod column (Merck AEG); UV 5 spectrum/second, 220, 254nm; flow rate 6.0mL/min; injection volume 1 to 10 μl;

Gradient conditions - mobile phase A was 95% water, 5% methanol with 0.05% formic acid; mobile phase B was 95% methanol, 5% water with 0.025% formic acid;

Gradient Time (minutes) %B

0 5

0.01 5

1.0 100

2 100

2.1 5

MS equipment: LC-MS experiments were performed using a Waters ZMD II mass spectrometer.

MS conditions: electrospray positive ionization; capillary voltage 3.5kV; cone voltage 30V; resolution and light source temperature are 250°C and 100°C, respectively; Internal scan delay.

Method 3:

HPLC equipment: Waters 600 series pumps (Waters Corporation), Waters 996 diode array detector and Gilson 215 autosampler (Gilson Corporation) were used for analysis. Data were acquired with OpenLynx processing using MassLynx 4.0 software.

HPLC conditions: 4.6×50mm, XTerra MS C ₁₈ , 5μm column (Waters Company); UV 10 spectrum/second, 220, 254nm; flow rate 4.0mL/min; injection volume 1 to 10μl;

Gradient conditions - mobile phase A was 95% water, 5% methanol with 0.05% formic acid; mobile phase B was 95% methanol, 5% water with 0.025% formic acid;

Gradient Time (minutes) %B

0 5

0.01 5

2.0 100

3.50 100

3.51 5

MS equipment: LC-MS experiments were performed using a Waters ZMD II mass spectrometer.

MS conditions: electrospray forward dissociation; capillary voltage 3.5kV; cone voltage 30V; resolution and light source temperature 250°C and 100°C, respectively; mass range 120 to 800 with a scan time of 0.5 seconds and an internal scan delay of 0.1 minutes.

Table I

compound structure name LCMS LCMS LCMS LCMS

Table II

Table III

Table IV

Example 16. Pharmaceutical formulations for oral and intravenous administration

A. Lozenges containing C5a antagonists as well as anti-arthritic agents that are not C5a receptor antagonists can be prepared as follows:

Composition Quantity

C5a receptor antagonist 5mg to 500mg

C5a receptor-inactivating therapeutics 1 mg to 500 mg

Diluents, binders, disintegrants, lubricants,

Excipients q.s. 200mg to 400mg

B. Lozenges containing a C5a receptor antagonist as the sole active ingredient can be prepared as follows:

Composition mg mg mg

C5a receptor antagonist 10 50

Microcrystalline Cellulose 70.4 352

Granular Mannitol 15.1 75.5

Sodium Carboxymethyl Cellulose 3.0 15.0

Colloidal silica 0.5 2.5

Magnesium stearate (micro powder) 1.0 5.0

Total (mg) 100 500

C. Tablets containing C5a receptor antagonists and C5a receptor inactivators can be prepared according to the following instructions:

Composition mg mg mg

C5a receptor antagonists 10 25

C5a receptor inactivating therapeutic agent 10 25

Microcrystalline Cellulose 40 100

Modified edible cornstarch 1.05 4.25

Magnesium stearate 1.25 0.5

D. Intravenous formulations containing C5a receptor antagonists and C5a receptor inactivators can be prepared as follows:

Composition Quantity

C5a receptor antagonist 0.5 to 10 mg

C5a receptor inactivating therapeutics 0.5 to 10 mg

Sodium citrate 5 to 50 mg

Citric acid 1 to 15 mg

Sodium chloride 1 to 8 mg

Water for injections up to 1.0 liters

E. Oral suspensions containing C5a receptor antagonists and C5a receptor inactivators can be prepared according to the following instructions:

Components Amount per 5mL dose

C5a receptor antagonist 5 to 100 mg

C5a receptor inactivating therapeutics 5 to 100 mg

Polyvinylpyrrolidone 150mg

Polyoxyethylene sorbitan monolaurate 25mg

Benzoic acid 10mg to have sorbitol

Solution (70%) 5mL

Example 17. Preparation of radiolabeled probes

Compounds provided herein are prepared as radiolabeled probes by compound synthesis using precursors that include at least one radioactive isotope atom. The radioactive isotope is preferably at least one of carbon (preferably 14C), hydrogen (preferably 3H), sulfur (preferably 32S), or iodine (preferably 125I). Such radiolabeled probes are conveniently synthesized by radioisotope suppliers who specialize in synthesizing radiolabeled probe compounds for clients. Such suppliers include Amershamcorporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard Inc., West Sacramento, CA; ChemSyn Corporation, Lexena, KS; American Radiochem, Inc., St.Louis, MO; and Moravek Biochemicals, Inc., Brea, CA.

Tritium-labeled probe compounds were also prepared by platinum-catalyzed exchange in tritium-labeled acetic acid, acid-catalyzed exchange in tritium-labeled trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations can also be conveniently accomplished by customers using the compounds provided herein as matrices for radiolabelling via the suppliers listed in the preceding paragraph. In addition, certain precursors may be suitably subjected to tritium-hydrogen exchange with tritium gas, reduction of unsaturated bonds with tritium gas, or reduction using sodium borotritide.

Example 18. Analysis of C5a receptor-mediated chemotaxis

This example provides a standard assay of C5a receptor mediated chemotaxis.

Human premonocyte U937 cells (or purified human or non-human neutrophils) were treated with dibutyryl cAMP for 48 hours prior to analysis. Human neutrophils or those from other mammalian species were used directly after isolation. Cells were pelleted and resuspended in medium containing 0.1% fetal bovin serum (FBS) and 10 μg/mL calcein AM (a fluorescent dye). The suspension was then incubated at 37°C for 30 minutes to allow the cells to take up the fluorescent dye. The suspension was then centrifuged briefly to pellet the cells, which were then resuspended at a concentration of approximately 3 x 106 cells/mL in medium containing 0.1% FBS. Aliquots of this cell suspension were transferred to clean test tubes containing vehicle (1% DMSO in medium containing 0.1% FBS) or various concentrations of test compounds and incubated at room temperature for at least 30 minute. Chemotaxis assays were performed in CHEMO TX 101-8, 96-well culture plates (Neuro Probe Inc; Gaithersburg, MD). The well bottom of the plate is filled with medium containing 0 to 10 nM C5a, preferably from the same mammalian species as the neutrophils or other cells (eg, human C5a from human U937 cells). The well tops of the plates are filled with cell suspensions (compound or vehicle treated). The plates were then placed in the tissue culture incubator for an additional 60 minutes. The top surface of the culture dish was washed with PBS to remove excess cell suspension. The number of cells that migrated to the bottom of the well was then measured using a fluorescence reader. The chemotaxis index (the ratio of mobile cells to the total number of packed cells) was then calculated for each compound concentration to determine EC50 values.

If used as a control group to confirm that the cells still retain chemotactic ability in the presence of the test compound, the bottom of the well of the culture plate can be filled with various concentrations of chemo-attractants instead of C5a, wherein the chemo-attractants Agents that do not mediate chemotaxis via the C5a receptor, such as zymosan-activated serum (ZAS), N-formylmethionyl-leucyl-phenylalanine (FMLP) or Leukotriene B4 (LTB4), preferably a compound provided herein, in this case has not been detected to inhibit chemotaxis. In the assay of C5a-mediated chemotaxis described above, preferred C5a receptor modulators exhibit an EC50 value of less than 1 μM.

Example 19. Expression of C5A receptors

By PCR using 1) forward primers with added Kozak ribosome binding sites and 2) reverse primers with no additional sequences added, and 3) whole Stratagene Human Fetal Brain cDNA library (Stratagene Human Fetal Brain cDNA library) as a template to obtain human C5a receptor cDNA. The sequence of the resulting PCR product is detailed in SEQ ID NO: 1 of PCT International Application WO 02/49993. The PCR product was subcloned into the Srf 1 position in the cloning vector pCR-Script AMP (STRATAGENE, La Jolla, CA). Then use the restriction enzymes EcoRI and NotI to cut it out, and then clone it in the appropriate direction into the baculovirus expression vector pBacPAK 9 (CLONTECH, Palo Alto, CA) that has been cut with EcoRI and NotI for expression.

Example 20. C5A Expressed Baculovirus Preparations

Human C5a (hC5a) receptor baculovirus expression vector and BACULOGOLD DNA (BDPharMingen, San Diego, CA) were co-transfected into Sf9 cells. Three days after transfection, the culture supernatant of Sf9 cells was obtained. The recombined virus-containing supernatant was supplemented with Hink's TNM-FH of Grace's salt and 4.1mML-Gln, 3.3g/L LAH, 3.3g/L ultra-microfiltration yeasttolate and 10% fetal calf serum inactivated by heat treatment Insect cell culture medium (JRH Biosciences, Kansas City) (hereinafter referred to as "insect cell culture medium") was serially diluted and subjected to plaque assay (plaqueassay) to identify recombinant plaques. Four days later, the recombinant plaques were picked and transferred to 1 mL of insect cell culture medium for amplification. Individual T25 flasks containing 2 x 106 Sf9 cells in 5 mL of insect cell culture medium were infected with each 1 mL volume of recombinant baculovirus (passage 0). After culturing at 27° C. for 5 days, the supernatant medium was obtained from each T25 infection solution to be used as the passage 1 inoculum.

Then select 2 of the 7 recombinant baculoviral clones to be used in the second round of amplification, and use 1 mL of passage 1 mother solution (passage lstock) to infect the cells that were divided into 2 T175 flasks. 1 x 108 cells in 100 mL of insect cell culture medium. 48 hours post-infection, passage 2 medium from each 100 mL prep was recovered and assayed for plaque potency. Recombinant receptor expression was confirmed by analysis of cytospin pellets from the second round of amplification by the affinity binding method described below. 1 liter of Sf9 cells was then infected with a multiplicity of infection of 0.1 to start the third round of scale-up. 40 hours after infection, the supernatant medium was recovered to produce the passage 3 baculovirus stock solution.

The remaining cell pellet was assayed using the method of DeMartino et al. (1994) J. Biol. Chem. 269(20): 14446-14450 (the binding assay taught on page 14447 is incorporated herein by reference). The affinity binding assay assay was modified as follows. Radioligand was 0.005 to 0.500 nM [125I]C5a (human recombinant) (New England Nuclear Company, Boston, MA); hC5a receptor-expressing baculovirus cells were used instead of 293 cells; the assay buffer Contains 50mM Hepes pH 7.6, 1mM CaCl2, 5mM MgCl2, 0.1% BSA pH 7.4, 0.1mM bacitracin, and 100KIU/mL aprotinin; use GF/C WHATMAN filter paper (presoaked in 1.0% polyethyleneimine for 2 hours); and the filter paper was washed twice with 5 mL of cold binding buffer without BSA, subtilisin, or aprotinin.

The potency of the passage 3 baculovirus mother solution was determined by plaque assay, virus infection dose, and culture time course analysis, and a binding assay was performed to determine the optimal receptor expression conditions.

The optimal infection parameters for hC5a receptor expression in up to 1 liter of Sf9 cell infection culture were found to be a virus infection dose of 0.1 and a culture time of 72 hours.

Example 21. Baculovirus infection

Log phase Sf9 cells (INVITROGEN, Carlsbad CA) were infected with one or more recombinant baculovirus stocks, and then cultured at 27°C in insect cell culture medium. Infection was carried out with virus directing hC5a receptor expression alone or in combination with three G-protein subunit-expressing virus strains: 1) murine Gαi2G-protein-encoding virus strain (BIOSIGNAL #V5J008), 2) bovine b1 G-protein-encoding virus strain (BIOSIGNAL #V5H012), and 3) human g2G-protein-encoding virus strain (BIOSIGNAL #V6B003), which are available from Biosignal Inc., Montreal.

The infection is conveniently carried out at a viral infective dose of 0.1:1.0:0.5:0.5. 72 hours after infection, cell suspension samples were analyzed for viability by trypan blue dye exclusion, and remaining Sf9 cells were obtained by centrifugation (3000 rpm/10 min/4°C).

Example 22. Purified recombinant insect cell membranes

The Sf9 cell pellet was resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 μg/mL leupeptin, 2 μg/mL aprotinin, 200 μM PMSF, and 2.5 mM EDTA, pH 7.4) medium and homogenize using a POLYTRON homogenizer (set 5 to 30 seconds). The homogenate was centrifuged (536 xg/10 min/4°C) to pellet nuclei. The supernatant containing the isolated cell membranes was transferred to a clean centrifuge tube, centrifuged (48,000×g/30 minutes/4° C.), and the resulting centrifuged pellet was resuspended in 30 mL of homogenization buffer. Repeat this centrifugation and resuspension step twice. The final pellet was resuspended in ice-cold Dulbecco's PBS containing 5 mM EDTA and stored in frozen aliquots at -80°C until use. The protein concentration of the resulting membrane preparation (hereinafter "P2 membrane") is conveniently measured using the Bradford protein assay (Bio-Rad Corporation, Hercules, CA). Based on this measurement, 1 liter of cell culture fluid typically yields 100 to 150 mg of total cell membrane proteins.

Example 23. Radioligand Binding Assay

The purified P2 cell membrane prepared by the above method was resuspended by Dounce homogenization (tight pestle) in binding buffer (50nM Hepes pH 7.6, 120mM NaCl, 1mM CaCl2, 5mM MgCl2, 0.1% BSA, pH 7.4, 0.1mM subtilisin, 100KIU/mL aprotinin).

Cell membranes (5 to 50 μg) were added to polypropylene test tubes containing 0.005 to 0.500 nM [125I]C5a ((human recombinant), New England Nuclear, Boston, MA) to a final assay volume of 0.25 ml for assay. Saturation binding assay. Nonspecific binding was determined in the presence of 300 nM hC5a (Sigma Chemical Company, St. Louis, MO) and represented less than 10% of total binding. GTPγS was added to two identical test tubes to a final concentration of 50 μM to evaluate the effect of guanine on receptor affinity.

Cell membranes (5 to 50 μg) were added to polypropylene tubes containing 0.030 nM [125I]C5a (human) for competition assays. A non-radioactive label displacer was added to each assay at a concentration ranging from 10-10M to 10-5M, resulting in a final volume of 0.250 mL. Nonspecific binding was determined in the presence of 300 nM hC5a (Sigma Chemical Company, St. Louis, MO) and represented less than 10% of total binding. Following incubation for 2 hours at room temperature, the reaction was terminated by rapid vacuum filtration. Samples were filtered on GF/C WHATMAN filter paper presoaked (2 hours in 1.0% polyethyleneimine before use) and rinsed with 5 mL of cold binding buffer without BSA, subtilisin, or aprotinin filter paper twice. The remaining bound radioactivity was quantified as gamma counts. With the aid of SIGMAPLOT software, the measured values were substituted into the Hill equation to determine K1 and Hill's number ("nH").

Example 24. GTP Binding Induced by Agonists

Agonist-stimulated GTP-γ35S binding ("GTP binding") activity can be used to identify agonist and antagonist compounds, and to distinguish neutral antagonist compounds from those with inverse agonist activity come out. This activity can also be used to detect facilitation mediated in part by antagonist compounds. Compounds analyzed in this assay are referred to herein as "test compounds". Agonist-stimulated GTP-binding activity was measured as follows: Four independent baculovirus strains (one directing hC5a receptor expression and three each directing three heterotrimeric Gproteins) were tested as described above. Individual expression of subunits) were used in the culture medium of infected Sf9 cells.

To confirm that the receptor/G-protein-α-β-γ combination is functionally responsive to the measured GTP-binding, hC5a (Sigma Chemical Company, St.Louis, Missouri, USA) was used as an agonist to evaluate in purified Agonist-stimulated GTP binding on cell membranes (prepared as described above).

P2 cell membranes were resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50nM Tris pH 7.0, 120nM NaCl, 2mM MgCl2, 2mM EGTA, 0.1% BSA, 0.1mM subtilisin, 100KIU /mL aprotinin, 5μM GDP), and then added to the reaction tube at a concentration of 30μg protein/reaction tube. After addition, the dose of agonist hC5a was increased over a concentration range from 10-12 M to 10-6 M, and the reaction was initiated by adding 100 pM GTP-γ35S to a final assay volume of 0.25 mL. In competition assays, a non-radiolabeled test compound (e.g., a compound of Formula 1) and 10 nM hC5au were added to each assay at a concentration range of 10-10M to 10-5M to yield 0.25 mL of the final volume.

Neutral antagonists that reduce C5a-stimulated GTP binding activity toward but not below baseline (in the absence of added C5a or other agonists and further in the absence of any test compound were tested in this assay concentration of GTP bound to the cell membrane).

Conversely, certain preferred compounds are characterized as inverse agonists if they reduce the GTP binding activity of receptor-containing cell membranes below baseline in the absence of added C5a. A test compound is characterized as a neutral antagonist if it exhibits antagonist activity in the absence of a C5a agonist without reducing GTP binding activity below baseline.

Antagonist test compounds that increased GTP binding activity above baseline in the absence of added hC5a were characterized by partial agonist activity in this assay. Preferred antagonist compounds provided herein do not increase GTP binding activity by more than 10% above baseline, preferably by no more than 5% above baseline, and optimally by no more than 2% above baseline.

Following incubation at room temperature for 60 minutes, the reaction was terminated by vacuum filtration on GF/C filter paper (pre-soaked in wash buffer, 0.1% BSA), followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 120 mM NaCl) Rinse twice. The amount of GTP-γ35S bound by the receptor (and thereby bound to the cell membrane) is determined by measuring the bound radioactivity, preferably by liquid scintillation spectroscopic analysis of the washed filtrate. Non-specific binding is determined using 10 mM GTPγ and typically corresponds to less than 5% of total binding. Above baseline, data are expressed as percentages. The results of these GTP binding assays were analyzed using SIGMAPLOT software (SPSS Inc., Chicago, IL).

Example 25. Calcium ion migration test

A. Response to C5a

U937 cells were grown in differentiation medium (1 mM dibutyryl cAMP in RPMI 1640 medium containing 10% fetal bovine serum) for 48 hours at 37°C, and then inoculated on a FLIPR™ plate reader (Molecular Devices company, Sunnyvale CA) 96-well culture plate. Cells were grown for an additional 24 hours (to 70 to 90% confluence) prior to analysis. Then wash once with Krebs Ringer solution. FLUO-3 calcium ion-sensitive dye (Molecular Probes Inc., Eugene, OR) was added to 10 μg/mL and cells were incubated with Krebslinger's solution for 1 to 2 hours at room temperature. The 96-well plates were then washed to remove excess dye. The fluorescent response, measured by excitation at 480 nM and emission at 530 nM, was monitored using a FLIPR™ device (Molecular Devices) immediately after addition of human C5a to cells to a final concentration of 0.01 to 30.0 nM. In response to agonist stimulation, differentiated U937 cells typically exhibit a signal of 5,000 to 50,000 Arbitrary Fluorescent Light Units.

B. Analytical Tests Used in Measuring ATP Responses

The differentiated U937 cells (prepared and tested as described above under "A. Response to C5a") were stimulated by the addition of ATP (but not C5a) to a final concentration of 0.01 to 30 μΜ. This stimulation typically elicits a signal of 1,000 to 12,000 random fluorescence units. Certain preferred compounds produce less than 10%, preferably less than 5%, and most preferably less than 2% change in the calcium ion mobilization signal when a control assay is performed in the presence or absence of the compound.

C. Assays Used to Identify Receptor Modulators: Analytical Assays for Antagonists and Agonists

Those of ordinary skill in the art will recognize that the calcium ion mobilization assay described above can be readily adapted for use in identifying test compounds as having agonist or antagonist activity at the human C5a receptor.

For example, to identify antagonist compounds, differentiated U937 cells were washed and incubated with Fluo-3 dye as described above. One hour before the measurement of the fluorescent signal, a subpopulation of cells is incubated with at least one compound to be tested at a concentration of 1 [mu]M. Immediately after the subsequent addition of 0.3 nM (final concentration) of human recombinant C5a, the fluorescence response was detected using a FLIPR™ plate reader. The antagonist compound elicits at least a 2-fold decrease in the fluorescent response relative to the fluorescent response measured in the presence of human C5a alone. Preferred antagonist compounds elicit at least a 5-fold, preferably at least 10-fold, and more preferably at least 20-fold reduction in the fluorescent response relative to the fluorescent response measured in the presence of human C5a alone. Agonist compounds elicit an increase in fluorescence in the absence of added C5a, which increase is at least partially blocked by known C5a receptor antagonists.

If multiple concentrations of the agonist compound are tested as described in the preceding paragraph, the concentration required to provide 50% inhibition of the 0.3 nMC5a response (hereinafter referred to as IC50) can be determined. IC50 values were calculated by substituting the percent inhibition calculated by dividing the relative fluorescence units (RFU) obtained at FLIPR to the antagonist compound concentration into the following equation:

y=m1*(1/(1+(m2/m0)m3)),

In the above equation, y=% inhibition of C5a-induced signaling, m0=antagonist compound concentration, m1=maximum inhibition of C5a-induced signaling by highest antagonist compound concentration, m2 is IC50, and m3=Hill slope. Data were plugged into this equation using least squares regression to determine IC50 values and Hill slope. Ki is calculated using the Cheng-Prusoff equation:

Ki＝IC50/(1/[L]/Kd)

In the above equation IC50 is determined in the manner described above, [L] is the concentration of C5a used in testing the activity of the antagonist compound, and Kd is the dissociation constant of recombinant human C5a.

Example 26. Assays for Assessing Agonist Activity of Small Molecule C5A Receptor Antagonists

Certain preferred compounds of Formula I are C5a receptor antagonists that do not possess significant (eg, greater than 5%) agonist activity in any of the C5a-mediated functional assays discussed herein . Such agonist activity can be assessed by measuring GTP binding mediated by the small molecule in the absence of the neutral agonist C5a, for example in assays for C5a-induced GTP binding as described above. Likewise, in calcium ion mobilization assays such as those described above, small molecule compounds can be directly assayed for their ability to stimulate calcium ion concentrations in the absence of the neutral agonist C5a. Certain compounds provided herein exhibit C5a agonist activity in the preferred range of 10% less, more preferably 5% less, and optimally 2% less than the response elicited by the neutral agonist C5a.

Embodiment 27.MDCK toxicity test

This example illustrates the evaluation of compound toxicity using the Renal Tubular Cell (MDCK cell) Cytotoxicity Assay

1 μl of test compound was added to each well of a clear bottom 96-well culture plate (PACKARD, Meriden, CT) such that the final concentration of the compound tested for this assay was 10 micromolar, 100 micromolar, or 200 micromolar concentration. Add solvent without test compound to control wells.

MDCK cells were fixed under sterile conditions according to the instructions of the ATCC data sheet, ATCC number CCL-34 (American Type Culture Collection, Manassas, VA). The fused MDCK cells were trypsinized, recovered and diluted with warm (37C) medium (VITACELL (Minimum Essential Medium Eagle, ATCC catalog #30-2003) to a concentration of 0.1×106 cells/mL. Except five containing 100 μl no Add 100 μl of diluted cells to each well except for the standard curve of the warm medium in which the cells exist. Then culture the plate with continuous shaking at 37°C for 2 hours under 95% O ₂ and 5% CO ₂ After incubation, add 50 μl of mammalian cell lysis solution (components of PACKARD (Meriden, CT) ATP-LITE-M luminescent ATP detection kit) to each well, cover the well with PACKARD TOPSEAL label, and Shake at approximately 700 rpm for 2 minutes on a suitable shaker.

Compounds that induce toxicity will reduce ATP production relative to untreated cells. ATP production in treated and untreated MDCK cells is usually measured using the PACKARD ATP-LITE-M Luminescent ATP Detection Kit (Product No. 6016941) according to the manufacturer's instructions. Allow PACKARD ATP LITE-M Reagent to equilibrate to room temperature. Once equilibrated, the lyophilized matrix solution was reconstituted in 5.5 mL of matrix buffer solution (from kit). The lyophilized ATP standard solution was reconstituted in deionized water to provide a 10 nM fixative. For the 5 control wells, 10 μl of the serially diluted PACKARD standard was added to each standard curve control well such that the final concentrations for each serial well were 200 nM, 100 nM, 50 nM, 25 nM and 12.5 nM. PACKARD matrix solution (50 μl) was added to all wells, then the wells were re-covered and the plates were shaken on a suitable shaker at approximately 700 rpm for 2 minutes. A white PACKARD label was affixed to the bottom of each plate and the samples were dark-adapted by wrapping the plate in packaging foil and placing in the dark for 10 minutes. Luminescence was measured using a luminescence counter (for example, PACKARD TOPCOUNT Microdisc Scintillation and Luminescence Counter or TECAN SPECTRAFLUOR PLUS) at 22°C, and the ATP concentration was calculated from the standard curve. The ATP concentration of cells treated with the test compound is compared to the ATP concentration of untreated cells. Cells treated with 10 [mu]M of the preferred test compound exhibit an ATP concentration of at least 80%, preferably at least 90%, of that of untreated cells. Preferably, cells treated with the test compound have an ATP concentration of at least 50%, preferably at least 80%, of the ATP concentration detected in untreated cells when treated with a test compound at a concentration of 100 [mu]M.

Claims (111)

1. compound or its pharmacy acceptable salt shown in general formula I,

Wherein

R ₁Be selected from the Heterocyclylalkyl that (cycloalkyl) alkoxyl group that hydrogen, alkyl that selectivity is substituted, thiazolinyl that selectivity is substituted, alkynyl that selectivity is substituted, cycloalkyl that selectivity is substituted, cycloalkenyl group that selectivity is substituted, alkoxyl group that selectivity is substituted, cycloalkyloxy, selectivity that selectivity is substituted be substituted or selectivity are substituted;

R ₂Be selected from-XR _A,-(CR _AR _B) OR ₄,-CR _AR _BNR ₄R ₅Or-CR _AR _BQ;

R ₃Be selected from heterocycle-oxygen base that aryl that selectivity is substituted, cycloalkyl that selectivity is substituted, arylalkyl that selectivity is substituted, aryloxy that selectivity is substituted, alkoxy aryl that selectivity is substituted, heterocycle, selectivity that selectivity is substituted be substituted ,-O-(CR _AR _B) _m-Y ,-N (R _B)-(CR _AR _B) _m-XR _A,-N (R _B)-(CR _AR _B) _m-Y, wherein said heterocycle be saturated, unsaturated or aromaticity and have 1 to 3 the ring and each ring have 3 to 7 ring persons;

R ₄For:

(i) C ₂-C ₈Alkyl, C ₂-C ₈Thiazolinyl, C ₂-C ₈Alkynyl, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, list-or two-(C ₁-C ₄Alkylamino) C ₂-C ₄Alkyl, (3-to 7-element heterocycle alkyl) C ₀-C ₄Alkyl, aryl C ₀-C ₄Alkyl or heteroaryl C ₀-C ₄Alkyl, its each selectivity is substituted; Or (ii) and R ₅Link, and and R ₄And R ₅The common formation of the nitrogen of institute's bond has the heterocycle that 1 to 3 ring, each ring have 5 to 7 ring persons, and this heterocycle selectivity is substituted;

R ₅For:

(i) hydrogen;

(ii) C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, (C ₃-C ₇Carbocyclic ring) C ₀-C ₄Alkyl, its each group selectivity is substituted; Or

(iii) and R ₄Link and form the heterocycle that selectivity is substituted;

Ar for through single-, two-or the three-phenyl that replaces, the naphthyl that selectivity is substituted or selectivity be substituted have a heteroaryl that 1 to 3 ring, each ring have 5 to 7 ring persons;

R _AAnd R _B, identical or different, when occurring each time, be independently selected from:

(i) hydrogen or hydroxyl; Or

(ii) alkyl, cycloalkyl or (cycloalkyl) alkyl, its each selectivity replaces through one or more substituting groups, and described substituting group is independently selected from: ketone group, hydroxyl, halogen, cyano group, amino, C _1-6Alkoxyl group ,-NH (C _1-6Alkyl) ,-N (C _1-6Alkyl) (C _1-6Alkyl) ,-NHC (=O) (C _1-6Alkyl) ,-N (C _1-6Alkyl) C (=O) (C _1-6Alkyl) ,-NHS (O) _n(C _1-6Alkyl) ,-S (O) _n(C _1-6Alkyl) ,-S (O) _nNH (C _1-6Alkyl) ,-S (O) _nN (C _1-6Alkyl) (C _1-6Or Z alkyl);

X is independently selected from when occurring each time-CHR _B-,-O-,-C (=O)-,-C (=O) O-,-S (O) _n-,-NR _B-,-C (=O) NR _B-,-NR _BC (=O)-or-NR _BS (O) _n-;

Y and Z are independently selected from 3-to 7-member carbon ring group or heterocyclic group when occurring each time, these groups are saturated, unsaturated or aromaticity, and through one or more substituting group selectivity replacements, described substituting group is independently selected from halogen, ketone group, hydroxyl, amino, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group, list or two (C _1-4Alkyl) amino or-S (O) _n(alkyl);

Q is the heterocyclic group that the carbon ring group that is substituted of selectivity or selectivity are substituted, these groups are saturated, unsaturated or aromaticity, and comprise 3 to 18 annular atomses that are configured on 1,2 or 3 ring, described ring for through condense, volution or link with chemical bond;

M is independently selected from 0 to 8 integer when occurring each time; And

N is independently selected from 0,1 or 2 integer when occurring each time.

2. compound or its pharmacy acceptable salt shown in general formula I I,

Wherein

Ar for through single-, two-or the three-phenyl that replaces, the naphthyl that selectivity is substituted or selectivity be substituted have a heteroaryl that 1 to 3 ring, each ring have 5 to 7 ring persons;

A is OR ₄, NR ₄R ₅Or CR ₄(XR _y) ₂

R ₁Be selected from the Heterocyclylalkyl that (cycloalkyl) alkoxyl group that hydrogen, alkyl that selectivity is substituted, thiazolinyl that selectivity is substituted, alkynyl that selectivity is substituted, cycloalkyl that selectivity is substituted, cycloalkenyl group that selectivity is substituted, alkoxyl group that selectivity is substituted, cycloalkyloxy, selectivity that selectivity is substituted be substituted or selectivity are substituted;

R ₃Be selected from halogen, amino, cyano group, alkyl that selectivity is substituted, thiazolinyl that selectivity is substituted, alkynyl that selectivity is substituted, cycloalkyl that selectivity is substituted, alkoxyl group that selectivity is substituted, cycloalkyloxy that selectivity is substituted, aryl that selectivity is substituted, arylalkyl that selectivity is substituted, aryloxy that selectivity is substituted, alkoxy aryl that selectivity is substituted, heterocycle, selectivity that selectivity is substituted be substituted heterocycle-oxygen base ,-E-(CR _CR _D) _m-Z ,-E-(CR _CR _D) _m-XR _A, wherein said heterocycle has 1 to 3 ring, each ring and has 3 to 7 ring persons,

R ₄For:

(i) C ₂-C ₈Alkyl, C ₂-C ₈Thiazolinyl, C ₂-C ₈Alkynyl, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, list-or two-(C ₁-C ₄Alkyl) amino C ₂-C ₄Alkyl, (3-to 7-element heterocycle alkyl) C ₀-C ₄Alkyl, aryl C ₀-C ₄Alkyl or heteroaryl C _0-4Alkyl, its each replace through 0 to 4 substituting group, described substituting group is independently selected from R _x, C ₂-C ₄Alkyloyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkoxyl group, (3 to 7 Yuans ring Heterocyclylalkyls) C ₀-C ₄Alkyl or XR _yOr

(ii) and R ₅Link, and and R ₄And R ₅The common formation of the nitrogen of institute's bond has 1 to 3 ring, each ring and has 5 heterocycles to individual 7 ring persons, and wherein said heterocycle independently is selected from R through 0 to 4 _x, ketone group or W-Z substituting group replace;

R ₅For:

(i) hydrogen;

(ii) C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, (C ₃-C ₇Carbocyclic ring) C ₀-C ₄Alkyl, its each group replaces through 0 to 3 substituting group, and described substituting group is independently selected from halogen, hydroxyl, amino, cyano group, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy; Or

(iii) and R ₄Link and form the heterocycle that selectivity is substituted;

R ₈And R ₉Be independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkylamino or (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl;

E is single covalent linkage, oxygen or NR _A

X be single covalent linkage ,-CR _AR _B-,-O-,-C (=O)-,-C (=O) O-,-S (O) _n-or-NR _B-;

And

R _yFor:

(i) hydrogen; Or

(ii) C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₂-C ₁₀Alkynyl, (C ₃-C ₁₀Carbocyclic ring) C ₀-C ₄Alkyl or (3 to 10 element heterocycle) C ₀-C ₄Alkyl, its each group replaces through 0 to 6 substituting group, and described substituting group is independently selected from R _x, ketone group ,-NH (C ₁-C ₆Alkyloyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyloyl) ,-NHS (O _n) C ₁-C ₆Alkyl ,-N (S (O _n) (C ₁-C ₆Alkyl) ₂,-S (O _n) NHC ₁-C ₆Alkyl or-S (O _n) N (C ₁-C ₆Alkyl) ₂

W be single covalent linkage ,-CR _AR _B-,-NR _B-or-O-;

Z is independently selected from 3-to 7-member carbocyclic ring or heterocycle when occurring each time, its each group replaces through 0 to 4 substituting group, described substituting group be independently selected from halogen, ketone group ,-COOH, C (O) NH ₂,-CH ₂COOH ,-CH ₂C (O) NH ₂, hydroxyl, amino, cyano group, cyano methyl, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, C ₁-C ₆Alkoxy carbonyl ,-CH ₂COO (C ₁-C ₆Alkyl), singly-or two-(C ₁-C ₆Alkyl) amino, (C ₁-C ₆Alkyl) (2-ethanamide) amino or-S (O _n) C ₁-C ₆Alkyl;

R _AAnd R _BWhen occurring each time, be independently selected from:

(i) hydrogen; Or

(ii) C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₂-C ₁₀Alkynyl, saturated or fractional saturation (C ₃-C ₁₀Carbocyclic ring) C ₀-C ₄Alkyl or saturated or fractional saturation (3 to 10 element heterocycle) C ₀-C ₄Alkyl, its each group replaces through 0 to 6 substituting group, and described substituting group is independently selected from ketone group, hydroxyl, halogen, cyano group, amino, C ₁-C ₆Alkoxyl group, list-or two-(C ₁-C ₄Alkyl) amino ,-COOH ,-C (=O) NH ₂,-NHC (=O) (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) C (=O) (C ₁-C ₆Alkyl) ,-NHS (O _n) C ₁-C ₆Alkyl, SO ₃H ,-SO ₂NH ₂,-S (O _n) C ₁-C ₆Alkyl ,-S (O _n) NHC ₁-C ₆Alkyl ,-S (O _n) N (C ₁-C ₆Alkyl) C ₁-C ₆Alkyl or Z;

R _CAnd R _DBe independently selected from R _A, hydroxyl, C _1-6Alkoxyl group or ketone group;

R _xWhen occurring each time, be independently selected from halogen, hydroxyl, amino, cyano group, nitro ,-COOH ,-C (=O) NH ₂, C ₁-C ₆Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, list-or two-(C ₁-C ₆Alkyl) amino, C ₁-C ₆Alkoxyl group, C ₁-C ₂Hydroxyalkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Halogenated alkoxy, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl or-S (O _n) C ₁-C ₆Alkyl;

M is independently selected from 0 to 8 integer when occurring each time; And

N is independently selected from 0,1 or 2 integer when occurring each time.

3. compound as claimed in claim 2 or salt, wherein R ₁Be not hydrogen.

4. compound as claimed in claim 2 or salt, wherein R ₁Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl.

5. compound as claimed in claim 4 or salt, wherein R ₁Be C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl group.

6. compound as claimed in claim 5 or salt, wherein R ₁Be methyl, ethyl or methoxyl group.

7. compound as claimed in claim 2 or salt, wherein:

R ₃Be selected from alkoxyl group, cycloalkyloxy, phenyl, 4 to 7 element heterocycles ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CR _CR _D) _m-Q or Q, its each replace through 0 to 3 substituting group, this substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, (C _1-6Alkyl) (CR _AR _B) _j-T) amino, single-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q;

R _CAnd R _DIdentical or different, and when occurring each time, be independently selected from hydrogen, ketone group, C _1-4Alkyl, hydroxyl or C _1-4Alkoxyl group;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl);

J is 0 to 6 integer; And

Q is the saturated heterocyclic that comprises 4 to 7 ring persons and have tie point on carbon or nitrogen-atoms.

8. compound as claimed in claim 7 or salt, wherein R ₃Be pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q.

9. compound as claimed in claim 7 or salt, wherein R ₃Be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group or E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles.

10. compound as claimed in claim 7 or salt, wherein R ₃Be C _1-6Alkoxyl group, through the C of carboxylic acid-substituted _1-6Alkoxyl group, C _3-7Residue shown in cycloalkyloxy or the following general formula:

Wherein:

E is O, NR _DOr single covalent linkage;

M is 0 to 4 integer;

P and q are independently selected from 0 to 5 integer, make 2≤p+q≤5;

G ₁Be CH, CR ₁₀Or N;

G ₂Be CH, CR ₁₀, NH, NR _E, O or S;

R ₁₀Represent one or two to be selected from following substituting group: halogen, cyano group, hydroxyl, ketone group, (CH ₂) _j-T, N (methyl) (CH ₂) _j-T, methyl, ethyl, methoxyl group, oxyethyl group, single methyl fluoride, difluoromethyl or trifluoromethyl or single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;

R _EBe selected from R _D, T or CH ₂T;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl); And

J is 0 to 6 integer.

11. compound as claimed in claim 7 or salt, wherein R ₃Have following general formula:

Wherein:

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl);

G ₁Be N or CH; And

J is 0,1,2 or 3.

12. compound as claimed in claim 2 or salt, wherein

R ₄For:

(i) C ₂-C ₈Alkyl, C ₂-C ₈Thiazolinyl, C ₂-C ₈Alkynyl, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, list or two-(C ₁-C ₄Alkylamino) C ₂-C ₄Alkyl, (3-to 7-element heterocycle alkyl) C ₀-C ₄Alkyl, phenyl C ₀-C ₄Alkyl, pyridyl C ₀-C ₄Alkyl, pyrimidyl C ₀-C ₄Alkyl, thienyl C ₀-C ₄Alkyl, imidazolyl C ₀-C ₄Alkyl, pyrryl C ₀-C ₄Alkyl, pyrazolyl C ₀-C ₄Alkyl, benzisothiazole base or tetralyl, its each replace through 0 to 4 substituting group, described substituting group is independently selected from R _x, C ₂-C ₄Alkyloyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkoxyl group, (3-to 7-element heterocycle alkyl) C ₀-C ₄Alkyl or XR _yOr

(ii) and R ₅Link, and and R ₄And R ₅The common formation of the nitrogen of institute's bond has the heterocycle that 1 to 3 ring, each ring have 5 to 7 ring persons, and this heterocycle is independently selected from R through 0 to 4 _x, ketone group or W-Z substituting group replace; And

R ₅For:

(i) hydrogen;

(ii) C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl or (C ₃-C ₇Carbocyclic ring) C ₀-C ₄Alkyl, its each group replaces through 0 to 3 substituting group, and described substituting group is to be independently selected from halogen, hydroxyl, amino, cyano group, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy; Or

(iii) and R ₄Link and form the heterocycle that replaces through selectivity.

13. compound as claimed in claim 2 or salt, wherein A is NR ₄R ₅

14. compound as claimed in claim 13 or salt, wherein:

R ₄Be selected from (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, phenyl C ₀-C ₄Alkyl, pyridyl C ₀-C ₄Alkyl, pyrimidyl C ₀-C ₄Alkyl, thienyl C ₀-C ₄Alkyl, imidazolyl C ₀-C ₄Alkyl, pyrryl C ₀-C ₄Alkyl, pyrazolyl C ₀-C ₄Alkyl, indyl C ₀-C ₄Alkyl, indazolyl C ₀-C ₄Alkyl, Benzocycloalkene base C ₀-C ₄Alkyl, decahydro naphthyl C ₀-C ₄Alkyl, benzisothiazole base C ₀-C ₄Alkyl, tetrahydric quinoline group C ₀-C ₄Alkyl or tetralyl C ₀-C ₄Alkyl, its each replace through 0 to 4 substituting group, described substituting group is independently selected from R _x, single-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkoxyl group, (3 to 7 element heterocycle alkyl) C ₀-C ₄Alkyl, C ₂-C ₄Alkyloyl or C ₂-C ₄Alkyloyl oxygen base; And

R ₅Be C _1-6Alkyl, C _2-6Thiazolinyl or (C ₃-C ₇Carbocyclic ring) C ₀-C ₄Alkyl.

15. compound as claimed in claim 13 or salt, wherein R ₄And R ₅In conjunction with the heterocycle that contains 1 or 2 fused rings or volution that forms saturated or fractional saturation; Wherein this heterocycle replaces through 0 to 4 substituting group, described substituting group be independently selected from halogen, hydroxyl, amino, cyano group ,-COOH ,-CH ₂COOH, C _1-6Alkoxy carbonyl ,-CH ₂CO ₂-C _1-6Alkyl ,-C (=O) NH ₂, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, list-or two-(C ₁-C ₆Alkyl) amino, C ₁-C ₆Alkoxyl group, C ₁-C ₂Haloalkyl, C ₁-C ₂Halogenated alkoxy, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl ,-S (O _n) C ₁-C ₆Alkyl, SO ₃H, SO ₂NH ₂Or phenyl.

16. compound as claimed in claim 15 or salt, wherein R ₄And R ₅In conjunction with forming saturated 4 to 7 element heterocycles through 0 to 3 substituting group replacement, described substituting group is independently selected from halogen, hydroxyl, amino, cyano group, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoro-methoxy ,-COOH ,-CH ₂COOH, C _1-2Alkoxy carbonyl or-CH ₂CO ₂-C _1-2Alkyl.

17. as the compound or the salt of claim 16, wherein this heterocycle is azepan base, morpholinyl, high morpholinyl, Pyrrolizidine base, piperazinyl, high piperazinyl, piperidyl or homopiperidinyl.

18. compound as claimed in claim 15 or salt, wherein R ₄And R ₅In conjunction with forming the heterocycle that contains 2 rings, wherein each ring replaces through 0 to 3 substituting group, and described substituting group is to be independently selected from halogen, hydroxyl, amino, cyano group, C ₁-C ₂Alkyl, C ₁-C ₂Alkoxyl group, trifluoromethyl, difluoromethyl, trifluoromethoxy or difluoro-methoxy.

19. compound as claimed in claim 18 or salt, wherein said heterocycle are tetrahydrochysene quinoline quinolyl, tetrahydro isoquinolyl, decahydroquinolyl, Decahydroisoquinolinpreparation base, indazolyl, indoline base, phenylimidazole base, Bi Ding Bing oxazinyl or benzoxazinyl.

20. compound as claimed in claim 13 or salt, wherein said compound are according to general formula III:

Wherein:

R ₁₃Represent 0 to 3 to be independently selected from following substituting group:

(i) R _xOr

(ii) phenyl or pyridyl; Its each group replaces through 0 to 4 substituting group, and described substituting group is independently selected from halogen, hydroxyl, amino, cyano group, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Halogenated alkoxy, list-or two-(C ₁-C ₄Alkyl) amino; And

G is CH ₂, sulphur, oxygen or NR _ER wherein _EFor:

(i) hydrogen; Or

(ii) C ₁-C ₆Alkyl, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, phenyl or 5 to 6 Yuans hetero-aromatic rings, its each group is independently selected from R through 0 to 3 _xSubstituting group replace.

21. compound as claimed in claim 20 or salt, wherein G is an oxygen.

22. compound as claimed in claim 20 or salt, wherein R ₁₃Represent 0 to 2 substituting group that is independently selected from halogen, methyl, methoxyl group, ethyl, phenyl or phenoxy group, wherein each phenyl or phenoxy group group are selected from R through 0 to 3 _xSubstituting group replace.

23. compound as claimed in claim 20 or salt, wherein

R ₁Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl;

R ₃Be selected from alkoxyl group, cycloalkyloxy, phenyl, 4 to 7 element heterocycles ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CR _CR _D) _m-Q or Q, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two (C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q;

R _CAnd R _DIdentical or different, and be independently selected from hydrogen, ketone group, C when occurring each time _1-4Alkyl, hydroxyl or C _1-4Alkoxyl group;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl);

J is 0 to 6 integer;

Q is the saturated heterocyclic that comprises 4 to 7 ring persons, and tie point is carbon or nitrogen-atoms;

R ₈And R ₉For being independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₁-C ₆Thiazolinyl, (C ₃-C ₆Cycloalkyl) C ₀-C ₄Alkyl or C ₁-C ₆Alkoxyl group; And

Ar is phenyl, 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, indazolyl, indyl, pyrryl, furyl or triazolyl, its each group selectivity through single-, two-or three-replace.

24. compound as claimed in claim 23 or salt, wherein R ₃Be pyridyl, pyrimidyl, pyrazinyl, piperazine rattle away base, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q.

25. compound as claimed in claim 23 or salt, wherein R ₃Be to be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group, E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

26. compound as claimed in claim 23 or salt, wherein R ₃Be C _1-6Alkoxyl group, through the C of carboxylic acid-substituted _1-6Alkoxyl group, C _3-7Cycloalkyl oxy, or the residue shown in the following general formula:

Wherein:

E is O, NR _DOr single covalent linkage;

M is 0 to 4 integer;

P and q are independently selected from 0 to 5 integer, make 2≤p+q≤5;

G ₁Be CH, CR ₁₀Or N;

G ₂Be CH, CR ₁₀, NH, NR _E, O or S;

R ₁₀Represent one or two to be selected from following substituting group: halogen, cyano group, hydroxyl, ketone group, (CH ₂) _j-T, methyl, ethyl, methoxyl group, oxyethyl group, single methyl fluoride, difluoromethyl, trifluoromethyl, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;

R _EBe selected from R _D, T or CH ₂T;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl); With

J is 0 to 6 integer.

27. compound as claimed in claim 23 or salt, wherein R ₃Have following general formula:

Wherein:

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl);

G ₁Be N or CH; And

J is 0,1,2 or 3.

28. compound as claimed in claim 23 or salt, wherein

R ₃Be selected from phenyl, phenoxy group, benzyloxy, its each replace through 0 to 2 group, described group is selected from halogen, cyano group, hydroxyl, carboxylic acid ester groups, C _1-4Alkyl, C _1-4Haloalkyl, C _1-4Alkoxyl group, C _1-4Halogenated alkoxy, α, ω-C _1-3Alkylene dioxy base, sulfydryl C _1-4Alkyl, C _1-4Alkyl sulfone and C _1-4Alkyl sulfoxide; Or

R ₃Be selected from E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

29. compound as claimed in claim 13 or salt, wherein compound has following general formula:

Wherein:

R ₁₀And R ₁₁For being independently selected from hydrogen, C ₁-C ₆Alkyl, C ₁-C ₂Haloalkyl or C ₃-C ₇Cycloalkyl (C ₀-C ₂Alkyl); And

R ₁₂Represent 0 to 3 to be independently selected from following substituting group: R _x, single-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkoxyl group or YZ; Or two contiguous R ₁₂Be connected to form and condense 5-to 7-member carbocyclic ring or heterocycle.

30. compound as claimed in claim 29 or salt, wherein

R ₁₂Represent 0 to 3 to be independently selected from following substituting group: halogen, hydroxyl, amino, cyano group, C ₁-C ₄Alkyl, list-or two-(C ₁-C ₂Alkyl) amino, C ₁-C ₄Alkoxyl group, C ₁-C ₂Haloalkyl, C ₁-C ₂Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₂Alkyl.

31. compound as claimed in claim 29 or salt, wherein;

R ₁Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Alkynyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl;

R ₃Be selected from alkoxyl group, cycloalkyloxy, phenyl, 4 to 7 element heterocycles ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CR _CR _D) _m-Q or Q, its each substituting group replaces through 0 to 3 substituting group, and described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, (C _1-6Alkyl) (CR _AR _B) _j-T) amino, single-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl);

J is 0 to 6 integer;

R ₈And R ₉For being independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₁-C ₆Thiazolinyl, (C ₃-C ₆Cycloalkyl) C ₀-C ₄Alkyl or C ₁-C ₆Alkoxyl group; And

Ar is phenyl, 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, indazolyl, indyl, pyrryl, furyl or triazolyl, its each selectivity through single-, two-or three-replace.

32. compound as claimed in claim 31 or salt, wherein R ₃Be pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q.

33. compound as claimed in claim 31 or salt, wherein R ₃Be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group or E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

34. compound as claimed in claim 31 or salt, wherein R ₃Be C _1-6Alkoxyl group, through the C of carboxylic acid-substituted _1-6Alkoxyl group, C _3-7Cycloalkyl oxy, or the residue shown in the following general formula:

Wherein:

E is O, NR _DOr single covalent linkage;

M is 0 to 4 integer;

P and q are independently selected from 0 to 5 integer, make 2≤p+q≤5;

G ₁Be CH, CR ₁₀Or N;

G ₂Be CH, CR ₁₀, NH, NR _E, O or S;

R ₁₀Represent one or two to be selected from following substituting group: halogen, cyano group, hydroxyl, ketone group, (CH ₂) _j-T, methyl, ethyl, methoxyl group, oxyethyl group, single methyl fluoride, difluoromethyl, trifluoromethyl, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;

R _EBe selected from R _D, T or CH ₂T;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl); And

J is 0 to 6 integer.

35. compound as claimed in claim 31 or salt, wherein R ₃Have following general formula:

Wherein:

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl);

G ₁Be N or CH; And

J is 0,1,2 or 3.

36. compound as claimed in claim 31 or salt, wherein

R ₃Be selected from phenyl, phenoxy group, benzyloxy, its each group replaces through 0 to 2 substituting group, and described substituting group is selected from halogen, cyano group, hydroxyl, carboxylic acid ester groups, C _1-4Alkyl, C _1-4Haloalkyl, C _1-4Alkoxyl group, C _1-4Halogenated alkoxy, α, ω-C _1-3Alkylene dioxy base, sulfydryl C _1-4Alkyl, C _1-4Alkyl sulfone and C _1-4Alkyl sulfoxide; Or

R ₃Be to be selected from E-(CH ₂) _m-Q, wherein E is not for existing O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

37. compound as claimed in claim 13 or salt, wherein compound has following general formula:

Wherein:

R ₁₂And R ₁₃For representing 0 to 3 independently to be selected from R independently _xSubstituting group;

R ₁₄Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₂Haloalkyl or (C ₃-C ₇Cycloalkyloxy) C ₀-C ₂Alkyl, COOH, CONH ₂, CH ₂COOH, CH ₂CONH ₂, C _1-6Alkoxy carbonyl, CH ₂CO ₂-C _1-6Alkyl or SO ₃H; And

X is 0,1 or 2.

38. compound as claimed in claim 37 or salt, wherein x is 1.

39. compound as claimed in claim 37 or salt, wherein:

R ₁₂And R ₁₃Be the substituting group of representing 0 to 2 to be independently selected from halogen, methyl, methoxyl group or ethyl independently; And

R ₁₄Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl or C ₃-C ₇Cycloalkyl (C ₀-C ₂Alkyl).

40. compound as claimed in claim 37 or salt, wherein:

R ₁Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl;

R ₃Be selected from alkoxyl group, cycloalkyloxy, phenyl, 4 to 7 element heterocycles ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CR _CR _D) _m-Q or Q, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q;

R _CAnd R _DIdentical or different, and when occurring each time, be independently selected from hydrogen, ketone group, C _1-4Alkyl, hydroxyl or C _1-4Alkoxyl group;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl);

J is 0 to 6 integer;

Q is the saturated heterocyclic that comprises 4 to 7 ring persons, and wherein tie point is carbon or nitrogen-atoms;

R ₈And R ₉Be independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₁-C ₆Thiazolinyl, (C ₃-C ₆Cycloalkyl) C ₀-C ₄Alkyl or C ₁-C ₆Alkoxyl group; And

Ar be through single-, two-or the three-phenyl that replaces; Perhaps 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, indyl, indazolyl or triazolyl, its each selectivity through single-, two-or three-replace.

41. compound as claimed in claim 40 or salt, wherein R ₃Be pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q.

42. compound as claimed in claim 40 or salt, wherein R ₃Be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group, E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

43. compound as claimed in claim 40 or salt, wherein R ₃Be C _1-6Alkoxyl group, through the C of carboxylic acid-substituted _1-6Alkoxyl group, C _3-7Cycloalkyloxy, or the residue shown in the following general formula:

Wherein:

E is O, NR _DOr single covalent linkage;

M is 0 to 4 integer;

P and q are independently selected from 0 to 5 integer, make 2≤p+q≤5;

G ₁Be CH, CR ₁₀Or N;

G ₂Be CH, CR ₁₀, NH, NR _E, O or S;

R ₁₀Represent one or two to be selected from following substituting group: halogen, cyano group, hydroxyl, ketone group, (CH ₂) _j-T, methyl, ethyl, methoxyl group, oxyethyl group, single methyl fluoride, difluoromethyl, trifluoromethyl, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;

R _EBe selected from R _D, T or CH ₂T;

T is CO ₂H, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl); And

J is 0 to 6 integer.

44. compound as claimed in claim 40 or salt, wherein R ₃Have following general formula:

Wherein:

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl);

G ₁Be N or CH; And

J is 0,1,2 or 3.

45. compound as claimed in claim 40 or salt, wherein R ₃Be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group or E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

46. compound as claimed in claim 13 or salt, wherein this compound has following general formula:

Wherein:

R ₁₂And R ₁₃Represent 0 to 3 to be independently selected from R _xSubstituting group;

G is CH ₂, NH, sulphur or oxygen;

G ₃Be N, CH or CR _xAnd

X is 0,1 or 2.

47. compound as claimed in claim 46 or salt, wherein x is 1.

48. as the compound or the salt of claim 46, wherein:

R ₁₂And R ₁₃Represent 0 to 2 substituting group that is independently selected from halogen, methyl, methoxyl group or ethyl independently.

49. compound as claimed in claim 46 or salt, wherein:

R ₁Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl;

R ₃Be selected from alkoxyl group, cycloalkyloxy, phenyl, 4 to 7 element heterocycles ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CR _CR _D) _m-Q or Q, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl);

J is 0 to 6 integer;

R ₈And R ₉Be independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₁-C ₆Thiazolinyl, (C ₃-C ₆Cycloalkyl) C ₀-C ₄Alkyl or C ₁-C ₆Alkoxyl group; And

Ar be through single-, two-or the three-phenyl that replaces; Perhaps 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, indyl, indazolyl, pyrryl, furyl or triazolyl, its each group selectivity through single-, two-or three-replace.

50. compound as claimed in claim 49 or salt, wherein R ₃Be pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q.

51. as the compound or the salt of claim 49, wherein R ₃Be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group, E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

52. compound as claimed in claim 49 or salt, wherein R ₃Be C _1-6Alkoxyl group, through the C of carboxylic acid-substituted _1-6Alkoxyl group, C _3-7Cycloalkyloxy, or the residue of following general formula:

Wherein:

E is O, NR _DOr single covalent linkage;

M is 0 to 4 integer;

P and q are independently selected from 0 to 5 integer, make 2≤p+q≤5;

G ₁Be CH, CR ₁₀Or N;

G ₂Be CH, CR ₁₀, NH, NR _E, O or S;

R ₁₀Represent one or two to be selected from following substituting group: halogen, cyano group, hydroxyl, ketone group, (CH ₂) _j-T, methyl, ethyl, methoxyl group, oxyethyl group, list-, two-or trifluoromethyl or single-, two-or trifluoromethoxy;

R _EBe selected from R _D, T or CH ₂T;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl); And

J is 0 to 6 integer.

53. compound as claimed in claim 49 or salt, wherein R ₃Have and be selected from the residue shown in the following general formula;

Wherein T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl);

G ₁Be N or CH; And

J is 0,1,2 or 3.

54. compound as claimed in claim 13 or salt, wherein said compound has following general formula:

Wherein:

R ₁₂And R ₁₃Represent 0 to 3 to be independently selected from R independently _xSubstituting group;

G is CH ₂, NH or oxygen; And

X is 0,1 or 2.

55. compound as claimed in claim 54 or salt, wherein x is 1.

56. compound as claimed in claim 54 or salt, wherein G is CH ₂

57. compound as claimed in claim 54 or salt, wherein R ₁₂And R ₁₃For representing 0 to 3 to be independently selected from following substituting group independently: halogen, hydroxyl, amino, cyano group, C ₁-C ₄Alkyl, list-or two-(C ₁-C ₂Alkyl) amino, C ₁-C ₄Alkoxyl group, C ₁-C ₂Haloalkyl, C ₁-C ₂Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₂Alkyl.

58. compound as claimed in claim 57 or salt, wherein R ₁₂And R ₁₃Represent 0 to 2 to be independently selected from halogen, C independently ₁-C ₂Alkyl or C ₁-C ₂The substituting group of alkoxyl group.

59. compound as claimed in claim 57 or salt, wherein:

R ₅Be C ₁-C ₆Alkyl; With

R ₁₂And R ₁₃Each represents 0 to 2 substituting group that is independently selected from halogen, methyl, methoxyl group or ethyl.

60. compound as claimed in claim 57 or salt, wherein:

R ₁Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl;

R ₃Be selected from alkoxyl group, cycloalkyloxy, phenyl, 4 to 7 element heterocycles ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CR _CR _D) _m-Q or Q, its each group replaces through 0 to 3 substituting group, and described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl);

J is 0 to 6 integer;

R ₈And R ₉Be independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₁-C ₆Thiazolinyl, (C ₃-C ₆Cycloalkyl) C ₀-C ₄Alkyl or C ₁-C ₆Alkoxyl group; And

Ar be through single-, two-or the three-phenyl that replaces; Perhaps 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, indyl, indazolyl or triazolyl, its each selectivity through single-, two-or three-replace.

61. compound as claimed in claim 60 or salt, wherein R ₃Be pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q.

62. compound as claimed in claim 60 or salt, wherein R ₃Be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group, E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

63. compound as claimed in claim 60 or salt, wherein R ₃Be C _1-6Alkoxyl group, through the C of carboxylic acid-substituted _1-6Alkoxyl group, C _3-7Cycloalkyloxy, or the residue shown in the following general formula:

Wherein:

E is O, NR _DOr single covalent linkage;

M is 0 to 4 integer;

P and q are independently selected from 0 to 5 integer, make 2≤p+q≤5;

G ₁Be CH, CR ₁₀Or N;

G ₂Be CH, CR ₁₀, NH, NR _E, O or S;

R ₁₀Represent one or two to be selected from following substituting group: halogen, cyano group, hydroxyl, ketone group, (CH ₂) _j-T, methyl, ethyl, methoxyl group, oxyethyl group, single methyl fluoride, difluoromethyl, trifluoromethyl, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;

R _EBe selected from R _D, T or CH ₂T;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl); And

J is 0 to 6 integer.

64. compound as claimed in claim 60 or salt, wherein R ₃For having the residue of following general formula;

Wherein T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl);

G ₁Be N or CH; And

J is 0,1,2 or 3.

65. compound as claimed in claim 2 or salt, wherein:

A is OR ₄And

R ₄Be C ₂-C ₆Alkyl, C ₂-C ₆Thiazolinyl, phenyl C ₀-C ₄Alkyl, naphthyl C ₀-C ₄Alkyl, pyridyl C ₀-C ₄Alkyl, pyrimidyl C ₀-C ₄Alkyl, thienyl C ₀-C ₄Alkyl, imidazolyl C ₀-C ₄Alkyl or pyrryl C ₀-C ₄Alkyl, its each replace through 0 to 4 substituting group, described substituting group is independently selected from R _x, single-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkoxyl group, (3 to 7 element heterocycle alkyl) C ₀-C ₄Alkyl or C ₂-C ₄Alkyloyl.

66. as the described compound of claim 65 or salt, wherein R ₄Be phenyl, benzyl, pyridyl or pyridylmethyl, its each group replaces through 0 to 4 substituting group, and described substituting group is independently selected from R _x, single-or two-(C ₁-C ₄Alkyl) amino C ₀-C ₄Alkyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkoxyl group, (3 to 7 element heterocycle alkyl) C ₀-C ₄Alkyl or C ₂-C ₄Alkyloyl.

67. as described compound of claim 65 or salt, wherein:

R ₁Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl;

R ₃Be selected from alkoxyl group, cycloalkyloxy, phenyl, 4 to 7 element heterocycles ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CR _CR _D) _m-Q or Q, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, (C _1-6Alkyl) ((CR _AR _B) _j-T) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl);

J is 0 to 6 integer;

R ₈And R ₉Be independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₁-C ₆Thiazolinyl, (C ₃-C ₆Cycloalkyl) C ₀-C ₄Alkyl or C ₁-C ₆Alkoxyl group; And

Ar be through single-, two-or the three-phenyl that replaces; Perhaps 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, indyl, indazolyl or triazolyl, its each group selectivity through single-, two-or three-replace.

68. as the described compound of claim 67 or salt, wherein R ₃Be pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, (C _1-6Alkyl) ((CR _AR _B) _j-T) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q.

69. as the described compound of claim 67 or salt, wherein R ₃Be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group, E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

70. as the described compound of claim 67 or salt, wherein R ₃Be C _1-6Alkoxyl group, through the C of carboxylic acid-substituted _1-6Alkoxyl group, C _3-7Cycloalkyloxy, or the residue of following general formula:

Wherein:

E is O, NR _DOr single covalent linkage;

M is 0 to 4 integer;

P and q are independently selected from 0 to 5 integer, make 2≤p+q≤5;

G ₁Be CH, CR ₁₀Or N;

G ₂Be CH, CR ₁₀, NH, NR _E, O or S;

R ₁₀Represent one or two to be selected from following substituting group: halogen, cyano group, hydroxyl, ketone group, (CH ₂) _j-T, N (methyl) (CH ₂) _j-T, methyl, ethyl, methoxyl group, oxyethyl group, single methyl fluoride, difluoromethyl, trifluoromethyl, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;

R _EBe selected from R _D, T or CH ₂T;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl); And

J is 0 to 6 integer.

71. as the described compound of claim 67 or salt, wherein R ₃Have following general formula:

Wherein:

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, or SO ₂(C _1-6Alkyl);

G ₁Be N or CH; And

J is 0,1,2 or 3.

72. as described compound of claim 65 or salt, wherein this compound has following general formula:

Wherein:

D is CH or N;

R ₂₁Represent 0 to 3 to be independently selected from R _xOr LR _dSubstituting group; Or two in abutting connection with R ₂₁The group bond forms and to condense 5-to 7-member carbocyclic ring or heterocycle and this carbocyclic ring or heterocycle and be independently selected from R through 0 to 3 _xSubstituting group replace;

L be single covalent linkage or-CH ₂-; And

R _dBe piperazinyl, morpholinyl, piperidyl or Pyrrolizidine base.

73. as described compound of claim 72 or salt, wherein:

R ₂₁Represent 0 to 3 to be independently selected from R _xOr LR _dSubstituting group;

R ₁Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy or (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl;

R ₃Be selected from alkoxyl group, cycloalkyloxy, phenyl, 4 to 7 element heterocycles ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CR _CR _D) _m-Q or Q, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, (C _1-6Alkyl) ((CR _AR _B) _j-T) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl);

J is 0 to 6 integer;

R ₈And R ₉Be independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₁-C ₆Thiazolinyl, (C ₃-C ₆Cycloalkyl) C ₀-C ₄Alkyl or C _1-6Alkoxyl group; And

Ar be through single-, two-or the three-phenyl that replaces; Perhaps 1-naphthyl, 2-naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, indyl, indazolyl or triazolyl, its each selectivity through single-, two-or three-replace.

74. as the described compound of claim 73 or salt, wherein R ₃Be pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base, its each replace through 0 to 3 substituting group, described substituting group is selected from halogen, cyano group, hydroxyl, ketone group, (CR _AR _B) _j-T, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q.

75. as the described compound of claim 73 or salt, wherein R ₃Be selected from C _1-6Alkoxyl group, C _3-8Cycloalkyloxy, through the C of carboxylic acid-substituted _1-6Alkoxyl group, E-(CH ₂) _m-Q, wherein E for do not exist, O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

76. as the described compound of claim 73 or salt, wherein R ₃Be C _1-6Alkoxyl group, through the C of carboxylic acid-substituted _1-6Alkoxyl group, C _3-7Cycloalkyloxy, or the residue of following general formula:

Wherein:

E is O, NR _DOr single covalent linkage;

M is 0 to 4 integer;

P and q are independently selected from 0 to 5 integer, make 2≤p+q≤5;

G ₁Be CH, CR ₁₀Or N;

G ₂Be CH, CR ₁₀, NH, NR _E, O or S;

R ₁₀Represent one or two to be selected from following substituting group: halogen, cyano group, hydroxyl, ketone group, (CH ₂) _j-T, N (methyl) (CH ₂) _j-T, methyl, ethyl, methoxyl group, oxyethyl group, single methyl fluoride, difluoromethyl, trifluoromethyl, single fluorine methoxyl group, difluoro-methoxy or trifluoromethoxy;

R _EBe selected from R _D, T or CH ₂T;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl); And

J is 0 to 6 integer.

77. as the described compound of claim 73 or salt, wherein R ₃Have following general formula:

Wherein T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂Or SO ₂(C _1-6Alkyl);

G ₁Be N or CH; And

J is 0,1,2 or 3.

78., wherein have the group of following general formula as described compound of claim 73 or salt

Be selected from naphthyl, tetralyl, benzofuryl, Ben Bing Er Evil cyclopentadienyl, indanyl, indyl, indazolyl, Ben Bing Er Evil cyclopentadienyl, benzo [1,4] alkyl dioxin and benzoxazolyl, its each be independently selected from R through 0 to 3 _xSubstituting group replace.

79. compound or its pharmacy acceptable salt shown in general formula I X,

Wherein:

Ar be through single-, two or trisubstd phenyl, wherein phenyl is selected from following substituting group through one to three and replaces: hydroxyl, halogen, cyano group, amino, nitro ,-COOH, aminocarboxyl ,-SO ₂NH ₂, C _1-6Alkyl, C _1-6Thiazolinyl, C _1-6Alkynyl, C _1-6Haloalkyl, C _1-6Aminoalkyl group, C _1-6Hydroxyalkyl, C _1-6Carboxyalkyl, C _1-6Alkoxyl group, C _1-6Halogenated alkoxy, C _1-6Alkyl sulfenyl, C _1-6Alkyloyl, C _1-6Alkyloyl oxygen base, C _3-6Alkane ketone, C _1-6Alkyl oxide, list or two-(C _1-6Alkyl) amino C _0-6Alkyl ,-NHC (=O) (C _1-6Alkyl) ,-N (C _1-6Alkyl) C (=O) (C _1-6Alkyl) ,-NHS (O) _n(C _1-6Alkyl) ,-(C _1-6Alkyl) C (=O) NH ₂,-(C _1-6Alkyl) C (=O) NH (C _1-6Alkyl) ,-(C _1-6Alkyl) C (=O) NH (C _1-6Alkyl) (C _1-6Alkyl) ,-S (O) _n(C _1-6Alkyl) ,-S (O) _nNH (C _1-6Alkyl) ,-S (O) _nN (C _1-6Alkyl) (C _1-6Alkyl) or Z; Or

Ar is selected from naphthyl or heteroaryl, its each replace through 0 to 4 substituting group, described substituting group is independently selected from: hydroxyl, halogen, cyano group, amino, nitro ,-COOH, aminocarboxyl ,-SO ₂NH ₂, C _1-6Alkyl, C _1-6Thiazolinyl, C _1-6Alkynyl, C _1-6Haloalkyl, C _1-6Aminoalkyl group, C _1-6Hydroxyalkyl, C _1-6Carboxyalkyl, C _1-6Alkoxyl group, C _1-6Halogenated alkoxy, C _1-6Alkyl sulfenyl, C _1-6Alkyloyl, C _1-6Alkyloyl oxygen base, C _3-6Alkane ketone, C _1-6Alkyl oxide, list or two-(C _1-6Alkyl) amino C _0-6Alkyl ,-NHC (=O) (C _1-6Alkyl) ,-N (C _1-6Alkyl) C (=O) (C _1-6Alkyl) ,-NHS (O) _n(C _1-6Alkyl) ,-(C _1-6Alkyl) C (=O) NH ₂,-(C _1-6Alkyl) C (=O) NH (C _1-6Alkyl) ,-(C _1-6Alkyl) C (=O) NH (C _1-6Alkyl) (C _1-6Alkyl) ,-S (O) _n(C _1-6Alkyl) ,-S (O) _nNH (C _1-6Alkyl) ,-S (O) _nN (C _1-6Alkyl) (C _1-6Alkyl) or Z;

A is OR ₄, NR ₄R ₅Or CR ₄R ₅XR _y

R ₁Be selected from hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, alkoxyl group, cycloalkyloxy or (cycloalkyl) alkoxyl group, its each replace through 0 to 4 group, described group is independently selected from the group that phenyl wherein replaces through following one to three substituting group, and described substituting group is independently selected from: hydroxyl, halogen, cyano group, amino, nitro ,-COOH, aminocarboxyl ,-SO ₂NH ₂, C _1-6Alkyl, C _1-6Thiazolinyl, C _1-6Alkynyl, C _1-6Haloalkyl, C _1-6Aminoalkyl group, C _1-6Hydroxyalkyl, C _1-6Carboxyalkyl, C _1-6Alkoxyl group, C _1-6Halogenated alkoxy, C _1-6Alkyl sulfenyl, C _1-6Alkyloyl, C _1-6Alkyloyl oxygen base, C _3-6Alkane ketone, C _1-6Alkyl oxide, list or two-(C _1-6Alkyl) amino C _0-6Alkyl ,-NHC (=O) (C _1-6Alkyl) ,-N (C _1-6Alkyl) C (=O) (C _1-6Alkyl) ,-NHS (O) _n(C _1-6Alkyl) ,-(C _1-6Alkyl) C (=O) NH ₂,-(C _1-6Alkyl) C (=O) NH (C _1-6Alkyl) ,-(C _1-6Alkyl) C (=O) NH (C _1-6Alkyl) (C _1-6Alkyl) ,-S (O) _n(C _1-6Alkyl) ,-S (O) _nNH (C _1-6Alkyl) ,-S (O) _nN (C _1-6Alkyl) (C _1-6Alkyl) or Z;

R ₄For:

(i) C ₂-C ₈Alkyl, C ₂-C ₈Thiazolinyl, C ₂-C ₈Alkynyl, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, list-or two-(C ₁-C ₄Alkylamino) C ₂-C ₄Alkyl, (3-to 7-element heterocycle alkyl) C ₀-C ₄Alkyl, phenyl C ₀-C ₄Alkyl or hetero-aromatic ring C _0-4Alkyl, its each replace through 0 to 4 substituting group, described substituting group is independently selected from R _x, C ₂-C ₄Alkyloyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkyl, list-or two-(C ₁-C ₄Alkyl) amino C ₁-C ₄Alkoxyl group, (3 to 7 Yuans ring Heterocyclylalkyls) C ₀-C ₄Alkyl or XR _yOr

(ii) and R ₅Link, and and R ₄And R ₅The common formation of the nitrogen of institute's bond has the heterocycle that 1 to 3 ring, each ring have 5 to 7 ring persons, and this heterocycle is independently selected from R through 0 to 4 _x, ketone group or W-Z substituting group replace;

R ₅For:

(i) hydrogen;

(ii) C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, (C ₃-C ₇Carbocyclic ring) C ₀-C ₄Alkyl, its each group selectivity replaces through 0 to 3 substituting group, and described substituting group is independently selected from halogen, hydroxyl, amino, cyano group, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, methylamino, dimethylamino, trifluoromethyl or trifluoromethoxy; Or

(iii) and R ₄Link and form the heterocycle that selectivity is substituted;

R ₈And R ₉Be independently selected from hydrogen, halogen, hydroxyl, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkylamino or C ₃-C ₇Cycloalkyl C ₀-C ₄Alkyl;

R ₁₃Represent 0 to 3 to be independently selected from following substituting group:

(i) R _xOr

(ii) phenyl and pyridyl; Its each replace through 0 to 4 substituting group, described substituting group is independently selected from halogen, hydroxyl, amino, cyano group, C ₁-C ₄Alkyl, C ₁-C ₄Alkoxyl group, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Halogenated alkoxy, list-or two-(C ₁-C ₄Alkyl) amino;

X be single covalent linkage ,-CR _AR _B-,-O-,-C (=O)-,-C (=O) O-,-S (O) _n-or-NR _B-;

R _yFor:

(i) hydrogen; Or

(ii) C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₂-C ₁₀Alkynyl, (C ₃-C ₁₀Carbocyclic ring) C ₀-C ₄Alkyl or (3-to 10 element heterocycle) C ₀-C ₄Alkyl, its each replace through 0 to 6 substituting group, described substituting group is independently selected from R _x, ketone group ,-NH (C ₁-C ₆Alkyloyl) ,-N (C ₁-C ₆Alkyl) (C ₁-C ₆Alkyloyl) ,-NHS (O _n) C ₁-C ₆Alkyl ,-N (S (O _n) (C ₁-C ₆Alkyl) ₂,-S (O _n) NHC ₁-C ₆Alkyl or-S (O _n) N (C ₁-C ₆Alkyl) ₂

W be single covalent linkage ,-CR _AR _B-,-NR _B-or-O-;

Z is independently selected from 3-to 7-member carbocyclic ring or heterocycle at every turn when occurring, its each group replaces through 0 to 4 substituting group, described substituting group be independently selected from halogen, ketone group ,-COOH, hydroxyl, amino, cyano group, C ₁-C ₆Alkyl, C ₁-C ₆Alkoxyl group, C ₁-C ₆Haloalkyl, C ₁-C ₆Halogenated alkoxy, list-or two-(C ₁-C ₆Alkyl) amino or-S (O _n) C ₁-C ₆Alkyl;

R _AAnd R _BWhen occurring each time, be independently selected from:

(i) hydrogen; Or

(ii) C ₁-C ₁₀Alkyl, C ₂-C ₁₀Thiazolinyl, C ₂-C ₁₀(the C of alkynyl, saturated or fractional saturation ₃-C ₁₀Carbocyclic ring) C ₀-C ₄((3 to 10 element heterocycle) C of alkyl or saturated or fractional saturation ₀-C ₄Alkyl, its each replace through 0 to 6 substituting group, described substituting group is independently selected from ketone group, hydroxyl, halogen, cyano group, amino, C ₁-C ₆Alkoxyl group, list-or two-(C ₁-C ₄Alkyl) amino ,-COOH ,-C (=O) NH ₂,-SO ₂NH ₂,-NHC (=O) (C ₁-C ₆Alkyl) ,-N (C ₁-C ₆Alkyl) C (=O) (C ₁-C ₆Alkyl) ,-NHS (O _n) C ₁-C ₆Alkyl ,-S (O _n) C ₁-C ₆Alkyl ,-S (O _n) NHC ₁-C ₆Alkyl ,-S (O _n) N (C ₁-C ₆Alkyl) C ₁-C ₆Alkyl or Z;

R _CAnd R _DBe independently selected from R _A, hydroxyl, C _1-6Alkoxyl group or ketone group;

R _xWhen occurring each time, be independently selected from halogen, hydroxyl, amino, cyano group, nitro ,-COOH ,-C (=O) NH ₂, C ₁-C ₆Alkoxy carbonyl, list-or two-(C ₁-C ₆Alkyl) aminocarboxyl, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, list-or two-(C ₁-C ₆Alkyl) amino, C ₁-C ₆Alkoxyl group, C ₁-C ₂Hydroxyalkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Halogenated alkoxy, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl or-S (O _n) C ₁-C ₆Alkyl;

T is CO ₂H, CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₃H, SO ₂NH ₂, (C=O) CH ₂NH ₂, or SO ₂(C _1-6Alkyl); And

N is independently selected from 0,1 and 2 integer when occurring each time.

80. as described compound of claim 79 or salt, wherein:

Ar is phenyl, pyridyl or pyrimidyl, its each replace through 0 to 4 substituting group, described substituting group is independently selected from halogen, hydroxyl, cyano group, amino, nitro, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₂Haloalkyl, C ₁-C ₆Alkoxyl group or C ₁-C ₂Halogenated alkoxy;

Q is 1;

A is OR ₄

R ₁Be hydrogen, methyl or ethyl;

R ₄Be (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl, (3 to 7 element heterocycle alkyl) C ₀-C ₄Alkyl, phenyl C ₀-C ₄Alkyl or heteroaryl C _0-4Alkyl, its each be independently selected from R through 0 to 4 _xSubstituting group replace;

R ₈And R ₉Be independently selected from hydrogen or C ₁-C ₆Alkyl;

R ₁₃Represent 0 to 3 to be independently selected from R _xSubstituting group;

R _AAnd R _BWhen occurring each time, be independently selected from hydrogen, methyl or ethyl;

R _xWhen occurring each time, be independently selected from halogen, hydroxyl, amino, cyano group, nitro ,-COOH ,-C (=O) NH ₂, C ₁-C ₆Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, list-or two-(C ₁-C ₆Alkyl) amino, C ₁-C ₆Alkoxyl group, C ₁-C ₂Hydroxyalkyl, C ₁-C ₂Haloalkyl, C ₁-C ₂Halogenated alkoxy, (C ₃-C ₇Cycloalkyl) C ₀-C ₄Alkyl or-S (O _n) C ₁-C ₆Alkyl; And

T is CONH ₂, C _1-6Alkoxy carbonyl, list-or two-(C _1-6Alkyl) aminocarboxyl, SO ₂NH ₂, (C=O) CH ₂NH ₂Or SO ₂(C _1-6Alkyl).

81. compound as claimed in claim 43 or salt, wherein this compound is according to general formula X:

Wherein:

R ₁₂And R ₁₃Represent 0 to 3 to be independently selected from R independently of one another _xSubstituting group;

R ₁₄Be hydrogen, C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₂-C ₆Alkynyl, C ₁-C ₂Haloalkyl or (C ₃-C ₇Cycloalkyl) C ₀-C ₂Alkyl, COOH, CONH ₂, CH ₂COOH, CH ₂CONH ₂, C _1-6Alkoxy carbonyl or CH ₂CO ₂-C _1-6Alkyl; And

X is 0,1 or 2.

82. as described compound of claim 65 or salt, wherein this compound is according to general formula X I:

Wherein:

D is CH or N;

R ₁₃Represent 0 to 3 substituting group that is independently selected from hydroxyl, methyl or ethyl;

R ₂₁Represent 0 to 3 to be independently selected from R _xOr LR _FSubstituting group; Or two in abutting connection with R ₂₁The group bond forms and to condense 5-to 7-member carbocyclic ring or heterocycle and this carbocyclic ring or heterocycle and be independently selected from R through 0 to 3 _xSubstituting group replace;

L be single covalent linkage or-CH ₂-; And

R _FBe piperazinyl, morpholinyl, piperidyl or Pyrrolizidine base.

83. the compound of a following general formula or its pharmacologically acceptable salts

Wherein:

R ₁Be selected from (cycloalkyl) alkoxyl group that hydrogen, alkyl that selectivity is substituted, thiazolinyl that selectivity is substituted, alkynyl that selectivity is substituted, cycloalkyl that selectivity is substituted, cycloalkenyl group that selectivity is substituted, alkoxyl group that selectivity is substituted, cycloalkyloxy that selectivity is substituted and selectivity are substituted;

R ₃Be selected from heterocycle-oxygen base that aryl that selectivity is substituted, aralkyl that selectivity is substituted, aryloxy that selectivity is substituted, alkoxy aryl that selectivity is substituted, heterocycle, selectivity that selectivity is substituted be substituted ,-O-(CR _AR _B) _m-Y ,-N (R _B)-(CR _AR _B) _m-XR _AOr-N (R _B)-(CR _AR _B) _m-Y, wherein said heterocycle be saturated, unsaturated or aromatic, have 1 to 3 the ring and each ring 3 to 7 ring persons are arranged;

R ₄And R ₅Independently be selected from:

(i) hydrogen or hydroxyl; Or

Alkyl, cycloalkyl or (cycloalkyl) alkyl of (ii) comprising 1 to 8 carbon atom, its each replace and optionally contain one or more pairs of keys or triple bond through selectivity;

Ar for through single-, two-or the three-phenyl that replaces, the naphthyl that selectivity is substituted, the heteroaryl that selectivity is substituted;

R _AAnd R _BIdentical or different, when occurring each time, be independently selected from:

(i) hydrogen or hydroxyl; Or

(ii) alkyl, cycloalkyl or (cycloalkyl) alkyl, its each group selectivity replaces through one or more substituting groups, and described substituting group is independently selected from ketone group, hydroxyl, halogen, cyano group, amino, C _1-6Alkoxyl group ,-NH (C _1-6Alkyl) ,-N (C _1-6Alkyl) (C _1-6Alkyl) ,-NHC (=O) (C _1-6Alkyl) ,-N (C _1-6Alkyl) C (=O) (C _1-6Alkyl) ,-NHS (O) _n(C _1-6Alkyl) ,-S (O) _n(C _1-6Alkyl) ,-S (O) _nNH (C _1-6Alkyl) ,-S (O) _nN (C _1-6Alkyl) (C _1-6Alkyl) or Z;

X occurs being independently selected from each time-CHR _B-,-O-,-C (=O)-,-C (=O) O-,-S (O) _n-,-NR _B-,-C (=O) NR _B-,-S (O) _nNR _B-,-OC (=S) S-,-NR _BC (=O)-,-OSiH _n(C _1-4Alkyl) _2-n-or-NR _BS (O) _n-;

Y and Z are independently selected from saturated, unsaturated or aromatic carbocyclic ring of 3-to 7-member or heterocyclic group at every turn when occurring, its each selectivity replaces through one or more substituting groups, and described substituting group is independently selected from halogen, ketone group, hydroxyl, amino, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group, list-or two (C _1-4Alkyl) amino or-S (O) _n(alkyl), described 3-to 7-element heterocycle group contains the heteroatoms of one or more N of being selected from, O or S, and tie point is carbon or nitrogen;

M is independently selected from 0 to 8 integer when occurring each time; And

N is independently selected from 0,1 or 2 when occurring each time.

84. as the described compound of claim 83 or salt, wherein R ₁Be hydrogen, C _1-6Alkyl, C _1-6Alkoxyl group, halogen, C _1-6Haloalkyl, C _1-6Halogenated alkoxy or (C _3-8Cycloalkyl) C _1-6Alkyl.

85. as described compound of claim 84 or salt, wherein

R ₃For phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazyl, oxazolyl, isoxazolyl, pyrryl, furyl, triazolyl, piperidyl, piperazinyl, Pyrrolizidine base, azetidinyl, azepan base or Diazesuberane base ,-O (CH ₂) _nPhenyl ,-O (CH ₂) _nPyridyl ,-E-(CH ₂) _m-Q or Q, its each group replaces through 0 to 3 substituting group, and described substituting group is selected from halogen, cyano group, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Haloalkyl, C _1-6Halogenated alkoxy, list-or two-(C _1-6Alkyl) amino, benzyl, S (O) _nC _1-6Alkyl, α, ω-C _1-4Alkylene, α, ω-C _1-4Alkylene oxygen base, α, ω-C _1-4Alkylene dioxy base ,-E-(CH ₂) _m-Q or Q; And

Q is the saturated heterocyclic that comprises 4 to 7 ring persons, and its tie point is nitrogen or carbon atom.

86. as described compound of claim 85 or salt, wherein

R ₃Be selected from phenyl, phenoxy group, benzyloxy, its each group replaces through 0 to 2 substituting group, and described substituting group is selected from halogen, cyano group, hydroxyl, carboxylic acid ester groups, C _1-4Alkyl, C _1-4Haloalkyl, C _1-4Alkoxyl group, C _1-4Halogenated alkoxy, α, ω-C _1-3Alkylene dioxy base, sulfydryl C _1-4Alkyl, C _1-4Alkyl sulfone or C _1-4Alkyl sulfoxide; Or

R ₃Be selected from E-(CH ₂) _m-Q, wherein E is O, NH or N (C _1-6Alkyl) and Q be saturated 4 to 7 element heterocycles and wherein tie point be carbon or nitrogen-atoms.

87. as described compound of claim 83 or salt, wherein this compound has following general formula:

Wherein:

Ar for through single-, two-or the heteroaryl that is substituted of the three-phenyl that replaces, the naphthyl that selectivity is substituted or selectivity;

R ₁Be selected from hydrogen, the alkyl that selectivity is substituted, the thiazolinyl that selectivity is substituted, the alkynyl that selectivity is substituted, the cycloalkyl that selectivity is substituted, the cycloalkenyl group that selectivity is substituted, the alkoxyl group that selectivity is substituted, the alkoxyl group that selectivity is substituted, the alkoxyl group that selectivity is substituted, cycloalkyloxy or the selectivity that selectivity is substituted and be substituted (cycloalkyl) alkoxyl group;

R ₄And R ₅Be independently selected from:

(i) hydrogen or hydroxyl; Or

Alkyl, cycloalkyl or (cycloalkyl) alkyl of (ii) comprising 1 to 8 carbon atom, each selectivity contains one or more pairs of keys or triple bond, and each selectivity replaces through one or more substituting groups, and described substituting group is independently selected from ketone group, hydroxyl, halogen, cyano group, amino, C _1-6Alkoxyl group ,-NH (C _1-6Alkyl) ,-N (C _1-6Alkyl) (C _1-6Alkyl) ,-NHC (=O) (C _1-6Alkyl) ,-N (C _1-6Alkyl) C (=O) (C _1-6Alkyl) ,-NHS (O) _n(C _1-6Alkyl) ,-S (O) _n(C _1-6Alkyl) ,-S (O) _nNH (C _1-6Alkyl) ,-S (O) _nN (C _1-6Alkyl) (C _1-6Alkyl) or Z;

E is oxygen, NH or N (C _1-6Alkyl);

G ₁Be oxygen, sulphur, nitrogen or carbon;

G ₂Be nitrogen or carbon, wherein G ₁And G ₂At least one be not carbon;

P is 0,1 or 2;

Q is 0,1 or 2, wherein p and q and be at least 1;

R ₆When occurring each time, be independently selected from hydrogen, halogen, hydroxyl, C _1-4Alkyl, C _1-4Alkoxyl group, C _1-4Fluoro-alkyl or C _1-4Fluoroalkyl;

K is 0 to 3 integer; And

M is 0 to 4 integer.

88. as the described compound or its salt of claim 83, wherein this compound has following general formula:

Wherein:

Ar for through single-, two-or the heteroaryl that is substituted of the three-phenyl that replaces, the naphthyl that selectivity is substituted or selectivity;

R ₁Be selected from hydrogen, the alkyl that selectivity is substituted, the thiazolinyl that selectivity is substituted, the alkynyl that selectivity is substituted, the cycloalkyl that selectivity is substituted, the cycloalkenyl group that selectivity is substituted, the alkoxyl group that selectivity is substituted, the alkoxyl group that selectivity is substituted, the alkoxyl group that selectivity is substituted, cycloalkyloxy or the selectivity that selectivity is substituted and be substituted (cycloalkyl) alkoxyl group;

R ₄And R ₅Be independently selected from:

(i) hydrogen or hydroxyl; Or

Alkyl, cycloalkyl or (cycloalkyl) alkyl of (ii) comprising 1 to 8 carbon atom, each optionally contains one or more pairs of keys or triple bond, and each optionally replaces through one or more substituting groups, and described substituting group is independently selected from ketone group, hydroxyl, halogen, cyano group, amino, C _1-6Alkoxyl group ,-NH (C _1-6Alkyl) ,-N (C _1-6Alkyl) (C _1-6Alkyl) ,-NHC (=O) (C _1-6Alkyl) ,-N (C _1-6Alkyl) C (=O) (C _1-6Alkyl) ,-NHS (O) _n(C _1-6Alkyl) ,-S (O) _n(C _1-6Alkyl) ,-S (O) _nNH (C _1-6Alkyl) ,-S (O) _nN (C _1-6Alkyl) (C _1-6Alkyl) or Z;

E is single covalent linkage, O, NH or N (C ₁-C ₆Alkyl);

G ₂Be nitrogen, CH or CR ₆

R ₆When occurring each time, be independently selected from hydrogen, halogen, hydroxyl, cyano group, carboxylic acid ester groups, C _1-4Alkyl, C _1-4Alkoxyl group, C _1-4Fluoro-alkyl, C _1-4Fluoroalkyl, C _1-4Mercaptoalkyl, C _1-4Alkyl sulfone or C _1-4Alkyl sulfoxide;

K is 0 to 3 integer; And

M is 0 to 4 integer.

89. as each described compound or salt in the claim 1 to 88, wherein said compound in vitro shows IC in the chemotaxis (chemotaxis) of C5a receptor mediation or the calcium current dynamic test in standard ₅₀Be 500nM or lower.

90. as described compound of claim 89 or salt, wherein said compound in vitro shows IC in the chemotaxis of C5a receptor mediation or the calcium current dynamic test in standard ₅₀Be 25nM or lower.

91. as each described compound or salt in the claim 1 to 88, wherein said compound is less than 5% short effect activity at GTP in conjunction with showing in testing.

92. a medical component, it comprises at least a as each described compound or salt in the claim 1 to 88, and acceptable supporting agent of physiology or vehicle.

93., wherein this medical component is mixed with injection liquid, gasification sprays, breast frost, gel, pill, capsule, syrup or dermal osmosis patch as the described medical component of claim 92.

Make the cell of expressing C5a receptor and contact 94. a method that suppresses cell C5a receptor signaling activity, this method comprise, thereby reduction is conducted by the signal that C5a receptor carries out as each described at least a compound or salt in the claim 1 to 88.

95. as the described method of claim 94, wherein said contact is carried out in living animal.

96. as the described method of claim 95, wherein said animal is human.

97. one kind outer in vitro suppresses the method that C5a is bonded to C5a receptor, this method comprise with C5a receptor with as each described at least a compound or salt in the claim 1 to 88 contacting under inhibition C5a and the C5a receptor bonded consumption under certain condition with being enough to detect.

98. one kind is suppressed the method that C5a is bonded to C5a receptor in the human patients body, this method is included in the cell that will express C5a receptor in the human body and contacts under the bonded consumption of C5a and the cell of the C5a receptor of cloning by expression in vitro being enough to suppress as each described at least a compound or salt in the claim 1 to 88 with detecting, thereby inhibition C5a is bonded to C5a receptor in patient's body.

99. a treatment suffers from the patient's of inflammation method, this method comprise with the treatment significant quantity be administered to the patient as each described compound or salt in the claim 1 to 88.

100. a treatment suffers from the patient's of rheumatic arthritis, psoriasis, cardiovascular disorder, reperfusion injury or bronchial asthma method, this method comprise with the treatment significant quantity be administered to the patient as each described compound or salt in the claim 1 to 88.

101. a treatment suffers from the patient's of apoplexy, myocardial infarction, atherosclerosis, ischemic heart disease or ischemia reperfusion injury method, this method comprise with the treatment significant quantity be administered to the patient as each described compound or salt in the claim 1 to 88.

102. a treatment suffers from the patient's of fibrocyst method, this method comprise with the treatment significant quantity be administered to the patient as each described compound or salt in the claim 1 to 88.

103. a method that suppresses the cell chemotaxis of C5a receptor mediation, this method comprise with the mammals leukocyte cell with treat contacting of significant quantity as each described compound or salt in the claim 1 to 88.

104. the method for C5a receptor in the position tissue sample, this method comprises:

(a) will contain the tissue sample of C5a receptor and each described compound in the claim 1 to 88 of detectable label, contact under this compound and the C5a receptor bonded condition allowing;

And

(b) detect binding compounds.

105. as the described method of claim 104, wherein said compound is through radiolabeled.

106. the pharmaceutical preparation of a packing, said preparation comprises:

(a) pack in the container as the described medical component of claim 92; With

(b) use this constituent treatment to suffer from the patient's of inflammation explanation.

107. the pharmaceutical preparation of a packing, said preparation comprises:

(a) pack in the container as the described medical component of claim 92; With

(b) use this constituent treatment to suffer from the patient's of rheumatic arthritis, psoriasis, cardiovascular disorder, reperfusion injury or bronchial asthma explanation.

108. the pharmaceutical preparation of a packing, said preparation comprises:

(a) pack in the container as the described medical component of claim 92; With

(b) use this constituent treatment to suffer from the patient's of apoplexy, myocardial infarction, atherosclerosis, ischemic heart disease or ischemia reperfusion injury explanation.

109. one kind as the purposes in the medicine of the illness that preparation treatment responds to the regulating effect of C5a receptor of each described compound or salt in the claim 1 to 88.

110. as the described purposes of claim 109, wherein said illness is rheumatic arthritis, psoriasis, cardiovascular disorder, reperfusion injury, bronchial asthma disease, apoplexy, myocardial infarction, atherosclerosis, ischemic heart disease, ischemia reperfusion injury or fibrocyst.

111. compound as claimed in claim 1 is selected from:

2-(2, the 6-3,5-dimethylphenyl)-4-methoxyl group-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2, the 6-3,5-dimethylphenyl)-4-(2-fluorophenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

4-(2, the 6-difluorophenyl)-2-(2, the 6-3,5-dimethylphenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2, the 6-3,5-dimethylphenyl)-4-methyl-6-phenyl-N, N-dipropyl pyrimidine-5-amine;

2-(2, the 6-3,5-dimethylphenyl)-4-ethyl-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2, the 6-3,5-dimethylphenyl)-4-methyl-N, N-dipropyl-6-pyridine-2-yl pyrimidines-5-amine;

2-(2, the 6-3,5-dimethylphenyl)-4-(3-p-methoxy-phenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2, the 6-3,5-dimethylphenyl)-4-methyl-6-(3-aminomethyl phenyl)-N, N-dipropyl pyrimidine-5-amine;

4-(1,3-benzo dioxy-5-yl)-2-(2, the 6-3,5-dimethylphenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2, the 6-3,5-dimethylphenyl)-4-methyl-N, N-dipropyl-6-[3-(trifluoromethoxy) phenyl] pyrimidine-5-amine;

4-(3-chloro-phenyl-)-2-(2, the 6-3,5-dimethylphenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2, the 6-3,5-dimethylphenyl)-4-(3-ethoxyl phenenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2, the 6-dichlorophenyl)-4-methoxyl group-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methoxyl group-6-methyl-N, N-dipropyl pyrimidine-5-amine;

4-(1,3-benzo dioxy-5-yl)-2-(2,6-diethyl phenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

4-(2,3-dihydro-1,4-benzodioxane-6-yl)-2-(2, the 6-3,5-dimethylphenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

3-[5-(dipropyl amino)-4-methoxyl group-6-methylpyrimidine-2-yl]-2, the 4-dimethyl phenol;

2-(2, the 6-difluorophenyl)-4-methoxyl group-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-(2,3-dihydro-1,4-benzodioxane-6-yl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-N, N-dipropyl pyrimidine-5-amine;

3-[4-(1,3-benzo dioxy-5-yl)-5-(dipropyl amino)-6-methylpyrimidine-2-yl]-2, the 4-dimethyl phenol;

4-{[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] the oxygen base }-2-methylbutane-2-alcohol;

2-(2,6-diethyl phenyl)-4-(2-isopropoxy oxyethyl group)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

4-[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] cyanobenzene;

2-(2,6-diethyl phenyl)-4-(4-ethoxyl phenenyl)-6-methyl-N, N-dipropyl pyrimidine-5-amine;

3-{[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] the oxygen base }-propane-1-alcohol;

1-{[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] the oxygen base }-propane-2-alcohol;

2-(2,6-diethyl phenyl)-4-methyl-6-(2-morpholine-4-base oxethyl)-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-N, N-dipropyl-6-(2-Pyrrolizidine-1-base oxethyl) pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-[3-(dimethylamino) propoxy-]-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-6-{[4-(methylthio group) phenmethyl] the oxygen base }-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-6-{[4-(methylsulfonyl) phenmethyl] the oxygen base }-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-{3-[(2R, 6S)-2,6-thebaine-4-yl] propoxy-}-6-methyl-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-6-methyl-N～4～-(2-morpholine-4-base ethyl)-N～5～, N～5～-dipropyl pyrimidine-4, the 5-diamines;

2-(2,6-diethyl phenyl)-6-methyl-N～4～-(2-piperidines-1-base ethyl)-N～5～, N～5～-dipropyl pyrimidine-4, the 5-diamines;

4-[(1-phenmethyl piperidin-4-yl) oxygen base]-2-(2,6-diethyl phenyl)-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-6-[(3-methyl trimethylene oxide-3-yl) methoxyl group]-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-6-[(1-methyl piperidine-3-yl) oxygen base]-N, N-dipropyl pyrimidine-5-amine;

(2S, 3S)-3-{[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] the oxygen base } butane-2-alcohol;

2-(2,6-diethyl phenyl)-4-methyl-6-[2-(1-methylpyrrole pyridine-2-yl) oxyethyl group]-N, N-dipropyl pyrimidine-5-amine;

(2R, 3R)-3-{[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] the oxygen base } butane-2-alcohol;

2-(2,6-diethyl phenyl)-4-methyl-6-[(1-methyl piperidine-4-yl) oxygen base]-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-6-(piperidin-4-yl oxygen base)-N, N-dipropyl pyrimidine-5-amine; 1-[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] piperidines-4-alcohol;

2-(2,6-diethyl phenyl)-4-[2-(dimethylamino) oxyethyl group]-6-methyl-N, N-dipropyl pyrimidine-5-amine;

(2R, 3S)-3-{[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] the oxygen base } butane-2-alcohol;

(1S, 2R)-2-{[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] the oxygen base } cyclopentanol;

2-(2,6-diethyl phenyl)-4-methyl-N, N-dipropyl-6-(1H-1,2,4-triazol-1-yl) pyrimidine-5-amine;

N-[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl]-2-hydroxy-n-methylacetamide;

3-{[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl] the oxygen base }-2, the 2-neopentanoic acid;

2-(2,6-diethyl phenyl)-4-methyl-N, N-dipropyl-6-(1H-pyrazol-1-yl) pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-6-[(1-methylpyrrole pyridine-3-yl) oxygen base]-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-N, N-dipropyl-6-(pyridin-3-yl oxygen base) pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-6-[2-(4-epoxy morpholine-4-yl) oxyethyl group]-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-4-methyl-6-[(4-methylbenzene methyl) oxygen base]-N, N-dipropyl pyrimidine-5-amine;

2-(2,6-diethyl phenyl)-N～4～-[3-(dimethylamino)-2,2-dimethyl propyl]-6-methyl-N～5～, N～5～-dipropyl pyrimidine-4, the 5-diamines;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-(2-isopropoxy oxyethyl group)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

N-{[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 1-phenylbenzene methylamine;

N-{[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

4-{[{[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] methyl } (methyl) amino] methyl } methyl benzoate;

1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl]-N-(3-phenetole methyl)-N-methyl methylamine;

2-(2,6-diethyl phenyl)-4-methoxyl group-6-methyl-5-(1-propyl group butyl) pyrimidine;

2-(2,6-diethyl phenyl)-5-(1-oxyethyl group butyl)-4-methoxyl group-6-methylpyrimidine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-oxyethyl group-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

4-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] heptane-4-alcohol;

(1R)-and N-{[2-(2,6-diethyl phenyl)-4-(2-isopropoxy oxyethyl group)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-N-(4-methoxyl group-2-[3-(methoxymethyl) phenyl]-6-methylpyrimidine-5-yl } methyl)-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

2-(2,6-diethyl phenyl)-N-(2-methoxy ethyl)-N, 6-dimethyl-5 ({ methyl [(1R)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-amine;

(1S)-and N-{[4-(cyclobutyl oxygen base)-2-(2,6-diethyl phenyl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[4-(cyclopentyloxy)-2-(2,6-diethyl phenyl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4,6-dimethyl pyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-isopropoxy-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-isobutoxy-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[4-trimethylene oxide-1-base-2-(2,6-diethyl phenyl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl]-N-methyl-N-(quinoline-3-ylmethyl) methylamine;

1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl]-N-methyl-N-[(8-Methylimidazole [1,2-a] pyridine-2-yl also) methyl] methylamine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-ethyl-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-isobutyl--6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-N-{[2-(2,6-diethyl phenyl)-4-[(1S)-2-methoxyl group-1-methyl ethoxy]-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-morpholine-4-yl pyrimidines-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

N-butyl-2-(2,6-diethyl phenyl)-N, 6-dimethyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-amine;

2-[[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] (methyl) amino] ethanol;

2-(2,6-diethyl phenyl)-N-(2-methoxy ethyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-amine;

2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl)-N-propyl group pyrimidine-4-amine;

2-(2,6-diethyl phenyl)-N, 6-dimethyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl)-N-propyl group pyrimidine-4-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-Pyrrolizidine-1-yl pyrimidines-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[4-azepan-1-base-2-(2,6-diethyl phenyl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-thiomorpholine-4-yl pyrimidines-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-(4-methylpiperazine-1-yl) pyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-(4-phenylpiperazine-1-yl) pyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-(4-methyl piperidine-1-yl) pyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidines-4-alcohol;

2-(2,6-diethyl phenyl)-N-(2-methoxyl group-1-methylethyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-amine;

2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl)-N-[(2S)-tetrahydrofuran (THF)-2-ylmethyl] pyrimidine-4-amine;

2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl)-N-[(2R)-tetrahydrofuran (THF)-2-ylmethyl] pyrimidine-4-amine;

1-{[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] amino } propane-2-alcohol;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-phenoxy pyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-nitrile;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-(3,3-lupetidine-1-yl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-(3,5-lupetidine-1-yl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-pyridin-4-yl pyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidines-4-carboxylic acid, ethyl ester;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] and piperidin-4-yl } methyl alcohol;

2-{1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidin-4-yl } ethanol;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperazine-1-yl pyrimidines-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidin-4-yl } carboxylic acid;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl]-the D-proline;

4-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1R)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperazine-2-ketone;

(1R)-and N-{[4-(4-ethanoyl piperazine-1-yl)-2-(2,6-diethyl phenyl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1R)-and N-{[2-(2,6-diethyl phenyl)-4-(1H-imidazoles-1-yl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(1R)-and N-{[2-(2,6-diethyl phenyl)-4-methyl-6-(1H-pyrazol-1-yl) pyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

1-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl } piperidines-4-alcohol;

1-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl } piperidines-3-alcohol;

2-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-1,2,3, the 4-tetrahydroisoquinoline;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidines-3-alcohol;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] Pyrrolizidine-3-alcohol;

(1S)-and N-{[4-(amino methyl)-2-(2,6-diethyl phenyl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

2-(2,6-diethyl phenyl)-5-[(3,3-lupetidine-1-yl) methyl]-4-methyl-6-piperidines-1-yl pyrimidines;

1-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl } azepan;

4-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl } morpholine;

1-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl } piperidines-4-carboxylic acid, ethyl ester;

(1-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl } piperidines-3-yl) methyl alcohol;

2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-carboxylic acid;

2-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl]-the 1-phenylethyl alcohol;

2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-methane amide;

N-{[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] methyl } ethanamide;

5-[1-(4-ethanoyl piperazine-1-yl) butyl]-2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine;

(1-{1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] butyl } piperidin-4-yl) methyl alcohol;

2-(1-{1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] butyl } piperidin-4-yl) ethanol;

2-{1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidin-4-yl } propane-2-alcohol;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidin-4-one-;

4-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

2-(2,6-diethyl phenyl)-5-[1-(4-ethyl piperazidine-1-yl) butyl]-4-methoxyl group-6-methylpyrimidine;

5-[1-(4-cyclopentyl-based piperazine-1-yl) butyl]-2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine;

2-(4-{1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] butyl } piperazine-1-yl) ethanol;

4-{1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] butyl } morpholine;

(2R, 6S)-4-{1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] butyl }-2, the 6-thebaine;

1-[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl]-N-(1H-indoles-5-ylmethyl)-N-methyl methylamine;

4-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-6-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

2-(2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } the oxygen base)-N, the N-dimethyl amine;

4-[2-(2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } the oxygen base) ethyl] morpholine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-(4-sec.-propyl piperazine-1-yl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

(4-{1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] butyl } piperazine-1-yl) ethyl acetate;

4-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] and piperazine-1-yl } ethyl acetate;

4-{1-[2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine-5-yl] butyl } piperazine-1-carboxylic acid, ethyl ester;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl]-4-methyl piperidine-4-alcohol;

5-[1-(4-ethanoyl-2-methylpiperazine-1-yl) butyl]-2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine;

5-[1-(4-ethanoyl-2,6-lupetazin-1-yl) butyl]-2-(2,6-diethyl phenyl)-4-methoxyl group-6-methylpyrimidine;

4-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] and piperazine-1-yl } acetate;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-(4-ethyl piperazidine-1-yl)-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

2-(2,6-diethyl phenyl)-5-{1-[4-(sec.-propyl alkylsulfonyl) piperazine-1-yl] butyl }-4-methoxyl group-6-methylpyrimidine;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-(2-Pyrrolizidine-1-base oxethyl) pyrimidine;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-(2-piperidines-1-base oxethyl) pyrimidine;

1-[6-methyl-5-[(6-methyl-2,3-dihydro-4H-pyrido [3,2-b] [1,4] oxazine-4-yl) methyl]-2-(5-Methyl-1H-indole-4-yl) pyrimidine-4-yl] piperidin-4-one-;

4-[2-(2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } the oxygen base) propyl group] morpholine;

4-[3-(2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } the oxygen base) propyl group] morpholine;

2-(2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } the oxygen base)-N, N-diethyl propane-1-amine;

(1S)-N-(2-(2,6-diethyl phenyl)-4-[(2S, 6S)-2,6-thebaine-4-yl]-6-methylpyrimidine-5-yl } methyl)-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

N-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-3-oxyethyl group-N, 6-lutidine-2-amine;

2-(2,6-diethyl phenyl)-4-(1,1-dioxy base isothiazole pyridine-2-yl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-the 6-methylpyrimidine;

4-(amino methyl)-1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidines-4-alcohol;

4-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-2, the 2-thebaine;

(1S)-and N-{[2-(2,6-diethyl phenyl)-4-[2,2-thebaine-4-yl]-6-methylpyrimidine-5-yl] methyl }-the N-methyl isophthalic acid, 2,3,4-naphthane-1-amine;

5-sec.-propyl-4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-(2-morpholine-4-base oxethyl) pyrimidine-2-base]-the 1H-indazole;

N-(1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl]-4-hydroxy piperidine-4-yl } methyl) Toluidrin;

N-(1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl]-4-hydroxy piperidine-4-yl } methyl) ethanamide;

1,1 '-[2-(2,6-diethyl phenyl)-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4,6-two bases] two (2-methylpropanes-2-alcohol);

2-(2,6-diethyl phenyl)-5-{[2-(3, the 4-Dimethoxyphenyl) piperidines-1-yl] methyl }-4-methyl-6-piperidines-1-yl pyrimidines;

(2S, 6S)-4-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-2, the 6-thebaine;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidines-4-methane amide;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperidines-3-methane amide;

2-{4-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] piperazine-1-yl } ethanamide;

4-{[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] the oxygen base } benzamide;

4-{[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] the oxygen base }-the 2-hydroxybenzamide;

3-(2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } the oxygen base) trimethylene oxide-1-vinyl carboxylates;

4-(trimethylene oxide-3-base oxygen base)-2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-the 6-methylpyrimidine;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-piperazine-1-yl pyrimidines;

1-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-the 4-methyl isophthalic acid, the 4-Diazesuberane;

4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-carboxylic acid tert-butyl ester;

4-{2-(2,6-diethyl phenyl)-6-methyl-5-[(6-methyl-2,3-dihydro-4H-pyrido [3,2-b] [1,4] oxazine-4-yl) methyl] pyrimidine-4-yl } piperazine-1-carboxylic acid tert-butyl ester;

(4-{2-(2,6-diethyl phenyl)-6-methyl-5-[(6-methyl-2,3-dihydro-4H-pyrido [3,2-b] [1,4] oxazine-4-yl) methyl] pyrimidine-4-yl } piperazine-1-yl) (ketone group) methyl acetate;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-(4-pyrimidine-2-base piperazine-1-yl) pyrimidine;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-(4-pyridine-2-base piperazine-1-yl) pyrimidine;

2-(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl)-the N-methylacetamide;

5-[(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) methyl]-2,4-dihydro-3H-1,2,4-triazole-3-ketone;

4-{[2-(2,6-diethyl phenyl)-4-(4-sec.-propyl piperazine-1-yl)-6-methylpyrimidine-5-yl] methyl }-6-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

4-{[2-(2,6-diethyl phenyl)-4-methyl-6-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) pyrimidine-5-yl] methyl }-6-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

2-(4-{2-(2,6-diethyl phenyl)-6-methyl-5-[(6-methyl-2,3-dihydro-4H-pyrido [3,2-b] [1,4] oxazine-4-yl) methyl] pyrimidine-4-yl } piperazine-1-yl)-N-sec.-propyl ethanamide;

2-(4-{2-(2,6-diethyl phenyl)-6-methyl-5-[(6-methyl-2,3-dihydro-4H-pyrido [3,2-b] [1,4] oxazine-4-yl) methyl] pyrimidine-4-yl } piperazine-1-yl) ethanamide;

4-{[2-(2,6-diethyl phenyl)-4-methyl-6-(4-pyridine-2-base piperazine-1-yl) pyrimidine-5-yl] methyl }-6-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

4-{[2-(2,6-diethyl phenyl)-4-methyl-6-(4-pyrimidine-2-base piperazine-1-yl) pyrimidine-5-yl] methyl }-6-methyl-3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazine;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl]-1,2-dihydro-3H-pyrazoles-3-ketone;

4-{[2-(2,6-diethyl phenyl)-6-methyl-5-[(6-methyl-2,3-dihydro-4H-pyrido [3,2-b] [1,4] oxazine-4-yl) methyl] pyrimidine-4-yl] piperazine-1-sulphonamide;

2-(2,6-diethyl phenyl)-N, N, 6-trimethylammonium-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-amine;

1-{2-(2,6-diethyl phenyl)-6-methyl-5-[(6-methyl-2,3-dihydro-4H-pyrido [3,2-b] [1,4] oxazine-4-yl) methyl] pyrimidine-4-yl } piperidines-4-methane amide;

4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-carboxylic acid 2-oxyethyl group-1,1-dimethyl-2-ketone group ethyl ester;

2-(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl)-the 2 Methylpropionic acid ethyl ester;

2-(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl)-2 Methylpropionic acid;

4-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl } heptane-3, the 5-diketone;

N-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-N-[(1S)-1,2,3, and 4-naphthane-1-yl] glycine;

N-{[2-(2,6-diethyl phenyl)-4-methyl-6-piperidines-1-yl pyrimidines-5-yl] methyl }-N-[(1S)-1,2,3, and 4-naphthane-1-yl] the glycine ethyl ester;

1-[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-four naphthalenes-1-yl] amino } methyl) pyrimidine-4-yl]-4-hydroxy piperidine-4-methane amide;

2-{[2-(2,6-diethyl phenyl)-6-methyl-5-({ methyl [(1S)-1,2,3,4-naphthane-1-yl] amino } methyl) pyrimidine-4-yl] amino } propane-1-alcohol;

1-[2-(2,6-diethyl phenyl)-5-(1-propyl group butyl) pyrimidine-4-yl]-4-hydroxyl pyridine-4-methane amide;

2-(2,6-diethyl phenyl)-4-isopropoxy-5-(1-propyl group butyl) pyrimidine;

4-{[2-(2,6-diethyl phenyl)-5-(1-propyl group butyl) pyrimidine-4-yl] amino }-the 2-hydroxybenzamide;

2-(2,6-diethyl phenyl)-N, N-dimethyl-5-(1-propyl group butyl) pyrimidine-4-amine;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4, the 6-dimethyl pyrimidine;

5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(2-sec.-propyl-6-aminomethyl phenyl)-4, the 6-dimethyl pyrimidine;

2-(4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-{4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(2-methoxyl group-6-aminomethyl phenyl)-6-methylpyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-(4-{2-(5-sec.-propyl-1H-indazole-4-yl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(3-ethyl-1H-indazole-4-yl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methyl-2-[2-(trifluoromethyl) phenyl] pyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2, the 6-Dimethoxyphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(5-fluoro-2-aminomethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2-chloro-6-p-methoxy-phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2, the 5-dichlorophenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2-ethoxyl phenenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2, the 5-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2-ethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-{4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(2-methoxyl group-5-aminomethyl phenyl)-6-methylpyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-(4-{2-(5-chloro-2-p-methoxy-phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(5-fluoro-2-p-methoxy-phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-[2-(methoxymethyl) phenyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-{4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methyl-2-(3-picoline-2-yl) pyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-(4-{2-(5-chloro-2-aminomethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2-fluoro-6-p-methoxy-phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2-fluoro-5-p-methoxy-phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-{4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(5-methoxyl group-2-aminomethyl phenyl)-6-methylpyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-(4-{2-(2, the 3-Dimethoxyphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(5-chloro-2-ethoxyl phenenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-{4-{5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methyl-2-[2-(trifluoromethoxy) phenyl] pyrimidine-4-yl } piperazine-1-yl } ethanamide;

2-(4-{2-(5-cyano group-2-fluorophenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-{4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(2-methoxypyridine-3-yl)-6-methylpyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-(4-{2-(2-chloro-phenyl-)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2, the 3-dichlorophenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2, the 5-dimethoxy phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2, the 4-dimethoxy phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2,4 difluorobenzene base)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2-fluoro-4-aminomethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2, the 3-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2-fluoro-5-aminomethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(4-fluoro-2-aminomethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-{4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methyl-2-(2) pyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-(4-{2-(2-fluoro-4,6-Dimethoxyphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-(2,5-two fluoro-3-p-methoxy-phenyls)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

1-(2-(2-chloro-6-p-methoxy-phenyl)-6-methyl-5-{[methyl (1,2,3,4-naphthane-1-yl) amino] methyl } pyrimidine-4-yl) piperidines-4-methane amide;

1-(2-(2, the 6-3,5-dimethylphenyl)-6-methyl-5-{[methyl (1,2,3,4-naphthane-1-yl) amino] methyl } pyrimidine-4-yl) piperidines-4-methane amide;

2-(4-{2-(2-cyano-phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-[2-fluoro-6-(trifluoromethyl) phenyl]-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) acetate;

2-(4-{2-[2-chloro-6-(trifluoromethoxy) phenyl]-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-(4-{2-[5-fluoro-2-(trifluoromethyl) phenyl]-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-{4-[5-[(2,4-two fluorophenoxies) methyl]-2-(2, the 6-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-[4-(2-(2, the 6-3,5-dimethylphenyl)-5-{[2-fluoro-5-(trifluoromethyl) phenoxy group] methyl }-6-methylpyrimidine-4-yl) piperazine-1-yl] ethanamide;

2-[4-(2-(2, the 6-3,5-dimethylphenyl)-5-{[2-fluoro-3-(trifluoromethyl) phenoxy group] methyl }-6-methylpyrimidine-4-yl) piperazine-1-yl] ethanamide;

2-{4-[5-[(5-chloro-2-methylphenoxy) methyl]-2-(2, the 6-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-(2,6-diethyl phenyl)-5[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methoxyl group-6-methylpyrimidine;

4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-2-carboxylic acid's methyl esters;

4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-2-carboxylic acid;

4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-1-methylpiperazine-2-carboxylate methyl ester;

1-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-4-methyl piperidine-4-carboxylic acid;

(3S)-and 1-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperidines-3-carboxylic acid;

4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-1-methylpiperazine-2-carboxylic acid;

N-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-N-methyl glycine;

1-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperidines-2-carboxylic acid;

N-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-D-figured silk fabrics amino acid;

N-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-N-methyl D-figured silk fabrics amino acid;

4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester;

(3R)-and 1-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperidines-3-carboxylic acid;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-(1,2,3,6-tetrahydropyridine-4-yl) pyrimidine;

(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-1,4-Diazesuberane-1-yl) acetate;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-(3-methylpiperazine-1-yl) pyrimidine;

(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) methyl acetate;

2-(2,6-diethyl phenyl)-4-(1-ethyl-1,2,3,6-tetrahydropyridine-4-yl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-the 6-methylpyrimidine;

2-(2,6-diethyl phenyl)-4-(1-ethyl piperidine-4-yl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-the 6-methylpyrimidine;

[4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3,6-dihydropyridine-1 (2H)-yl] methyl acetate;

2-(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) acetate;

1-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methyl piperidine-3-carboxylic acid;

(4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(3,3-lupetidine-1-yl) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) acetonitrile;

4-[5-(3,4-dihydro-isoquinoline-2 (1H)-ylmethyl)-2-(2, the 6-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl] and piperazine-1-yl } acetonitrile;

4-[5-[(diisobutyl amino) methyl]-2-(2, the 6-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl] piperazine-1-yl } acetonitrile;

2-{4-[5-(3,4-dihydro-isoquinoline-2 (1H)-ylmethyl)-2-(2, the 6-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl] piperazine-1-yl } acetonitrile;

2-{4-[5-[(diisobutyl amino) methyl]-2-(2, the 6-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl] piperazine-1-yl } ethanamide;

2-(4-{2-(2,6-diethyl phenyl)-5-[(3,3-lupetidine-1-yl) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanamide;

2-[4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3,6-dihydropyridine-1 (2H)-yl] ethanamide;

1-{2-(2, the 5-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methyl piperidine-3-carboxylic acid;

1-{2-(2, the 5-dichlorophenyl)-5-[(3,3-lupetidine-1-yl) methyl]-6-methylpyrimidine-4-yl }-3,3-lupetidine-4-alcohol;

2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-the 4-methyl-6-[(3R)-3-methylpiperazine-1-yl] pyrimidine;

2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-the 4-methyl-6-[(3S)-3-methylpiperazine-1-yl] pyrimidine;

2-(4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperidines-1-yl) ethanamide;

2-(4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-yl) ethanol;

2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-[4-(2-methoxy ethyl) piperazine-1-yl]-the 6-methylpyrimidine;

1-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methyl piperidine-3-carboxylic acid;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2S)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

(3S)-and 1-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methyl piperidine-3-carboxylic acid;

(3S)-and 1-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methyl piperidine-3-carboxylic acid;

2-{ (2R)-4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(2-methoxyl group-6-aminomethyl phenyl)-6-methylpyrimidine-4-yl]-2-methylpiperazine-1-yl } ethanamide;

2-((2R)-4-{2-(2-chloro-6-p-methoxy-phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2-fluoro-5-aminomethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(5-chloro-2-aminomethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methyl-2-[2-(trifluoromethoxy) phenyl] pyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 5-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

1-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-hydroxy piperidine-3-carboxylic acid;

2-((3R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methylpiperazine-1-yl) ethanamide;

2-((3S)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methylpiperazine-1-yl) ethanamide;

4-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl } piperazine-1-nitrile;

2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-4-methyl-6-[4-(1H-tetrazolium-5-yl) piperazine-1-yl] pyrimidine;

(3R)-and 1-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methyl piperidine-3-carboxylic acid;

(3R)-and 1-{2-(2,6-diethyl phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-3-methyl piperidine-3-carboxylic acid;

Rel-2-(2, the 6-3,5-dimethylphenyl)-4-[(2R, 5S)-2,5-lupetazin-1-yl]-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-the 6-methylpyrimidine;

Rel-2-{ (2R, 5S)-4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methyl-2-(2-aminomethyl phenyl) pyrimidine-4-yl]-2,5-lupetazin-1-yl } ethanamide;

Rel-2-((2R, 5S)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2,5-lupetazin-1-yl) ethanamide;

Rel-2-((2R, 5S)-4-{2-(2, the 5-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2,5-lupetazin-1-yl) ethanamide;

Rel-2-((2R, 5S)-4-{5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methyl-2-phenyl pyrimidine-4-yl }-2,5-lupetazin-1-yl) ethanamide;

Rel-2-((2R, 5S)-4-2-(2-fluorophenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl)-2,5-lupetazin-1-yl) ethanamide;

Rel-2-{ (2R, 5S)-4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(2-p-methoxy-phenyl)-6-methylpyrimidine-4-yl]-2,5-lupetazin-1-yl } ethanamide;

Rel-2-{ (2R, 5S)-4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(2-methoxypyridine-3-yl)-6-methylpyrimidine-4-yl]-2,5-lupetazin-1-yl } ethanamide;

2-((2R)-4-{2-(2-cyano-phenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-{ (2R)-4-[5-[(5-sec.-propyl-2-methylphenoxy) methyl]-2-(2-methoxypyridine-3-yl)-6-methylpyrimidine-4-yl]-2-methylpiperazine-1-yl } ethanamide;

2-(2,6-diethyl phenyl)-4-methyl-6-(3-methylpiperazine-1-yl)-N, N-dipropyl pyrimidine-5-amine; 2-{4-[2-(2,6-diethyl phenyl)-5-(dipropyl amino)-6-methylpyrimidine-4-yl]-2-methylpiperazine-1-yl } ethanamide;

2-((2R)-4-{2-(3,5-dimethyl isoxazole-4-yl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

3-{4-[(3R)-4-(2-amino-2-ketone group ethyl)-3-methylpiperazine-1-yl]-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-2-yl }-the 4-fluorobenzamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl] pyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(5-cyano group-2-fluorophenyl)-5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

(2S)-4-[2-(2, the 5-3,5-dimethylphenyl)-5-(isopropoxy methyl)-6-methylpyrimidine-4-yl]-2-sec.-propyl piperazine-1-carboxylic acid tert-butyl ester;

2-(2, the 5-3,5-dimethylphenyl)-5-(isopropoxy methyl)-4-[(3S)-3-sec.-propyl piperazine-1-yl]-the 6-methylpyrimidine;

2-{ (2S)-4-[5-[(2, the 5-dichlorophenoxy) methyl]-2-(2, the 5-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl]-2-sec.-propyl piperazine-1-yl } ethanamide;

2-{ (2S)-4-[5-[(2, the 3-dichlorophenoxy) methyl]-2-(2, the 5-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl]-2-sec.-propyl piperazine-1-yl } ethanamide;

2-{ (2S)-4-[2-(2, the 5-3,5-dimethylphenyl)-5-(isobutoxy methyl)-6-methylpyrimidine-4-yl]-2-sec.-propyl piperazine-1-yl } ethanamide;

2-{ (2S)-4-[5-(2,4 dichloro benzene oxygen base) methyl]-2-(2, the 5-3,5-dimethylphenyl)-6-methylpyrimidine-4-yl }-2-sec.-propyl piperazine-1-yl } ethanamide;

2-((2S, 5R)-4-{5-[(5-sec.-propyl-2-methylphenoxy) methyl]-6-methyl-2-phenyl pyrimidine-4-yl }-2,5-lupetazin-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-ethyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(3-ethoxy phenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(3-isopropoxy phenoxy group) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-[(2R)-4-(2-(2, the 6-3,5-dimethylphenyl)-6-methyl-5-{[2-methyl-5-(trifluoromethyl) phenoxy group] methyl } pyrimidine-4-yl)-2-methylpiperazine-1-yl] ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(4-fluoro-5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-ethyl-4-fluoro-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(4-fluoro-2,5-dimethyl phenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(5-ethyl-3-fluoro-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(3-ethyl-2-fluoro-6-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(3-ethyl-6-fluoro-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(4-ethyl-2-fluoro-6-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(3-fluoro-5-sec.-propyl-2-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-((2R)-4-{2-(2, the 6-3,5-dimethylphenyl)-5-[(2-fluoro-3-sec.-propyl-6-methylphenoxy) methyl]-6-methylpyrimidine-4-yl }-2-methylpiperazine-1-yl) ethanamide;

2-[(2R)-and 4-(2-(2, the 6-3,5-dimethylphenyl)-5-{[(6-sec.-propyl-3-picoline-2-yl) oxygen base] methyl }-6-methylpyrimidine-4-yl)-2-methylpiperazine-1-yl] ethanamide;

2-[(2R)-and 4-(2-(2, the 6-3,5-dimethylphenyl)-5-{[(6-sec.-propyl-3-methylpyrazine-2-yl) oxygen base] methyl }-6-methylpyrimidine-4-yl)-2-methylpiperazine-1-yl] ethanamide;

2-[(2R)-and 4-(2-(2, the 6-3,5-dimethylphenyl)-5-{[(5-sec.-propyl-2-methylpyrazine-3-yl) oxygen base] methyl }-6-methylpyrimidine-4-yl)-2-methylpiperazine-1-yl] ethanamide;

2-((S)-3-{[2-(2,6-dimethyl-phenyl)-5-(5-sec.-propyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine-4-yl]-methyl-amino }-Pyrrolizidine-1-yl)-ethanamide;

2-((R)-3-{[2-(2,6-dimethyl-phenyl)-5-(5-sec.-propyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine-4-yl]-methyl-amino }-Pyrrolizidine-1-yl)-ethanamide;

2-((R)-1-[2-(2,6-dimethyl-phenyl)-5-(5-sec.-propyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine-4-yl]-Pyrrolizidine-3-yl }-ethyl-amino)-ethanamide;

2-((S)-1-[2-(2,6-dimethyl-phenyl)-5-(5-sec.-propyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine-4-yl]-Pyrrolizidine-3-yl }-ethyl-amino)-ethanamide;

2-{ (R)-3-[2-(2,6-dimethyl-phenyl)-5-(5-sec.-propyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine-4-base oxygen base]-Pyrrolizidine-1-yl }-ethanamide;

2-{ (S)-3-[2-(2,6-dimethyl-phenyl)-5-(5-sec.-propyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine-4-base oxygen base]-Pyrrolizidine-1-yl }-ethanamide; Or

2-{3-[2-(2,6-dimethyl-phenyl)-5-(5-sec.-propyl-2-methyl-phenoxymethyl)-6-methyl-pyrimidine-4-base oxygen base]-trimethylene oxide-1-yl }-ethanamide.