CN101668524B

CN101668524B - Pyrazole derivatives as 11-beta-hsd1 inhibitors

Info

Publication number: CN101668524B
Application number: CN200880004653XA
Authority: CN
Inventors: M·J·帕克; J·S·斯科特; A·斯托克; P·R·O·惠塔莫尔
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2007-02-12
Filing date: 2008-02-11
Publication date: 2012-10-24
Anticipated expiration: 2028-02-11
Also published as: ZA200905235B; CN101668524A

Abstract

A compound of formula (I): and pharmaceutically -acceptable salts thereof wherein the variable groups are defined within; their use in the inhibition of 11ssHSD1, processes for making them and pharmaceutical compositions comprising them are also described.

Description

Pyrazole derivatives as the 11-beta-HSD 1 inhibitors

The present invention relates to compound or pharmaceutically acceptable salt thereof.These chemical compounds have people 11-beta-hydroxysteroid dehydrogenase 1 type enzyme (11 β HSD1) to be suppressed active and correspondingly in the condition of illness treatment that comprises metabolism syndrome, has to be worth and to can be used in homoiothermic animal (like the mankind's) the Therapeutic Method.The invention still further relates to said chemical compound manufacturing approach, relate to the pharmaceutical composition that contains them, also relate to their purposes in the medicine that suppresses the intravital 11 β HSD1 of homoiothermic animal (like the mankind) is made.

Glucocorticoids (in human body, be hydrocortisone, in rodent, be corticosterone) is the contrary hormone of regulating, that is, they are to effect (Dallman MF, Strack AM, people such as Akana SF, 1993 of glucagon; Front Neuroendocrinol 14,303-347).They are regulated the expression of liver enzyme related in the gluconeogenesis and increase the substrate supply through from fatty tissue, discharging glycerol (steatolysis of raising) and from muscle, discharging aminoacid (protein synthesis of reduction and the protein degradation of raising).It also is important (people such as Bujalska IJ, 1999 that glucocorticoids pro-adipose cell is divided into the mature fat cell aspect that can store triglyceride; Endocrinology 140,3188-3196).This possibly be vital (Bjorntorp P & Rosmond R 2000 in glucocorticoids that " stress " brings out and condition of illness that central obesity (itself being type 2 diabetes mellitus, hypertension and cardiovascular diseases's strong risk factor) is associated; Int.J.Obesity 24, S80-S85).

Nowadays be recognized that; Glucocorticoid activity not only receives the control of cortisol secretion; Also organizing on the aspect receptor 1 activity hydrocortisone and nonactive corticosterone at the 11-beta hydroxysteroid dehydrogenase---and the mutual control of changing in 11 β HSD1 (it activates corticosterone) and 11 β HSD2 (its passivation hydrocortisone) the effect cell down (Sandeep TC Walker BR 2001 Trends inEndocrinol Metab.12,446-453).Initial use carbenoxolone (antiulcerative that suppresses 11 β HSD1 and 2) treatment to show that this mechanism possibly be important in human body, this treatment (people such as Walker BR, 1995; J.Clin.Endocrinol.Metab.80 3155-3159) causes the insulin sensitivity of raising, shows that 11 β HSD1 possibly come fully to regulate the effect (people 1995 such as Walker BR of insulin through the tissue level that reduces active glucocorticoids; J.Clin.Endocrinol.Metab.80,3155-3159).

Clinically, CS is excessive relevant with hydrocortisone, and hydrocortisone is excessive not to be tolerated with glucose again, central obesity (being caused by exciting of adipose cell differentiation before in this depot fat place (depot)), dyslipidemia are relevant with hypertension.CS and metabolism syndrome show many tangible similarities.(people such as Jessop DS, 2001 although metabolism syndrome is not associated with excessive circulation cortisol levels usually; J.Clin.Endocrinol.Metab.86,4109-4114), but the active expectation of unusual 11 high β HSD1 has same affect in the tissue.In obese people, according to showing, although have the level of plasma cortisol similar or lower with thin matched group, 11 β HSD1 in the subcutaneous fat are active greatly to be strengthened (people such as Rask E, 2001; J.Clin.Endocrinol.Metab.1418-1421).In addition, the much higher 11 β HSD1 activity levels of relevant with metabolism syndrome central authorities fat (central fat) expression ratio subcutaneous fat (people 1997 such as Bujalska IJ; Lancet 349,1210-1213).Therefore, between glucocorticoids, 11 β HSD1 and metabolism syndrome, seem the existence contact.

The mice that 11 β HSD1 knock out show the response that weakens by stress or fat cause fast and the gluconeogenesis enzyme activation that brings out than the glucocorticoid of hypoglycemia level (people 1997 such as KotelevtsevY; Proc.Natl.Acad.Sci USA 94 14924-14929), shows the effectiveness at blood sugar lowering and hepatic glucose output facet that is suppressed in the type 2 diabetes mellitus of 11 β HSD1.In addition, the HDL cholesterol of low triglyceride, raising and the apolipoprotein AI level of raising are composed, had to these mice expressed atheroma lipoproteins.(people 2001 such as Morton NM; J.Biol.Chem.276,41293-41300).This phenotype is expressed owing to the liver of the raising of catabolism of fat enzyme and PPAR α.This shows that once more 11 β HSD1 are suppressed at the effectiveness in the treatment of dyslipidemia of metabolism syndrome.

The most convictive evidence of getting in touch between metabolism syndrome and the 11 β HSD1 is to the recent research of crossing the transgenic mice express 11 β HSD1 (people 2001 such as Masuzaki H; Science 294,2166-2170).When under fatty specificity promoter control, expressing, 11 β HSD1 transgenic mices have high fat content, central obesity, insulin resistance diabetes, hyperlipidemia and the hyperphagia of corticosterone.Most important ground, the 11 β HSD1 activity levels that improve in the fat of these mices are similar to observed that kind in fat object.Liver 11 β HSD1 activity and plasma corticosterone sterone level are normal, and still, the hepatic portal vein level of corticosterone is increased to 3 times, and this is considered to the reason of these metabolic effects in the liver.

In general, be clear that now, through only in fat, crossing expression 11 β HSD1, can in mice, simulate complete metabolism syndrome simply with the level that is similar to fat human body.

11 β HSD1 tissue distribution are extensive, and overlapping with the tissue distribution of glucocorticoid receptor (GR).Therefore, the inhibition of 11 β HSD1 can be in the effect of resisting glucocorticoids aspect many physiology/pathology potentially.11 β HSD1 are present in people's skeletal muscle, and glucocorticoid is fully to prove (people 2001 such as Whorwood CB in the document to insulin to the antagonism of the anabolic action of Protein Turnover and glucose metabolism; J.Clin.Endocrinol.Metab.86,2296-2308).Therefore skeletal muscle necessarily be based on the important target thing of the therapy of 11 β HSD1.

Glucocorticoids also reduces insulin secretion, and this possibly aggravate the influence of the insulin resistance that glucocorticoid brings out.Islets express 11 β HSD1 and carbenoxolone can suppress the influence that the 11-dehydrocorticosterone discharges insulin (people 2000 such as Davani B; J.Biol.Chem.275,34841-34844).Therefore, in treating diabetes, 11 beta hsd 1 inhibitors maybe be not only act on insulin resistant organizing on the aspect, also improved insulin secretion itself.

Also regulate skeleton development and bone function through the glucocorticoid effect.11 β HSD1 are present in human osteoclast and the osteoblast, and show the constant (people 2000 such as Cooper MS of the decline of bone resorption indication and bone formation indication with the healthy volunteer of carbenoxolone treatment; Bone 27,375-381).The active inhibition of 11 β HSD1 can be used as the protective mechanism in the osteoporosis treatment in the bone.

Glucocorticoids also possibly participated in oculopathy, like glaucoma.11 β HSD1 have shown the intraocular pressure that influences the people, and the inhibition of 11 β HSD1 estimates to alleviate the intraocular pressure (people 2001 such as Rauz S of the raising relevant with glaucoma; Investigative Opthalmology & VisualScience 42,2037-2042).

In the rodent and the mankind, between 11 β HSD1 and metabolism syndrome, all there be convictive the contact.Evidence shows, the medicine that suppresses 11 β HSD1 at 2 type obese diabetes patient body internal specifics can come blood sugar lowering through reducing the glycogen heteroplasia, alleviates central obesity, improves atherogenic lipoprotein phenotype, brings high blood pressure down and reduces insulin resistant.Insulin effect in the muscle can strengthen, and also can improve the insulin secretion from the β cell on this island.

At present two main generally acknowledged definition are arranged about metabolism syndrome.

1) the Adult Treatment Panel of metabolism syndrome (ATP III 2001 JMA) definition shows, if the patient has in the following symptom three or more, then has metabolism syndrome:

As far as at least 40 inches of male (102 centimetres), as far as the actual measurement waistline of 35 inches of women (88 centimetres);

At least the serum triglyceride level of 150mg/dl (1.69mmol/l);

The male is less than 40mg/dl (1.04mmol/l), and the women is less than the HDL cholesterol levels of 50mg/dl (1.29mmol/l);

At least the blood pressure of 135/80mm Hg; And/or the blood glucose (serum glucose) of 110mg/dl (6.1mmol/l) at least.

2) following definition has been recommended in WHO consultation (consultation), and it does not imply cause effect relation and be proposed as and can in good time improved operation define:

The patient has at least a following situation: glucose does not tolerate, impaired glucose tolerance (IGT) or diabetes and/or insulin resistant; And two kinds or more kinds of following situation:

The arterial pressure that improves;

The plasma triglyceride that improves;

Central obesity;

Microdose urine protein.

We have found that the compound or pharmaceutically acceptable salt thereof that defines among the present invention is effective 11 beta hsd 1 inhibitors and correspondingly in the condition of illness treatment that is associated with metabolism syndrome, has value.We have been found that also chemical compound of the present invention has improved character, and this makes them become the better material standed for as medicine.For example, generally speaking, chemical compound of the present invention has good oral bioavailability rate, keeps simultaneously rendeing a service.Therefore, this compounds is estimated can be through suppressing disease or the symptom that 11 β HSD1 treat than excellent oral result being provided under the low dosage and therefore being specially adapted to treat or preventing.

Compare with other 11 beta hsd 1 inhibitors well known in the prior art, chemical compound of the present invention also possibly have excellent effectiveness and/or favourable physical property and/or favourable toxicity situation and/or favourable metabolism status.For example, generally speaking, chemical compound of the present invention has the acceptable free drug content that combines experiment to record through plasma protein.

The compound or pharmaceutically acceptable salt thereof of formula (1) correspondingly is provided:

Wherein:

Q is O, S or singly-bound;

R ¹Be C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _3-7Cycloalkyl, heterocyclic radical, aryl C _1-3Alkyl, heteroaryl C _1-3Alkyl, C _3-7Cycloalkyl C _1-3Alkyl, C _3-7Cycloalkyl C _2-3Thiazolinyl or C _3-7Cycloalkyl C _2-3Alkynyl, [they are optional separately by 1,2 or 3 substituent group replacement, and said substituent group is independently selected from C _1-3Alkyl, hydroxyl, halogen, oxo, cyanic acid, trifluoromethyl, C _1-3Alkoxyl, C _1-3Alkyl S (O) _n-(wherein n is 0,1,2 or 3), R ⁵CON (R ⁵')-, (R ⁵') (R ⁵") NC (O)-, R ⁵' C (O) O-, R ⁵' OC (O)-, (R ⁵') (R ⁵") NC (O) N (R ⁵' ")-, R ⁵SO ₂N (R ⁵")-and (R ⁵') (R ⁵") NSO ₂-(R wherein ⁵Be optional by 1,2 or 3 substituted C of substituent group that is selected from hydroxyl, halogen or cyanic acid _1-3Alkyl; And R ⁵' and R ⁵" be independently selected from hydrogen and be independently selected from hydroxyl, halogen, C with optional by 1,2 or 3 _1-3The substituted C of the substituent group of alkoxyl, carboxyl and cyanic acid _1-3Alkyl, or R ⁵' and R ⁵" form 4-7 unit saturated rings with the nitrogen-atoms that links to each other with them)];

R ²Be selected from heterocyclic radical, C _3-7Cycloalkyl (CH ₂) _m-and C _6-12Multi-ring alkyl (CH ₂) _m-(wherein m is 0,1 or 2, and this ring is optional is independently selected from R by 1,2 or 3 ⁶Substituent group replace);

R ³Be selected from hydrogen, C _1-4Alkyl C _3-5Cycloalkyl and C _3-5Methyl cycloalkyl (they are optional separately by 1,2 or 3 fluorine atom replacement);

R ²And R ³Form optional 1 or 2 the additional ring hetero atom that is selected from nitrogen, oxygen and sulfur and optional of containing with the nitrogen-atoms that links to each other with them and be fused to saturated monocycle, dicyclo or bridged-ring system on saturated, fractional saturation or the undersaturated monocycle, wherein the gained member ring systems is optional is independently selected from R by 1,2 or 3 ⁷Substituent group replace;

R ⁶And R ⁷Be independently selected from hydroxyl, halogen, oxo, carboxyl, cyanic acid, trifluoromethyl, R ⁹, R ⁹O-, R ⁹CO-, R ⁹C (O) O-, R ⁹CON (R ⁹')-, (R ⁹') (R ⁹") NC (O)-, (R ⁹') (R ⁹") N-, R ⁹S (O) _a-(wherein a is 0 to 2), R ⁹' OC (O)-, (R ⁹') (R ⁹") NSO ₂-, R ⁹SO ₂N (R ⁹")-, (R ⁹') (R ⁹") NC (O) N (R ⁹' ")-, [wherein this phenyl and heteroaryl are optional is fused on the 5-or 6-unit ring that phenyl, heteroaryl or optional contain 1,2 or 3 heteroatomic saturated or fractional saturation that is independently selected from nitrogen, oxygen and sulfur; and the gained member ring systems is optional is replaced by 1,2 or 3 substituent group, and said substituent group is independently selected from C for phenyl and heteroaryl _1-4Alkyl, hydroxyl, cyanic acid, trifluoromethyl, trifluoromethoxy, halogen, C _1-4Alkoxyl, C _1-4Alkoxy C _1-4Alkyl, amino, N-C _1-4Alkyl amino, two-N, N-(C _1-4Alkyl) amino, N-C _1-4Alkyl-carbamoyl, two-N, N-(C _1-4Alkyl) carbamoyl, C _1-4Alkyl S (O) _r-, C _1-4Alkyl S (O) _rC _1-4Alkyl (wherein r is 0,1 or 2)];

R ⁹Be independently selected from optional by hydroxyl, halogen, C _1-4The substituted C of alkoxyl, carboxyl or cyanic acid _1-3Alkyl;

R ⁹', R ⁹" and R ⁹' " be independently selected from hydrogen and be independently selected from hydroxyl, halogen, C with optional by 1,2 or 3 _1-4The substituted C of the substituent group of alkoxyl, carboxyl and cyanic acid _1-3Alkyl);

A is that (this phenyl or heteroaryl ring are chosen wantonly on ring carbon atom by 1,2 or 3 R for phenyl or heteroaryl ring ¹⁰Group replace and the ring nitrogen that in heteroaryl, can get on by R ¹¹Replace);

R ¹⁰Be independently selected from C _1-4Alkyl, hydroxyl, cyanic acid, trifluoromethyl, trifluoromethoxy, halogen, C _1-4Alkoxyl, C _1-4Alkoxy C _1-4Alkyl, amino, N-C _1-4Alkyl amino, two-N, N-(C _1-4Alkyl) amino, N-C _1-4Alkyl-carbamoyl, two-N, N-(C _1-4Alkyl) carbamoyl, C _1-4Alkyl S (O) _s-, C _1-4Alkyl S (O) _sC _1-4Alkyl (wherein s is 0,1 or 2)];

R ¹¹Independently for choosing wantonly by 1,2 or 3 substituted C of fluorine atom _1-3Alkyl;

X is direct key, C _3-4Cycloalkanes two bases (cycloalkandiyl), C _3-4Ring alkylidene (cycloalkanylidene) ,-C (R ¹²) (R ¹³)-,-C (R ¹²) (R ¹³) C (R ¹⁴) (R ¹⁵)-,-CH ₂O-or-CH ₂S (O) _t-(wherein t is 0,1 or 2);

Y is direct key, C _3-4Cycloalkanes two bases, C _3-4The ring alkylidene ,-C (R ¹⁶) (R ¹⁷)-or-C (R ¹⁸) (R ¹⁹) C (R ²⁰) (R ²¹)-;

R wherein ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰And R ²¹Be independently selected from hydrogen and methyl.

In this manual, term " alkyl " had both comprised straight chained alkyl, comprised branched alkyl again, but mentioned independently alkyl, during like " propyl group ", only refered in particular to linear form.For example, " C _1-4Alkyl " comprise propyl group, isopropyl and the tert-butyl group.But, mention independently alkyl, during like " propyl group ", only refer in particular to linear form, and mention independently branched alkyl, during like " isopropyl ", only refer in particular to this side chain form.Similar agreement is applicable to other group, therefore, and " C _1-4Alkoxy C _1-4Alkyl " comprise 1-(C _1-4Alkoxyl) propyl group, 2-(C _1-4Alkoxyl) ethyl and 3-(C _1-4Alkoxyl) butyl.Term " halogen " is meant fluorine, chlorine, bromine and iodine.

In office when selecting substituent group to be selected from " one or more " group, it being understood that this definition comprises, all substituent groups all are selected from specifies one of group, or substituent group is selected from two kinds of specifying in the group or more kinds of.

4-7 unit saturated rings is (for example at R ⁵' and R ⁵" and with nitrogen-atoms that they link to each other between form) be to contain the monocycle of nitrogen-atoms as unique annular atoms.

Only if indicate separately, " heteroaryl " is the complete undersaturated monocycle that contains 5 or 6 atoms, and wherein at least 1,2 or 3 annular atoms is independently selected from nitrogen, sulfur or oxygen, only if indicate separately, they can be that carbon connects.Theheterocyclic nitrogen atom can be chosen wantonly oxidized to form corresponding N-oxide.The instance of term " heteroaryl " and suitable implication are thienyl, furyl, thiazolyl, pyrazolyl 、 isoxazolyl, imidazole radicals, pyrrole radicals, thiadiazolyl group, isothiazolyl, triazolyl, pyrimidine radicals, pyrazinyl, pyridazinyl and pyridine radicals.Especially, " heteroaryl " is meant thienyl, furyl, thiazolyl, pyridine radicals, imidazole radicals or pyrazolyl.

" heterocyclic radical " is to have 1-3 the saturated monocycle of 4-7 unit that is selected from the ring hetero atom of nitrogen, oxygen and sulfur.Epithio can be chosen wantonly and be oxidized to SO ₂

C _3-7Cycloalkyl ring is the saturated carbon ring that contains 3 to 7 annular atomses.

C _3-4Cycloalkanes two basic rings are the saturated carbon rings that contain 3 or 4 annular atomses.It is the diradical that on the different rings carbon atom, has free radical.

C _3-4Ring alkylene basic ring is the saturated carbon ring that contains 3 or 4 annular atomses.It is the diradical that on identical ring carbon atom, has free radical.

The polynaphthene basic ring is that wherein at least 2 rings condense together or the member ring systems of 2 shared annular atomses of ring (volution) wherein.

Only if indicate separately, " choose wantonly and contain 1 or 2 the heteroatomic saturated monocycle of additional ring, dicyclo or bridged-ring system that is selected from nitrogen, oxygen and sulfur " contained 4-14 annular atoms.Especially, monocycle contains 4-7 annular atoms, and dicyclo contains 6-14 annular atoms, and bridged-ring system contains 6-14 annular atoms.Monocyclic instance comprises piperidyl, piperazinyl and morpholinyl.The instance of dicyclo comprises decahydronaphthalenes and 2,3,3a, 4,5,6,7,7a-octahydro-1H-indenes.

Bridged-ring system is that wherein two or more keys are the common member ring systems of two or more makeup rings.The instance of bridged-ring system comprises 1,3,3-trimethyl-6-azabicyclo [3.2.1] octane, 2-aza-bicyclo [2.2.1] heptane and 7-azabicyclo (2,2,1) heptane, 1-and 2-adamantyl.

Only if indicate separately, " saturated, fractional saturation or undersaturated monocycle " is 4-7 unit ring.Instance comprises, cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group and phenyl.

The instance of " choosing wantonly and containing 1,2 or 3 5-or 6-unit ring that is independently selected from the heteroatomic saturated or fractional saturation of nitrogen, oxygen and sulfur " comprises piperidyl, piperazinyl and morpholinyl.

" C _1-4Alkoxyl " instance comprise methoxyl group, ethyoxyl and propoxyl group." C _1-4Alkoxy C _1-4Alkyl " instance comprise methoxy, ethoxyl methyl, propoxyl group methyl, 2-methoxy ethyl, 2-ethoxyethyl group and 2-propoxyl group ethyl." C _1-4Alkyl S (O) _n(wherein n is 0 to 2) " instance comprise methyl mercapto, ethylmercapto group, methyl sulfinyl, ethylsulfinyl-1 base, mesyl and ethylsulfonyl." C _1-4Alkyl S (O) _qC _1-4Alkyl (wherein q is 0 to 2) " instance comprise methyl mercapto, ethylmercapto group, methyl sulfinyl, ethylsulfinyl-1 base, mesyl, ethylsulfonyl, methylthiomethyl, ethylmercapto group methyl, methyl sulfinyl methyl, ethylsulfinyl-1 ylmethyl, mesyl methyl and ethylsulfonyl methyl." C _1-4Alkanoyl " instance comprise propiono and acetyl group." N-(C _1-4Alkyl) amino " instance comprise methylamino and ethylamino." N, N-(C _1-4Alkyl) ₂Amino " instance comprise N, N-dimethylamino, N, N-diethylamino and N-ethyl-N-methylamino." C _2-4Thiazolinyl " instance be vinyl, pi-allyl and 1-acrylic." C _2-4Alkynyl " instance be acetenyl, 1-propinyl and 2-propynyl." N-(C _1-4Alkyl) carbamoyl " instance be methylamino carbonyl and ethylamino carbonyl." N, N-(C _1-4Alkyl) ₂Carbamoyl " instance be dimethylamino carbonyl and Methylethyl amino carbonyl." C _3-7Cycloalkyl C _1-3Alkane alkyl (alkalkyl) " instance comprise cyclopropyl methyl, 2-cyclopropyl ethyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl." C _3-7Cycloalkyl C _2-3Alkane thiazolinyl (alkalkenyl) " instance comprise 2-cyclopropyl vinyl, 2-cyclopenta vinyl and 2-cyclohexyl vinyl." C _3-7Cycloalkyl C _2-3Alkane alkynyl (alkalkynyl) " instance comprise 2-cyclopropyl acethlene base, 2-cyclopenta acetenyl and 2-cyclohexyl-acetylene base.

" C _3-7Cycloalkyl (CH ₂) _m-" instance comprise cyclopropyl methyl, 2-cyclopropyl ethyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl.C _6-12Multi-ring alkyl (CH ₂) _m-instance comprise norborny dicyclo [2.2.2] octane (CH ₂) _m-, dicyclo [3.2.1] octane (CH ₂) _m-and 1-and 2-adamantyl (CH ₂) _m-.

The suitable officinal salt of chemical compound of the present invention for example is; Enough acid-addition salts of chemical compound of the present invention of alkalescence; For example, with the acid-addition salts of for example inorganic or organic acid (for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citric acid or maleic acid).In addition, enough the suitable officinal salt of tart chemical compound of the present invention is an alkali metal salt, for example; Sodium or potassium salt; Alkali salt, for example calcium or magnesium salt, ammonium salt, or with the salt that the acceptable cationic organic base of physiology is provided; For example, with the salt of methylamine, DMA, trimethylamine, piperidines, morpholine or three-(2-hydroxyethyl) amine.

The chemical compound of some formulas (1) possibly have chiral centre and/or geometrical isomerism center (E-and Z-isomer), it being understood that the present invention includes to have 11 β HSD1 inhibition active all such optical isomers, diastereomer and geometric isomer.

The present invention relates to have any and all tautomeric forms that 11 β HSD1 suppress the chemical compound of active formula (1).

What it is also understood that is that some chemical compound of formula (1) can be with solvation form and non-solvent form, for example hydrated form existence.It being understood that the present invention includes and have active all the such solvation forms of 11 β HSD1 inhibition.

The invention still further relates to formula (I) but the vivo hydrolysable ester of chemical compound.But vivo hydrolysable ester is to decompose those esters that produce parent carboxylic in animal body.

The chemical compound of formula (1) is provided in one embodiment of the invention.The officinal salt of the chemical compound of formula (1) is provided in another embodiment.

The chemical compound of formula (Ia) is provided in one aspect of the invention:

R wherein ¹, R ²And R ³As above define and R ¹⁰Be selected from hydrogen, C _1-4Alkyl, trifluoromethyl, C _1-4Alkoxyl and C _1-4Alkyl S-.In another aspect, R ¹⁰Be selected from hydrogen, methyl, trifluoromethyl, methoxyl group and methyl mercapto.In another aspect, R ¹⁰Be hydrogen.

In another aspect of this invention, the chemical compound of formula (Ib) is provided:

The concrete implication of variable group is following.This type implication can be used for the chemical compound of formula (1) in due course with preceding text or the specified any definition of hereinafter, claim or embodiment.R ¹, R ²And R ³Can be used for the chemical compound of formula (Ia) with the definition of variable in these groups:

The definition of Q

A) in one aspect in, the chemical compound of the formula that the present invention relates to as above define (I), wherein Q is O.

B) in another aspect, Q is S.

C) in another aspect, Q is a singly-bound.

R ¹ Definition

A) in one aspect in, R ¹Be to choose wantonly to be independently selected from C by 1,2 or 3 _1-3Alkyl, hydroxyl, halogen, oxo, cyanic acid, fluorine, trifluoromethyl and C _1-3The substituted C of the substituent group of alkoxyl _3-6Cycloalkyl.

B) in another aspect, R ¹Be C _3-6Cycloalkyl.

C) in another aspect, R ¹Be to choose wantonly to be independently selected from C by 1,2 or 3 _1-3Alkyl, hydroxyl, halogen, oxo, cyanic acid, fluorine, trifluoromethyl and C _1-3The substituted C of the substituent group of alkoxyl _3-6Cycloalkyl C _1-2Alkyl.

D) in another aspect, R ¹Be C _3-4Cycloalkyl C _1-2Alkyl.

E) in another aspect, R ¹Be to choose wantonly to be independently selected from C by 1,2 or 3 _1-3Alkyl, hydroxyl, halogen, oxo, cyanic acid, trifluoromethyl and C _1-3The substituted C of the substituent group of alkoxyl _1-4Alkyl.

F) in another aspect, R ¹Be C _1-4Alkyl.

G) in another aspect, R ¹Be to choose wantonly to be independently selected from C by 1 or 2 _1-3Alkyl, hydroxyl, halogen, oxo, cyanic acid, trifluoromethyl and C _1-3The substituted propyl group of the substituent group of alkoxyl.

H) in another aspect, R ¹It is propyl group.

R ² Definition

A) in one aspect in, R ²Be selected from C _3-7Cycloalkyl (CH ₂) _m-and C _6-12Multi-ring alkyl (CH ₂) _m-(wherein m is 0,1 or 2 and this ring is optional is independently selected from R by 1,2 or 3 ⁶Substituent group replace), wherein m is 0,1 or 2.

B) in another aspect, R ²Be selected from C _5-7Cycloalkyl (CH ₂) _m-and C _8-12Multi-ring alkyl (CH ₂) _m-(wherein this ring is optional is independently selected from R by 1,2 or 3 ⁶Substituent group replace) and wherein m be 0,1 or 2.

C) in another aspect, R ²Be selected from C _5-7Cycloalkyl (CH ₂) _m-, C _7-10Bicyclic alkyl (CH ₂) _m-and C ₁₀Tricyclic alkyl (CH ₂) _m-(wherein cycloalkyl, bicyclic alkyl and tricyclic alkyl ring are optional is independently selected from R by 1,2 or 3 ⁶Substituent group replace) and wherein m be 0,1 or 2.

D) more on the one hand in, R ²Be selected from C _5-7Cycloalkyl (CH ₂) _m-, C _7-10Bicyclic alkyl (CH ₂) _m-and adamantyl (wherein cycloalkyl, bicyclic alkyl and tricyclic alkyl ring are optional is independently selected from R by 1,2 or 3 ⁶Substituent group replace) and wherein m be 0,1 or 2.

The definition of m

A) in one aspect in, m is 0 or 1.

R ³ Definition

A) in one aspect in, R ³Be C _1-4Alkyl.

B) in another aspect, R ³Be hydrogen, methyl or ethyl.

C) in another aspect, R ³Be hydrogen.

D) in another aspect, R ³It is methyl.

E) in another aspect, R ³It is ethyl.

F) in another aspect, R ³It is cyclopropyl.

R ² And R ³ Definition together

A) in another aspect, R ²And R ³Form saturated 5 or 6-unit monocycle, 6-12 unit's dicyclo or 6-12 unit bridged-ring system with the nitrogen-atoms that links to each other with them; It is optional contain 1 or 2 additional ring hetero atom that is selected from nitrogen, oxygen and sulfur and its optional be fused to saturated, fractional saturation or the aryl monocycle on, wherein the gained member ring systems is optional is independently selected from R by 1,2 or 3 ⁷Substituent group replace.

R ⁶ Definition

A) in one aspect in, R ⁶Be independently selected from hydroxyl, R ⁹O-, R ⁹CO-and R ⁹C (O) O-, wherein R ⁹As above definition.

B) in another aspect, R ⁶Be independently selected from hydroxyl, R ⁹O-, R ⁹CO-and R ⁹C (O) O-, wherein R ⁹Be optional by C _1-4The C of alkoxyl or carboxyl substituted _1-3Alkyl.

C) in another aspect, R ⁶Be independently selected from R ⁹CON (R ⁹')-, R ⁹SO ₂N (R ⁹")-and (R ⁹') (R ⁹") NC (O) N (R ⁹' ")-;

R wherein ⁹As above definition.

D) in another aspect, R ⁶Be independently selected from R ⁹CON (R ⁹')-, R ⁹SO ₂N (R ⁹")-and (R ⁹') (R ⁹") NC (O) N (R ⁹' ")-;

R ⁹Be optional by C _1-4The C of alkoxyl or carboxyl substituted _1-3Alkyl;

R ⁹', R ⁹" and R ⁹' " be independently selected from hydrogen and choose wantonly by C _1-4The C of alkoxyl or carboxyl substituted _1-3Alkyl).

E) in another aspect, R ⁶Be independently selected from (R ⁹') (R ⁹") NC (O)-and (R ⁹') (R ⁹") N-;

R wherein ⁹' and R ⁹" as above definition.

F) in another aspect, R ⁶Be independently selected from (R ⁹') (R ⁹") NC (O)-and (R ⁹') (R ⁹") N-;

R wherein ⁹' and R ⁹" be independently selected from hydrogen and choose wantonly by C _1-4The C of alkoxyl or carboxyl substituted _1-3Alkyl.

G) in one aspect in, R ⁶Be selected from methyl, trifluoromethyl, chlorine, fluorine, bromine, methoxyl group, ethyoxyl, trifluoromethoxy, mesyl, ethylsulfonyl, methyl mercapto, ethylmercapto group, amino, N-methylamino, N-ethylamino, amino, the N of N-propyl group; N-dimethylamino, N; N-Methylethyl amino or N, the N-diethylamino.

H) in another aspect, R ⁶Be optional substituted phenyl, pyridine radicals or pyrimidine radicals.

I) in another aspect, R ⁶Be optional substituted pyridine-2-base, pyridin-3-yl or pyridin-4-yl.

R ⁷ Definition

A) in another aspect, R ⁷Be independently selected from hydroxyl, halogen, oxo, cyanic acid, trifluoromethyl, R ⁹And R ⁹O-(R wherein ⁹As above definition).

B) in another aspect, R ⁷Be independently selected from hydroxyl, halogen, trifluoromethyl, R ⁹And R ⁹O-(R wherein ⁹As above definition).

R ⁹ Definition

A) in one aspect in, R ⁹Be independently selected from C _1-3Alkyl.

R ⁹ ', R ⁹ " and R ⁹ ' " definition

A) in one aspect in, R ⁹', R ⁹" and R ⁹' " be independently selected from hydrogen and C _1-3Alkyl.

The definition of Y

A) in one aspect in, Y be independently selected from direct key ,-CH ₂-with-CH ₂CH ₂-.

B) in one aspect in, Y is independently selected from-CH ₂-with-CH ₂CH ₂-.

C) in another aspect, Y is direct key.

The definition of A

A) in one aspect in, A is optional by R ¹⁰Substituted phenyl.

B) in another aspect, A is optional by R ¹⁰And R ¹¹Substituted heteroaryl.

C) in another aspect, A is optional by R ¹⁰And R ¹¹Substituted thienyl.

D) in another aspect, A is optional by R ¹⁰And R ¹¹Substituted pyridine radicals.

E) in another aspect, A is a benzene-1,4-two bases.

R ¹⁰ Definition

A) in one aspect in, R ¹⁰Be independently selected from C _1-4Alkyl, hydroxyl, cyanic acid, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, halogen, C _1-4Alkoxyl and C _1-4Alkoxy C _1-4Alkyl.

B) in another aspect, R ¹⁰Be independently selected from methyl, ethyl, hydroxyl, cyanic acid, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, halogen, methoxyl group, ethyoxyl, methoxy and ethoxyl methyl.

C) in another aspect, R ¹⁰Be independently selected from methyl, ethyl, cyanic acid, trifluoromethyl, trifluoromethoxy, difluoro-methoxy, halogen, methoxyl group, ethyoxyl.

R ¹¹ Definition

A) in one aspect in, R ¹¹Be independently selected from C _1-3Alkyl, trifluoromethyl and difluoromethyl.

B) in one aspect in, R ¹¹Be independently selected from methyl, ethyl, trifluoromethyl and difluoromethyl.

The definition of X

A) in one aspect in, X be independently selected from direct key ,-CH ₂-,-CHMe-,-CMe ₂-,-CH ₂CH ₂-,-CH ₂O-and-CH2S-.

B) in one aspect in, X is independently selected from-CH ₂-,-CHMe-,-CMe ₂-,-CH ₂CH ₂-,-CH ₂O-and-CH2S-.

C) in another aspect, X is independently selected from ring propylidene base, ring Aden alkyl, cyclopropane-1,2-two base and Tetramethylene .-1,2-two bases.

D) in another aspect, X is direct key.

In one aspect, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷, R ¹⁸, R ¹⁹, R ²⁰And R ²¹Be hydrogen.

In one aspect, R ¹Optional by 0 substituent group replacement.

In one aspect, R ¹Optional by 1 substituent group replacement.

In one aspect, R ¹Optional by 2 substituent groups replacements.

In one aspect, R ¹Optional by 3 substituent groups replacements.

In one aspect, R ²Optional by 0 substituent group replacement.

In one aspect, R ²Optional by 1 substituent group replacement.

In one aspect, R ²Optional by 2 substituent groups replacements.

In one aspect, R ²Optional by 3 substituent groups replacements.

In one aspect, R ³Optional by 0 substituent group replacement.

In one aspect, R ³Optional by 1 substituent group replacement.

In one aspect, R ³Optional by 2 substituent groups replacements.

In one aspect, R ³Optional by 3 substituent groups replacements.

In one aspect, by R ²And R ³The group that forms together is optional to be replaced by 0 substituent group.

In one aspect, by R ²And R ³The group that forms together is optional to be replaced by 1 substituent group.

In one aspect, by R ²And R ³The group that forms together is optional to be replaced by 2 substituent groups.

In one aspect, by R ²And R ³The group that forms together is optional to be replaced by 3 substituent groups.

In one aspect, A is optional to be replaced by 0 substituent group.

In one aspect, A is optional to be replaced by 1 substituent group.

In one aspect, A is optional to be replaced by 2 substituent groups.

In one aspect, A is optional to be replaced by 3 substituent groups.

In one aspect, R ⁶And R ⁷In phenyl and heteroaryl optionally independently replaced by 0 substituent group.

In one aspect, R ⁶And R ⁷In phenyl and heteroaryl optionally independently replaced by 1 substituent group.

In one aspect, R ⁶And R ⁷In phenyl and heteroaryl optionally independently replaced by 2 substituent groups.

In one aspect, R ⁶And R ⁷In phenyl and heteroaryl optionally independently replaced by 3 substituent groups.

In one aspect of the invention, Q is that direct key and X are direct keys.

The combination of the above-mentioned definition of use discloses the particular type of chemical compound of the present invention in Table A.For example, in table with R ²For " a " in the hurdle of title is meant that preceding text are to R ²The definition that provides (a), and " I " is meant first definition that the variable in the chemical compound of formula (I) is provided in this explanation beginning place.R ⁶And R ⁷Be R ²With by R ²And R ³Optional substituent group on the group that forms together.R ²And R ³Certainly be unsubstituted or by to R ⁶And R ⁷The value of listing replaces."-" in the hurdle of R6 and R7 shows relevant R ²Group or by R ²And R ³The group that forms together is unsubstituted.Table A is meant the chemical compound of formula (1).

Table A

Type

Q

R ¹

R ²

R ⁶

R ³

R ²And R ³Together

R ⁷

X

Y

A

1

I

a

I

-

I

2

I

a

-

I

3

I

b

a

I

-

a

4

a

I

-

I

a

5

c

I

a

I

-

a

6

b

c

-

a

g

d

c

a

7

b

d

b

g

b

-

d

c

b

8

b

e

c

g

b

-

d

c

a

9

b

f

d

-

c

-

d

c

e

10

b

h

d

-

c

-

d

c

e

In table B, use the particular type of the combination of above-mentioned definition with the chemical compound of the open formula (1a) of mode like the his-and-hers watches category-A.

Table B

Type

R ¹

R ²

R ⁶

R ³

R ²And R ³Together

R ⁷

1a

I

-

2a

a

-

I

3a

b

a

I

-

4a

I

-

I

5a

I

a

I

-

6a

c

-

a

g

7a

d

b

g

b

-

8a

e

c

g

c

-

9a

f

d

-

10a

h

d

-

In table C, use the particular type of the combination of above-mentioned definition with the chemical compound of the open formula (1b) of mode like the his-and-hers watches category-A.

Table C

Type

R ¹

R ²

R ⁶

R ³

R ²And R ³Together

R ⁷

1b

I

-

2b

a

-

I

3b

b

a

I

-

4b

I

-

I

5b

I

a

I

-

6b

c

-

a

g

7b

d

b

g

b

-

8b

e

c

g

c

-

9b

f

d

-

10b

h

d

-

The further type of chemical compound has formula (1), or its officinal salt, wherein:

Q is a singly-bound;

X is direct key, C _3-4Cycloalkanes two bases, C _3-4The ring alkylidene ,-C (R ¹²) (R ¹³)-,-C (R ¹²) (R ¹³) C (R ¹⁴) (R ¹⁵)-,-CH ₂O-or-CH ₂S (O) _t-(wherein t is 0,1 or 2);

The further again type of chemical compound has formula (1), or its officinal salt, wherein:

Q is a singly-bound;

X is that direct key and Y are direct key, C _3-4Cycloalkanes two bases, C _3-4The ring alkylidene ,-C (R ¹⁶) (R ¹⁷)-or-C (R ¹⁸) (R ¹⁹) C (R ²⁰) (R ²¹)-; Or

X is direct key, C _3-4Cycloalkanes two bases, C _3-4The ring alkylidene ,-C (R ¹²) (R ¹³)-,-C (R ¹²) (R ¹³) C (R ¹⁴) (R ¹⁵)-,-CH ₂O-or-CH ₂S (O) _t-(wherein t is 0,1 or 2) and Y are direct keys;

Q is a singly-bound;

X is direct key;

Y is direct key, C _3-4Cycloalkanes two bases, C _3-4The ring alkylidene ,-C (R ¹⁶) (R ¹⁷)-or-C (R ¹⁸) (R ¹⁹) C (R ²⁰) (R ²¹)-; Or

X is direct key, C _3-4Cycloalkanes two bases, C _3-4The ring alkylidene ,-C (R ¹²) (R ¹³)-,-C (R ¹²) (R ¹³) C (R ¹⁴) (R ¹⁵)-,-CH ₂O-or-CH ₂S (O) _t-(wherein t is 0,1 or 2); And

Y is direct key,

In another aspect of this invention, suitable combination thing of the present invention is any or multiple or its officinal salt among the embodiment.

In another aspect of this invention, suitable combination thing of the present invention is any or multiple or its officinal salt in the following compounds:

4-[4-[[(1S, 3R)-5-hydroxyl-2-adamantyl] carbamoyl]-5-propylthio alkyl-pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid;

4-[4-(1-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid;

4-[4-(N-cyclohexyl-N-methyl-carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid;

4-[4-(oxirane-4-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid;

4-[5-propylthio alkyl-4-[3-[2-(trifluoromethyl) phenyl] pyrrolidine-1-carbonyl] pyrazol-1-yl] benzoic acid;

4-[4-(cyclohexyl carboxyamide base)-5-cyclopropyl-pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-cyclopropyl-pyrazol-1-yl] benzoic acid;

4-[4-(1-adamantyl carbamoyl)-5-cyclopropyl-pyrazol-1-yl] benzoic acid;

4-[4-(cyclohexyl-methyl-carbamoyl)-5-cyclopropyl-pyrazol-1-yl] benzoic acid;

4-[5-cyclopropyl-4-[(4-hydroxyl-1-adamantyl) carbamoyl] pyrazol-1-yl] benzoic acid;

2-[4-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] phenyl] acetic acid;

2-[4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] phenyl] acetic acid;

4-(4-cyclohexyl carboxyamide base-5-propylthio alkyl-pyrazol-1-yl methyl)-benzoic acid;

3-(4-cyclohexyl carboxyamide base-5-propylthio alkyl-pyrazol-1-yl methyl)-benzoic acid;

3-[4-(diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl methyl]-benzoic acid;

4-[4-(diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl methyl]-benzoic acid;

4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-(1-methyl cyclopropyl) pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-cyclopenta-pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-ethyl pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-propane-2-base pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-cyclobutyl pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-methyl-pyrazol-1-yl] benzoic acid;

4-(the 5-tert-butyl group-4-(cyclohexyl carboxyamide base)-1H-pyrazol-1-yl) benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-cyclohexyl sulfane base-pyrazol-1-yl] benzoic acid;

4-[4-(1-adamantyl carbamoyl)-5-cyclohexyl sulfane base-pyrazol-1-yl] benzoic acid;

4-[5-cyclohexyl sulfane base-4-[(5-hydroxyl-2-adamantyl) carbamoyl] pyrazol-1-yl] benzoic acid;

4-[5-cyclohexyl sulfane base-4-[[5-(difluoro-methoxy)-2-adamantyl] carbamoyl] pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-cyclopenta sulfane base-pyrazol-1-yl] benzoic acid;

4-[4-(1-adamantyl carbamoyl)-5-cyclopenta sulfane base-pyrazol-1-yl] essence of Niobe;

4-[5-cyclopenta sulfane base-4-[[(1R, 3S)-5-hydroxyl-2-adamantyl] carbamoyl] pyrazol-1-yl] essence of Niobe;

4-[4-[[5-(difluoro-methoxy)-2-adamantyl] carbamoyl]-5-propylthio alkyl pyrazole-1-yl] benzoic acid;

4-[4-(cyclohexyl carboxyamide base)-5-cyclopenta sulfane base-pyrazol-1-yl] benzoic acid;

4-[4-(cyclohexyl carboxyamide base)-5-cyclohexyl sulfane base-pyrazol-1-yl] benzoic acid;

4-[5-suberyl sulfane base-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-ethyl sulfane base-pyrazol-1-yl] benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-methyl sulfane base-pyrazol-1-yl] benzoic acid;

4-[4-(5-mesyl-diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-benzoic acid;

4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-2-methoxyl group-benzoic acid;

4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-3-methyl-benzoic acid;

4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-2-(trifluoromethyl) benzoic acid; Or

4-[4-(diamantane (obsolete)-2-base carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl] benzoic acid.

Another aspect of the present invention provides the method for the compound or pharmaceutically acceptable salt thereof of preparation formula (1), this method (only if wherein indicate separately, variable group is suc as formula defining in (1)) comprise technology a) or b) in any:

A) hydrolysis of the ester of formula (2):

R wherein ²²It is alkyl or aryl; Or

B) Z in the chemical compound of formula (3) is changed into carboxyl:

Wherein Z is the functional group that can change into carboxylic acid;

Therefore if necessary or desirable:

I) chemical compound of formula (1) is transformed another chemical compound of an accepted way of doing sth (1);

Ii) remove any protection base;

Iii) split enantiomer;

Iv) form its officinal salt.

Another examples for compounds that well known to a person skilled in the art the chemical compound conversion accepted way of doing sth (1) of formula (1) comprises that functional group changes each other; Like hydrolysis, hydrogenation, hydrogenolysis, oxidation or reduction, and/or other is functionalized to pass through standard reaction (like the coupling or the nucleophilic displacement reaction of amide or metal catalytic).

Above-mentioned technology is a) to b) appropraite condition following.

Technology a) can be according to ester group (R ²²) character under acidity or alkali condition, carry out, but can under alkali condition, (for example use sodium hydrate aqueous solution) usually, use suitable solvent, carry out like methanol.Usually, this reaction is carried out at ambient temperature, and still, some esters possibly require to use microwave or traditional heating (for example 30-100 ℃ temperature) cracking.R ²²Suitable instance comprise methyl, ethyl, the tert-butyl group, phenyl, benzyl and to methoxy-benzyl, particularly methyl or ethyl.

The chemical compound of formula (2) can be through methods known in the art and the usually reaction manufacturing of the chemical compound of chemical compound and the formula (5) of through type (4):

This type reaction can be through directly handling ester or passing through R with amine ²³Carboxylic acid carried out traditional amide coupling reaction then and carries out in the middle of ester group was hydrolyzed into.Method and standard conditions that quadrature (orthogonal) is removed ester group are well known by persons skilled in the art, if R for example ²²Be ethyl and R ²³Be the tert-butyl group, R then ²³Can be at selective splitting under the acid condition.

For example; Can be at suitable solvent, in dichloromethane, under the situation of for example adding suitable coupling agents (or combination of coupling agent) (like HOBT and EDCI); For example choose wantonly and under suitable alkali (like triethylamine or N, N-two-different-propylamine) exists, carry out amide formation.Usually, this is reflected under 0-60 ℃ the temperature of ambient temperature or rising and carries out.

Q be sulfur, oxygen or nitrogen-atoms formula (4) chemical compound can through methods known in the art and usually the reaction of the chemical compound of through type (6) by the displacement manufacturing of suitable leaving group (L):

Wherein L is suitable leaving group, for example halogen or TFMS root (particularly fluorine or chlorine), R ²²Be alkyl or aryl and R ²⁴Be-OR ²³Or NR ²R ³

Can for example use suitable nucleopilic reagent (for example propanethiol), in suitable solvent (like DMF), for example in the presence of suitable alkali (for example hexamethyl two silicon Azide (disilazide) sodium (NaHMDS)), replace.Usually, when L was chlorine, this reaction was carried out at ambient temperature, and still, some reactions possibly require to use microwave or traditional heating (for example under 30-100 ℃ temperature).

The chemical compound of formula (6) can through methods known in the art and usually the functional group of the chemical compound of through type (7) change each other and make.

R wherein ²²Be alkyl or aryl and R ²⁴Be-OR ²³Or NR ²R ³

These class methods are known in the art and can use combination of agents (like the combination of nitrite tert-butyl and copper halide) in suitable solvent (like acetonitrile), to carry out.Usually, when for example L is chlorine, use microwave or traditional heating, for example under 60-100 ℃, carry out this reaction in the temperature that raises.

The chemical compound of formula (7) can be through methods known in the art and the usually reaction manufacturing of the enol ether of hydrazine and the formula (9) of through type (8).

R wherein ²²Be alkyl or aryl, R ²⁴Be-OR23 or NR ²R ³And R ²⁵It is alkyl.Especially, R ²⁵Be methyl or ethyl.

These class methods are known in the art and common in suitable solvent (like ethanol), for example in the presence of suitable alkali (like DIPEA), carry out.Usually, use microwave or traditional heating, for example under 60-100 ℃, carry out this reaction in the temperature that raises.The hydrazine of formula (8) is knownly in the Chemistry Literature maybe can use standard conditions well known by persons skilled in the art preparation.

The chemical compound of formula (9) can be through methods known in the art and the functionalized manufacturing of the ketone nitrile of through type (10) usually.

R wherein ²⁴Be-OR23 or NR ²R ³

These class methods are known in the art and use combination of agents (like the combination of pure acetic anhydride and triethyl orthoformate) to carry out usually.Usually, use microwave or traditional heating, for example under 60-100 ℃, carry out this reaction in the temperature that raises.The ketone nitrile of formula (10) is knownly in the Chemistry Literature maybe can use standard conditions well known by persons skilled in the art preparation.

Q is that the chemical compound of single bonded formula (4) also can be through the methods known in the art preparation; And be usually directed to the functionalized ketone ester (wherein X represents dialkyl amido (like dimethylamino) or low-carbon alkoxy (like methoxy or ethoxy)) of the formula that forms (11B), and subsequently with the reaction of the hydrazine of formula (8)

The ketone ester of formula (11B) is knownly in the Chemistry Literature maybe can use standard conditions well known by persons skilled in the art preparation; Comprise through acid chloride and Meldrum ' s acid (referring to; J.Org.Chem.2001 for example; 26,6756) gained intermediate and pure HOR are followed in the reaction in the presence of alkali (like pyridine) in atent solvent (like dichloromethane) subsequently ²³Reaction (referring to, J.Org.Chem.1978 for example, 43,2087).

Q is that the chemical compound of single bonded formula (2) also can and be usually directed to the functionalized keto-amide (wherein X ' represents dialkyl amido (like dimethylamino) or low-carbon alkoxy (like methoxy or ethoxy)) of the formula that forms (12) through methods known in the art preparations, and subsequently with the reaction of the hydrazine of formula (8)

The keto-amide of formula (13) is knownly in the Chemistry Literature maybe can use standard conditions well known by persons skilled in the art preparation, comprises reaction or the reaction through enolate anion (it is through generating with highly basic (like LDA) processing ketone) and suitable isocyanates through amine and suitable acid chloride (its optional processed by corresponding sour original position).

Technology b) instance is to use the carbonylation of metal catalytic that aryl halide is changed into aryl carboxylic acid.The instance of this type technology is known in the art; And in suitable solvent (like ethanol/dioxane); For example use appropriate catalyst or catalyst combination (for example Herrmann ' s catalyst is together with Fu ' s salt); In the presence of suitable carbon monoxide source (for example hexacarbonylmolybdenum) or gaseous state CO, in the presence of the combination (for example DMAP/DIPEA) of suitable alkali or alkali, carry out usually.Usually, use microwave or traditional heating, for example under 100-180 ℃, carry out this reaction in the temperature that raises.Those of skill in the art will recognize that choice of Solvent depends on the character of isolating product, for example alcoholic solvent often causes ester to separate, its can be subsequently in the post processing of this reaction cracking to produce suitable acid.Those skilled in the art also will appreciate that, synthetic all methods of chemical compound that can be through being used for description formula (2) obtain the chemical compound of formulas (3).

In addition, can be prepared as follows the chemical compound of formula (3):

The suitable functionalized part of through type (3A) is reacted so that the precursor of formula (3) to be provided with the unsubstituted pyrazoles of the N of formula (3B)

Wherein L ' be can react (when Y is connected to this ring and goes up through sp3 carbon) at SN2 or in the SNAr reaction (when Y was connected to this ring when last through sp2 carbon; Optional by suitable transition-metal catalyst catalysis; For example Buchwald displacement) by metathetical leaving group, and wherein optionally relates to pyrazoles (3B) in by alkali (like potassium tert-butoxide) deprotonation.L ' is a leaving group, like chlorine, bromine or iodine.

Above-mentioned reaction can be carried out under standard conditions well known by persons skilled in the art.Above-mentioned intermediate can be buied, be as known in the art maybe can through known procedure and/or through on show program preparation.

Recognize; After in the various substituent groups in the chemical compound of the present invention some can or follow above-mentioned technology closely before above-mentioned technology; Introduce or generate through the substitution reaction of standard aromatics, and therefore be included in the method for the present invention aspect through traditional functional group modification method.This type reaction and modification comprise, for example, introduce substituent group through aromatics substitution reaction, substituent reduction, substituent alkylation and substituent oxidation.Reagent that this class method is used and reaction condition are known in the chemical field.The instantiation of aromatics substitution reaction comprises and uses concentrated nitric acid to introduce nitro, uses that for example acyl halide and lewis acid (like aluminum chloride) are introduced acyl group under Friedel Crafts condition; Use alkyl halide and lewis acid (like aluminum chloride) under Friedel Crafts condition, to introduce alkyl; With introducing halo group.The instantiation of modification comprises through for example handling nitroreduction one-tenth amino with ferrum with the Raney nickel catalytic hydrogenation or under heating in the presence of the hydrochloric acid; The alkyl sulfenyl is oxidized to alkyl sulfinyl or alkyl sulphonyl.

Also to recognize, in this paper mentions some reactions, maybe be necessary/desirably protect any sensitive group in the chemical compound.Situation and the suitable guard method that must or preferably protect are well known by persons skilled in the art.Can use traditional protection base (for example referring to T.W.Green, Protective Groups in Organic Synthesis, JohnWiley and Sons, 1991) according to standard practices.Therefore, if reactant comprises the group like amino, carboxyl or hydroxyl and so on, this group of protection possibly be desirable in some reactions that this paper mentions.

The protection base that is fit to amino or alkyl amino for example is, acyl group, and alkanoyl for example is like acetyl group; Alkoxy carbonyl, for example methoxycarbonyl, ethoxy carbonyl or tert-butoxycarbonyl, aryl methoxy carbonyl; For example benzyloxycarbonyl, or aroyl, for example benzoyl.The deprotection condition of above-mentioned protection base must become with the selection of protection base.Therefore, for example, can be for example through removing acyl group, like alkanoyl or alkoxy carbonyl, or aroyl with suitable alkali (like alkali metal hydroxide, for example Lithium hydrate or sodium hydroxide) hydrolysis.Perhaps; Can for example pass through with suitable acid (example hydrochloric acid, sulphuric acid or phosphoric acid; Or trifluoroacetic acid) acyl group is removed in processing; Like tert-butoxycarbonyl, and can be for example through going up hydrogenation at catalyst (carrying palladium like carbon) or removing the aryl methoxy carbonyl through handling with lewis acid (for example three (trifluoroacetic acid) boron), like benzyloxycarbonyl.Other protection base that is fit to primary amino radical is a phthalyl for example, and it can be removed through handling with alkylamine (for example azanol) or with hydrazine.

The protection base that is fit to hydroxyl for example is, acyl group, for example alkanoyl (like acetyl group), aroyl (for example benzoyl), or aryl methyl (for example benzyl).The deprotection condition of above-mentioned protection base must become with the selection of protection base.Therefore, for example, can be for example through removing acyl group, like alkanoyl or aroyl with suitable alkali (like alkali metal hydroxide, for example Lithium hydrate or sodium hydroxide) hydrolysis.Perhaps, can for example remove aryl methyl, like benzyl through going up hydrogenation at catalyst (carrying palladium) like carbon.

The protection base that is fit to carboxyl is an esterified group for example; Methyl or ethyl for example for example through removing with alkali (like sodium hydroxide) hydrolysis; Or for example can be through with acid (organic acid for example; Like trifluoroacetic acid) handle the tert-butyl group of removing, or for example can be through going up the benzyl that hydrogenation is removed at catalyst (carrying palladium like carbon).

Can use in the chemical field known conventional art to remove the protection base in any stage easily in synthetic.

As stated, specified chemical compound has 11 β HSD1 inhibition activity among the present invention.Can use following assay method (assay) to assess these character.

Assay method

The corticosterone that can use emulative homogeneous phase time discrimination fluorescence assay method (HTRF) to measure to be caused by 11 β HSD1 oxo-reductase activities is to conversion (the CisBio International of active steroid hydrocortisone; R&D; Administration and Europe Office; In VitroTechnologies-

/Bioassays BP 84175; 30204Bagnols/CezeCedex, France.Cortisol bulk HTRF kit:Cat No.62CORPEC).

The terminal 6-His labelling of the N-total length people 11 β HSD1 enzymes of use baculovirus expression ( ^*1) carries out the evaluation and test of chemical compound as herein described.Use copper chelate post this enzyme of from the cell lysates of detergent stabilisation, purifying.The inhibitor of 11 β HSD1 reduces the conversion of corticosterone to hydrocortisone, and this discerns through the signal increase in above-mentioned assay method.

With compound dissolution to be tested in dimethyl sulfoxine (DMSO) to 10mM, and in containing the chemical examination buffer of 1%DMSO, further be diluted to 10 times of final chemical examination concentration.Then with diluted compounds transfer to black 384 orifice plates (Matrix, Hudson NH, USA) in.

By corticosterone (Sigma, Poole, Dorset, UK; 160nM), the G-6-P ester (Roche Diagnostics, 1mM), NADPH (Sigma, Poole, Dorset; 100 μ M), G-6-P ester dehydrogenase (Roche Diagnostics, 12.5 mcg/ml), EDTA (Sigma, Poole; Dorset, UK, 1mM), chemical examination buffer (K ₂HPO ₄/ KH ₂PO ₄, chemically examine in the 20 microlitre cumulative volumes that 100mM) pH 7.5, reorganization 11 β HSD1 [adopting suitably dilution can be 1: 1000 dilution rate of enzyme storing with the instance of the dilution rate that produces feasible chemical examination window-suitable] and test compound constitute.The chemical examination plate was cultivated 25 minutes down at 37 ℃, after this came stopped reaction through adding 10 microlitre 0.5mM glycyrrhizic acids (glycerrhetinic acid) and conjugation hydrocortisone (XL665 or D2).Add then 10 microlitres anti--hydrocortisone cryptate and with the plate sealing and at room temperature cultivated 6 hours.Measurement under 665nm and 620nm fluorescence and use the Envision plate reader to calculate 665nm: the 620nm ratio.

Use the IC of these each chemical compounds of data computation then ₅₀Value (Origin 7.5, Microcal software, and Northampton MA, USA) and/or the inhibition % under 30 M chemical compounds.

^*1 The Journal of Biological Chemistry, the 26th volume, No 25, the 16653-16658 pages or leaves

Chemical compound of the present invention shows less than 30 μ M and preferred IC less than 5 μ M usually ₅₀

For example, obtain following result:

Following table has shown that the % of people 11-HSD under the experimental concentration of 30 M chemical compounds suppresses.

Can test the oral bioavailability rate of chemical compound of the present invention as follows:

Bioavailability in PK research is measured

Chemical compound in 25%HPBCD-sorrensons pH of buffer 5.5 preparations with 2mg/kg (2ml/kg) intravenously administrable and oral with 5mg/kg (5ml/kg).For these two kinds of approach, all before administration, extracted blood sample (200 microlitre) in 0.25,0.5,1,2,3,4,5,6,8 and 24 hour after the administration and through centrifugal preparation blood plasma.Following analysed for plasma sample.Through the standard P K-method, use suitable PK software (WinNon-Lin) to calculate PK parameter (clearance rate, volume of distribution, bioavailability, absorption fraction etc.).

The bioanalysis of plasma sample

This guide is used for giving unification compound or expected compound medicine box (cassette) back manual preparation plasma sample at all used in discovery DMPK PK species.Described through opening and obtained (open access) (LC-MS/MS) or the analysis carried out of manual method (LC-MS).

Content

1. material

2. general extracting process

3. the sample instance list that uses general plate to arrange

4. opening is obtained batch submission (Open Access Batch Submission) and a systems inspection

5. drape over one's shoulders inferior acceptance criteria through (Batch Pass)

1. material

Solvent: methanol, acetonitrile and DMSO

Water: purification or the HPLC grade

1 milliliter of shallow 96-orifice plate or eppendorf pipe

2 milliliters of deep hole 96-orifice plates with cover

Blank (contrast) blood plasma

2. general extracting process

Use DMSO with compound dissolution to 1 mg/ml,, it is counted consideration if any salt factor is arranged.Can use the DMSO storing to make all calibration & quality control (QC) samples:

2.i single compound analysis

2.i.a the preparation of calibration and QC sample:

1. be prepared as follows standard solution:

Storing dilution ng/ml	Methanol volume ml	Storing volume ml	Normal concentration ng/ml	Concentration ng/ml behind the diluted plasma
					1mg/ml 100,000 50,000 20,000 10,000 5,000 1,000 500 200 100 50	0.9 0.5 0.75 0.5 0.5 2 0.5 0.75 0.5 0.5 0.5	0.1 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5	100,000 50,000 20,000 10,000 5,000 1,000 500 200 100 50 10	10,000 5,000 2,000 1,000 500 100 50 20 10 5 1

2. 50 microlitre blank plasmas are transferred in the hole of 1 milliliter of 96 orifice plate (shallow bore hole).

3. each standard solution of 5 microlitres is transferred in other hole of this plate.

4. in each hole, add 50 microlitre blank plasmas.

5. in order to produce the QC sample, with 100ng/ml, 1000ng/ml and 10, three 5 mul aliquots samples of 000ng/ml standard solution add (following 3 QC of each concentration) in this plate to.

6. in these each, add 50 microlitre blank plasmas.

7. with in each PK sample transfer to 1 of 50 microlitres milliliter 96 orifice plates.

8. in each PK sample, add 5 microliter methanol (chemical compound).

9. guarantee that through vortex mixed all preparations fully mix.

10. dilution has intravenous (IV) and oral (PO) dosage form to 10 mcg/ml (for example, be made into 2 mg/ml and expect that diluted 1: 200 of the preparation of concentration is to produce 10 mcg/ml solution) of expection concentration in methanol.

11. 6 * 50 microlitre blood plasma aliquots are added in this plate.The IV preparation of 5 microlitres dilution is added in three holes, repeat with 3 holes of PO preparation and all the other.

12. through 100 microlitres are contained estimate mutually inside the Pass the acetonitrile of mark (1 mcg/ml) add in all calibrations, QC, PK and the formulation samples and come precipitating proteins.

13. before centrifugal 4, under the 000g with this plate vortex mixed 10 minutes.

14. 100 microlitre supernatant are transferred in the hole of 2 milliliter of 96 orifice plate (drawing) referring to strake down.Care should be used to does not disturb pill.

15. in last hole, add～1.5 milliliters of 50: 50 methanol: water.

16. for the analysis in the triple quad system: in each sample, add 400 microliters of water (HPLC grade).The gentle mixing.

17. with 100 microlitres 100, each standard solution liquid storage of 000ng/ml adds in 2 milliliters of plates and adds 900 microliters of water.Add interior standard specimen article in another hole (referring to the plate drawing).These are used for chemical compound tuning (making tuning solution at plate drawing subscript).

18. for the analysis on the plateform system: 100 microliters of water (HPLC grade) are added in each sample.The gentle mixing.

19. use and process 5, all chemical compounds of compound solution manual adjustment of 000ng/ml (with 100 microlitres 50, the 000ng/ml standard solution adds in 900 microliters of water).

2.ii box dosage is analyzed

2.iia the preparation of calibration and QC sample:

Annotate:, regulate the required quantity of methyl alcohol of dilution 1 mg/ml liquid storage according to existing chemical compound amount for the boxlike administration.

1. each 1 mg/ml liquid storage that 100 microlitres are required adds in the phial.

2. add volume required methanol to produce 1 milliliter of cumulative volume.

3. as single compound analysis, carry out all other steps (above-mentioned steps 2-16).

2.iii surpass under the situation that quantizes the upper limit (ULOQ) at the PK sample.

1. as above prepare further calibration curve and QC sample (step 1-6).

2. shift to surpass ULOQ＜50 microlitres (for example 25 microlitres) PK sample.

3. add in these samples to produce the final blood plasma volume of 50 microlitres enough contrasting blood plasma.The dilution that record carries out.

4. all residue PK samples of transferase 45 0 microlitre.

5. prepare all formulation samples and extract all samples (step 8-16) as stated.

Annotate: can check the upper limit concentration that is used to produce calibration curve, still, take every caution against error and avoid the saturated of HPLC post or MS equipment.Therefore recommend dilution PK sample.

2.iv under the situation of sensitivity difference (high quantification lower limit)

Annotate: quantize to prescribe a time limit down or when LLOQ is higher than 10ng/ml, be regarded as high LLOQ when most of PCs are lower than.When running into arbitrary these situation, should be suitable for following method.

According to further aspect of the present invention, provide to comprise like the compound or pharmaceutically acceptable salt thereof of the embodiment that gives a definition and the pharmaceutical composition of pharmaceutically acceptable diluent or carrier.

Compositions of the present invention can be to be fit to oral form (but for example tablet, lozenge, hard or soft capsule, water slurry or oil suspension, Emulsion dispersion powder or granule, syrup or elixir); Be fit to the form (for example cream, ointment, gel or aqueous or oily solution or suspension) of topical, the form (for example fine-powder or liquid aersol) of suitable inhalation; Be fit to be blown into the form (aseptic aqueous solution or the oil solution that for example are used for intravenous, subcutaneous, intramuscular or intramuscular administration, or the suppository of using as rectally) of the outer injection of form (for example fine-powder) or suitable intestinal of administration.Usually, the compositions that is fit to oral form is preferred.

Compositions of the present invention can use conventional medicament excipient well known in the art to obtain through traditional program.Therefore, estimate that oral compositions can contain, for example, one or more coloring agent, sweeting agent, correctives and/or antiseptic.

The pharmaceutically acceptable excipient that is fit to tablet comprises, inert diluent for example is like lactose, sodium carbonate, calcium phosphate or calcium carbonate; Granulating agent and disintegrating agent are like corn starch or alginic acid; Binding agent is like starch; Lubricant is like magnesium stearate, stearic acid or Talcum; Antiseptic such as ethylparaben or propyl ester, and antioxidant are like ascorbic acid.Tablet can for coating not or in either case with traditional coating materials well known in the art and program coating changing their disintegrates in gastrointestinal tract and active component subsequently absorbs, or improve their stability and/or outward appearance.

Compositions for oral use can be the form of hard gelatin capsule (wherein active component mixes with inert solid diluent such as calcium carbonate, calcium phosphate or Kaolin) or Perle (wherein active component and water or oil are like Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil).

Waterborne suspension contains active component and one or more suspending agents of fine powder form usually, like sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and arabic gum; Dispersant or wetting agent; Like the condensation product (for example Myrj 45) of lecithin or alkylene oxide and fatty acid or the condensation product of oxirane and long chain aliphatic (for example 17 ethyleneoxy hexadecanol (heptadecaethyleneoxycetanol)); Or oxirane and, or oxirane and derived from the condensation product (for example polyoxyethylene sorbitol monoleate) of the partial ester of fatty acid and hexitol or oxirane and derived from the condensation product (for example polyoxyethylene sorbitan monoleate) of the partial ester of fatty acid and hexitan derived from the condensation product (for example polyoxyethylene sorbitol monoleate) of the partial ester of fatty acid and hexitol or the condensation product (for example 17 ethyleneoxy hexadecanol (heptadecaethyleneoxycetanol)) of oxirane and long chain aliphatic.This waterborne suspension also can contain one or more antiseptic (like ethylparaben or propyl ester), antioxidant (like ascorbic acid), coloring agent, correctives and/or sweeting agent (like sucrose, glucide or aspartame).

Through active component is suspended in vegetable oil (like Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois) or the mineral oil (like liquid paraffin), can prepare oily suspensions.This oily suspensions also can contain thickening agent, for example Cera Flava, hard paraffin or hexadecanol.Can add sweeting agent, for example those sweeting agents listed of preceding text and correctives are to provide good to eat oral formulations.These compositionss can be preserved through adding antioxidant (like ascorbic acid).

But be suitable for containing active component and dispersant or wetting agent, suspending agent and one or more antiseptic usually through adding dispersion powder and the granule that water prepares waterborne suspension.Suitable dispersant or wetting agent and suspending agent mentioned with preceding text those be example.Also possibly there is other excipient, for example sweeting agent, correctives and coloring agent.

Pharmaceutical composition of the present invention also can be the oil-in-water emulsion form.Oil phase can be vegetable oil, like olive oil or Oleum Arachidis hypogaeae semen, or mineral oil, like the mixture of liquid paraffin or any of these oil.Suitable emulsifying agent can for example be naturally occurring natural gum; Like Radix Acaciae senegalis or Tragacanth; Naturally occurring phospholipid is like Semen sojae atricolor, lecithin, derived from the ester of fatty acid and hexitan or the condensation product (for example polyoxyethylene sorbitan monoleate) of partial ester (for example dehydrating sorbitol monooleate) and said partial ester and oxirane.This Emulsion also can contain sweeting agent, correctives and antiseptic.

Can be with sweeting agent for example glycerin, propylene glycol, sorbitol, aspartame or agent of sucrose syrup blend and elixir, and also can contain demulcent, antiseptic, correctives and/or coloring agent.

This pharmaceutical composition also can be injectable sterile aqueous or oily suspensions form, and said suspension can use one or more suitable dispersants or wetting agent and the suspending agent preparation that preceding text have mentioned according to known procedure.Injectable sterile preparation can also be at nontoxic parenteral acceptable diluent or injectable sterile solution or the suspension in the solvent, the for example solution in 1,3 butylene glycol.

Compositions through inhalation can be traditional pressurised aerosol form, and it is arranged to distribute active component with the aerosol form that contains subdivided solids or drop.Can use traditional aerosol propellants, like volatility fluorinated hydrocarbons or hydrocarbon, and the aerosol utensil is arranged to the active component of distribution and computation amount traditionally.

About the further information of preparation, the reader can be with reference to Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), the 25.2nd chapter in the 5th of PergamonPress 1990 the volume.

Combine with one or more excipient must to become with main body of being treated and specific administration approach with the amount of the active component of making one-pack type.For example, people's preparations for oral administration contains usually, for example with suitably with 0.5 milligram of excipient (it can not wait for about 5 to about 98 weight % of the total compsn) compounding of convenient amount to 2 gram activating agents.Unit dosage forms contain usually about 1 milligram to about 500 milligrams of active component.About the further information of route of administration and dosage, the reader can be with reference to Comprehensive Medicinal Chemistry (CorwinHansch; Chairman of Editorial Board), the 25.3rd chapter in the 5th of Pergamon Press 1990 the volume.

We have found that, the chemical compound that defines among the present invention, or its officinal salt is effective 11 beta hsd 1 inhibitors and correspondingly in the condition of illness treatment that is associated with metabolism syndrome, has value.

It being understood that in this article it is meant as 1 when using a technical term " metabolism syndrome ") and/or 2) the middle metabolism syndrome that defines or this syndromic any other generally acknowledged definition.The synonym of used " metabolism syndrome " comprises Reaven ' s Syndrome, insulin resistance syndrome and syndrome X in this area.It being understood that in this article it also is meant Reaven syndrome, insulin resistance syndrome and syndrome X when using a technical term " metabolism syndrome ".

According to further aspect of the present invention, the as above compound or pharmaceutically acceptable salt thereof of the formula (1) of definition in the preventative or therapeutic treatment method that is used in homoiothermic animal (like the people) is provided.

Therefore, according to this aspect of the invention, the as above compound or pharmaceutically acceptable salt thereof of the formula (1) of definition as medicament is provided.

According to another characteristic of the invention, providing as above, the compound or pharmaceutically acceptable salt thereof of the formula (1) of definition is being used in homoiothermic animal (like the people) body, producing the purposes that the inhibiting medicament of 11 β HSD1 is made.

When mentioning generation or causing 11 β HSD1 inhibitory action, this suitably is meant the treatment of metabolism syndrome.Perhaps, when mentioning generation 11 β HSD1 inhibitory action, this is meant the treatment of diabetes, obesity, hyperlipidemia, hyperglycemia, hyperinsulinemia or hypertension, particularly diabetes and obesity.Perhaps, when mentioning generation 11 β HSD1 inhibitory action, this is meant glaucoma, osteoporosis, tuberculosis, dementia, cognitive disorder or depressed treatment.

Perhaps, mentioning when producing 11 β HSD1 inhibitory action, this is meant the treatment of cognitive disorder, as improves individual cognitive competence, for example through improving verbal fluency property, nonverbal memory or logical memory, or is used to treat mild cognitive impairment.Referring to for example WO03/086410 and wherein contained list of references, and Proceedings of National Academy of Sciences (PNAS), 2001,98 (8), 4717-4721.

Perhaps; When mentioning generation 11 β HSD1 inhibitory action, this is meant atherosclerosis therapy, postpones atherosclerotic outbreak and/or reduces atherosclerotic risk---referring to for example J.Experimental Medicine, 2005; 202 (4), 517-527.

Perhaps, when mentioning generation 11 β HSD1 inhibitory action, this is meant the treatment of Alzheimer's disease and/or neurodegenerative disease.

Further characteristic according to this aspect of the invention provides in homoiothermic animal (like the people) body of this type of needs treatment, to produce the inhibiting method of 11 β HSD1, and it comprises the compound or pharmaceutically acceptable salt thereof of said animal being used the formula (1) of effective dose.

Except their application in medicine; The compound or pharmaceutically acceptable salt thereof of formula (1) also can be used as the part of the exploration of new therapeutic agent as exploitation and the pharmacological tool in the standardization external and the in vivo test system, and said external and in vivo test system are used for evaluating and testing at laboratory animal (for example cat, Canis familiaris L., rabbit, monkey, rat and mice) effect of 11 beta hsd 1 inhibitors.

The inhibition of 11 β HSD1 as herein described can be used as unique therapy and uses, or except theme of the present invention, can also comprise one or more other material and/or treatments.This type therapeutic alliance can independently be treated part time, use and realize in succession or separately through each.Treatment can be in the monolithic agent or in the tablet that is separating simultaneously.For example, can comprise following main treatment classification with the medicament of 11 beta hsd 1 inhibitors, particularly those administering drug combinations of the present invention:

1) insulin and insulin analog;

2) insulin secretagogue comprises sulfonylureas (for example glibenclamide, glipizide), meals glucose regulator (for example repaglinide, Nateglinide), glucagon-like peptide 1 agonist (GLP1 agonist) (for example exenatide, Li Lalu peptide) and inhibitors of dipeptidyl IV (DPP-IV inhibitor);

3) euglycemic agent comprises PPAR gamma agonist (for example pioglitazone and rosiglitazone);

4) suppress the medicament (for example metformin) that hepatic glucose is exported;

5) be designed to reduce medicament (for example acarbose) from the glucose absorption of intestinal;

6) be designed to treat the medicament of the complication of long-term hyperglycemia, for example aldose reductase inhibitor

7) other anti-diabetic medicament; Comprise phosotyrosine inhibitors of phosphatases, glucose 6-inhibitors of phosphatases, glucagon receptor antagonist, activators of glucokinase, glycogen phosphorylase inhibitors, fructose 1,6 bisphosphatase inhibitor, glutamine: D-fructose-6-phosphoric acid salt transamination enzyme inhibitor;

8) antiadipositas drug (for example sibutramine and orlistat);

9) the unusual medicine of antilipemic is like HMG-CoA reductase inhibitor (Statins, for example pravastatin); PPAR alfa agonists (special type of shellfish, for example gemfibrozil); Bile acid chelating agent (cholestyramine); Cholesterol absorption inhibitor (phytostanol, synthetic inhibitor); Ileal bile acid absorption inhibitor (IBATi), cetp inhibitors and nicotinic acid and analog (nicotinic acid and slow releasing preparation);

10) antihypertensive is like Beta receptor blockers (for example atenolol, propranolol); ACE inhibitor (for example lisinopril); Calcium antagonist (for example nifedipine); Angiotensin receptor antagonist (for example Candesartan), alpha-2 antagonists and diuretic (for example FRS, benzthiazide);

11) hemostasis regulator is like antithrombotic, fibrinolysis activator and antiplatelet drug; The thrombin antagonist; The Xa factor inhibitor; The VIIa factor inhibitors; Antiplatelet drug (for example aspirin, clopidogrel); Anticoagulant (heparin and low-molecular-weight analog, hirudin) and warfarin;

12) anti-inflammatory agent is like nonsteroidal anti-inflammatory (for example aspirin) and steroid anti-inflammatory agent (for example corticosterone); With

13) prevent that glucose is by the resorbent medicament of kidney (SGLT inhibitor).

In above-mentioned other medicines compositions, technology, method, purposes and pharmacy characteristic, the alternative and preferred embodiment of chemical compound of the present invention as herein described also is suitable for.

Embodiment

Pass through the present invention of the following example illustration now, wherein, only if indicate separately, otherwise:

(i) temperature with degree centigrade (℃) provide; In room temperature or ambient temperature, promptly 18-25 ℃ temperature with under inert atmosphere (like argon), operate;

(ii) use rotary evaporator at decompression (600-4000Pa; 4.5-30mmHg) under carry out the evaporation of solvent at the highest 60 ℃ bath relaxing the bowels with purgatives of warm nature;

(iii) chromatography is meant the flash chromatography on silica gel;

(iv) common, through TLC following response process, and only exemplary providing of response time;

(v) yield only exemplary provide and be not necessarily through the process exploitation of making great efforts the value that can realize; More if desired materials repeat preparation;

(vi) provide the NMR data ( ¹H) time, it is a Δ value form of mainly diagnosing proton, provide with 1,000,000/umber (ppm) with respect to tetramethylsilane (TMS), 300 or 400MHz (only if indicating separately) use down full deuterium dimethyl sulfoxine (DMSO-d ₆) measure as solvent (only if indicating separately); Show peak multiformity: s thus, unimodal; D, doublet; Dd, doublet of doublet; Dt, two triplets; Dm, two multiplets; T, triplet; M, multiplet; Br, wide;

(vii) chemical symbol has their its ordinary meaning; Use SI units and symbol;

(viii) the solvent ratio is in volume: volume (v/v);

(ix) using directly, exposure probe (direct exposure probe) moves mass spectrum (MS) with chemi-ionization (CI) pattern with 70 electron-volts electronic energies; Ionization shown in wherein realizing through electron bombardment (EI), fast atom bombardment (FAB) or electron spray (ESP); Provide the value of m/z; Usually, only report the ion of indication parent quality.

(x) can use following abbreviation hereinafter or in the said method part:

Et ₂The O diethyl ether

The DMF dimethyl formamide

The DCM dichloromethane

DME 1, the 2-dimethoxy-ethane

MeOH methanol

EtOH ethanol

The TFA trifluoroacetic acid

The THF oxolane

The DMSO dimethyl sulfoxine

The HOBT I-hydroxybenzotriazole

EDCI (EDAC) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

The DIPEA diisopropyl ethyl amine

The DMAP 4-dimethylaminopyridine

The DEAD diethylazodicarboxylate

The EtOAc ethyl acetate

MgSO ₄Magnesium sulfate

The MTBE methyl tertiary butyl ether(MTBE)

NaHMDS hexamethyl two silicon Azide (disalazide) sodium

Embodiment 1

4-[4-((1R, 2S, 3S, 5S)-5-hydroxyl-diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrrole Azoles-1-yl]-benzoic acid

With 4-[4-((1R; 2S; 3S, 5S)-5-hydroxyl-diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-essence of Niobe (0.34 mM) (intermediate #1) is dissolved in the methanol (10 milliliters) and handles with 2M sodium hydroxide solution (0.84 milliliter, 1.7 mMs).This mixture was stirred 24 hours at ambient temperature, under reduced pressure remove methanol then through evaporation.Residue is dissolved in the water (10 milliliters), is acidified to pH4 with 2M HCl and also extracts with EtOAc (2 * 10 milliliters).With the extract water (10 milliliters) that merges and saline (10 milliliters) washing and dry (MgSO ₄) and evaporate the title compound (74 milligrams, 48%) that stays white solid.

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.66(3H，t)，1.18-1.30(2H，m)，1.42(2H，d)，1.58-1.80(6H，m)，1.88(2H，d)，2.06(3H，s)，2.62(2H，t)，3.95-4.06(1H，m)，4.42(1H，s)，7.71(2H，d)，7.95(1H，d)，8.09(2H，d)，8.16(1H，s)，13.19(1H，s)

MS?m/z?456M+H

Embodiment 2

4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid

With (190 milligrams of 4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] essence of Niobe; 0.42 mM) (intermediate #2) is dissolved in the methanol (10 milliliters) and uses 2M sodium hydrate aqueous solution (1.05 milliliters, 2.1 mMs) to handle at ambient temperature.This mixture was stirred 18 hours at ambient temperature, be heated to 65 ℃ then and kept again 2 hours.Vapourisation under reduced pressure removes methanol and water (25 milliliters) dilutes this clear solution.Adding 2M HCl extracts with ethyl acetate (2 * 25 milliliters) until pH4 and this mixture.With extract water (2 * 10 milliliters) that merges and saline (10 milliliters) washing, dry (MgSO ₄) and evaporate the title compound that produces white solid.(174 milligrams, 94%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.65(3H，t)，1.17-1.29(2H，m)，1.60(2H，d)，1.73(2H，s)，1.83(6H，s)，1.91-2.05(4H，m)，2.62(2H，t)，4.09(1H，d)，7.75(2H，d)，8.03(1H，d)，8.13(2H，d)，8.20(1H，s)

MS?m/z?440M+H

Embodiment 3

4-[4-(1-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid

4-[4-(1-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] essence of Niobe (143 milligrams, 0.32 mM) (intermediate #3) is dissolved in the methanol, and handles with the 2M sodium hydrate aqueous solution at ambient temperature.This mixture was stirred 18 hours at ambient temperature.Vapourisation under reduced pressure removes methanol and water (25 milliliters) dilutes this clear solution.Adding 2M HCl extracts with ethyl acetate (2 * 25 milliliters) until pH4 and this mixture.With extract water (2 * 10 milliliters) that merges and saline (10 milliliters) washing, dry (MgSO ₄) and evaporate the title compound (132 milligrams, 94%) that produces white solid.

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.69(3H，t)，1.25(2H，q)，1.66(6H，s)，2.06(9H，s)，2.65(2H，t)，7.51(1H，s)，7.66-7.69(2H，m)，8.07-8.10(3H，m)

MS?m/z?440M+H

Embodiment 4

4-[4-(N-cyclohexyl-N-methyl-carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid

With (162 milligrams of 4-[4-(cyclohexyl-methyl-carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] essence of Niobe (intermediate #4); 0.39 mM) be dissolved in the methanol (10 milliliters); And use 2M sodium hydrate aqueous solution (0.96 milliliter, 1.95 mMs) to handle at ambient temperature.This mixture was stirred 18 hours at ambient temperature.Vapourisation under reduced pressure removes methanol and water (25 milliliters) dilutes this clear solution.Adding 2M HCl extracts with ethyl acetate (2 * 25 milliliters) until pH4 and this mixture.With extract water (2 * 10 milliliters) that merges and saline (10 milliliters) washing, dry (MgSO ₄) and the evaporation generation foamed title compound of white solid (150 milligrams, 96%).

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.68(3H，t)，1.10-1.41(4H，m)，1.42-1.85(8H，m)，2.58(2H，t)，2.86(3H，s)，3.45-3.60(0.5H.m)，4.21-4.38(0.5H，m)，7.74(2H，d)，7.89(1H，s)，8.09(2H，d)

MS?m/z?402M+H

Embodiment 5

4-[4-(oxirane-4-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid

With (104 milligrams of 4-[4-(oxirane-4-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] essence of Niobe (intermediate #5); 0.26 mM) be dissolved in the methanol (5 milliliters); And use 2M sodium hydrate aqueous solution (0.65 milliliter, 1.29 mMs) to handle at ambient temperature.This mixture was stirred 18 hours at ambient temperature.Vapourisation under reduced pressure removes methanol and water (25 milliliters) dilutes this clear solution.Adding 2M HCl extracts with ethyl acetate (2 * 25 milliliters) until pH4 and this mixture.With extract water (2 * 10 milliliters) that merges and saline (10 milliliters) washing, dry (MgSO ₄) and evaporate the product (89 milligrams, 85%) that produces white solid.

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.68(3H，t)，1.19-1.31(2H，m)，1.47-1.56(2H，m)，1.77-1.81(2H，m)，2.71(2H，t)，3.29-3.43(2H，m)，3.85-3.89(2H，m)，3.94-4.04(1H，m)，7.67(2H，d)，8.03(1H，d)，8.09(2H，d)，8.16(1H，s)

MS?m/z?390M+H

Embodiment 6

4-[5-propylthio alkyl-4-[3-[2-(trifluoromethyl) phenyl] pyrrolidine-1-carbonyl] pyrazol-1-yl] benzene Formic acid

With (177 milligrams of 4-[5-propylthio alkyl-4-[3-[2-(trifluoromethyl) phenyl] pyrrolidine-1-carbonyl] pyrazol-1-yl] essence of Niobe (intermediate #6); 0.34 mM) in the mixture of methanol (5 milliliters) and 2M sodium hydroxide (0.855 milliliter, 1.71 mMs), stirred at ambient temperature 18 hours.Evaporation reaction mixture is to remove methanol.Residue is dissolved in the water (20 milliliters) and is acidified to pH4 with 2M HCl.Filtered and recycled gained white depositions is with water washing and dry to produce the title compound (116 milligrams, 68%) of white solid under vacuum.

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.64(3H，q)，1.14-1.26(2H，m)，1.67-1.76(1H，m)，1.89-1.98(2H，m)，2.42-2.59(3H，m)，3.62-3.82(1H，m)，3.93-4.01(1H，m)，5.24-5.43(1H，m)，7.43-7.48(2H，m)，7.58-7.75(4H，m)，8.00-8.20(3H，m)，13.18(1H，s)

MS?m/z?503M+H

Embodiment 7

4-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid

4-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] essence of Niobe (363 milligrams, 0.94 mM) (intermediate #11) is dissolved in the methanol (20 milliliters), and uses 2M sodium hydrate aqueous solution (2.35 milliliters) to handle at ambient temperature.This mixture was stirred 18 hours at ambient temperature, and vapourisation under reduced pressure is removed volatile matter then.Residue is dissolved in the water (25 milliliters) and adds 2M HCl until pH=4.This mixture is washed dry (MgSO with ethyl acetate (2 * 25 milliliters) extraction and with extract water (2 * 10 milliliters) that merges and saline (10 milliliters) ₄) and evaporate the title product that produces white solid.(300 milligrams, 85%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.68(3H，t)，1.14-1.39(7H，m)，1.57-1.61(1H，m)，1.72(2H，d)，1.84(2H，d)，2.70(2H，t)，3.75-3.78(1H，m)，7.65-7.69(2H，m)，7.90-7.93(1H，m)，8.07-8.13(2H，m)，8.14(1H，s)，13.20(1H，s)

MS?m/z?388M+H

Embodiment 8

3-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] benzoic acid

With (175 milligrams of 3-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] essence of Niobe; 0.45) (intermediate #12) be dissolved in the methanol (10 milliliters), handle and stirred at ambient temperature 18 hours with 2M sodium hydrate aqueous solution (1.125 milliliters).Vapourisation under reduced pressure removes methanol and water (25 milliliters) dilutes this clear solution.Adding 2M HCl extracts with ethyl acetate (2 * 25 milliliters) until pH4 and this mixture.With extract water (2 * 10 milliliters) that merges and saline (10 milliliters) washing, dry (MgSO ₄) and evaporate the title product that produces white solid.(115 milligrams, 65%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.67(3H，t)，1.14-1.39(7H，m)，1.57-1.61(1H，m)，1.70(2H，d)，1.82-1.85(2H，m)，2.70(2H，t)，3.74-3.79(1H，m)，7.66-7.71(1H，m)，7.78-7.82(1H，m)，7.91(1H，d)，8.03-8.06(2H，m)，8.13(1H，s)，13.29(1H，s)

MS?m/z?388M+H

Embodiment 9

4-[4-(cyclohexyl carboxyamide base)-5-propyl-pyrazole-1-yl] benzoic acid

4-[4-(cyclohexyl carboxyamide base)-5-propyl-pyrazole-1-yl] ethyl benzoate (130 milligrams, 0.34 mM) (intermediate #21) is dissolved in the methanol (10 milliliters), and uses 2M sodium hydrate aqueous solution (2.5 milliliters) to handle at ambient temperature.This mixture was stirred 18 hours at ambient temperature, and vapourisation under reduced pressure is removed methanol then.Residual water solution is acidified to pH=2 with the 2M aqueous hydrochloric acid solution.From solution, be settled out white solid, with its filtration, dry and to confirm as be required product (120 milligrams, quantitative response) under vacuum.

¹H?NMR(400.13MHz，DMSO-d ₆)δ0.73(3H，t)，1.12(1H，m)，1.23-1.31(1H，m)，1.28(3H，m)，1.36-1.43(2H，m)，1.59-1.63(1H，m)，1.73(2H，d)，1.80(2H，s)，2.97(2H，t)，3.73(1H，m)，7.59-7.61(2H，d)，7.95(1H，d)，8.09-8.11(2H，d)，8.21(1H，s)，13.27(1H，s)

MS?m/z?356M+H

Embodiment 10

4-[4-(cyclohexyl-methyl-carbamoyl)-5-propyl-pyrazole-1-yl] benzoic acid

4-[4-(cyclohexyl-methyl-carbamoyl)-5-propyl-pyrazole-1-yl] ethyl benzoate (intermediate #23,105 milligrams, 0.26 mM) is dissolved in the methanol (10 milliliters), and uses 2M sodium hydrate aqueous solution (2.5 milliliters) to handle at ambient temperature.This mixture was stirred 18 hours at ambient temperature, and vapourisation under reduced pressure is removed methanol then.Residual water solution is acidified to pH=2 with the 2M aqueous hydrochloric acid solution.From solution, be settled out white solid, with its filtration, dry and to confirm as be required product (96 milligrams, quantitative response) under vacuum.

¹H?NMR(400.13MHz，DMSO-d ₆)δ0.71(3H，t)，1.12-1.50(6H，m)，1.59-1.77(6H，m)，2.79(2H，t)，2.89(3H，s)，7.45-7.65(1H，m)，7.67(2H，d)，7.84-7.86(1H，m)，8.10(2H，d)，13.24(1H，s)

MS?m/z?370M+H

Embodiment 11

4-[4-(cyclohexyl carboxyamide base)-5-cyclopropyl-pyrazol-1-yl] benzoic acid

With (111 milligrams of 1-(4-bromophenyl)-N-cyclohexyl-5-cyclopropyl-pyrazole-4-carboxamide (intermediate #25); 0.29 mM), hexacarbonylmolybdenum is (38 milligrams; 0.14 mM), DMAP is (70 milligrams; 0.57 mM), DIPEA is (74 milligrams; 0.57 mM) and trans-two (acetate closes (acetato)) two [o-(two-o-tolyl phosphino-) benzyl] two palladiums (II) (14 milligrams, 0.015 mM) add in the microwave tube and be suspended in dioxane (2 milliliters) and the mixture of ethanol (2 milliliters) in.With this pipe add a cover and be heated to 150 ℃ 1 hour.Reactant mixture is evaporated to dried, residue is dissolved among the DCM (10 milliliters).Add 2MHCl (10 milliliters), this mixture of shake and through the filter that is separated.DCM solution is dried is loaded on the Ceelite with this, and through reclaiming product (gradient 0-50%EtOAc is in hexane) at the flash chromatography on the silica gel.Merge the product that pure fraction and evaporation produce white solid.This white solid is dissolved in the methanol (5 milliliters), handles and stirred at ambient temperature 5 hours with 2M NaOH solution (1 milliliter).With the reactant mixture concentrating under reduced pressure, water (20 milliliters) dilution with ether (2 * 10 milliliters) washing, is acidified to pH4 with 2M HCl and also extracts with EtOAc (3 * 10 milliliters).With extract water (10 milliliters) washing that merges, dry (MgSO4) and 4-[4-(cyclohexyl carboxyamide the base)-5-cyclopropyl-pyrazol-1-yl] benzoic acid of evaporation so that white solid to be provided.(40 milligrams, 40%)

According to the similar mode of embodiment #11, use suitable bromophenyl raw material preparing the following example:

Embodiment 16

2-[4-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] phenyl] acetic acid

With (210 milligrams of 2-[4-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] phenyl] methyl acetates (intermediate #33); 0.51 mM) be dissolved in the methanol (10 milliliters) and use at ambient temperature 2M sodium hydroxide solution (1.27 milliliters, 2.53 mMs) to handle.With this mixture stirred overnight, vapourisation under reduced pressure is removed methanol then.This clear aqueous solution water (20 milliliters) dilutes and is acidified to pH3 with 2M HCl.The gained white depositions is extracted in the ethyl acetate (2 * 20 milliliters).The extract that merges is with saline (10 milliliters) washing, and dry (MgSO4) and evaporation produce crude product.Make the polarity of water (containing 0.1%NH3) and MeCN successively decrease mixture as eluant through preparation HPLC purification of crude product.The fraction that will contain required compound is evaporated to be done so that 2-[4-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] phenyl] to be provided acetic acid.(84 milligrams, 41%)

1H?NMR(400.13MHz，DMSO-d ₆)δ0.72(3H，t)，1.20-1.36(7H，m)，1.60(1H，d)，1.73(2H，d)，1.85(2H，d)，2.69(2H，t)，3.69(2H，s)，3.77(1H，d)，7.42-7.47(4H，m)，7.86(1H，d)，8.10(1H，s)

MS?m/z(ESI+)(M+H)+402

Embodiment 17

2-[4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] phenyl] acetic acid

With (220 milligrams of 2-[4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] phenyl] methyl acetates (intermediate #34); 0.47 mM) be dissolved in the methanol (10 milliliters) and use at ambient temperature 2M sodium hydroxide solution (1.17 milliliters, 2.35 mMs) to handle.With this mixture stirred overnight, vapourisation under reduced pressure is removed methanol then.This clear aqueous solution water (20 milliliters) dilutes and is acidified to pH3 with 2M HCl.The gained white depositions is extracted in the ethyl acetate (2 * 20 milliliters).The extract that merges is with saline (10 milliliters) washing, and dry (MgSO4) and evaporation produce crude product.Make the polarity of water (containing 0.1%NH3) and MeCN successively decrease mixture as eluant through preparation HPLC purification of crude product.The fraction that will contain required compound is evaporated to be done so that 2-[4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] phenyl] to be provided acetic acid (66 milligrams, 31%).

1H?NMR(400.13MHz，DMSO-d ₆)δ0.70(3H，t)，1.23-1.32(2H，m)，1.62(2H，d)，1.74(2H，s)，1.86(6H，d)，1.99(4H，d)，2.62(2H，t)，3.70(2H，s)，4.11(1H，d)，7.45(2H，d)，7.50-7.52(2H，m)，8.02(1H，d)，8.12(1H，s)

MS?m/z(ESI+)(M+H)+454

Embodiment 18

4-(4-cyclohexyl carboxyamide base-5-propylthio alkyl-pyrazol-1-yl methyl)-benzoic acid

With (116 milligrams of 4-(4-cyclohexyl carboxyamide base-5-propylthio alkyl-pyrazol-1-yl methyl)-essence of Niobe; 0.28 (intermediate #40) and LiOH (47 milligrams, the 1.12 mMs) solution in MeOH (2 milliliters)/water (1 milliliter) stirred overnight at ambient temperature mM).Remove most of MeOH in a vacuum and handle gained solution, use EtOAc (2 *～15 milliliters) extraction then with citric acid (～10 milliliters).Merge organic layer, with saline (～10 milliliters) washing, dry (MgSO ₄), filter and evaporate the title compound (102 milligrams, 91%) of generation white solid.

1H?NMR(700.03MHz，CDCl ₃)δ0.89(3H，t)，1.22-1.30(4H，m)，1.41-1.46(2H，m)，1.48-1.53(2H，m)，1.62-1.64(1H，m)，1.71-1.73(1H，m)，1.98-2.00(2H，m)，2.56(2H，t)，3.99-4.04(1H，m)，5.59(2H，s)，7.27(2H，d)，7.37(1H，d)，8.05(2H，d)，8.16(1H，s)

MS?m/e?MH ⁺402。

Use said procedure to make the following example, but substitute 4-(4-cyclohexyl carboxyamide base-5-propylthio alkyl-pyrazol-1-yl methyl)-essence of Niobe with corresponding raw material

Embodiment 22

4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid

2M sodium hydrate aqueous solution (51.7 milliliters, 103.32 mMs) is added in 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] essence of Niobe (intermediate #56) (4.5 grams, 10.33 mMs) in methanol (100 milliliters).This mixture was stirred 1 hour down at 70 ℃, be cooled to ambient temperature then, concentrating under reduced pressure and water (100 milliliters) dilution.Reactant mixture is adjusted to pH 3 with 2M HCl.This reactant mixture is with EtOAc (500 milliliters) extraction and water (2 * 100 milliliters) and saturated brine (50 milliliters) washing in succession.Organic layer is dry through MgSO4, filters and evaporation generation light yellow solid.This solid is with EtOAc (20 milliliters) washing, and filtration is collected and be dry to produce 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid (3.89 grams, 89%) as white emulsus crystalline solid under vacuum.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.19(9H，s)，1.49(2H，d)，1.70-1.96(10H，m)，2.09(2H，d)，3.98-4.01(1H，m)，7.49-7.53(2H，m)，7.61(1H，s)，8.06-8.09(2H，m)，8.20(1H，d)，13.30(1H，s)

m/z(ESI+)(M+H)+＝422

M.p.308.8 ℃ (beginning)

Also can be prepared as follows embodiment 22:

Sodium hydrate aqueous solution (2M) (2.5 equivalent) was added in the suspension of 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] stirring of essence of Niobe (intermediate #56) (1.0 equivalent) in methanol (10vol) by part through 5 minutes down at 20 ℃ (heat release 20-27 ℃).The gained suspension is heated to 70 ℃ (sheath temperature), (in approximately 60-65 ℃ of following batch of backflow) 1 hour (accomplishing) through LCMS.This orange reaction mixture is cooled to 20 ℃ (solution still slightly muddy) and filters to remove small amount of solid through celite.Then filtrating is poured into flange (flange) flask and added entry (25vol).Then this mixture is adjusted to pH 3 (very thickness becomes) with 2M HCl (approximately 800-850 milliliter).Filter this aqueous solution then and light yellow solid is used water washing; Blot whole night; And with acetonitrile with final with acetonitrile/diethyl ether washing in 1: 1, and under vacuum 50 ℃ of down dry 72 hours (weekends) 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid (80%) with the generation solid, shaped.

The about 50 milligrams of 4-that as above process [4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid (form 1) is contained in the phial that has magnetic stirring bar, and adds about 2 milliliters of acetonitriles.Then this phial is used sealing of lid.Then this slurry is stirred down at 50 ℃ in the heating stirrer with magnetic stirring capacity.After 3 days, take off sample from this plate, take off lid, and make slurry dry under environmental condition, then through XRPD and dsc analysis.Confirm that through XRPD this form (form 2) is crystalline, and find out and be different from last form.This material has the fusing point of 310.3 ℃ (beginnings).It has the 2 θ peaks at 18.0 and 17.7 places that use the CuKa radiation to record.

About 20 milligrams of 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid (form 1) is contained in the phial that has magnetic stirring bar; And add about 2 ml methanol; Then this phial is used sealing of lid, and on the magnetic agitating plate, stir.After 3 days, take off sample from this plate, take off lid, and make slurry dry under environmental condition, then through XRPD and dsc analysis.Confirm that through XRPD this form (form 3) is crystalline, and find out be different from before observed form.This material has the fusing point of 309.4 ℃ (beginnings).It has the 2 θ peaks at 18.7 and 11.7 places that use the CuKa radiation to record.

4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid of about 20 milligrams of forms 1 and the material of 20 milligrams of forms 3 are contained in the phial that has magnetic stirring bar; And add about 2 milliliters of ethyl acetate; Then this phial is used sealing of lid, and on the magnetic agitating plate, stir.After 3 days, take off sample from this plate, take off lid, and make slurry dry under environmental condition, then through XRPD and dsc analysis.Confirm that through XRPD this form (form 4) is crystalline, and find out be different from before observed form.This material (form 4) has the fusing point of 309.1 ℃ (beginnings).It has the 2 θ peaks at 16.2 and 20.6 places that use the CuKa radiation to record.

The 4-that as above processes [4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid (form 1) is suspended in the acetonitrile (7vol) inoculation 5 grams (form 4) and slurrying 3 days (85 ℃ of sheath temperature) under refluxing.Take out sample and check (showing 2 peaks) through DSC.Sample refluxing down 3 days (weekend) of restir, is cooled to 20 ℃, filters, with acetonitrile diethyl ether washing then, blot and under vacuum 50 ℃ down dry 48 hours to produce light yellow solid (form 4) (960 restrain 90%).

Embodiment 23

4-[4-(2-adamantyl carbamoyl)-5-(1-methyl cyclopropyl) pyrazol-1-yl] benzoic acid

With (8.45 milliliters of 2N sodium hydrate aqueous solutions; 16.90 mM) at room temperature add 4-[4-(2-adamantyl carbamoyl)-5-(1-methyl cyclopropyl) pyrazol-1-yl] essence of Niobe (intermediate #57) to; 1.221 gram, 2.82 mMs) in the agitating solution in methanol (25 milliliters).Gained solution was stirred 1 hour down and stirred overnight at room temperature at 70 ℃.

Reactant mixture is evaporated to dried, is dissolved in again in the water (15 milliliters) and with 2M HCl (10 milliliters) acidify.Be extracted into reactant mixture among the EtOAc (75 milliliters) then and water (10 milliliters) and saturated brine (10 milliliters) washing in succession.Organic layer is dry through MgSO4, filters and 4-[4-(2-adamantyl carbamoyl)-5-(the 1-methyl cyclopropyl) pyrazol-1-yl] benzoic acid (1.055 grams, 89%) of evaporation so that white solid to be provided.

m/z(ESI+)(M+H)+＝420；HPLC?t _R＝2.56min.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.51-0.53(2H，m)，0.68-0.69(2H，m)，1.54-1.58(5H，m)，1.73(2H，s)，1.84-1.87(6H，m)，1.95-1.99(2H，m)，2.06(2H，d)，4.03-4.09(1H，m)，7.44(1H，d)，7.67(2H，d)，8.06(1H，s)，8.11(2H，d)，13.16(1H，s)

Embodiment 24

4-[4-(2-adamantyl carbamoyl)-5-cyclopenta-pyrazol-1-yl] benzoic acid

With (4.10 milliliters of 2N sodium hydrate aqueous solutions; 8.19 mM) at room temperature add 611 milligrams of 4-[4-(2-adamantyl carbamoyl)-5-cyclopenta-pyrazol-1-yl] essence of Niobe (intermediate #62), 1.37 mMs to) in the agitating solution in methanol (15 milliliters).Gained solution was stirred 1 hour down at 70 ℃.

Reactant mixture is evaporated to dried, is dissolved in again in the water (15 milliliters) and with 2M HCl (6 milliliters) acidify.Filter the gained suspension then.With the product that reclaims with water washing (10 milliliters) and under vacuum dry 4-[4-(2-adamantyl carbamoyl)-5-cyclopenta-pyrazol-1-yl] benzoic acid (576 milligrams, 97%) with the generation white solid.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.43-1.55(4H，m)，1.74-1.85(12H，m)，1.94(2H，s)，2.03-2.12(4H，m)，2.99-3.08(1H，m)，3.98-4.03(1H，m)，7.53-7.55(2H，m)，7.74(1H，d)，8.09(1H，s)，8.10-8.12(2H，m)，13.30(1H，s)

m/z(ESI+)(M+H)+＝434；HPLC?t _R＝2.80min

With the used identical method of embodiment #24 by suitable intermediate preparation the following example.

Embodiment 28

4-[4-(2-adamantyl carbamoyl)-5-methyl-pyrazol-1-yl] benzoic acid

With (24.28 milliliters of 1M sodium hydroxide solutions; 24.28 mM) add in the suspension of the stirring of N-(2-adamantyl)-1-(4-cyano-phenyl)-5-methyl-pyrazole-4-carboxamide (intermediate #66) (1.25 grams, 3.47 mMs) in dioxane (25 milliliters).The gained suspension was stirred 7 hours down at 100 ℃.Reactant mixture is concentrated, and water (40 milliliters) dilutes, and filters through celite.Filtrating is with the acidify of 1M citric acid.The filtered and recycled precipitate is with water washing (3 * 20 milliliters) and dry down at 50 ℃ under vacuum.Through preparation HPLC (Phenomenex Gemini C18 110A (axia) post, 5 μ silicon dioxide, 30 mm dias, 100 mm lengths), make the polarity of water (containing 1% formic acid) and MeCN successively decrease chemical compound as this crude product of eluant purification.The fraction that will contain required compound is evaporated to 4-[4-(2-adamantyl the carbamoyl)-5-methyl-pyrazol-1-yl] benzoic acid of doing so that the yellow powder powder to be provided (550 milligrams, 42%).

1H?NMR(400.13MHz，DMSO-d ₆)δ1.45-1.54(2H，m)，1.70-1.88(8H，m)，1.90-2.00(2H，m)，2.05-2.18(2H，m)，2.56(3H，s)，4.00-4.10(1H，m)，7.57(1H，d)，7.67(2H，d)，8.11(2H，d)，8.29(1H，s)，13.25(1H，s)m/z(ESI+)(M+H)+＝380；

Embodiment 29

4-(the 5-tert-butyl group-4-(cyclohexyl carboxyamide base)-1H-pyrazol-1-yl) benzoic acid

With (132 milligrams of 1-(4-bromophenyl)-5-tert-butyl groups-N-cyclohexyl-1H-pyrazole-4-carboxamide (intermediate #82); 0.33 mM), hexacarbonylmolybdenum is (43.1 milligrams; 0.16 mM), trans-two (acetate closes) two [o-(two-o-tolyl phosphino-) benzyl] two palladiums (II) are (15.34 milligrams; 0.02 mM), 4-dimethylaminopyridine is (80 milligrams; 0.65 mM) and N-ethyl diisopropyl amine (0.113 milliliter, 0.65 mM) be suspended in dioxane (4 milliliters) and the water (1 milliliter) and be sealed in the microwave tube.To be reflected at and be heated to 150 ℃ of maintenances in the microwave reactor 1 hour and be cooled to RT.This reactant mixture is adjusted to pH3 with 2M HCl then, and filters through celite with DCM (20 milliliters) and water (10 milliliters) dilution.Separate organic layer, dry through MgSO4, filtration and evaporation are to provide crude product.

Through the preparation reversed-phase HPLC, make mixture that the polarity of water (containing 0.1%NH3) and MeCN successively decreases as eluant purification of crude product.The fraction that will contain required compound is evaporated to 4-(the 5-tert-butyl group-4-(cyclohexyl carboxyamide the base)-1H-pyrazol-1-yl) benzoic acid of doing so that white solid to be provided (18 milligrams, 14.92%).

1H?NMR(400.13MHz，DMSO-d6)δ1.15(1H，s)，1.20(9H，s)，1.25-1.4(4H，m)，1.58(1H，s)，1.71-1.74(2H，m)，1.82(2H，d)，3.18(1H，s)，7.48-7.50(2H，m)，7.60(1H，s)，8.05-8.10(3H，m)

m/z(ESI+)(M+H)+＝370

Embodiment 30

4-[4-(2-adamantyl carbamoyl)-5-cyclohexyl sulfane base-pyrazol-1-yl] benzoic acid

With (1.671 milliliters of 2M sodium hydrate aqueous solutions; 3.34 mM) in disposable 4-[4-(2-adamantyl the carbamoyl)-5-cyclohexyl sulfane base-pyrazol-1-yl] essence of Niobe (intermediate #84) (330 milligrams, 0.67 mM) that adds in methanol (10 milliliters).The gained mixture was stirred 18 hours down at 20 ℃.Concentrating reactant mixture also, water (50 milliliters) dilutes and washs with ether (20 milliliters).This aqueous solution is adjusted to pH 3 also with EtOAc (2 * 25 milliliters) extraction with 2M HCl, with the extract that merges water (2 * 20 milliliters) and saturated brine (20 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide 4-[4-(2-adamantyl carbamoyl)-5-cyclohexyl sulfane base-pyrazol-1-yl] benzoic acid (321 milligrams, 100%).

1H?NMR(400.13MHz，DMSO-d6)δ1.01-1.11(5H，m)，1.41(1H，s)，1.50-1.57(4H，m)，1.64(2H，d)，1.75(2H，s)，1.85(6H，s)，1.93-2.05(4H，m)，2.94(1H，s)，4.12(1H，d)，7.72-7.76(2H，m)，8.05(1H，d)，8.10-8.13(2H，m)，8.18(1H，s)，13.20(1H，s)

m/z(ESI+)(M+H)+＝480

According to the similar mode of embodiment #30, use suitable ester raw material preparing the following example.

Embodiment 34

4-[4-(2-adamantyl carbamoyl)-5-cyclopenta sulfane base-pyrazol-1-yl] benzoic acid

With (1.694 milliliters of 2M sodium hydrate aqueous solutions; 3.39 mM) in disposable 4-[4-(2-adamantyl the carbamoyl)-5-cyclopenta sulfane base-pyrazol-1-yl] essence of Niobe (intermediate #90) (325 milligrams, 0.68 mM) that adds in methanol (10 milliliters).The gained mixture was stirred 18 hours down at 20 ℃.Reactant mixture is concentrated and water (50 milliliters) dilution, wash with ether (20 milliliters).This aqueous solution is adjusted to pH 3 also with EtOAc (2 * 25 milliliters) extraction with 2M HCl, with the extract that merges water (2 * 20 milliliters) and saturated brine (20 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide 4-[4-(2-adamantyl carbamoyl)-5-cyclopenta sulfane base-pyrazol-1-yl] benzoic acid (307 milligrams, 97%).

1H?NMR(400.13MHz，DMSO-d6)δ1.17-1.25(2H，m)，1.41(4H，d)，1.65(4H，d)，1.74(2H，s)，1.85(6H，s)，1.96-2.02(4H，m)，3.31-3.33(1H，m)，4.12(1H，d)，7.75-7.77(2H，m)，8.08(1H，d)，8.10-8.15(2H，m)，8.19(1H，s)，13.20(1H，s)

m/z(ESI+)(M+H)+＝466

According to the similar mode of embodiment #34, use suitable ester raw material preparing the following example.

Embodiment 37

4-[4-[[5-(difluoro-methoxy)-2-adamantyl] carbamoyl]-5-propylthio alkyl pyrazole-1- Base] benzoic acid

With (2.050 milliliters of 2M sodium hydrate aqueous solutions; 4.10 mM) in disposable 4-[4-[[5-(difluoro-methoxy)-2-adamantyl] the carbamoyl]-5-propylthio alkyl pyrazole-1-yl] essence of Niobe (intermediate #95) (459 milligrams, 0.82 mM) that adds in methanol (10 milliliters).The gained mixture was stirred 18 hours down at 20 ℃, then 55 ℃ of following restir 4 hours.Reactant mixture is concentrated and water (50 milliliters) dilution, wash with ether (20 milliliters).This aqueous solution is adjusted to pH 3 also with EtOAc (2 * 25 milliliters) extraction with 2M HCl, with the extract that merges water (2 * 20 milliliters) and saturated brine (20 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide 4-[4-[[5-(difluoro-methoxy)-2-adamantyl] carbamoyl]-5-propylthio alkyl pyrazole-1-yl] benzoic acid (284 milligrams, 63.5%).

1H?NMR(400.13MHz，DMSO-d6)δ1.03-1.08(5H，m)，1.41-1.54(7H，m)，1.93(6H，d)，2.05(2H，d)，2.18(3H，d)，2.96(1H，d)，4.10(1H，t)，6.88(1H，t)，7.73(2H，d)，7.99(1H，d)，8.12(2H，d)，8.18(1H，s)，13.20(1H，s)

m/z(ESI+)(M+H)+＝506

Embodiment 38

4-[4-(cyclohexyl carboxyamide base)-5-cyclopenta sulfane base-pyrazol-1-yl] benzoic acid

With (4 milliliters of 2N sodium hydrate aqueous solutions; 8 mMs) at room temperature add 4-[4-(cyclohexyl carboxyamide base)-5-cyclopenta sulfane base-pyrazol-1-yl] essence of Niobe (intermediate #96) to; 233 milligrams, 0.55 mM) in the agitating solution in methanol (7 milliliters).With gained solution stirred overnight at room temperature.

Reactant mixture is evaporated to dry doubling is dissolved in again in the water (15 milliliters), and with 2M HCl (6 milliliters) acidify.Then reactant mixture is extracted in EtOAc (30 milliliters) and water (10 milliliters) and saturated brine (10 milliliters) washing in succession.Organic layer is dry through MgSO4, filters and 4-[4-(cyclohexyl carboxyamide the base)-5-cyclopenta sulfane base-pyrazol-1-yl] benzoic acid (217 milligram, 96%) of evaporation so that white solid to be provided.

m/z(ESI+)(M+H)+＝414

1H?NMR(400.13MHz，DMSO-d ₆)δ1.21-1.45(11H，m)，1.58-1.74(5H，m)，1.84-1.87(2H，m)，3.42-3.48(1H，m)，3.76-3.82(1H，m)，7.70(2H，d)，7.90-7.92(1H，d)，8.11(2H，d)，8.16(1H，s)，13.19(1H，s)

Embodiment 39

4-[4-(cyclohexyl carboxyamide base)-5-cyclohexyl sulfane base-pyrazol-1-yl] benzoic acid

By 4-[4-(cyclohexyl carboxyamide base)-5-cyclohexyl sulfane base pyrazol-1-yl] essence of Niobe (intermediate #97) through preparing 4-[4-(cyclohexyl carboxyamide base)-5-cyclohexyl sulfane base-pyrazol-1-yl] benzoic acid with the used identical method of embodiment #38

m/z(ESI+)(M+H)+＝428；HPLC?t _R＝2.67min.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.09(4H，m)，1.19-1.30(2H，m)，1.33-1.41(5H，m)，1.51-1.58(5H，m)，1.71-1.75(2H，m)，1.84-1.87(2H，m)，3.03-3.12(1H，m)，3.72-3.80(1H，m)，7.71(2H，d)，7.89-7.90(1H，d)，8.09-8.11(2H，m)，8.16(1H，s)，13.20(1H，s)

Embodiment 40

4-[5-suberyl sulfane base-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] benzoic acid

By 4-[5-suberyl sulfane base-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe (intermediate #98) through preparing 4-[5-suberyl sulfane base-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] benzoic acid with the used identical method of embodiment #38.

m/z(ESI+)(M+H)+＝442

1H?NMR(400.13MHz，DMSO-d6)δ1.16-1.52(15H，m)，1.58-1.67(3H，m)，1.71-1.75(2H，m)，1.84-1.87(2H，m)，3.30(1H，m)，3.78-3.81(1H，m)，7.67-7.70(2H，d)，7.90(1H，d)，8.09-8.12(2H，d)，8.16(1H，s)，13.18(1H，s)

Embodiment 41

4-[4-(2-adamantyl carbamoyl)-5-ethyl sulfane base-pyrazol-1-yl] benzoic acid

With (2.446 milliliters of 2M sodium hydrate aqueous solutions; 4.89 mM) in disposable 4-[4-(2-adamantyl the carbamoyl)-5-ethyl sulfane base-pyrazol-1-yl] essence of Niobe (intermediate #99) (430 milligrams, 0.98 mM) that adds in methanol (20 milliliters).The gained mixture was stirred 18 hours down at 20 ℃.Reactant mixture is concentrated, and water (50 milliliters) dilutes and is adjusted to pH 3 with 2M HCl.Filter the collecting precipitation thing, water (20 milliliters) washing and dry 4-[4-(2-adamantyl carbamoyl)-5-ethyl sulfane base-pyrazol-1-yl] benzoic acid (383 milligrams, 92%) under vacuum so that white solid to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.94(3H，t)，1.63(2H，d)，1.74(2H，s)，1.86(6H，d)，1.99(4H，d)，2.68(2H，q)，4.11(1H，t)，7.72-7.76(2H，m)，8.04(1H，d)，8.10-8.13(2H，m)，8.19(1H，s)，13.2(1H，s)

m/z(ESI+)(M+H)+＝426

Embodiment 42

4-[4-(2-adamantyl carbamoyl)-5-methyl sulfane base-pyrazol-1-yl] benzoic acid

By 4-[4-(2-adamantyl carbamoyl)-5-methyl sulfane base-pyrazol-1-yl] essence of Niobe (intermediate #100) through with the preparation of the used identical method of embodiment #41.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.61(2H，d)，1.74(2H，s)，1.86(6H，d)，2.00(4H，d)，2.30(3H，s)，4.11(1H，t)，7.72-7.75(2H，m)，8.01-8.04(1H，m)，8.10-8.14(2H，m)，8.19(1H，s)，13.2(1H，s)

m/z(ESI+)(M+H)+＝412

Embodiment 43

4-[4-(5-mesyl-diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]- Benzoic acid

With (27.5 milligrams of hydronium(ion) oxidation lithiums; 0.65 mM) add at ambient temperature in 4-[4-(5-mesyl-diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-suspension of essence of Niobe (intermediate #105) (116 milligrams, 0.22 mM) in methanol (4 milliliters)/water (2 milliliters).The gained suspension was stirred 18 hours at ambient temperature.Remove most of organic solvent in a vacuum and wash with gained solution with water (10 milliliters) dilution and with ether (10 milliliters).Water layer is acidified to～pH4 with 2M HCl, uses EtOAc (3 * 25 milliliters) extraction then.Merge the EtOAc layer, water (5 milliliters) and saturated brine (10 milliliters) washing in succession.Organic layer is dry through MgSO4, filters and 4-[4-(5-mesyl-diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-benzoic acid (113 milligram, 100%) of evaporation so that white solid to be provided.

1H?NMR(400.13MHz，DMSO-d6)δ0.68(3H，t)，1.22-1.31(2H，m)，1.57(2H，d)，1.96(2H，s)，2.00-2.16(7H，m)，2.20(2H，s)，2.65(2H，t)，2.87(3H，s)，4.09(1H，m)，7.74(2H，d)，8.05(1H，d)，8.12(2H，m)，8.19(1H，s)，13.20(1H，s)

MS?m/e?MH ⁺518

Embodiment 44

4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-2-methoxyl group-benzene Formic acid

With (1.256 milliliters of 2M sodium hydrate aqueous solutions; 2.51 mM) in disposable 4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-2-methoxyl group-essence of Niobe (intermediate #106) (243 milligrams, 0.50 mM) that adds in methanol (10 milliliters).The gained mixture was stirred 18 hours down at 20 ℃.

Reactant mixture is concentrated, and water (50 milliliters) dilutes and is adjusted to pH3 with 2M HCl.Filter the collecting precipitation thing, water (20 milliliters) washing and dry 4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-2-methoxyl group-benzoic acid (202 milligrams, 86%) under vacuum so that white solid to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.70(3H，t)，1.23-1.32(2H，m)，1.62(2H，d)，1.74(2H，s)，1.86(6H，d)，1.92-2.05(4H，m)，2.65(2H，t)，3.87(3H，s)，4.11(1H，d)，7.23-7.25(1H，m)，7.39(1H，d)，7.81(1H，d)，8.09(1H，d)，8.17(1H，s)，12.92(1H，s)

m/z(ESI+)(M+H)+＝470

Embodiment 45

4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-3-methyl-benzoic acid

With (1.904 milliliters of sodium hydroxide solutions; 3.81 disposable adding in 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-agitating solution of 3-methyl-ethyl benzoate (intermediate #113) (353 milligrams, 0.76 mM) in methanol (6 milliliters) mM).The gained suspension was stirred 16 hours down at 20 ℃.Evaporation gained mixture is to remove methanol and to wash with ether (20 milliliters).With reactant mixture with 2M HCl acidify.Filter the collecting precipitation thing, water (10 milliliters) washing and dry 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-3-methyl-benzoic acid (266 milligrams, 80%) under vacuum so that white solid to be provided.

¹H?NMR(300.073MHz，dmso)δ1.16(s，9H)，1.50(d，J＝12.6Hz，2H)，1.70(s，2H)，1.74-1.88(m，6H)，1.89-1.99(m，2H)，2.01-2.14(m，5H)，3.99(d，1H)，7.37(d，1H)，7.66(s，1H)，7.86(d，，1H)，7.94(s，1H)，8.05(d，1H)

m/z(ESI+)(M+H)+＝436

Embodiment 46

4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-2-(trifluoromethyl) benzene first Acid

By 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-3-methyl-ethyl benzoate (intermediate #117) through preparing 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-2-(trifluoromethyl) benzoic acid with the used identical method of embodiment #45.

1H?NMR(400.13MHz，CDCl ₃)δ1.29(9H，s)，1.71-1.79(6H，m)，1.91(6H，s)，2.07(2H，s)，4.24(1H，d)，6.20(1H，d)，7.63-7.66(1H，m)，7.70(1H，s)，7.79-7.80(1H，m)，8.00(1H，d)

MS?m/z(ESI+)(M+H)+＝490。

Embodiment 47:4-[4-(diamantane (obsolete)-2-base carbamoyl)-5-(trifluoromethyl)-1H-pyrazoles-1- Base] benzoic acid

With (1.056 milliliters of sodium hydroxide solutions; 2.11 mM) air next time property add in N-diamantane (obsolete)-2-base-1-(4-the cyano-phenyl)-agitating solution of 5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (intermediate #124) (250 milligrams, 0.60 mM) in methanol (10 milliliters).Gained solution was stirred 45 hours down at 65 ℃.The gained mixture is evaporated to dried, with residue be dissolved in ice/water (25 milliliters) and with this mixture with 2M HCl acidify.Filter the collecting precipitation thing; Water (25 milliliters) washing is also dry with (243 milligrams in 4-[4-(diamantane (obsolete)-2-base carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl] benzoic acid that white solid is provided under vacuum; 93%), it promptly uses without further purifying.

m/z(ESI+)(M+H)+＝434；HPLC?t _R＝2.57min。

1H?NMR(400.13MHz，DMSO-d ₆)δ1.49-1.53(2H，m)，1.71(2H，s)，1.80(5H，s)，1.84(1H，s)，1.93(2H，s)，2.05(2H，d)，3.98-4.05(1H，m)，7.63(2H，d)，8.11-8.14(3H，m)，8.34(1H，d)，13.30(1H，s)

Intermediate #1:4-[4-((1R, 2S, 3S, 5S)-5-hydroxyl-diamantane (obsolete)-2-base carbamoyl)-5-third Base sulfane base-pyrazol-1-yl]-essence of Niobe

With 1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid (intermediate #7) (160 milligrams, 0.5 mM), (1S, 3S; 4S; 5R)-4-amino-diamantane (obsolete)-1-alcohol (84 milligrams, 0.5 mM), HOBT (81 milligrams, 0.6 mM) and DIPEA (174 microlitres; 1 mM) be dissolved among the DMF (5 milliliters) and use at ambient temperature EDCI (115 milligrams, 0.6 mM) to handle.This mixture was stirred 18 hours at ambient temperature, use ethyl acetate (50 milliliters) dilution then, water (3 * 20 milliliters) and brine wash, dry (MgSO ₄) and evaporation stay brown jelly, it is purified to produce title compound (159 milligrams, 69%) through the chromatography (12 silicon dioxide 0-100%EtOAc/ isohexane) on silica gel

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.65(3H，t)，1.17-1.29(2H，m)，1.42(2H，d)，1.60-1.80(6H，m)，1.89(2H，d)，2.06(3H，s)，2.62(2H，t)，3.90(3H，s)，4.00(1H，d)，4.43(1H，s)，7.76(2H，d)，7.95(1H，d)，8.13(2H，d)，8.17(1H，s)

MS?m/z?470M+H

Intermediate #2:4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzene Methyl formate

With (160 milligrams of 1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid (intermediate #7); 0.5 mM), 2-adamantyl amine hydrochlorate is (94 milligrams; 0.5 mM), HOBT is (81 milligrams; 0.6 mM) and DIPEA (261 microlitres, 1.5 mMs) be dissolved among the DMF (5 milliliters) and use at ambient temperature EDCI (115 milligrams, 0.6 mM) to handle.This mixture was stirred 18 hours at ambient temperature, use ethyl acetate (50 milliliters) dilution then, water (3 * 20 milliliters) and brine wash, dry (MgSO ₄) and evaporate to stay white solid, it is purified to produce the title compound (203 milligrams, 92%) of white solid through chromatography on silica gel (12 gram silicon dioxide 0-50%EtOAc/ isohexane)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.65(3H，t)，1.17-1.29(2H，m)，1.60(2H，d)，1.73(2H，s)，1.83(6H，s)，1.91-2.05(4H，m)，2.62(2H，t)，3.90(3H，s)，4.09(1H，d)，7.79(2H，d)，8.03(1H，d)，8.13(2H，d)，8.16(1H，s)

MS?m/z?454M+H

Intermediate #3:4-[4-(1-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] benzene Methyl formate

With (160 milligrams of 1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid (intermediate #7); 0.5 mM), the 1-adamantanamines is (76 milligrams; 0.5 mM), HOBT (81 milligrams, 0.6 mM) and DIPEA (174 microlitres, 1.0 mMs) are dissolved among the DMF (5 milliliters); And use EDCI (115 milligrams, 0.6 mM) to handle at ambient temperature.This mixture was stirred 18 hours at ambient temperature, use ethyl acetate (50 milliliters) dilution then, water (3 * 20 milliliters) and brine wash, dry (MgSO ₄) also evaporate and remove volatile matter.Residue is purified to produce colourless gluey title compound (143 milligrams, 63%) through the chromatography on silica gel (12 gram silicon dioxide 0-50%EtOAc/ isohexane).

MS?m/z?454M+H

Intermediate #4:4-[4-(N-cyclohexyl-N-methyl-carbamoyl)-5-propylthio alkyl-pyrazoles-1- Base] essence of Niobe

With (160 milligrams of 1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid (intermediate #7); 0.5 mM), N-methylcyclohexyl amine is (57 milligrams; 0.5 mM), HOBT is (81 milligrams; 0.6 mM) and DIPEA (174 microlitres, 1.0 mMs) be dissolved among the DMF (5 milliliters) and use at ambient temperature EDCI (115 milligrams, 0.6 mM) to handle.This mixture was stirred 18 hours at ambient temperature, use ethyl acetate (50 milliliters) dilution then, water (3 * 20 milliliters) and brine wash, dry (MgSO ₄) also evaporate and remove volatile matter.Residue is purified to produce colourless gluey title compound (162 milligrams, 78%) through the chromatography on silica gel (12 gram silicon dioxide 0-70%EtOAc/ isohexane).

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.67(3H，t)，1.01-1.41(4H，m)，1.42-1.85(8H，m)，2.58(2H，t)，2.86(3H，s)，3.40-3.60(0.5H，m)，3.89(3H，s)，4.20-4.40(0.5H，m)7.78(2H，d)，7.91(1H，s)，8.12(2H，d)

MS?m/z?416M+H

Intermediate #5:4-[4-(oxirane-4-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl] Essence of Niobe

With 1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid (intermediate #7); (160 milligrams; 0.5 mM), 4-amino tetrahydro pyran (61 milligrams, 0.5 mM), HOBT (81 milligrams, 0.6 mM) and DIPEA (174 microlitres; 1.0 mM) be dissolved among the DMF (5 milliliters) and use at ambient temperature EDCI (115 milligrams, 0.6 mM) to handle.This mixture was stirred 18 hours at ambient temperature, use ethyl acetate (50 milliliters) dilution then, water (3 * 20 milliliters) and brine wash, dry (MgSO ₄) also evaporate and remove volatile matter.Residue is purified to produce the title compound (114 milligrams, 56%) of white solid through the chromatography on silica gel (12 gram silicon dioxide 0-100%EtOAc/ isohexane).

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.68(3H，t)，1.18-1.30(2H，m)，1.47-1.60(2H，m)，1.77-1.81(2H，m)，2.72(2H，t)，3.36-3.43(2H，m)，3.81-3.89(5H，m)，3.95-4.05(1H，m)，7.71(2H，d)，8.04(1H，d)，8.12(2H，d)，8.17(1H，s)

MS?m/z?403M+H

Intermediate #6:4-[5-propylthio alkyl-4-[3-[2-(trifluoromethyl) phenyl] pyrrolidine-1-carbonyl] Pyrazol-1-yl] essence of Niobe

1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid (intermediate #7) is dissolved among the DCM (3 milliliters).Add 1 DMF and oxalyl chloride (71 microlitres, 0.83 mM).This mixture was stirred 2 hours at ambient temperature, and vapourisation under reduced pressure is removed volatile matter then.With residue be dissolved among the DCM (5 milliliters) and add 3-[2-(trifluoromethyl) phenyl] pyrrolidine HCl (105 milligrams, 0.42 mM) to and the solution of DIPEA (217 microlitres, 1.25 mMs) in DCM (5 milliliters) in.Add entry (10 milliliters) and this mixture of vigorous stirring, and through the post that is separated.Filtrating is used the 0-20%EtOAc/DCM eluting through the chromatographic purification on silica gel, to produce the buttery title compound of clear, colorless (177 milligrams, 81%).

MS?m/z?518M+H

Intermediate #7:1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid

With 1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #8) (2.86 grams; 7.97 mM) be dissolved among the DCM (40 milliliters); Add TFA (10 milliliters), this mixture was stirred 3 hours at ambient temperature, reduction vaporization is to stay shallow brown oil then.Should produce the light brown solid by oil with the isohexane development, it passes through filtered and recycled, and dry to produce title compound under vacuum.(2.23g，89％)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.67(3H，t)，1.20-1.32(2H，m)，2.81(2H，t)，3.90(3H，s)，7.71(2H，d)，8.12(2H，d)，8.17(1H，s)，12.73(1H，s)

MS?m/z?321M+H

Intermediate #8:1-(4-methoxycarbonyl phenyl)-5-propylthio alkyl-pyrazoles-4-carboxylic acid tert-butyl ester

With 5-chloro-1-(4-methoxycarbonyl phenyl) pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #9) (2.016 grams; 6.0 mM) be dissolved in the butyronitrile (30 milliliters); Add potassium carbonate (2.48 grams, 18 mMs) with propanethiol (678 microlitres, 7.5 mMs) also with this mixture heated to refluxing 5 hours.Add ethyl acetate (150 milliliters), and with this mixture water (4 * 25 milliliters) washing, dry (MgSO ₄) and reduction vaporization.Residue is purified to produce limpid light yellow oily title compound through the chromatography on silica gel (120 gram silicon dioxide 0-25%EtOAc/ isohexane), and it slowly crystallizes into white solid (2.01 grams, 89%) when leaving standstill

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.67(3H，t)，1.25(2H，q)，1.54(9H，s)，2.76(2H，t)，3.89(3H，s)，7.70(2H，d)，8.11(3H，d)

MS?m/z?321M-tBut

Intermediate #9:5-chloro-1-(4-methoxycarbonyl phenyl) pyrazoles-4-carboxylic acid tert-butyl ester

Nitrite tert-butyl (2.9 milliliters, 24.22 mMs) and copper chloride (4.06 grams, 30.27 mMs) are added in the acetonitrile (150 milliliters) and be heated to 65 ℃.Add 5-amino-1-(4-methoxycarbonyl phenyl) pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #10) with solid form, produce violent gas release.After adding completion, continue heating 15 minutes again.Reactant mixture is cooled to ambient temperature, and water (500 milliliters) dilutes and extracts with ethyl acetate (3 * 100 milliliters).With extract water (2 * 100 milliliters) that merges and saline (100 milliliters) washing, dry (MgSO ₄) and reduction vaporization.Residue is purified to produce oily title compound (5.68 grams, 83%) through the chromatography on silica gel (120 gram silica columns, EtOAc/ hexane 0-50%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ1.53(9H，s)，3.87-3.90(3H，m)，7.78(2H，d)，8.15(2H，d)，8.20(1H，s)

MS?m/z?281M-tBut

Intermediate #105-amino-1-(4-methoxycarbonyl phenyl) pyrazoles-4-carboxylic acid tert-butyl ester

The cyanoacetic acid tert-butyl ester (14.1 grams, 100 mMs) is dissolved in the triethyl orthoformate (24.8 milliliters, 150 mMs).Add acetic anhydride (9.625 milliliters, 100 milliliters), and with this mixture heated to 125 ℃ maintenance 3 hours, vapourisation under reduced pressure was removed volatile matter then.Residue is dissolved in the ethanol (100 milliliters), and adds 4-hydrazino-benzoic acid methyl ester hydrochloride (intermediate #123) (6.06 grams, 30 mMs) and DIPEA (5.23 milliliters, 30 mMs).With this mixture heated to reflux 5 hours then reduction vaporization be dissolved in the ethyl acetate (300 milliliters) it and water (2 * 100 milliliters) and saline (100 milliliters) washing, drying (MgSO staying brown oil ₄) and evaporation.Residue is purified with the title compound (7.1 gram) that produces the yellow solid shape through the chromatography on silica gel (120 gram silicon dioxide, EtOAc/ hexane 0-50%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ1.51(9H，s)，3.88(3H，s)，6.43(2H，s)，7.67(1H，s)，7.73(2H，s)，8.08(2H，d)

MS?m/z?262M-tBut

Intermediate #11:4-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] benzene first The acid methyl ester

Be dissolved among the DMF (5 milliliters) and use at ambient temperature the 1M solution (1.16 milliliter) of NaHMDS in THF to handle propanethiol (88 milligrams, 1.16 mMs).After stirring 15 minutes, this clear solution is added in the suspension of 4-[5-chloro-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe (intermediate #15) (378 milligrams, 1.05 mMs) in DMF (10 milliliters).Continue at ambient temperature to stir 2 hours, then reactant mixture is diluted with ethyl acetate (100 milliliters), water (4 * 25 milliliters) washing and dry (MgSO ₄).Reduction vaporization is removed volatile matter to produce limpid oil, and it is through the chromatographic purification on silica gel, with ethyl acetate/hexane gradient (0-50%) eluting, to produce the title compound of white solid.(363 milligrams, 86%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.67(3H，t)，1.14-1.39(7H，m)，1.59(1H，d)，1.71-1.74(2H，m)，1.84(2H，d)，2.70(2H，t)，3.74-3.79(1H，m)，3.89(3H，s)，7.72(2H，d)，7.92(1H，d)，8.10-8.16(3H，m)

MS?m/z?402M+H

Intermediate #12:3-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] benzene first The acid methyl ester

Be dissolved among the DMF (3 milliliters) and use at ambient temperature the 1M solution (0.63 milliliter, 0.63 mM) of NaHMDS in THF to handle propanethiol (48 milligrams, 0.57 mM).After stirring 15 minutes, add the solution of 3-[5-chloro-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe (intermediate #19) (205 milligrams, 0.57 mM) in DMF (5 milliliters) and continue and stirred 2 hours.Add ethyl acetate (50 milliliters), and with this mixture water (3 * 20 milliliters) washing, dry (MgSO ₄) and evaporation generation oil, it is through the chromatographic purification on silica gel, with EtOAc/DCM gradient (0-25%) eluting, with the title compound (175 milligrams, 75%) that limpid colorless oil is provided

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.67(3H，t)，1.14-1.39(7H，m)，1.57-1.61(1H，m)，1.71-1.74(2H，m)，1.84(2H，d)，2.68-2.72(2H，m)，3.71-3.85(1H，m)，3.89(3H，s)，7.72(1H，t)，7.83-7.94(2H，m)，8.05-8.08(2H，m)，8.14(1H，s)

MS?m/z?402M+H

Intermediate #15:4-[5-chloro-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe

Nitrite tert-butyl (210 milligrams, 2.04 mMs) and copper chloride (342 milligrams, 2.55 mMs) are added in the acetonitrile (15 milliliters) and be heated to 65 ℃.Add 4-[5-amino-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe (intermediate #16) (581 milligrams, 1.7 mMs) with the solid form portioning, produce violent gas release.After add accomplishing, this reactant mixture 65 ℃ of following reheat 15 minutes, is cooled to ambient temperature, water (100 milliliters) dilution also extracts with ethyl acetate (3 * 50 milliliters).The extract that merges is washed dry (MgSO with saline (2 * 20 milliliters) ₄) and evaporation generation solid, it is through the chromatographic purification on silica gel, with the title compound (385 milligram, 65%) of EtOAc/ hexane gradient (0-30%) eluting with the generation white solid

¹H?NMR(300.072MHz，CDCl ₃)δ1.21(3H，d)，1.31-1.45(2H，m)，1.57-1.71(3H，m)，1.93-1.98(2H，m)，3.87-3.99(4H，m)，6.02(1H，d)，7.56-7.60(2H，m)，8.08-8.14(3H，m)

MS?m/z?362M+H

Intermediate #16:4-[amino 4-(cyclohexyl carboxyamide base) pyrazol-1-yl of 5-] essence of Niobe

2-cyanic acid-N-cyclohexyl-3-ethyoxyl-third-2-alkene amide (intermediate #17) (605 milligrams, 2.73 mMs) and 4-hydrazino-benzoic acid methyl ester hydrochloride (intermediate #123) (552 milligrams, 2.73 mMs) are suspended in the ethanol (20 milliliters).Add DIPEA (351 milligrams, 2.73 mMs) also with this mixture heated to 70 ℃ maintenance 1 hour.Reactant mixture is cooled to ambient temperature and filtered and recycled gained precipitate, with ether washing and dried in vacuum to produce the white solid title compound.(618 milligrams, 66%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ1.13(1H，d)，1.22-1.35(4H，m)，1.60(1H，d)，1.76(4H，d)，3.69-3.74(1H，m)，3.87(3H，s)，6.56(2H，s)，7.62(1H，d)，7.73-7.78(2H，m)，8.04(1H，s)，8.05-8.09(2H，m)

MS?m/z?343M+H

Intermediate #17:2-cyanic acid-N-cyclohexyl-3-ethyoxyl-third-2-alkene amide

2-cyanic acid-N-cyclohexyl-acetamide (intermediate #18) (1.35 grams, 8.09 mMs) is suspended in the acetic anhydride (20 milliliters).Add triethyl orthoformate (3.91 grams, 21 mMs) and with this mixture heated to refluxing 5 hours.Reactant mixture is cooled to ambient temperature and removes volatile matter to stay brown oil through evaporating in a vacuum; It is through the chromatographic purification on silica gel; With EtOAc/DCM gradient (0-10%) eluting, to produce the title compound (637 milligrams, 35%) of solid, shaped

¹H?NMR(300.073MHz，DMSO-d ₆)δ1.01-1.35(8H，m)，1.51-1.82(5H，m)，3.54-3.61(1H，m)，4.32(2H，q)，7.57(1H，d)，8.11(1H，t)

MS?m/z?223M+H

Intermediate #18:2-cyanic acid-N-cyclohexyl-acetamide

Cyanoacetic acid (4.26 grams, 50 mMs) and cyclohexylamine (4.96 grams, 50 mMs) are dissolved among the DCM (100 milliliters).Adding EDCI (10.51 grams, 55 mMs) also stirred this mixture 24 hours at ambient temperature.This reactant mixture water (2 * 100 milliliters) is washed; Dry (MgSO4) and evaporation are to stay the yellow solid residue, and it is through the chromatographic purification on silica gel, with EtOAc/DCM gradient (0-100%) eluting; With the title compound (5.66 grams, 68%) that white solid is provided.

¹H?NMR(300.073MHz，DMSO-d ₆)δ1.06-1.32(5H，m)，1.51-1.55(1H，m)，1.63-1.75(4H，m)，3.46-3.57(1H，m)，3.55(2H，s)，8.06-8.09(1H，m)

Intermediate #19:3-[5-chloro-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe

Nitrite tert-butyl (145 milligrams, 1.38 mMs) and copper chloride (236 milligrams, 1.76 mMs) are added in the acetonitrile (10 milliliters) and be heated to 65 ℃.Add 3-[5-amino-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe (intermediate #20) (400 milligrams, 1.38 mMs) with the solid form portioning, produce violent gas release.After adding completion, continue heating 15 minutes again, be cooled to ambient temperature then, water (50 milliliters) dilutes and extracts with ethyl acetate (3 * 25 milliliters).With extract water (2 * 20 milliliters) washing that merges, dry (MgSO ₄) and evaporation produce brown oil, it is through the chromatographic purification on silica gel, with EtOAc/ hexane gradient (0-50%) eluting so that the title compound of limpid colorless oil to be provided.(256 milligrams, 51%)

¹H?NMR(400.13MHz，CDCl ₃)δ1.15-1.25(3H，m)，1.32-1.43(2H，m)，1.58(1H，d)，1.65-1.71(2H，m)，1.94-1.98(2H，m)，3.89(3H，s)，3.91-3.98(1H，m)，6.04(1H，d)，7.55(1H，t)，7.66-7.68(1H，m)，8.08-8.10(2H，m)，8.15(1H，t)

MS?m/z?360M-H

Intermediate #20:3-[5-amino-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe

2-cyanic acid-N-cyclohexyl-3-ethyoxyl-third-2-alkene amide (intermediate #17) (605 milligrams, 2.73 mMs) and 3-hydrazino-benzoic acid methyl ester hydrochloride (552 milligrams, 2.73 mMs) are suspended in the ethanol (20 milliliters).Add DIPEA (352 milligrams, 2.73 mMs) also with this mixture heated to 70 ℃ maintenance 1 hour.Reactant mixture is cooled to ambient temperature and is concentrated into small size.Add entry (50 milliliters) and filtered and recycled gained solid, be dissolved in again in the ethyl acetate (50 milliliters), dry (MgSO ₄) and evaporation produce brown solid, it is with ether slurrying and the filtered and recycled title compound (443 milligrams, 47%) with generation light brown solid, shaped.

¹H?NMR(300.073MHz，DMSO-d ₆)δ1.20(5H，d)，1.61(1H，d)，1.72-1.75(2H，m)，1.80(2H，d)，3.70-3.74(1H，m)，3.88(3H，s)，6.47(2H，s)，7.59-7.69(2H，m)，7.84-7.88(1H，m)，7.91-7.94(1H，m)，8.01(1H，s)，8.12(1H，t)

MS?m/z?343M+H

Intermediate #214-[4-(cyclohexyl carboxyamide base)-5-propyl-pyrazole-1-yl] benzoic acid second Ester

With (159 milligrams of 1-(4-chlorphenyl)-N-cyclohexyl-5-propyl-pyrazole-4-carboxylic acid amides (intermediate #22); 0.46 mM), hexacarbonylmolybdenum is (61 milligrams; 0.23 mM), Herrmann ' s catalyst (trans-two-Mu-acetate closes two [2-(two-O-tolyl phosphino-) benzyl] two palladiums (II), 22 milligrams, 0.02 mM), DMAP are (113 milligrams; 0.92 DIPEA (161 L mM); 0.92 mM), Fu ' s salt (three-(tert-butyl group) Phosphonium Tetrafluoroboric acid hydrogen salt, 27 milligrams, 0.09 mM), dioxane (2 milliliters), ethanol (2 liters) sneak in the microwave tube.Then reactant mixture was heated 1 hour down at 150 ℃ through microwave.LC-MS shows and changes into product fully.Solvent evaporated under reduced pressure, and with reactant mixture with EtOAc (2 * 25 milliliters) extraction, water (10 milliliters), 2N HCl (10 milliliters) and saline (10 milliliters) wash.Organic facies is through MgSO ₄Dry also reduction vaporization is to produce the black jelly.(12g silicycle post, gradient: 1: 0 to 1: 1 hexane/EtOAc) purify also merges suitable fraction, and concentrate in a vacuum to produce the required compound (130 milligrams, 74%) of white solid to residue through column chromatography.

¹H?NMR(400.13MHz，CDCl ₃)δ0.76-0.81(3H，t)，1.09-1.21(3H，m)，1.36(5H，m)，1.45-1.55(2H，m)，1.61(1H，m)，1.67-1.72(2H，m)，1.96-1.98(2H，m)，2.89-2.93(2H，m)，3.85-3.92(1H，m)，4.35(2H，q)，5.62(1H，d)，7.41-7.44(2H，m)，7.71(1H，s)，8.10-8.13(2H，m)

MS?m/z?384M+H

Intermediate #22:1-(4-chlorphenyl)-N-cyclohexyl-5-propyl-pyrazole-4-carboxylic acid amides

In the suspension of 1-(4-chlorphenyl)-5-propyl-pyrazole-4-phosgene (can buy, 302 milligrams, 1.07 mMs) in DCM (5 milliliters), add 1 DMF, add cyclohexylamine (306 L, 2.68 mMs) then.Reactant mixture was at room temperature stirred 2 hours, stop then.

It extracts in DCM (10 milliliters), with 2N NaOH (5 milliliters), 2N HCl (5 milliliters), water (mL) and saline (5 milliliters) washing.Organic facies is through MgSO ₄Dry also reduction vaporization is to produce white solid (200 milligrams, 54%), and it promptly uses without further purifying.

¹H?NMR(400.13MHz，DMSO-d ₆)δ0.73(3H，t)，1.13(1H，d)，1.22-1.31(4H，m)，1.35-1.44(2H，m)，1.60-1.63(1H，m)，1.69-1.75(2H，m)，1.80-1.82(2H，m)，2.91(2H，t)，3.72-3.75(1H，m)，7.48-7.52(2H，m)，7.61-7.64(2H，m)，7.84(1H，d)，8.13(1H，s)

MS?m/z?346M+H

Intermediate #23:4-[4-(cyclohexyl-methyl-carbamoyl)-5-propyl-pyrazole-1-yl] benzene first Acetoacetic ester

With 1-(4-chlorphenyl)-N-cyclohexyl-N-methyl-5-propyl-pyrazole-4-carboxylic acid amides (intermediate #24), 101 milligrams, 0.28 mM), (37 milligrams of hexacarbonylmolybdenums; 0.14 mM), (trans-two-Mu-acetate closes two [2-(two-O-tolyl phosphino-) benzyl] two palladiums (II) to Herrmann ' s catalyst; 14 milligrams, 0.01 mM), DMAP (69 milligrams, 0.56 mM); DIPEA (98 L; 0.56 mM), Fu ' s salt (three-(tert-butyl group) Phosphonium Tetrafluoroboric acid hydrogen salt, 17 milligrams, 0.06 mM), dioxane (2 milliliters), ethanol (2 milliliters) sneak in the microwave tube.Then this reactant mixture was heated 1 hour down at 150 ℃ through microwave.

LC-MS shows and changes into product fully.In another microwave tube, repeat same reaction, and merge two reactant mixtures with post processing and purification.Solvent evaporated under reduced pressure, and with reactant mixture with EtOAc (2 * 25 milliliters) extraction, water (10 milliliters), 2N HCl (10 milliliters) and saline (10 milliliters) wash.Organic facies is through MgSO ₄Dry also reduction vaporization is to produce the black jelly.(12g silicycle post, gradient: 1: 0 to 1: 1 hexane/EtOAc) purify also merges suitable fraction, and concentrate in a vacuum to produce the required compound (105 milligrams, 61%) of white solid to residue through column chromatography.

¹H?NMR(400.13MHz，CDCl ₃)δ0.71-0.79(3H，t)，1.02-1.10(1H，m)，1.19(2H，t)，1.31-1.40(5H，m)，1.55-1.72(4H，m)，1.75-1.78(2H，m)，2.73-2.79(2H，m)，2.89(3H，m)，4.05(1H，q)，4.35(2H，q)，6.99-7.11(1H，m)，7.46(2H，d)，7.55(1H，s)，8.10-8.13(2H，d)

MS?m/z?398M+H

Intermediate #24:1-(4-chlorphenyl)-N-cyclohexyl-N-methyl-5-propyl-pyrazole-4-carboxylic acid amides

In the suspension of 1-(4-chlorphenyl)-5-propyl-pyrazole-4-phosgene (can buy, 302 milligrams, 1.07 mMs) in DCM (5 milliliters), adding 1 DMF, is N-methylcyclohexylamine (349 L, 2.68 mMs) then.Reactant mixture was at room temperature stirred 2 hours, stop then.

It is extracted in DCM (10 milliliters), with 2N NaOH (5 milliliters), 2N HCl (5 milliliters), water (5 milliliters) and saline (5 milliliters) washing.Organic facies is through MgSO ₄Dry also reduction vaporization is to produce colourless jelly (263 milligrams, 73%), and it promptly uses without further purifying.

¹H?NMR(400.13MHz，DMSO-d ₆)δ0.70(3H，t)，1.20-1.46(5H，m)，1.58-1.63(5H，m)，1.76-1.79(2H，m)，2.73-2.74(3H，m)，2.89(4H，m)，7.54-7.57(2H，m)，7.61-7.64(2H，m)

MS?m/z?360M+H

Intermediate #25:1-(4-bromophenyl)-N-cyclohexyl-5-cyclopropyl-pyrazole-4-carboxamide

1-(4-bromophenyl)-5-cyclopropyl-pyrazoles-4-carboxylic acid (intermediate #30) (237 milligrams, 0.77 mM) is suspended among the DCM (5 milliliters).Add a DMF, slowly add oxalyl chloride (200 microlitres, 2.32 mMs) then.Reactant mixture was stirred 4 hours at ambient temperature, then reduction vaporization.With residue be dissolved among the DCM (5 milliliters) and add cyclohexylamine (97 microlitres, 0.85 mM) to and the solution of DIPEA (403 microlitres, 2.32 mMs) in DCM (5 milliliters) in.This mixture was stirred 24 hours at ambient temperature, add entry (10 milliliters) then and make this mixture through the filter that is separated.From filtrating, reclaim product through flash column chromatography (SiO2, gradient 0-100%EtOAc is in isohexane).Merge 1-(4-bromophenyl)-N-cyclohexyl-5-cyclopropyl-pyrazole-4-carboxamide that pure fraction and evaporation produce white solid.(277 milligrams, 92%)

¹H?NMR(400.13MHz，DMSO-d ₆)δ0.39-0.43(2H，m)，0.84-0.89(2H，m)，1.12-1.20(1H，m)，1.24-1.36(4H，m)，1.61(1H，d)，1.69-1.75(2H，m)，1.87(2H，d)，2.14-2.21(1H，m)，3.72-3.77(1H，m)，7.73-7.79(3H，m)，7.92-7.98(1H，m)，8.07-8.10(2H，m)，13.17(1H，s)

MS?m/z(ESI+)(M+H)+390

According to the similar mode of intermediate #25, use suitable amine raw material, prepare following intermediate by 1-(4-bromophenyl)-5-cyclopropyl-pyrazoles-4-carboxylic acid (intermediate #30):

Intermediate #301-(4-bromophenyl)-5-cyclopropyl-pyrazoles-4-carboxylic acid

1-(4-bromophenyl)-5-cyclopropyl-pyrazoles-4-carboxylic acid, ethyl ester (intermediate #31) (423 milligrams, 1.29 mMs) is dissolved in the methanol (20 milliliters) and handles with 2M sodium hydrate aqueous solution (3.23 milliliters, 6.46 mMs).This mixture was stirred 24 hours at ambient temperature, and vapourisation under reduced pressure is removed methanol then.Residue is dissolved in the water (50 milliliters), is acidified to pH4 with 2M HCl and also extracts with EtOAc (3 * 25 milliliters).With the extract water and the brine wash that merge, dry (MgSO4) and 1-(4-the bromophenyl)-5-cyclopropyl-pyrazoles-4-carboxylic acid of evaporation to stay white solid.(343 milligrams, 87%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.46-0.57(2H，m)，0.82-0.87(2H，m)，1.98-2.11(1H，m)，7.55-7.62(2H，m)，7.71-7.75(2H，m)，7.94(1H，s)，12.32(1H，s)

MS?m/z(ESI+)(M+H)+309

Intermediate #31 1-(4-bromophenyl)-5-cyclopropyl-pyrazoles-4-carboxylic acid, ethyl ester

2-(cyclopropane carbonyl)-3-dimethylamino-third-2-olefin(e) acid ethyl ester (intermediate #32) (316 milligrams, 1.5 mMs) is dissolved in the ethanol (5 milliliters).Add 4-bromophenyl hydrazonium salt hydrochlorate (335 milligrams, 1.5 mMs) and DIPEA (264 microlitres, 1.5 mMs), and with this mixture heated to refluxing 2 hours.Reactant mixture is cooled to ambient temperature and reduction vaporization.Residue is dissolved among the DCM (10 milliliters), uses water washing, and topple over through the pipe that is separated.From filtrating, reclaim product through flash column chromatography (SiO2, gradient 0-25%EtOAc is in isohexane).Merge pure fraction and evaporation generation buttery 1-(4-bromophenyl)-5-cyclopropyl-pyrazoles-4-carboxylic acid, ethyl ester, its crystallization when leaving standstill (343 milligrams, 87%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.43-0.49(2H，m)，0.84-0.90(2H，m)，1.29(3H，t)，2.05-2.14(1H，m)，4.24(2H，q)，7.55-7.60(2H，m)，7.71-7.76(2H，m)，7.98(1H，d)

MS?m/z(ESI+)(M+)335

Intermediate #32 2-(cyclopropane carbonyl)-3-dimethylamino-third-2-olefin(e) acid ethyl ester

With 3-cyclopropane-3-oxo ethyl propionate (312 milligrams, 2 mMs) and N, dinethylformamide dimethyl-acetal (402 microlitres, 3 mMs) is dissolved in the dioxane (5 milliliters) and is heated to and refluxed 2 hours.Reactant mixture is cooled to ambient temperature and reduction vaporization to stay yellow oil, and it is purified through flash column chromatography (SiO2, gradient 0-100%EtOAc is in isohexane).Merge pure fraction and evaporation generation buttery 2-(cyclopropane carbonyl)-3-dimethylamino-third-2-olefin(e) acid ethyl ester.(316 milligrams, 74%)

¹H?NMR(300.073MHz，DMSO-d ₆)δ0.69-0.80(4H，m)，1.15-1.24(3H，m)，2.26-2.34(1H，m)，2.94(6H，s)，4.11(2H，q)，7.57(1H，s)

MS?m/z(ESI+)(M+H)+212

Intermediate #33:2-[4-[4-(cyclohexyl carboxyamide base)-5-propylthio alkyl-pyrazol-1-yl] benzene Base] methyl acetate

1-[4-(methoxycarbonyl methyl) phenyl]-5-propylthio alkyl-pyrazoles-4-carboxylic acid (intermediate #35) (220 milligrams, 0.66 mM) is dissolved among the DCM (5 milliliters) and adds 1 DMF.Add oxalyl chloride (176 microlitres, 1.96 mMs), and this mixture was stirred 3 hours at ambient temperature.Remove volatile matter through reduction vaporization, and the gained jelly is dissolved among the DCM (2 milliliters) again, add at ambient temperature in cyclohexylamine (66 milligrams, 0.66 mM) and the solution of DIPEA (230 microlitres, 1.32 mMs) in DCM (5 milliliters).Reactant mixture was stirred 2 hours at ambient temperature, with EtOAc (50 milliliters) dilution, water (2 * 10 milliliters) and saline (10 milliliters) washing, dry (MgSO4) and reduction vaporization.Residue is through 2-[4-[4-(cyclohexyl carboxyamide the base)-5-propylthio alkyl-pyrazol-1-yl] phenyl] methyl acetate so that white solid to be provided of purifying at the flash chromatography on the silica gel (gradient 0-100%EtOAc is in isohexane).(220 milligrams, 88%)

1H?NMR(300.073MHz，DMSO-d ₆)δ0.69(3H，t)，1.20-1.32(7H，m)，1.58(1H，d)，1.69-1.74(2H，m)，1.83(2H，d)，2.68(2H，t)，3.64(3H，s)，3.74-3.82(1H，m)，3.80(2H，s)，7.44(4H，s)，7.84-7.89(1H，m)，8.08(1H，s)

MS?m/z(ESI+)(M+H)+416

Intermediate #34:2-[4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazoles-1- Base] phenyl] methyl acetate

By 1-[4-(methoxycarbonyl methyl) phenyl]-5-propylthio alkyl-pyrazoles-4-carboxylic acid (intermediate #35) and 2-adamantyl amine hydrochlorate through with the used identical program preparation of intermediate #6.

1H?NMR(300.073MHz，DMSO-d ₆)δ0.67(3H，t)，1.15-1.31(2H，m)，1.61(2H，d)，1.73(2H，s)，1.83(6H，s)，1.96(4H，d)，2.61(2H，t)，3.64(3H，s)，3.80(2H，s)，4.09(1H，d)，7.40-7.52(4H，m)，8.02(1H，d)，8.11(1H，s)

MS?m/z(ESI+)(M+H)+468

Intermediate #35:1-[4-(methoxycarbonyl methyl) phenyl]-5-propylthio alkyl-pyrazoles-4-carboxylic acid

1-[4-(methoxycarbonyl methyl) phenyl]-5-propylthio alkyl-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #36) is dissolved among the DCM (10 milliliters).Adding TFA (2 milliliters) also stirred this mixture 5 hours at ambient temperature.Reduction vaporization volatile matter then, and with residue dry 1-[4-(methoxycarbonyl methyl) phenyl]-5-propylthio alkyl-pyrazoles-4-carboxylic acid so that the light brown oily to be provided under vacuum.(440 milligrams, 98%)

1H?NMR(300.073MHz，DMSO-d ₆)δ0.70(3H，t)，1.21-1.33(2H，m)，2.79(2H，t)，3.64(3H，s)，3.80(2H，s)，7.44(4H，s)，8.10(1H，s)

Intermediate #36:1-[4-(methoxycarbonyl methyl) phenyl]-5-propylthio alkyl-pyrazoles-4-carboxylic acid The tert-butyl ester

5-chloro-1-[4-(methoxycarbonyl methyl) phenyl] pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #37) (767 milligrams, 2.19 mMs) is dissolved in the butyronitrile (10 milliliters).Add potassium carbonate (906 milligrams, 6.57 mMs) and propanethiol (284 microlitres, 2.74 mMs), this mixture was heated 18 hours down at 90 ℃.Reactant mixture is cooled to ambient temperature and adds ethyl acetate (50 milliliters).This mixture water (4 * 25 milliliters) washing, dry (MgSO4) and reduction vaporization.Residue is through 1-[4-(methoxycarbonyl methyl) the phenyl]-5-propylthio alkyl-pyrazoles-4-carboxylic acid tert-butyl ester (527 milligrams, 62%) so that yellow oily to be provided of purifying at the flash chromatography on the silica gel (gradient 0-25%EtOAc is in isohexane).

1H?NMR(300.073MHz，DMSO-d ₆)δ0.70(3H，t)，1.27(2H，q)，1.53-1.54(9s，2.75(2H，t)，3.64(3H，s)，3.80(2H，s)，7.44(4H，s)，8.07-8.12(1H，m)

MS?m/z(ESI+)(M+H)+391

Intermediate #37:5-chloro-1-[4-(methoxycarbonyl methyl) phenyl] pyrazoles-4-carboxylic acid tert-butyl ester

Nitrite tert-butyl (419 microlitres, 3.49 mMs) and copper chloride (2) (585 milligrams, 4.37 mMs) are added in the acetonitrile (10 milliliters), and be heated to 65 ℃.Add 5-amino-1-[4-(methoxycarbonyl methyl) phenyl] pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #38) (965 milligrams, 2.91 mMs) as the solution in acetonitrile (5 milliliters), produce violent gas release.After adding completion, continue heating 15 minutes again.Reactant mixture is cooled to ambient temperature, and water (50 milliliters) dilutes and extracts with ethyl acetate (3 * 50 milliliters).With extract water (2 * 50 milliliters) that merges and saline (10 milliliters) washing; Dry (MgSO4) and evaporation produce brown oil, and it is through purifying to produce the title compound of yellow oily at the flash chromatography on the silica gel (gradient 0-50%EtOAc is in isohexane).(785 milligrams, 77%)

1H?NMR(300.073MHz，DMSO-d ₆)δ1.52(9H，s)，3.62-3.64(3H，m)，3.81(2H，s)，7.48-7.54(4H，m)，8.12(1H，s)

MS?m/z(ESI+)(M+H)+351

Intermediate #38:5-amino-1-[4-(methoxycarbonyl methyl) phenyl] pyrazoles-4-carboxylic acid tert-butyl ester

The cyanoacetic acid tert-butyl ester (3.525 grams, 25 mMs) is dissolved in the triethyl orthoformate (6.2 milliliters, 37.5 mMs).Add acetic anhydride (2.41 milliliters, 25 mMs) also with this mixture heated to 125 ℃ maintenance 3 hours.Remove volatile matter to stay orange oil through reduction vaporization then.This raw oil is dissolved in the methanol and adds 2-(4-diazanyl phenyl) methyl acetate hydrochlorate (intermediate #39) (1.62 gram, 7.5 mMs) and DIPEA (1.3 milliliters, 7.5 mMs).To refluxing 2 hours, be evaporated to dried then this mixture heated.Residue is dissolved in the ethyl acetate (100 milliliters); Water (2 * 50 milliliters) and saline (50 milliliters) washing; Dry (MgSO4) and evaporation stay crude product, and it is through purifying to produce the title compound of yellow solid shape at the flash chromatography on the silica gel (gradient 0-50%EtOAc is in isohexane).

(974 milligrams, 39%)

1H?NMR(300.073MHz，DMSO-d ₆)δ1.51(9H，d)，3.63(3H，s)，3.76(2H，s)，6.20(2H，s)，7.41(2H，d)，7.48(2H，d)，7.60(1H，s)

MS?m/z(ESI+)(M+H)+331

Intermediate #39:2-(4-diazanyl phenyl) methyl acetate hydrochlorate

The solution of 4-iodophenyl methyl acetate (4.25 grams, 15.39 mMs) is dissolved among the DMF (25 milliliters).Adding BOC-carbazic acid salt (2.44 grams, 18.47 mMs), 1,10-phenanthroline (278 milligrams, 1.54 mMs), Copper diiodide (147 milligrams, 0.77 mM) and cesium carbonate (7.0 grams, 21.55 mMs) also heat this mixture 60 minutes down at 120 ℃.Reactant mixture is diluted with ethyl acetate (25 milliliters); Water (3 * 10 milliliters) and saline (10 milliliters) washing; Dry (MgSO4) and evaporation are to stay brown oil, and it is through purifying to produce water white oil at the flash chromatography on the silica gel (gradient 0-50%EtOAc is in isohexane).This oil is dissolved in the 4M HCl dioxane (20 milliliters) and stirred at ambient temperature 3 hours, produce dense thick precipitate.Add diethyl ether (100 milliliters) and filtered and recycled precipitate, wash and dry 2-(4-diazanyl phenyl) methyl acetate hydrochlorate under vacuum to stay the light brown solid, shaped with ether (2 * 20 milliliters).(1.63 grams, 49%)

1H?NMR(300.073MHz，DMSO-d ₆)δ3.59(5H，s)，6.93(2H，d)，7.16(2H，d)，8.21(1H，s)，10.20(3H，s)

Intermediate #40:3-(4-cyclohexyl carboxyamide base-5-propylthio alkyl-pyrazol-1-yl methyl)-benzene Methyl formate

With (118 milligrams in 1-(4-methoxycarbonyl-benzyl)-5-propylthio alkyl-1H-pyrazoles-4-carboxylic acid (intermediate #44); 0.35 cyclohexylamine (49 L mM); 0.42 mM), EDAC is (75 milligrams; 0.39 mM) and the solution of DMAP (9 milligrams, 0.07 mM) in DCM (5 milliliters) stirred overnight at ambient temperature.Evaporating solvent and the gained residue is distributed between EtOAc (～30 milliliters) and citric acid (～20 milliliters) in a vacuum.Separate each layer and water layer is extracted with EtOAc (～10 milliliters) again.The organic layer that merges is washed dry then (MgSO with saline (～10 milliliters) ₄), filter and evaporation generation oil.This oil is through column chromatography (4g Si is with 20 to 60% EtOAc eluting in the IH) title compound (116 milligram, 79%) of purification to produce light yellow oily.

¹H?NMR(300.072MHz，CDCl ₃)δ0.81(3H，t)，1.13-1.25(3H，m)，1.30-1.48(4H，m)，1.52-1.69(3H，m)，1.89-1.94(2H，m)，2.47(2H，t)，3.83(3H，s)，3.88-3.98(1H，m)，5.49(2H，s)，7.18(2H，d)，7.24(1H，d)，7.92(2H，d)，8.07(1H，s)

MS?m/e?MH ⁺416。

Use corresponding raw material to make following intermediate through said procedure

Intermediate #44:1-(4-methoxycarbonyl-benzyl)-5-propylthio alkyl-1H-pyrazoles-4-carboxylic acid

TFA (1.5 milliliters) is added in 1-(4-methoxycarbonyl-benzyl)-5-propylthio alkyl-agitating solution of 1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #46) (274 milligrams, 0.70 mM) in DCM (6 milliliters).This reaction was stirred 3 hours at ambient temperature, then evaporation in a vacuum.With the gained jelly with the isohexane sonication to produce solid.Remove and desolvate, this white solid is dissolved among the EtOAc also evaporates in a vacuum then to produce the title compound (236 milligrams, 100%) of pale solid shape

¹H?NMR(300.072MHz，CDCl ₃)δ0.84(3H，t)，1.35-1.50(2H，m)，2.81(2H，t)，3.83(3H，s)，5.53(2H，s)，7.18-7.21(2H，d)，7.91-7.94(2H，d)，8.05(1H，s)

MS?m/e?MH ⁺335

Intermediate #45:1-(3-methoxycarbonyl-benzyl)-5-propylthio alkyl-1H-pyrazoles-4-carboxylic acid

1-(4-methoxycarbonyl-benzyl)-5-propylthio alkyl-1H-pyrazoles-4-carboxylic acid tert-butyl ester is replaced to 1-(3-methoxycarbonyl-benzyl)-5-propylthio alkyl-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #47), the chemical compound of processing with the mode that is similar to intermediate 44.

¹H?NMR(300.072MHz，CDCl ₃)δ0.85(3H，t)，1.37-1.49(2H，m)，2.82(2H，t)，3.83(3H，s)，5.52(2H，s)，7.33-7.34(2H，m)，7.88-7.91(2H，m)，8.05(1H，s)

MS?m/e[M-H] ^-333.

Intermediate #46:1-(4-methoxycarbonyl-benzyl)-5-propylthio alkyl-1H-pyrazoles-4-carboxylic acid uncle Butyl ester

With (397 milligrams of 5-chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #48); 1.13 mM) be dissolved in the butyronitrile (8 milliliters); Add potassium carbonate (470 milligrams, 3.40 mMs) and propanethiol (128 l, 1.41 mMs); And with this mixture heated to refluxing, and under this temperature stirred overnight.This reactant mixture is transferred in the microwave phial (to use～5 milliliters of extra butyronitrile to guarantee shift fully), added 3 equivalent propanethiols again, and this is reflected at 180 ℃ of heating 4 hours down.Add EtOAc (～50 milliliters) and this mixture water (3 *～20 milliliters) and saline (～20 milliliters) are washed dry then (MgSO ₄), filter and evaporation generation yellow oil.Purify this oil to produce the title compound (274 milligrams, 62%) of yellow oily through column chromatography (12g Si is with 10 to 50% EtOAc eluting in IH).

¹H?NMR(300.072MHz，CDCl ₃)δ0.90(3H，t)，1.40-1.52(2H，m)，1.55(9H，s)，2.84(2H，t)，3.90(3H，s)，5.57(2H，s)，7.25(2H，d)，7.96-8.00(3H，m)

MS?m/e?MH ⁺391

Intermediate #47:1-(3-methoxycarbonyl-benzyl)-5-propylthio alkyl-1H-pyrazoles-4-carboxylic acid uncle Butyl ester

5-chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester is replaced to 5-chloro-1-(3-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester, the chemical compound of processing with the mode that is similar to intermediate #46.

¹H?NMR(300.072MHz，CDCl ₃)δ0.91(3H，t)，1.42-1.54(2H，m)，1.56(9H，s)，2.84(2H，t)，3.90(3H，s)，5.56(2H，s)，7.37-7.41(2H，m)，7.93-7.97(3H，m)

MS?m/e?MH ⁺391

Intermediate #48:5-chloro-1-(4-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester

Nitrite tert-butyl (417 l, 3.48 mMs) and copper chloride (583 milligrams, 4.35 mMs) are added in the acetonitrile (20 milliliters) and be heated to 65 ℃.Dropwise add 5-amino-1-(4-methoxycarbonyl-benzyl)-solution of 1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #50) in acetonitrile (～4 milliliters).After adding completion, continue heating 15 minutes again.Be cooled to ambient temperature, water (～100 milliliters) dilutes and extracts with ethyl acetate (3 *～40 milliliters).With extract water (2 *～20 milliliters) that merges and saline (～20 milliliters) washing, dry (MgSO4) filters and flashes to oil.Chromatographic isolation (40 gram silica columns, EtOAc/ hexane 10-50%) is to produce the title compound (397 milligrams, 39%) of pale solid shape.

¹H?NMR(300.072MHz，CDCl ₃)δ1.49(9H，s)，3.83(3H，s)，5.33(2H，s)，7.19(2H，d)，7.84(1H，s)，7.93(2H，d)

MS?m/e[M+Na] ⁺373。

Intermediate #49:5-chloro-1-(3-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester

5-amino-1-(4-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester is replaced to 5-amino-1-(3-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #51), the chemical compound of processing with the mode that is similar to intermediate #48.

¹H?NMR(300.072MHz，CDCl ₃)δ1.49(9H，s)，3.84(3H，s)，5.32(2H，s)，7.33-7.35(2H，m)，7.84(1H，s)，7.88-7.93(2H，m)

MS?m/e[M- ^tBu+H] ⁺295。

Intermediate #50:5-amino-1-(4-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester

The cyanoacetic acid tert-butyl ester (600 milligrams, 4.25 mMs) is dissolved in the triethyl orthoformate (1.06 milliliters, 6.38 mMs), adds acetic anhydride (0.40 milliliter, 4.25 mMs) also with this mixture heated to 125 ℃ maintenance 2 hours.Evaporate this solution to stay yellow oil.Should be dissolved in again in the ethanol (5 milliliters) also with 4-diazanyl methyl-essence of Niobe hydrochlorate (intermediate #52) (230 milligrams, 1.06 mMs) and DIPEA (184 l, 1.06 mMs) processing by oil.The gained mixture heated to refluxing 2 hours, is cooled to ambient temperature and evaporation to stay brown oil then.This oil is dissolved in the ethyl acetate (50 milliliters), water (2 * 20 milliliters) and saline (20 milliliters) washing, dry (MgSO4) then filters and evaporation.With the title compound (214 milligram, 43%) of residue chromatographic isolation (40 gram silicon dioxide EtOAc/ hexane 0-50%) with generation yellow solid shape.

¹H?NMR(300.072MHz，CDCl ₃)δ1.55(9H，s)，3.90(3H，s)，4.86(2H，s)，5.18(2H，s)，7.21(2H，d)，7.62(1H，s)，8.00(2H，d)

MS?m/e[M-H] ^-330

Intermediate #51:5-amino-1-(3-methoxycarbonyl-benzyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester

4-diazanyl methyl-essence of Niobe hydrochlorate is replaced to 3-diazanyl methyl-essence of Niobe hydrochlorate (intermediate #53), the chemical compound of processing with the mode that is similar to intermediate #50.

¹H?NMR(300.072MHz，CDCl ₃)δ1.47(9H，s)，3.84(3H，s)，4.75(2H，s)，5.11(2H，s)，7.26(1H，d)，7.36(1H，t)，7.55(1H，s)，7.83(1H，s)，7.90(1H，d)

MS?m/e?MH ⁺332。

Intermediate #52:4-diazanyl methyl-essence of Niobe hydrochlorate

With the stirred overnight at ambient temperature of the solution among the 4M HCl (100 milliliters) of 4-[[(2-methylpropane-2-yl) oxygen base carbonyl-[(2-methylpropane-2-yl) oxygen base carbonylamino] amino] methyl] essence of Niobe (intermediate #54) (3.3 gram, 8.67 mMs) in dioxane.Removal of solvent under reduced pressure also is dissolved in the gained solid among the hot MeOH.Filter this hot suspension, evaporate in a vacuum then to produce solid.This solid is developed with ether, filtered, then dry title compound (1.5 grams, 80%) under fine vacuum to produce the yellow solid shape.

¹H?NMR(300.073MHz，DMSO-d ₆)δ3.85(3H，s)，4.13(2H，s)，7.55(2H，d)，7.93(2H，d)

Intermediate #53:3-diazanyl methyl-essence of Niobe hydrochlorate

4-[[(2-methylpropane-2-yl) oxygen base carbonyl-[(2-methylpropane-2-yl) oxygen base carbonylamino] amino] methyl] benzoate is replaced to 3-[[(2-methylpropane-2-yl) oxygen base carbonyl-[(2-methylpropane-2-yl) oxygen base carbonylamino] amino] methyl] benzoate (intermediate #55), the chemical compound of processing with the mode that is similar to intermediate #52.

¹H?NMR(300.073MHz，DMSO-d ₆)δ3.86(3H，s)，4.13(2H，s)，7.52(1H，t)，7.70(1H，d)，7.91(1H，d)，8.02(1H，s)，8.77(4H，br?s)

MS?m/e?MH ⁺181。

Intermediate #54:4-[[(2-methylpropane-2-yl) oxygen base carbonyl-[(2-methylpropane-2-yl) oxygen base Carbonylamino] amino] methyl] essence of Niobe

NaH (362 milligrams, 9.04 mMs) is added in the agitating solution of hydrazono-di-tert-butyl dicarboxylate (2 grams, 8.61 mMs) in anhydrous THF (50 milliliters).This reaction was stirred 10 minutes at ambient temperature, used the solution-treated of 4-(bromomethyl) essence of Niobe (1.98 grams, 8.61 mMs) in anhydrous THF (20 milliliters) then.This reaction was stirred 4 hours at ambient temperature.This is reflected between ether (～100 milliliters) and the water (～100 milliliters) distributes.Separate each layer and water layer is extracted with ether (～50 milliliters) again.The combined ether layer, with saline (～50 milliliters) washing, dry (MgSO ₄), filter and evaporation generation title compound (3.3 grams, 100%).

¹H?NMR(300.073MHz，DMSO-d ₆)δ.1.38(18H，s)，3.84(3H，s)，4.52(2H，br?s)，7.42(2H，d)，7.90(2H，d)，9.19(1H，s)

MS?m/e[M+Na] ⁺403。

Intermediate #55:3-[[(2-methylpropane-2-yl) oxygen base carbonyl-[(2-methylpropane-2-yl) oxygen base Carbonylamino] amino] methyl] essence of Niobe

4-(bromomethyl) essence of Niobe is replaced to 3-(bromomethyl) essence of Niobe, the chemical compound of processing with the mode that is similar to intermediate #54.

¹H?NMR(400.13MHz，DMSO-d ₆)δ1.39(18H，s)，3.86(3H，s)，4.50-4.58(2H，m)，7.45-7.52(1H，m)，7.57(1H，d)，7.85-7.90(2H，m)，9.25(1H，s)

MS?m/e[M+Na] ⁺403。

Intermediate #56:4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid Methyl ester

With 4-hydrazino-benzoic acid methyl ester hydrochloride (intermediate #123) (3.04 grams; 15.00 disposable (2)-N-(2-the adamantyl)-2-(dimethylamino methylene)-4 that adds in ethanol (100 milliliters) mM); In the 4-dimethyl-3-oxo-pentanamide (intermediate #58) (4.99 grams, 15 mMs).Add 5 acetic acid, and gained solution was stirred 2 hours down at 80 ℃.Reactant mixture is concentrated and with EtOAc (500 milliliters) dilution, water (200 milliliters) and saturated brine (200 milliliters) wash in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] essence of Niobe of doing so that the yellow solid shape to be provided (4.66 grams, 71.3%).

1H?NMR(400.13MHz，DMSO-d ₆)δ1.19(9H，s)，1.50(2H，d)，1.69-1.95(10H，m)，2.09(2H，d)，3.91(3H，s)，3.99(1H，d)，7.53-7.56(2H，m)，7.62(1H，s)，8.09-8.12(2H，m)，8.20(1H，d)

m/z(ESI+)(M+H)+＝436

Intermediate #56 also can be prepared as follows:

With 2-(4-(methoxycarbonyl) phenyl) chlorination

(intermediate #123) (1 equivalent); Acetic acid (0.023 equivalent) adds (2Z)-N-(2-adamantyl)-2-(dimethylamino-methylene)-4 under nitrogen then, in the solution of 4-dimethyl-3-oxo-pentanamide (intermediate #58) (1 equivalent) in methanol (200 volume).This mixture was stirred 1.5 hours down refluxing, cool off, be concentrated into and be lower than 3.5 volumes, and the gained suspension is diluted with ethyl acetate (96 volume).This suspension water (34.4 volume) washing is to obtain solution, and it washs with saline (34.4 volume), dry (MgSO ₄) and be concentrated into dried.The slurrying and stirring 15 minutes in MTBE (9 volume) of this crude product.Filter this light yellow solid, with MTBE (11.4 volume) washing and dry down at 60 ℃ under vacuum.

TLC DCM: MeOH, 9: 1, product R _f0.86 (trace impurity R _f0.68)

mp?193.6-194.5℃

Intermediate #57:4-[4-(2-adamantyl carbamoyl)-5-(1-methyl cyclopropyl) pyrazol-1-yl] Essence of Niobe

With 4-hydrazino-benzoic acid methyl ester hydrochloride (intermediate #123) (0.809 gram; 3.99 disposable (Z)-N-(2-adamantyl)-3-dimethylamino-2-(the 1-methyl cyclopropane carbonyl) third-2-alkene amide (intermediate #59) that adds in ethanol (30 milliliters) mM); 1.320 gram, 3.99 mMs) in.Add 5 acetic acid, and gained solution was stirred 2 hours down at 80 ℃.Reactant mixture is concentrated and with EtOAc (100 milliliters) dilution, water (50 milliliters) and saturated brine (50 milliliters) wash in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to dried to provide as the solid 4-of white emulsus [4-(2-adamantyl carbamoyl)-5-(1-methyl cyclopropyl) pyrazol-1-yl] essence of Niobe (1.221 grams, 70.5%).

m/z(ESI+)(M+H)+＝434；HPLC?t _R＝2.98min。

1H?NMR(400.13MHz，DMSO-d ₆)δ0.48-0.51(2H，m)，0.67-0.69(2H，m)，1.54-1.57(5H，m)，1.73(2H，s)，1.83-1.86(6H，m)，1.97(2H，s)，2.04-2.07(2H，m)，3.90(3H，s)，4.05-4.10(1H，m)，7.50(1H，d)，7.71(2H，d)，8.09(1H，s)，8.13(2H，d)

Intermediate #58: (2)-N-(2-adamantyl)-2-(dimethylamino methylene)-4, the 4-dimethyl -3-oxo-pentanamide

With N; Dinethylformamide dimethyl-acetal (3.02 milliliters, 22.71 mMs) adds N-(2-adamantyl)-4 under nitrogen, 4-dimethyl-3-oxo-pentanamide (intermediate #60) (5.25g; 18.93 mM) 1, in the stirred suspension in the 4-dioxane (50 milliliters).The gained mixture was stirred 2 hours down at 100 ℃.Reactant mixture is evaporated to dried, and the shallow lacteous of gained frost emulsus solid is dry (2)-N-(2-adamantyl)-2-(dimethylamino methylene)-4 to be provided, 4-dimethyl-3-oxo-pentanamide (5.83 grams, 93%) under vacuum.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.13(9H，s)，1.47(2H，d)，1.69-1.83(10H，m)，2.03(2H，d)，2.92(6H，s)，3.90(1H，d)，7.24(1H，s)，7.94(1H，d)

m/z(ESI+)(M+H)+＝333

Intermediate #58 also can be prepared as follows:

With N, dinethylformamide dimethyl-acetal (1.2 equivalent) adds N-(2-adamantyl)-4 under nitrogen, and 4-dimethyl-3-oxo-pentanamide (intermediate #60) (1 equivalent) is 1, in the solution in the 4-dioxane (9.6 volume).This mixture was heated 5 hours under refluxing, be cooled to room temperature then.Remove in a vacuum and desolvate, and this light yellow solid directly is used in next stage.

TLC hexane: EtOAc, 1: 1, product R _f0.94 (impurity: R _f0.06+0.66)

mp?143.6-147.6℃

Intermediate #59: (Z)-N-(2-adamantyl)-3-dimethylamino-2-(1-methyl cyclopropane carbonyl) Third-2-alkene amide

By N-(2-adamantyl)-3-(1-methyl cyclopropyl)-3-oxo-propionic acid amide. (intermediate #61) through with the preparation of the used identical method of intermediate #58

1H?NMR(400.13MHz，DMSO-d ₆)δ0.54-0.55(2H，m)，0.91-0.94(2H，m)，1.26(3H，s)，1.51(2H，d)，1.69(2H，s)，1.72-1.85(8H，m)，1.92(2H，d)，3.00(6H，s)，3.90-3.92(1H，m)，7.57(1H，s)，8.08(1H，s)

(intermediate #60): N-(2-adamantyl)-4,4-dimethyl-3-oxo-pentanamide

The two 1M solution (22.84 milliliter, 22.84 mMs) of (trimethyl silyl) lithium amide in THF of general add among the THF (25 milliliters) and under nitrogen, are cooled to-78 ℃.Dropwise added 3 through 5 minutes, the solution of 3-dimethyl-2-butanone (2.287 grams, 22.84 mMs) in THF (25 milliliters).Gained solution was stirred 15 minutes down at-78 ℃ under nitrogen.Added the solution of 2-isocyanato-diamantane (obsolete) (processing through the method for the 864th page of R.Reck&C.Jochims Chem.Ber.115 (1982)) (3.68 grams, 20.76 mMs) in THF (20 milliliters) by 2-adamantyl amine hydrochlorate through 5 minutes.Gained solution was stirred 1 hour down at-78 ℃, be warming up to 20 ℃ through 1 hour then.Pour reactant mixture into saturated NH ₄Among the Cl (150 milliliters) and with EtOAc (2 * 100 milliliters) extraction, organic layer water (50 milliliters) and saline (50 milliliters) washing, dry through MgSO4, filtration and evaporation are to provide yellow oil.Crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to the N-(2-adamantyl)-4 that does so that white solid to be provided, 4-dimethyl-3-oxo-pentanamide (4.64 grams, 81%).

1H NMR (400.13MHz, DMSO-d ₆) δ 1.08-1.09 (9H, m), 1.50 (2H, d), 1.66-1.89 (10H, m); 1.95-2.00 (2H, m), 3.53 (1.4H, s), 3.80-3.94 (1H, m); 5.30 (0.3H, s), 7.77-7.87 (1H, m), 14.43 (0.3H, s) (2: 1 mixture of ketone and enol form)

m/z(ESI+)(M+H)+＝278

Intermediate #60 also can be prepared as follows.

Sodium hydrate aqueous solution (3M) (5 volume) is added in the stirred suspension of 2-adamantyl amine hydrochlorate (1 equivalent) in water (5 volume).DCM (5 volume) is added in the dense thick suspension of gained and separates each phase.Water is with DCM (4 * 5 volume) extraction, and the Organic substance that merges concentrates the unhindered amina that produces white solid.

Under nitrogen, add valeryl ethyl acetate (1 equivalent) to said unhindered amina in xylene in the suspension of (6.5 volume), with this mixture in the stirring down 6.5 hours that refluxes.This batch of material is cooled to room temperature and is concentrated into dried.With residue with toluene (3 * 1 volume) then hexane (3 * 1 volume) purge.With the gained solid in hexane 50 ℃ of following steaming and decoctings 5 minutes, be cooled to room temperature then.Filter white solid, with hexane (2 volume) washing, and at air drying.

TLC hexane: EtOAc, 1: 1, product R _f0.66

mp?124.5-125.1℃

Intermediate #61:N-(2-adamantyl)-3-(1-methyl cyclopropyl)-3-oxo-propionic acid amide.

By 1-(1-methyl cyclopropyl) ethyl ketone through preparing m/z (ESI+) (M+H) +=276 with the used identical method of intermediate #60; HPLC t _R=2.26min.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.76-0.78(2H，m)，1.18-1.20(2H，m)，1.25(3H，s)，1.50(2H，d)，1.70-1.80(11H，m)，1.95(2H，d)，3.82(1H，d)，7.83(1H，d)

Intermediate #62:4-[4-(2-adamantyl carbamoyl)-5-cyclopenta-pyrazol-1-yl] benzoic acid Methyl ester

With 4-hydrazino-benzoic acid methyl ester hydrochloride (intermediate #123) (0.712 gram; 3.51 disposable (Z)-N-(2-adamantyl)-2-(Pentamethylene. the carbonyl)-3-dimethylamino-third-2-alkene amide (intermediate #67) that adds in ethanol (30 milliliters) mM); 1.21 gram, 3.51 mMs) in.Add 5 acetic acid and gained solution is descended stirring 2 hours at 80 ℃, be cooled to ambient temperature then, produce precipitate.Filter reaction mixture also reclaims product; With ethanol (10 milliliters) and water (10 milliliters) washing; Dry 4-[4-(2-adamantyl carbamoyl)-5-cyclopenta-pyrazol-1-yl] essence of Niobe (0.620 gram, 39.4%) under vacuum then to produce white solid.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.48-1.53(4H，m)，1.71-1.85(12H，m)，1.94(2H，s)，2.02-2.12(4H，m)，2.98-3.09(1H，m)，3.90(3H，s)，3.98-4.03(1H，m)，7.57-7.60(2H，m)，7.74-7.76(1H，m)，8.10-8.15(3H，m)

m/z(ESI+)(M+H)+＝448；HPLC?t _R＝3.26min。

With the used identical method of intermediate #62 by the following intermediate of suitable raw material preparing.

Intermediate #66:N-(2-adamantyl)-1-(4-cyano-phenyl)-5-methyl-pyrazole-4-carboxamide

With (0.031 milliliter of acetic acid; 0.50 disposable (2E)-N-(2-adamantyl)-2-(dimethylamino methylene)-3-oxo-butyramide (intermediate #71) (1.45 grams that add in ethanol (40 milliliters) mM); 4.99 mM) and in the 4-cyano-phenyl hydrazonium salt hydrochlorate (0.847g, 4.99 mMs).The gained suspension was stirred 3 hours down at 80 ℃.Reactant mixture is concentrated and washs with EtOAc (75 milliliters), water (50 milliliters) and saturated brine (50 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 20 to 50%EtOAc is in isohexane.Pure fraction is evaporated to N-(2-adamantyl)-1-(4-cyano-phenyl)-5-methyl-pyrazole-4-carboxamide (1.3 grams, 72%) of doing so that the orange solids shape to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.45-1.58(2H，m)，1.70-1.9(8H，m)，1.92-1.99(2H，m)，2.05-2.15(2H，m)，2.57(3H，s)，4.00-4.06(1H，m)，7.59(1H，d)，7.79(2H，d)，8.05(2H，d)，8.32(1H，s)

m/z(ESI+)(M+H)+＝361；

Intermediate #67: (Z)-N-(2-adamantyl)-2-(Pentamethylene. carbonyl)-3-dimethylamino-third-2- The alkene amide

With N; Dinethylformamide dimethyl-acetal (0.587 milliliter, 4.42 mMs) adds to 1, the N-(2-adamantyl) in the 4-dioxane (25 milliliters)-3-cyclopenta-3-oxo-propionic acid amide. (intermediate #72); In (1.023 grams, 3.53 mMs).Gained solution was stirred 2 hours down at 100 ℃.The gained mixture is evaporated to dried so that (Z)-N-(2-adamantyl)-2-(Pentamethylene. carbonyl)-3-dimethylamino-third-2-alkene amide (1.210 grams, 99%) to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.45-1.50(4H，m)，1.54-1.68(8H，m)，1.72-1.85(8H，m)，2.00(2H，d)，2.97(6H，s)，3.05-3.15(1H，m)，3.95(1H，d)，7.42(1H，s)，8.30(1H，d)

With the used identical method of intermediate #67 by the following intermediate of suitable raw material preparing.

Intermediate #72:N-(2-adamantyl)-3-cyclopenta-3-oxo-propionic acid amide.

With 2-adamantanamine hydrochloride (1.641 grams; 8.74 mM) add 5-(Pentamethylene. carbonyl)-2 in toluene (30 milliliters) to, 2-dimethyl-1,3-dioxane-4; 6-diketone (intermediate #77); In (2.1 grams, 8.74 mMs) and the N-ethyl diisopropyl amine (1.512 milliliters, 8.74 mMs).The gained suspension was stirred 2 hours down at 110 ℃.Reactant mixture is diluted with EtOAc (100 milliliters), and use 2M HCl (20 milliliters) and water (2 * 50 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 100%EtOAc is in isohexane.Pure fraction is evaporated to does so that brown buttery N-(2-adamantyl)-3-cyclopenta-3-oxo-propionic acid amide. (1.030 grams, 40.7%) to be provided, it is crystallization when leaving standstill.

1H NMR (400.13MHz, DMSO-d ₆) δ 1.46-1.59 (7H, m), 1.60-1.78 (16H, m), 1.90-2.00 (2H, m), 2.95-3.03 (1H, m), 3.84 (0.9H, d), 3.90 (0.1H, d), 7.78 (0.1H, d), 7.93 (0.9H, d), 14.21 (0.1H, s) 9: 1 ketone: enol form

With the used identical method of intermediate #72 by the following intermediate of suitable raw material preparing.

Intermediate #77:5-(Pentamethylene. carbonyl)-2,2-dimethyl-1,3-dioxane-4,6-diketone

With (1.100 milliliters of Pentamethylene. phosgenes; 9.05 mM) (1.304 restrain the solution in DCM (5 milliliters) under nitrogen, dropwise adding isopropylidene malonate to through 10 minutes under 5 ℃; 9.05 mM) and in the agitating solution of pyridine (1.464 milliliters, 18.10 mMs) in DCM (20 milliliters).Gained solution was stirred 1 hour down at 5 ℃, be warming up to 20 ℃ then, and restir 1 hour.Reactant mixture is diluted with DCM (100 milliliters), and use 2M HCl (2 * 50 milliliters), water (50 milliliters) and saturated brine (50 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product, brown buttery 5-(Pentamethylene. carbonyl)-2,2-dimethyl-1,3-dioxane-4,6-diketone (2.100 grams, 97%).

1H?NMR(400.13MHz，DMSO-d ₆)δ1.51-1.60(5H，m)，1.61-1.68(3H，s)，1.70-1.79(4H，m)，1.84-1.98(2H，m)，2.89-3.00(1H，m)，4.04(1H，s

With the used identical method of intermediate #77 by the following intermediate of suitable raw material preparing.

Intermediate #82:1-(4-the bromophenyl)-5-tert-butyl group-N-cyclohexyl-1H-pyrazole-4-carboxamide

With (2)-2-(dimethylamino methylene)-4,4-dimethyl-3-oxo-ethyl valerate (intermediate #83) (1.24 grams, 5.88 mMs) is dissolved in the ethanol (20 milliliters).Add 4-bromophenyl hydrazine HCl (1.32 grams, 5.88 mMs) and DIPEA (1.02 milliliters, 5.88 mMs).This mixture heated to refluxing 2 hours, is cooled to ambient temperature and reduction vaporization.Residue is dissolved among the DCM (50 milliliters), water (2 * 10 milliliters) washing, dry (MgSO4) and evaporation are to provide crude product.This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 25%EtOAc is in isohexane.Pure fraction is evaporated to dried so that 1-(4-bromophenyl)-5-tert-butyl group-N-cyclohexyl-1H-pyrazole-4-carboxamide (627 milligrams, 32%) to be provided

1H?NMR(300.073MHz，DMSO-d ₆)δ1.23(9H，s)，1.29(3H，t)，4.24(2H，q)，7.39-7.41(2H，m)，7.69-7.72(2H，m)，7.92(1H，s)

m/z(ESI+)(M+H)+＝353

Intermediate #83: (2)-2-(dimethylamino methylene)-4,4-dimethyl-3-oxo-valeric acid second Ester

With pivaloyl ethyl acetate (1.72 grams, 10 mMs) and N, dinethylformamide dimethyl-acetal (1.68 milliliters, 12.5 mMs) is dissolved in the dioxane (20 milliliters) and is heated to and refluxed 3 hours.Reactant mixture is cooled to ambient temperature and reduction vaporization to stay crude product.This crude product to be through (gradient 0 to 100%EtOAc is in hexane) (the 2)-2-(dimethylamino methylene)-4 so that colorless oil to be provided that purifies at the flash chromatography on the silica gel, 4-dimethyl-3-oxo-ethyl valerate, and it is crystallization when leaving standstill.(1.24 grams, 54%)

1H?NMR(300.073MHz，DMSO-d ₆)δ1.11(9H，d)，1.18(3H，t)，2.82(6H，s)，4.04(2H，q)，7.31(1H，s)

m/z(ESI+)(M+H)+＝228

Intermediate #84:4-[4-(2-adamantyl carbamoyl)-5-cyclohexyl sulfane base-pyrazoles-1- Base] essence of Niobe

With (191 milligrams of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; 1.00 mM) under 20 ℃ nitrogen next time property add (300 milligrams of 5-(hexamethylene sulfenyl)-1-(4-(methoxycarbonyl) phenyl) in DMF (7 milliliters)-1H-pyrazoles-4-carboxylic acid (intermediate #88) to; 0.83 mM), the 2-adamantanamine hydrochloride is (172 milligrams; 0.92 mM) and in the N-ethyl diisopropyl amine (0.432 milliliter, 2.50 mMs).The gained mixture was stirred 18 hours down at 20 ℃.

Reactant mixture is diluted with EtOAc (75 milliliters), and water (4 * 25 milliliters) and saturated brine (25 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to 4-[4-(2-adamantyl the carbamoyl)-5-cyclohexyl sulfane base-pyrazol-1-yl] essence of Niobe of doing so that the white crystalline solid shape to be provided (349 milligrams, 85%).

1H?NMR(300.073MHz，DMSO-d6)δ1.05(5H，d)，1.39-1.54(5H，m)，1.62(2H，d)，1.73(2H，s)，1.83(6H，s)，1.94-2.01(4H，m)，2.92(1H，s)，3.89(3H，s)，4.09(1H，d)，7.76(2H，d)，8.04(1H，d)，8.12(2H，d)，8.17(1H，s)

m/z(ESI+)(M+H)+＝494

Mode to be similar to intermediate #84 prepares following intermediate by 5-(hexamethylene sulfenyl)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid (intermediate #88) and suitable amine.

Intermediate #88:5-cyclohexyl sulfane base-1-(4-methoxycarbonyl phenyl) pyrazoles-4-carboxylic acid

Trifluoroacetic acid (4.72 milliliters, 61.46 mMs) is added in 5-(hexamethylene sulfenyl)-1-(4-(methoxycarbonyl) the phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #89) (2.56 grams, 6.15 mMs) in CH2Cl2 (40 milliliters).Gained solution was stirred 24 hours down at 20 ℃.Reactant mixture is evaporated to dried, be dissolved in again in the dioxane (20 milliliters) and revaporization to 5-(hexamethylene sulfenyl)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid (2.25 grams, 100%) of doing so that the white crystalline solid shape to be provided.

1H?NMR(400.13MHz，DMSO-d6)δ1.04-1.11(5H，m)，1.42(1H，s)，1.51(2H，s)，1.59(2H，d)，3.31-3.22(1H，m)，3.91(3H，s)，7.70-7.73(2H，m)，8.11-8.15(2H，m)，8.19(1H，s)，12.66(1H，s)

MS?m/z(ESI+)(M+H)+＝361。

Intermediate #89:5-cyclohexyl sulfane base-1-(4-methoxycarbonyl phenyl) pyrazoles-4-carboxylic acid uncle fourth Ester

Two (trimethyl silyl) sodium amides (10.69 milliliters, 10.69 mMs) are dropwise added under nitrogen in the cyclohexylmercaptan (1.307 milliliters, 10.69 mMs) in DMF (35 milliliters).Gained solution was stirred 30 minutes down at 20 ℃.Dropwise add the solution of 5-chloro-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #9) (3 grams, 8.91 mMs) in DMF (10 milliliters) then, and the gained mixture was stirred 2 hours down at 20 ℃.

This reactant mixture is diluted with EtOAc (200 milliliters), and water (4 * 50 milliliters) and saturated brine (50 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

Crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 25%EtOAc is in isohexane.Pure fraction is evaporated to 5-(hexamethylene sulfenyl)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (2.56 grams, 69.0%) of doing so that colorless oil to be provided, and it is crystallization when leaving standstill.

1H?NMR(400.13MHz，DMSO-d6)δ0.95-1.05(5H，m)，1.35(1H，s)，1.42-1.55(13H，d)，3.12(1H，d)，3.81(3H，s)，7.69-7.72(2H，m)，8.11-8.14(2H，m)，8.16(1H，s)

m/z(ESI+)(M+H)+＝417

Intermediate #90:4-[4-(2-adamantyl carbamoyl)-5-cyclopenta sulfane base-pyrazoles-1- Base] essence of Niobe

With (199 milligrams of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; 1.04 mM) 20 ℃ nitrogen next time property add (300 milligrams of 5-(encircling penta sulfenyl)-1-(4-(methoxycarbonyl) phenyl) in DMF (7 milliliters)-1H-pyrazoles-4-carboxylic acid (intermediate #93) to; 0.87 mM), the 2-adamantanamine hydrochloride is (179 milligrams; 0.95 mM), I-hydroxybenzotriazole is (140 milligrams; 1.04 mM) and in the N-ethyl diisopropyl amine (0.450 milliliter, 2.60 mMs).The gained mixture was stirred 18 hours down at 20 ℃.

Reactant mixture is diluted with EtOAc (75 milliliters), and water (4 * 25 milliliters) and saturated brine (25 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

Crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to 4-[4-(2-adamantyl the carbamoyl)-5-cyclopenta sulfane base-pyrazol-1-yl] essence of Niobe of doing so that the white crystalline solid shape to be provided (336 milligrams, 81%).

1H?NMR(400.13MHz，DMSO-d6)δ1.17-1.25(2H，m)，1.35-1.42(4H，m)，1.65(4H，d)，1.74(2H，s)，1.87(6H，d)，1.96-2.02(4H，m)，3.25-3.35(1H，m)，3.91(3H，s)，4.12(1H，t)，7.78-7.82(2H，m)，8.08(1H，d)，8.13-8.16(2H，m)，8.19(1H，s)

m/z(ESI+)(M+H)+＝480m/z(ESI+)(M+H)+＝480

Mode to be similar to intermediate #90 prepares following intermediate by 5-(encircling penta sulfenyl)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid (intermediate #93) and suitable amine.

Intermediate #93:5-cyclopenta sulfane base-1-(4-methoxycarbonyl phenyl) pyrazoles-4-carboxylic acid

Trifluoroacetic acid (2.63 milliliters, 34.29 mMs) is added in 5-(encircling penta sulfenyl)-1-(4-(methoxycarbonyl) the phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #94) (1.38 grams, 3.43 mMs) in CH2Cl2 (25 milliliters).Gained solution was stirred 24 hours down at 20 ℃.Reactant mixture is evaporated to dried, is dissolved in the dioxane (20 milliliters) again, revaporization is to 5-(encircling penta sulfenyl)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid (1.180 grams, 99%) of doing so that the white crystalline solid shape to be provided.

1H?NMR(400.13MHz，DMSO-d6)δ1.20-1.26(2H，m)，1.37-1.47(4H，m)，1.65-1.73(2H，m)，3.65-3.71(1H，m)，3.86-3.96(3H，m)，7.68-7.76(2H，m)，8.11-8.15(2H，m)，8.19(1H，s)，12.84(1H，s)MS m/z(ESI-)(M-H)-＝345

Intermediate #94:5-cyclopenta sulfane base-1-(4-methoxycarbonyl phenyl) pyrazoles-4-carboxylic acid uncle fourth Ester

Two (trimethyl silyl) sodium amides (7.13 milliliters, 7.13 mMs) are dropwise added under nitrogen in the cyclopentanethiol (0.761 milliliter, 7.13 mMs) in DMF (25 milliliters).Gained solution was stirred 30 minutes down at 20 ℃.Dropwise add the solution of 5-chloro-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #9) (2 grams, 5.94 mMs) in DMF (10 milliliters) then, and the gained mixture was stirred 2 hours down at 20 ℃.Reactant mixture is diluted with EtOAc (200 milliliters), and water (4 * 50 milliliters) and saturated brine (50 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.Crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 25%EtOAc is in isohexane.Pure fraction is evaporated to 5-(encircling penta sulfenyl)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (1.380 grams, 57.7%) of doing so that colorless oil to be provided, and it is crystallization when leaving standstill.

1H?NMR(300.073MHz，DMSO-d6)δ1.14-1.24(2H，m)，1.35-1.47(4H，m)，1.54(9H，s)，1.60-1.77(2H，m)，3.54-3.58(1H，m)，3.90(3H，s)，7.71(2H，d)，8.11(2H，d)，8.14(1H，d)

MS?m/z(ESI+)(M+H)+＝403。

Intermediate #95:4-[4-[[5-(difluoro-methoxy)-2-adamantyl] carbamoyl]-5-propylthio Alkyl pyrazole-1-yl] essence of Niobe

With (250 milligrams of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; 1.31 disposable (349 milligrams of the 1-(4-methoxycarbonyl phenyl) in DMF (10 milliliters)-5-propylthio alkyl pyrazole-4-carboxylic acid (intermediate #7) that add to mM); 1.09 mM), 5-(difluoro-methoxy) diamantane (obsolete)-2-amine (intermediate #121) is (260 milligrams; 1.20 mM), I-hydroxybenzotriazole is (176 milligrams; 1.31 mM) and in the N-ethyl diisopropyl amine (0.376 milliliter, 2.18 mMs).The gained mixture was stirred 5 hours down at 20 ℃.

With EtOAc (100 milliliters) dilution, water (4 * 25 milliliters) and saturated brine (25 milliliters) wash in succession with reactant mixture.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

Crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to 4-[4-[[5-(difluoro-methoxy)-2-adamantyl] the carbamoyl]-5-propylthio alkyl-pyrazol-1-yl] essence of Niobe of doing so that the white crystalline solid shape to be provided (338 milligrams, 59.8%).

1H?NMR(400.13MHz，DMSO-d6)δ0.68(3H，t)，1.21-1.30(2H，m)，1.51(2H，d)，1.90-1.97(6H，m)，2.05(2H，d)，2.15-2.20(3H，m)，2.65(2H，t)，3.91(3H，s)，4.09(1H，d)，6.88(1H，t)，7.76-7.79(2H，m)，7.98(1H，d)，8.13-8.16(2H，m)，8.19(1H，s)

m/z(ESI+)(M+H)+＝520

Intermediate #96:4-[4-(cyclohexyl carboxyamide base)-5-cyclopenta sulfane base-pyrazol-1-yl] benzene first The acid methyl ester

In the solution of cyclopenta mercaptan (0.071 milliliter, 0.66 mM) in DMF (2 milliliters), add the 1N solution (0.66 milliliter, 0.66 mM) of NaHMDS in THF.This reaction was stirred 2 minutes at ambient temperature, added to then in the solution of 4-[5-chloro-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe (intermediate #15) (200 milligrams, 0.55 mM) in DMF (3 milliliters).

Reactant mixture was at room temperature stirred 2 hours.Reactant mixture is evaporated to dried, is dissolved in again among the DCM (50 milliliters), and with saturated NH4Cl (10 milliliters), water (10 milliliters) and saline (10 milliliters) washing.Its through MgSO4 dry and solvent evaporated under reduced pressure to produce solid.Crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to dried so that solid, shaped 4-[4-(cyclohexyl carboxyamide base)-5-cyclopenta sulfane base-pyrazol-1-yl] to be provided essence of Niobe (233 milligrams, 98%).

m/z(ESI+)(M+H)+＝428

Intermediate #97:4-[4-(cyclohexyl carboxyamide base)-5-cyclohexyl sulfane base pyrazol-1-yl] benzene first The acid methyl ester

By cyclohexylmercaptan and 4-[5-chloro-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe (intermediate #15) through preparing 4-[4-(cyclohexyl carboxyamide base)-5-cyclohexyl sulfane base pyrazol-1-yl] essence of Niobe with the used identical method of intermediate #96.

m/z(ESI+)(M+H)+＝442

Intermediate #98:4-[5-suberyl sulfane base-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] benzene first The acid methyl ester

By ring heptanthiol and 4-[5-chloro-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe (intermediate #15) through preparing 4-[5-suberyl sulfane base-4-(cyclohexyl carboxyamide base) pyrazol-1-yl] essence of Niobe with the used identical method of intermediate #96.

m/z(ESI+)(M+H)+＝456；HPLC?tR＝3.27min。

1H?NMR(300.072MHz，CDCl3)δ1.08-1.48(15H，m)，1.56-1.72(5H，m)，1.91-1.97(2H，m)，2.84-2.93(1H，m)，3.90(3H，s)，3.93-4.02(1H，m)，7.57-7.65(3H，m)，8.08-8.12(2H，d)，8.22(1H，s)

Intermediate #99:4-[4-(2-adamantyl carbamoyl)-5-ethyl sulfane base-pyrazol-1-yl] Essence of Niobe

With (396 milligrams of N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride; 2.07 disposable (324 milligrams of 2-adamantanamine hydrochlorides that add in DMF (10 milliliters) mM); 1.72 mM), 5-(ethylmercapto group)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid is (528 milligrams; 1.72 mM) in (intermediate #101), I-hydroxybenzotriazole (279 milligrams, 2.07 mMs) and the N-ethyl diisopropyl amine (0.885 milliliter, 5.17 mMs).The gained mixture was stirred 18 hours down at 20 ℃.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to 4-[4-(2-adamantyl the carbamoyl)-5-ethyl sulfane base-pyrazol-1-yl] essence of Niobe of doing so that white solid to be provided (430 milligrams, 56.8%).

1H?NMR(400.13MHz，DMSO-d ₆)δ0.94(3H，t)，1.62(2H，d)，1.74(2H，s)，1.86(6H，d)，1.96-2.02(4H，m)，2.68(2H，q)，3.91(3H，s)，4.11(1H，t)，7.76-7.80(2H，m)，8.04(1H，d)，8.13-8.16(2H，m)，8.20(1H，s)

m/z(ESI+)(M+H)+＝440

Intermediate #100:4-[4-(2-adamantyl carbamoyl)-5-methyl sulfane base-pyrazol-1-yl] Essence of Niobe

Prepare through the method identical by 4-[4-(2-adamantyl carbamoyl)-5-methyl sulfane base-pyrazol-1-yl] essence of Niobe (intermediate #102) with intermediate #101.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.61(2H，d)，1.74(2H，s)，1.86(6H，s)，1.95-2.04(4H，m)，2.29(3H，s)，3.91(3H，s)，4.11(1H，t)，7.76-7.79(2H，m)，8.02(1H，d)，8.13-8.16(2H，m)，8.19(1H，s)

m/z(ESI+)(M+H)+＝426

Intermediate #101:5-(ethylmercapto group)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid

Trifluoroacetic acid (1.324 milliliters, 17.24 mMs) is added in 5-(ethylmercapto group)-1-(4-(methoxycarbonyl) the phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #103) (625 milligrams, 1.72 mMs) in CH2Cl2 (25 milliliters).Gained solution was stirred 24 hours down at 20 ℃.

Reactant mixture is evaporated to dried, and is dissolved in the dioxane (20 milliliters) again, revaporization is to 5-(ethylmercapto group)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid (528 milligrams, 100%) of doing so that white solid to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.96(3H，t)，2.88(2H，q)，3.91(3H，s)，7.70-7.74(2H，m)，8.12-8.15(2H，m)，8.19(1H，s)，12.72(1H，s)

m/z(ESI+)(M+H)+＝307

Intermediate #102:5-(methyl mercapto)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid

Prepare through the method identical by 1-(4-(methoxycarbonyl) phenyl)-5-(methyl mercapto)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #104) with intermediate #101.

1H?NMR(400.13MHz，DMSO-d ₆)δ2.40(3H，s)，3.90(3H，d)，7.72-7.75(2H，m)，8.10-8.14(2H，m)，8.17(1H，s)，12.77(1H，s)

m/z(ESI+)(M+H)+＝293

Intermediate #103:5-(ethylmercapto group)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid uncle fourth Ester

Two (trimethyl silyl) sodium amides (3.56 milliliters, 3.56 mMs) are dropwise added under nitrogen in the ethyl mercaptan (0.264 milliliter, 3.56 mMs) in DMF (10 milliliters).Gained solution was stirred 30 minutes down at 20 ℃.Disposable adding 5-chloro-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #9) (1 gram, 2.97 mMs), and the gained suspension stirred 5 hours down at 20 ℃.Reactant mixture is diluted with EtOAc (100 milliliters), and water (4 * 25 milliliters) and saturated brine (25 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 30%EtOAc is in isohexane.The fraction that will contain product is evaporated to 5-(ethylmercapto group)-1-(4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (0.625 gram, 58.1%) of doing so that the white crystalline solid shape to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.96(3H，t)，1.55-1.56(9H，m)，2.84(2H，q)，3.91(3H，s)，7.70-7.73(2H，m)，8.10-8.15(3H，m)

m/z(ESI+)(M+H)+＝363

Intermediate #104:1-(4-(methoxycarbonyl) phenyl)-5-(methyl mercapto)-1H-pyrazoles-4-carboxylic acid uncle fourth Ester

By (intermediate #9) and sodium methyl mercaptide through with (intermediate #103) used similar method preparation

1H?NMR(400.13MHz，DMSO-d ₆)δ1.56(9H，s)，2.38(3H，s)，3.91(3H，s)，7.72-7.74(2H，m)，8.10-8.17(3H，m)

m/z(ESI+)(M+H)+＝349

Intermediate #105:4-[4-(5-mesyl-diamantane (obsolete)-2-base carbamoyl)-5-propyl group sulfane Base-pyrazol-1-yl]-essence of Niobe

With (127 milligrams of 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; 0.66 mM) under nitrogen, add (152 milligrams of 1-(4-(methoxycarbonyl) phenyl)-5-(rosickyite base) in DCM (7 milliliters)-1H-pyrazoles-4-carboxylic acid (intermediate #7) at ambient temperature to; 0.47 mM), the basic amine of 5-mesyl-diamantane (obsolete)-2-(through the preparation of the method described in Bioorganic&MedicinalChemistry Letters 17 (2007) 527-532) is (109 milligrams; 0.47 mM), 4-dimethylaminopyridine is (11.59 milligrams; 0.09 mM) and in the triethylamine (0.132 milliliter, 0.95 mM).Gained solution was stirred 20 hours at ambient temperature.

Reactant mixture is evaporated to dried, and is dissolved in again among the EtOAc (50 milliliters), use 1N citric acid (25 milliliters), water (20 milliliters) and saturated brine (20 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.This crude product is through quick silicon dioxide chromatographic purification, and gradient 20 to 100%EtOAc is in isohexane.Pure fraction is evaporated to 4-[4-(5-mesyl-diamantane (obsolete)-2-base carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-essence of Niobe (116 milligrams, 46.0%) of doing so that white solid to be provided.

1H?NMR(400.13MHz，CDCl3)δ0.76(3H，t)，1.31-1.40(2H，m)，1.71(2H，d)，1.96(2H，d)，2.11(2H，s)，2.15-2.30(5H，m)，2.33(2H，s)，2.54(2H，t)，2.78(3H，s)，3.97(3H，s)，4.30-4.40(1H，m)，7.71(2H，d)，8.07(1H，d)，8.20(2H，d)，8.30(1H，s)

MS?m/e?MH ⁺532。

Intermediate #106:4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazoles-1- Base]-2-methoxyl group-essence of Niobe

With (197 milligrams of N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride; 1.03 disposable (161 milligrams of 2-adamantanamine hydrochlorides that add in DMF (10 milliliters) mM); 0.86 mM), 1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-5-(rosickyite base)-1H-pyrazoles-4-carboxylic acid (intermediate #107) is (300 milligrams; 0.86 mM), I-hydroxybenzotriazole is (139 milligrams; 1.03 mM) and in the N-ethyl diisopropyl amine (0.440 milliliter, 2.57 mMs).The gained mixture was stirred 18 hours down at 20 ℃.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to 4-[4-(2-adamantyl carbamoyl)-5-propylthio alkyl-pyrazol-1-yl]-2-methoxyl group-essence of Niobe (243 milligrams, 58.7%) of doing so that colorless oil to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.69(3H，t)，1.24-1.32(2H，m)，1.62(2H，d)，1.74(2H，s)，1.86(6H，d)，1.95-2.02(4H，m)，2.65(2H，t)，3.83(3H，s)，3.88(3H，s)，4.11(1H，d)，7.26-7.29(1H，m)，7.44(1H，d)，7.83(1H，d)，8.09(1H，d)，8.18(1H，s)

m/z(ESI+)(M+H)+＝484

Intermediate #107:1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-5-(rosickyite base)-1H-pyrazoles-4- Carboxylic acid

Trifluoroacetic acid (1.194 milliliters, 15.55 mMs) is added in 1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-5-(rosickyite the base)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #108) (632 milligrams, 1.55 mMs) in CH2Cl2 (15 milliliters).Gained solution was stirred 24 hours down at 20 ℃.

Reactant mixture is evaporated to dried; And be dissolved in again in the dioxane (20 milliliters); Revaporization is to 1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-5-(rosickyite base)-1H-pyrazoles-4-carboxylic acid (540 milligrams, 99%) of doing so that colorless oil to be provided, and it solidifies when leaving standstill.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.72(3H，t)，1.25-1.34(2H，m)，2.85(2H，t)，3.57(1H，s)，3.83(3H，s)，3.87(3H，s)，7.19-7.22(1H，m)，7.36-7.36(1H，m)，7.82(1H，d)，8.18(1H，s)，12.6(1H，s)

m/z(ESI+)(M+H)+＝351

Intermediate #108:1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-5-(rosickyite base)-1H-pyrazoles -4-carboxylic acid tert-butyl ester

The two 1M solution of (trimethyl silyl) sodium amide in THF (3.60 milliliters, 3.60 mMs) are dropwise added under nitrogen in the 1-propanethiol (0.326 milliliter, 3.60 mMs) in DMF (10 milliliters).Gained solution was stirred 30 minutes down at 20 ℃.5-chloro-1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #109) (1.1 grams, 3.00 mMs) is added with the solution form in DMF (5 milliliters), and the gained mixture was stirred 5 hours down at 20 ℃.Reactant mixture is diluted with EtOAc (100 milliliters), and water (4 * 25 milliliters) and saturated brine (25 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.The fraction that will contain product is evaporated to 1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-5-(rosickyite base)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (0.642 gram, 52.7%) of doing so that colorless oil to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ0.72(3H，t)，1.29(2H，q)，1.55(9H，s)，2.79(2H，t)，3.83(3H，s)，3.87(3H，s)，7.19-7.22(1H，m)，7.36(1H，d)，7.82(1H，d)，8.14(1H，s)

m/z(ESI+)(M+H)+＝407

Intermediate #109:5-chloro-1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid The tert-butyl ester

In the disposable nitrite tert-butyl (0.649 milliliter, 5.46 mMs) that adds in acetonitrile (25 milliliters) of copper chloride (II) (0.917 gram, 6.82 mMs), and be warming up to 50 ℃.The gained mixture is stirred down at 50 ℃, add 5-amino-1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (intermediate #110) (1.58 grams, 4.55 mMs) with the solid form portioning simultaneously.After adding completion, reactant mixture was stirred 15 minutes down at 50 ℃, be cooled to 20 ℃ then.Reactant mixture is diluted with EtOAc (100 milliliters), and water (2 * 50 milliliters) and saturated brine (25 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Fraction is evaporated to 5-chloro-1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (1.120 grams, 67.1%) of doing so that yellow oily to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.55(9H，s)，3.83(3H，s)，3.88(3H，s)，7.26-7.29(1H，m)，7.42(1H，d)，7.84(1H，d)，8.20(1H，s)

m/z(ESI+)(M+H)+＝367

Intermediate #110:5-amino-1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic Tert-butyl acrylate

Add in the cyanoacetic acid tert-butyl ester (4.29 milliliters, 30 mMs) and the triethyl orthoformate (7.48 milliliters, 45.00 mMs) acetic anhydride (2.83 milliliters, 30.00 mMs) is disposable.The gained mixture was stirred 3 hours down at 125 ℃, and vapourisation under reduced pressure is removed volatile matter then.Gained oil is dissolved in the ethanol (50 milliliters); With 4-diazanyl-2-methoxybenzoic acid methyl ester hydrochloride (intermediate #111) (2.094 grams; 9.00 mM) and N-ethyl diisopropyl amine (1.572 milliliters, 9.00 mMs) handle, and stirred 4 hours down at 80 ℃.

Reactant mixture is concentrated and with EtOAc (200 milliliters) dilution, water (2 * 100 milliliters) and saturated brine (50 milliliters) wash in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to 5-amino-1-(3-methoxyl group-4-(methoxycarbonyl) phenyl)-1H-pyrazoles-4-carboxylic acid tert-butyl ester (1.640 grams, 52%) of doing so that the orange solids shape to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.52(9H，s)，3.81(3H，s)，3.89(3H，s)，6.47(2H，s)，7.21-7.23(1H，m)，7.30(1H，d)，7.68(1H，s)，7.81(1H，d)

m/z(ESI+)(M+H)+＝348

Intermediate #111:4-diazanyl-2-methoxybenzoic acid methyl ester hydrochloride

1-(3-methoxyl group-4-(methoxycarbonyl) phenyl) hydrazine carboxylic acid's tert-butyl ester (intermediate #112) (4.86 grams, 16.40 mMs) is added in the 4M solution of hydrogen chloride (61.5 milliliters, 246 mMs) in dioxane.Gained solution was stirred 5 hours down at 20 ℃.With reactant mixture be evaporated to dry doubling with rough residue with Et2O development to produce solid, it is filtered collects, and under vacuum dry 4-diazanyl-2-methoxybenzoic acid methyl ester hydrochloride (3.50 grams, 92%) to produce the light green color solid, shaped.

1H?NMR(400.13MHz，DMSO-d ₆)δ3.73(3H，s)，3.81(3H，s)，6.53-6.56(1H，m)，6.79(1H，d)，7.66(1H，d)，8.79(1H，s)，10.44(3H，s)

m/z(ESI+)(M+H)+＝197

Intermediate #112:1-(3-methoxyl group-4-(methoxycarbonyl) phenyl) hydrazine carboxylic acid's tert-butyl ester

With Copper diiodide (I) (0.213 gram; 1.12 mM) under nitrogen, add in DMF (75 milliliters) 1; 10-phenanthroline (0.403 gram, 2.24 mMs), tert-butyl carbazate (3.55 grams, 26.83 mMs), cesium carbonate (10.20 grams; 31.30 mM) and in the 4-iodo-2-methoxybenzoic acid methyl ester (6.53 gram, 22.36 mMs).The gained mixture was stirred 1 hour down at 100 ℃.Also water (4 * 100 milliliters) and saturated brine (50 milliliters) wash in succession with EtOAc (400 milliliters) dilution with reactant mixture.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.

This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 50%EtOAc is in isohexane.Pure fraction is evaporated to 1-(3-methoxyl group-4-(methoxycarbonyl) phenyl) hydrazine carboxylic acid's tert-butyl ester (4.86 grams, 73.4%) of doing so that solid, shaped to be provided.

1H?NMR(400.13MHz，DMSO-d ₆)δ1.50(9H，s)，3.76(3H，s)，3.80(3H，s)，5.11(2H，s)，7.25-7.28(1H，m)，7.39(1H，d)，7.64(1H，d)

m/z(ESI+)(M+H)+＝297

Intermediate #113:4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-3-first Base-ethyl benzoate

With (647 milligrams of N-(2-adamantyl)-1-(4-chloro-2-methyl-phenyl)-5-tert-butyl group-pyrazole-4-carboxamide (intermediate #114); 1.52 mM), hexacarbonylmolybdenum is (0.102 milliliter; 0.76 mM), 4-dimethylaminopyridine is (371 milligrams; 3.04 mM), the N-ethyl diisopropyl amine is (0.529 milliliter; 3.04 mM), trans-two-mu-acetate closes two [2-(two-o-tolyl phosphino-) benzyl] two palladiums (II) (71.4 milligrams, 0.08 mM) and three-tert-butyl group phosphine tetrafluoroborate (88 milligrams, 0.30 mM) and is suspended in ethanol (6 milliliters) and the dioxane (6.00 milliliters) and is sealed in the microwave tube.With this be reflected at be heated in the microwave reactor 150 ℃ 1 hour and be cooled to room temperature.Reactant mixture is evaporated to dried, is dissolved among the EtOAc (100 milliliters) again, water (10 milliliters) washing is filtered, and uses 2M HCl (10 milliliters) and saturated brine (10 milliliters) to wash then.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 25%EtOAc is in isohexane.Pure fraction is evaporated to 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-3-methyl-ethyl benzoate (352 milligrams, 50.0%) of doing so that colorless oil to be provided.

m/z(ESI+)(M+H)+＝3.22；HPLC?t _R＝464min。

¹H?NMR(300.072MHz，cdcl3)δ1.25(s，9H)，1.42(t，3H)，1.66-1.95(m，12H)，2.01-2.10(m，2H)，2.13(s，3H)，4.22(d，1H)，4.41(q，2H)，6.14(d，1H)，7.31(d，1H)，7.68(s，1H)，7.94(d，1H)，8.01(s，1H)

Intermediate #114:N-(2-adamantyl)-1-(4-chloro-2-methyl-phenyl)-5-tert-butyl group-pyrazoles-4- Carboxylic acid amides

With (515 milligrams of N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (intermediate #115); 2.68 disposable (420 milligrams of 2-adamantanamine hydrochlorides that add in DMF (10 milliliters) mM); 2.24 mM), the 5-tert-butyl group-1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carboxylic acid is (655 milligrams; 2.24 mM), in I-hydroxybenzotriazole (363 milligrams, 2.68 mMs) and the N-ethyl diisopropyl amine (1.149 milliliters, 6.71 mMs).The gained mixture was stirred 18 hours down at 20 ℃.This reactant mixture is with Et2O (100 milliliters) dilution, and water (3 * 25 milliliters) and saturated brine (25 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide required product N-(2-adamantyl)-1-(4-chloro-2-methyl-phenyl)-5-tert-butyl group-pyrazole-4-carboxamide (860 milligrams, 90%).

¹H?NMR(300.072MHz，cdcl3)δ1.26(s，9H)，1.51-2.18(m，17H)，4.22(d，1H)，6.12(d，1H)，7.17(d，1H)，7.25(d，1H)，7.31(s，1H)，7.65(s，1H)

The intermediate #115:5-tert-butyl group-1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carboxylic acid

By the 5-tert-butyl group-1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (intermediate #116) through preparing the 5-tert-butyl group-1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carboxylic acid with the used identical method of intermediate #119.

¹H?NMR(300.072MHz，cdcl3)δ1.30(s，9H)，2.04(s，3H)，7.15(d，1H)，7.26(d，1H)，7.31(s，1H)，8.16(s，1H)

m/z(ESI+)(M+H)+＝293

The intermediate #116:5-tert-butyl group-1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester

With (1.553 milliliters of N-ethyl diisopropyl amines; 8.97 mM) add (4-chloro-2-aminomethyl phenyl) hydrazonium salt hydrochlorate in ethanol (30 milliliters) (1.733 grams to; 8.97 mM) and (Z)-2-((dimethylamino) methylene)-4; In the 4-dimethyl-3-oxopentanoic acid ethyl ester (intermediate #83) (2.04 grams, 8.97 mMs).Gained solution was stirred 2 hours down at 90 ℃.Reactant mixture is evaporated to dried, and is dissolved among the DCM (50 milliliters) water (2 * 10 milliliters) washing in succession again.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 10%EtOAc is in isohexane.Pure fraction is evaporated to dried so that the orange buttery 5-tert-butyl group-1-(4-chloro-2-aminomethyl phenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (0.891 gram, 30.9%) to be provided.

¹H?NMR(300.072MHz，cdcl3)δ1.29(s，9H)，1.38(t，3H)，2.03(s，3H)，4.31(q，2H)，7.14(d，1H)，7.23(d，1H)，7.29(d，1H)，8.04(s，1H)

m/z(ESI+)(M+H)+＝321

Intermediate #117:4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazoles-1- Base]-2-(trifluoromethyl) ethyl benzoate

By N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl) the phenyl]-5-tert-butyl group-pyrazole-4-carboxamide (intermediate #118) through preparing 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl]-2-(trifluoromethyl) ethyl benzoate with the used identical method of intermediate #113.

¹H?NMR(300.072MHz，CDCl ₃)δ1.27-1.33(9H，m)，1.42(3H，t)，1.74-1.79(5H，m)，1.85-1.91(7H，m)，2.06(2H，s)，4.23(1H，d)，4.44(2H，q)，6.13(1H，d)，7.62(1H，d)，7.62(1H，t)，7.75-7.76(1H，m)，7.92(1H，d)

m/z(ESI+)(M+H)+＝518

Intermediate #118:N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl) the phenyl]-5-tert-butyl group-pyrrole Azoles-4-carboxylic acid amides

By the 5-tert-butyl group-1-(4-chloro-3-(trifluoromethyl) phenyl)-1H-pyrazoles-4-carboxylic acid (intermediate #119) through preparing N-(2-adamantyl)-1-[4-chloro-3-(trifluoromethyl) the phenyl]-5-tert-butyl group-pyrazole-4-carboxamide with the used identical method of intermediate #114.

¹H?NMR(300.072MHz，cdcl3)δ1.29(s，9H)，1.55-1.97(m，12H)，2.06(s，2H)，4.22(d，1H)，6.12(d，1H)，7.48(d，1H)，7.62(d，1H)，7.63(s，1H)，7.71(s，1H)

m/z(ESI+)(M+H)+＝480

The intermediate #119:5-tert-butyl group-1-(4-chloro-3-(trifluoromethyl) phenyl)-1H-pyrazoles-4-carboxylic acid

Add in the agitating solution of the 5-tert-butyl group-1-(4-chloro-3-(trifluoromethyl) phenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (intermediate #120) (1 gram, 2.67 mMs) in methanol (20 milliliters) sodium hydroxide solution (6.67 milliliters, 13.34 mMs) is disposable.The gained suspension was stirred 6 hours down at 80 ℃.Evaporation gained mixture washs with ether (20 milliliters) to remove methanol.Reactant mixture with 2M HCl acidify, is extracted with ethyl acetate (2 * 30 milliliters).Merge organic layer, and water (10 milliliters) and saline (10 milliliters) washing, dry through MgSO4, filtration and evaporation are to provide the pure 5-tert-butyl group-1-(4-chloro-3-(trifluoromethyl) phenyl)-1H-pyrazoles-4-carboxylic acid (0.766 gram, 83%).

¹H?NMR(300.072MHz，cdcl3)δ1.36(s，9H)，7.47(d，1H)，7.63(d，1H)，7.70(s，1H)，8.12(s，1H)

m/z(ESI+)(M+H)+＝345

The intermediate #120:5-tert-butyl group-1-(4-chloro-3-(trifluoromethyl) phenyl)-1H-pyrazoles-4-carboxylic acid second Ester

By (Z)-2-((dimethylamino) methylene)-4,4-dimethyl-3-oxopentanoic acid ethyl ester (intermediate #83) and (4-chloro-3-(trifluoromethyl) phenyl) hydrazonium salt hydrochlorate are through preparing the 5-tert-butyl group-1-(4-chloro-3-(trifluoromethyl) phenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester with the used identical method of intermediate #116.

¹H?NMR(300.072MHz，cdcl3)δ1.32(s，9H)，1.38(t，3H)，4.32(q，2H)，7.46(d，1H)，7.61(d，1H)，7.68(s，1H)，7.98(s，1H)

m/z(ESI+)(M+H)+＝375

Intermediate #121: (1R, 2S, 3S, 5S)-5-difluoro-methoxy-diamantane (obsolete)-2-base amine

Will be at the ((1R among the MeOH (5 milliliters); 2S; 3S, 5S)-5-difluoro-methoxy-diamantane (obsolete)-2-yl)-benzyq carbamate (intermediate #122) (255 milligrams, 0.73 mM) and palladium (10%; On carbon) (25 milligrams, 0.23 mM) stirred under 1 atmospheric pressure and ambient temperature 22 hours under nitrogen atmosphere.This reactant mixture filters through celite, vacuum evaporating solvent with produce limpid buttery (1R, 2S, 3S, 5S)-5-difluoro-methoxy-diamantane (obsolete)-2-base amine (130 milligrams, 82%).

1H?NMR(400.13MHz，CDCl3)δ1.38-1.44(5H，m)，1.91-2.00(9H，m)，2.14(1H，s)，3.05(1H，s)，6.15-6.54(1H，t)

m/z(ESI+)(M+H)+＝218

Intermediate #122: ((1R, 2S, 3S, 5S)-5-difluoro-methoxy-diamantane (obsolete)-2-yl)-the carbamic acid benzyl Ester

With 2; The solution of 2-two fluoro-2-(fluorosulfonyl) acetic acid (0.237 milliliter, 2.30 mMs) in acetonitrile (2 milliliters) under 45 ℃ under nitrogen through dropwise adding ((1R, 2S in 1 hour to; 3S; 5S)-5-hydroxyl-diamantane (obsolete)-2-yl)-benzyq carbamate (346 milligrams, 1.15 mMs) and the agitating solution of Copper diiodide (I) (7.78 microlitres, 0.23 mM) in acetonitrile (10 milliliters) in.Gained solution was stirred 15 minutes down at 45 ℃.Reactant mixture is evaporated to dried, and is dissolved among the EtOAc (50 milliliters) water (50 milliliters) and saturated brine (25 milliliters) washing in succession again.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.This crude product is through quick silicon dioxide chromatographic purification, and gradient 0 to 30%EtOAc is in isohexane.With pure fraction be evaporated to do with provide colorless oil ((1R, 2S, 3S, 5S)-5-difluoro-methoxy-diamantane (obsolete)-2-yl)-benzyq carbamate (269 milligrams, 66.7%).

1H?NMR(400.13MHz，DMSO-d6)δ1.35(2H，d)，1.86(4H，d)，1.94(4H，t)，2.06(3H，s)，3.65(1H，m)，5.04(2H，s)，6.65-7.03(1H，t)，7.29-7.42(6H，m)

Intermediate #123:4-hydrazino-benzoic acid methyl ester hydrochloride

4M hydrogen chloride (100 milliliters, 399.60 mMs) in dioxane is added in the 4-hydrazino-benzoic acid (15.2 grams, 99.90 mMs) in MeOH (200 milliliters).The gained suspension was stirred 5 hours down at 90 ℃.After being cooled to 20 ℃; Filter the collecting precipitation thing; With Et2O (100 milliliters) washing and dry so that 2-(4-(methoxycarbonyl) phenyl) chlorination

(16.50 grams to be provided under vacuum; 82%), is white emulsus solid.

m/z(ESI-)(M-H)-＝165；HPLC?t _R＝1.12min。

1H?NMR(400.13MHz，DMSO-d6)δ3.81(3H，s)，6.99-7.02(2H，m)，7.86-7.90(2H，m)，8.98(1H，s)，10.47(3H，s)

Intermediate #123 also can be prepared as follows:

Methanolic hydrochloric acid solution (4M) (4 equivalents, newly formed) is added under nitrogen in the suspension of 4-hydrazino-benzoic acid (1 equivalent) in methanol (12.6 volume).

This mixture in the stirring down 3 hours that refluxes, is cooled to then and is lower than 15 ℃.Solid collected by filtration, with MTBE (6.5 volume) washing, and at air drying to produce solid product.

TLC DCM: MeOH, 9: 1, product Rf 0.87

mp?233.8-234.6℃

Intermediate #124:N-diamantane (obsolete)-2-base-1-(4-cyano-phenyl)-5-(trifluoromethyl)-1H-pyrazoles -4-carboxylic acid amides

With 2-adamantanamine hydrochloride (0.375 gram; 2.00 mM) nitrogen next time property add 1-(4-cyano-phenyl)-5-(trifluoromethyl)-1H-pyrazoles-4-carboxylic acid (intermediate #125) in DMF (10 milliliters) (0.562 gram to; 2 mMs), I-hydroxybenzotriazole (0.297 gram; 2.20 mM), in N-ethyl diisopropyl amine (1.384 milliliters, 8.00 mMs) and 1-(3-the dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.460 gram, 2.40 mMs).

Gained solution was at room temperature stirred 16 hours.Reactant mixture is poured on the water (75 milliliters), and with EtOAc (2 * 50 milliliters) extraction, organic layer is dry through MgSO4, and filtration and evaporation are to provide beige solid.Crude product is through quick silicon dioxide chromatographic purification, and gradient 20 to 60%EtOAc is in isohexane.Pure fraction is evaporated to N-diamantane (obsolete)-2-base-1-(4-cyano-phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (0.480 gram, 57.9%) of doing so that white solid to be provided.

m/z(ESI+)(M+H)+＝415；HPLC?t _R＝2.82min。

1H?NMR(400.13MHz，DMSO-d ₆)δ1.51(2H，d)，1.70(2H，s)，1.81(5H，s)，1.84(1H，s)，1.92(2H，s)，2.04(2H，d)，4.01(1H，t)，7.73(2H，d)，8.08-8.11(2H，m)，8.18(1H，s)，8.34(1H，d)。

Intermediate #125:1-(4-cyano-phenyl)-5-(trifluoromethyl)-1H-pyrazoles-4-carboxylic acid

With trimethyl silane potassium alcoholate (3.32 gram, 23.28 mMs) nitrogen next time property add in 1-(4-cyano-phenyl)-5-(the trifluoromethyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (intermediate #126) (2.4 grams, 7.76 mMs) in THF (50 milliliters).The gained suspension was at room temperature stirred 3 hours.Reactant mixture is evaporated to dried, and is dissolved in again among the EtOAc (100 milliliters), use 0.1M HCl (50 milliliters), water (50 milliliters) and saturated brine (50 milliliters) washing in succession.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.To obtain solid, it filters collects and dry 1-(4-cyano-phenyl)-5-(trifluoromethyl)-1H-pyrazoles-4-carboxylic acid (1.600 grams, 73.3%) to produce the orange solids shape under vacuum this rough solid with the isohexane development.Directly be used in next stage.

m/z(ESI+)(M-H)-＝280；HPLC?t _R＝1.86min。

1H?NMR(400.13MHz，DMSO-d ₆)δ7.78-7.80(2H，m)，8.07-8.10(2H，m)，8.26(1H，s)，13.39(1H，s)

Intermediate #126:1-(4-cyano-phenyl)-5-(trifluoromethyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester

With (Z)-2-(ethyoxyl methylene)-4; 4; 4-three fluoro-ethyl 3-oxobutanoates (2.41 grams; 10.03 mM) solution in ethanol (10 milliliters) dropwise adds in the agitating solution of 4-diazanyl benzonitrile hydrochlorate (1.702 grams, 10.03 mMs) in ethanol (50 milliliters) that is cooled to-10 ℃.Gained solution was at room temperature stirred 16 hours.Reactant mixture is evaporated to dried, and residue is dissolved among the EtOAc (100 milliliters) water (50 milliliters) and saturated brine (50 milliliters) washing in succession again.Organic layer is dry through MgSO4, and filtration and evaporation are to provide crude product.Crude product is through quick silicon dioxide (120 gram) chromatographic purification, and gradient 10 to 60%EtOAc is in isohexane.Pure fraction is evaporated to 1-(4-cyano-phenyl)-5-(trifluoromethyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (2.400 grams, 77%) of doing so that white solid to be provided.

m/z(ESI+)(M+H)+＝310；HPLC?t _R＝2.51min。

1H?NMR(400.13MHz，DMSO-d ₆)δ1.31(3H，t)，4.33(2H，q)，7.81-7.84(2H，m)，8.10-8.13(2H，m)，8.38-8.38(1H，m)

Claims

1. compound or pharmaceutically acceptable salt thereof, said chemical compound is 4-[4-(2-adamantyl the carbamoyl)-5-tert-butyl group-pyrazol-1-yl] benzoic acid.

2. pharmaceutical composition, it comprises compound or pharmaceutically acceptable salt thereof as claimed in claim 1, in conjunction with pharmaceutically acceptable diluent or carrier.