CN102272111A - 1,2 -thiazol yl derivatives as cannabinoid receptor ligands - Google Patents

1,2 -thiazol yl derivatives as cannabinoid receptor ligands Download PDF

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CN102272111A
CN102272111A CN2009801536988A CN200980153698A CN102272111A CN 102272111 A CN102272111 A CN 102272111A CN 2009801536988 A CN2009801536988 A CN 2009801536988A CN 200980153698 A CN200980153698 A CN 200980153698A CN 102272111 A CN102272111 A CN 102272111A
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subunit
isothiazole
butyl
tertiary butyl
chloro
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W.A.凯罗尔
T.科拉萨
T.李
D.W.奈尔逊
M.V.帕特尔
S.佩迪
A.佩雷斯-梅德拉诺
X.王
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Abbott GmbH and Co KG
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Abstract

The present application relates to an isothiazolylidene containing compounds of Formula (I), wherein R1, R2, R3, R4, and L are as defined in the specification, compositions comprising such compounds, and methods for treating conditions and disorders using such compounds and compositions.

Description

As 1 of cannabinoid receptor ligand, 2-thiazolyl derivative
The application is to be the part continuation of the U.S. Patent application 12/100,731 on April 10th, 2008 applying date, and it requires the applying date is the right of priority of the U.S. Provisional Application 60/923,951 on April 17th, 2007.Further, the application is to be the non-provisional application of the U.S. Provisional Application 61/111,041 on November 4th, 2008 applying date.All these applications are incorporated herein by reference with its full content.
Technical field
The application relates to the compound that contains isothiazole subunit (isothiazolylidene), comprises such compound compositions and uses the such compound and the method for combination treatment situation and illness.
Background technology
(-)-△ 9-tetrahydrocannabinol (△ 9-THC) be the main psychoactive composition of hemp, it by with two kinds of cannaboids (CB) receptor subtype CB 1And CB 2The various therapeutic actions of performance interact.CB 1Acceptor is expressed at the central nervous system height, and lower at various cardiovascular organizations that are arranged in periphery and gastrointestinal system expression degree.By contrast, CB 2Acceptor is expressed the highest in multiple lymphoid organ and immune system cell, and immune system cell comprises spleen, thymus gland, tonsil, marrow, pancreas and mastocyte.
By △ 9The effect that influences spirit that-THC and other non-selective CB agonist cause is by CB 1Receptor-mediated.These CB 1Receptor-mediated effect is for example glad, calm, hypothermia, catalepsy and anxiety disorder have limited non-selective CB agonist exploitation and clinical application.The latest study proves CB 2Conditioning agent is an analgesic agent in the preclinical models of nociceptive pain and neuropathic pain, does not cause and CB 1The harmful side effect that receptor activation is relevant.Therefore, selectivity target CB 2The compound of acceptor is the attractive method of the new anodyne of exploitation.
Pain is modal disease symptoms, also is that the patient is to the most normal symptom of telling of doctor.Pain is usually by time length (acute to chronic), intensity (slight, medium and serious) and type (nocuity is to neuropathic) classification.
Nociceptive pain is the types of pain of knowing most that tissue injury causes, and the nociceptor that can be positioned at damaging part detects.After the infringement, this position becomes the source of occurent pain and tenderness.It is believed that this pain and tenderness are " acute " nociceptive pain.This pain and tenderness, finally disappear when healing is finished along with healing alleviates gradually.The example of acute injury pain comprises operation technique (post-operative pain) and fracture.Even may there not be permanent nerve injury, " chronic " nociceptive pain is by due to some illness, and wherein pain continues more than 6 months.The example of chronic injury pain comprises osteoarthritis, rheumatoid arthritis and flesh bone disorders (for example backache), cancer pain etc.
IASP (International Association for the Study of Pain) is defined as neuropathic pain " pain that is caused or caused by primary lesion or nervous system dysfunction ".Although final brain is felt as passage and nociceptive pain and neuropathic pain identical of the nerve impulse of pain, neuropathic pain and noxious stimulation have nothing to do.The term neuropathic pain comprises the pain syndrome of the Different types of etiopathogenises of wide region.3 types neuropathic pain of normal diagnosis is diabetic neuropathy, carcinomatous neuropathy and HIV pain.In addition, diagnose out neuropathic pain in multiple other illness patient, these pain comprise multiple other illness of trigeminal neuralgia, postherpetic neuralgia, traumatic neurodynia, fibromyalgia, phantom limb and unclear or unknown cause.
Pain management cause of disease spectrum remains main public health problem, and patient and clinical technology personnel are seeking the strategy of improvement, with effective pain management.Still there are not at present the therapy or the medicine of effectively treating all types of nociceptive pains and neuropathic pain states.The compounds of this invention is new CB 2Receptor modulators, this type of conditioning agent have the effectiveness of treatment pain, and these pain comprise nociceptive pain and neuropathic pain.
The lip-deep CB of immunocyte 2The effect of these acceptors of the position indicating of acceptor in immunomodulatory and inflammation.The latest study proves CB 2Receptors ligand has immunomodulatory and antiinflammatory property.Therefore, with CB 2The compound of acceptor interaction will be provided for treating the pharmacotherapy of the uniqueness of immunity and inflammatory conditions.
Summary of the invention
Provide as CB in this article 2The compound of receptors ligand and pharmaceutical composition and the method for using these compounds and its medicine composite for curing illness.
The compound of formula (I) is disclosed herein
Figure 197598DEST_PATH_IMAGE001
Or its medicinal acceptable salt, solvate, prodrug or combination, wherein
L is C=O, C=S, S (O) 2, or C=NCN;
R 1Be alkyl, thiazolinyl, alkynyl ,-(CR aR b) m-OH ,-(CR aR b) m-O (alkyl) ,-(CR aR b) m-CN, haloalkyl, G 1,-NR Z1R Z5, or-OR Z5
R Z5Be alkyl, haloalkyl, G 1a,-(CR aR b) m-G 1a,-(CR aR b) n-OR Z1,-(CR aR b) n-N (R Z1) (R Z1) ,-(CR aR b) m-C (O) O (R Z1) ,-(CR aR b) m-C (O) R Z1,-(CR aR b) m-C (O) N (R Z1) (R Z1) ,-(CR aR b) m-S (O) 2R Z1,-(CR aR b) m-S (O) 2N (R Z1) (R Z1), or-(CR aR b) m-CN;
R 2Be alkyl, thiazolinyl, alkynyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-S (R Zb) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) N (R Z1) (R Z2a) ,-(CR aR b) m-SO 2N (R Z1) (R Z2a) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-SO 2(R Zd) ,-SO 2(R Zd) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1
R 3Be hydrogen, alkyl, halogen ,-CN ,-G 2, haloalkyl, or-(CR aR b) m-G 2
R 4Be alkyl, thiazolinyl, alkynyl ,-(CR aR b) n-CN ,-(CR aR b) n-OH ,-(CR aR b) n-O (alkyl), haloalkyl, G 2, or-(CR aR b) m-G 2Or
R 2And R 3, or R 3And R 4With the atom that they were connected to, formation contains zero or other two keys, zero or one other be selected from O, S, N and N (H) heteroatomic five-, six-or seven-first monocycle ring, each described monocycle ring is unsubstituted independently or is selected from following substituting group (R by 1,2,3,4 or 5 21) replace: oxo, alkyl, thiazolinyl, alkynyl, halogen ,-CN ,-O (R 1a) ,-C (O) OH ,-C (O) O (alkyl) ,-C (O) (R 1a) ,-N (R Z3) (R 3a) ,-N (R 3a) C (O) R 1a,-N (R 3a) C (O) O (R 1a) ,-N (R 3a) C (O) N (R Z3) (R 3a) ,-N (R 3a) S (O) 2(R 2a) ,-N (R 3a) S (O) 2N (R Z3) (R 3a) ,-SO 2(R 2a) ,-C (O) N (R Z3) (R 3a) ,-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN ,-(CR 1gR 1h) u-O (R 1a), and haloalkyl; Two the adjacent or non-adjacent atoms of each randomly connect by the alkylidene bridge of 1,2,3 or 4 carbon atom in the described monocycle ring; With two substituting group (R on same carbon atom 21), with described carbon atom, randomly formation contains 0,1 or 2 first monocycle ring of heteroatomic 3-6 that is selected from O, S and N (H);
R Za, when occurring each time, be hydrogen independently, alkyl, haloalkyl ,-(CR cR d) p-O (alkyl), G 1,-(CR cR d) q-CN, or-(CR cR d) q-G 1
R Zb, when occurring each time, be hydrogen independently, alkyl, haloalkyl, G 1, or-(CR cR d) q-G 1
R Z1, when occurring each time, be hydrogen independently, alkyl, or haloalkyl;
R Z2a, when occurring each time, be hydrogen independently, alkyl, haloalkyl, G 1, or-(CR cR d) q-G 1,
R Z2b, when occurring each time, be hydrogen independently, alkyl, haloalkyl, G 1,-C (O) R Zc,-C (O) OR Zc,-C (O) N (R Z1) (R Zc) ,-S (O) 2R Zd,-S (O) 2N (R Z1) (R Zc), or-(CR cR d) q-G 1,
R Zc, when occurring each time, be hydrogen independently, alkyl, haloalkyl, G 1, or-(CR eR f) t-G 1
R Zd, when occurring each time, be alkyl independently, haloalkyl, G 1, or-(CR eR f) t-G 1
G 1And G 1a, when occurring each time, be aryl independently of one another, heteroaryl, cycloalkyl, cycloalkenyl group, or heterocycle, wherein each G 1And G 1aBe unsubstituted independently or being selected from following substituting group by 1,2,3,4 or 5 replaces: alkyl, thiazolinyl, alkynyl, alkoxyl group thiazolinyl, hydroxyl thiazolinyl, halogen ,-CN, oxo ,-G 2,-NO 2,-C (R 1a)=N-O (R 1a) ,-OC (O) R 1a,-OC (O) N (R Z3) (R 3a) ,-SR 1a,-S (O) 2R 2a,-S (O) 2N (R Z3) (R 3a) ,-C (O) R 1a,-C (O) OR 1a,-C (O) N (R Z3) (R 3a) ,-L 1-A 1,-N (R 3a) C (O) R 1a,-N (R 3a) S (O) 2R 2a,-N (R 3a) C (O) O (R 1a) ,-N (R 3a) C (O) N (R Z3) (R 3a) ,-(CR 1gR 1h) u-NO 2,-(CR 1gR 1h) u-OR 1a,-(CR 1gR 1h) u-OC (O) R 1a,-(CR 1gR 1h) u-OC (O) N (R Z3) (R 3a) ,-(CR 1gR 1h) u-SR 1a,-(CR 1gR 1h) u-S (O) 2R 2a,-(CR 1gR 1h) u-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-C (O) R 1a,-(CR 1gR 1h) u-C (O) OR 1a,-(CR 1gR 1h) u-C (O) N (R Z3) (R 3a) ,-(CR 1gR 1h) u-N (R Z3) (R 3a) ,-(CR 1gR 1h) u-N (R 3a) C (O) R 1a,-(CR 1gR 1h) u-N (R 3a) S (O) 2R 2a,-(CR 1gR 1h) u-N (R 3a) C (O) O (R 1a) ,-(CR 1gR 1h) u-N (R 3a) C (O) N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN, and haloalkyl;
A 1Be R 1a,-(CR 1gR 1h) u-A 2,-N (R Z3) C (O) R 1a,-N (R Z3) C (O) OR 2a,-N (R Z3) (R 1a), or-N=C (R Z3) (R 1a);
A 2Be-C (O) R 1a,-S (O) 2R 2a, CON (R Z3) (R 3a), CSN (R Z3) (R 3a) ,-SO 2N (R Z3) (R 3a) ,-CN ,-C (=NOR 1a) R 1a,-N (R 3a) C (O) R 1a,-N (R 3a) C (O) OR 2a,-N (R 3a) S (O) 2R 2a,-N (R 3a) C (O) N (R Z3) (R 3a) ,-N (R 3a) S (O) 2N (R Z3) (R 3a), or-L 2-R Z6
R Z6Be alkoxyalkyl, hydroxyalkyl, cyano group alkyl, halogenated alkoxy alkyl, G 2, or-(CR kR x) v-G 2
L 1And L 2Be O or N (R independently of one another Z3);
R 1aAnd R 3a, when occurring each time, be hydrogen independently of one another, alkyl, alkynyl, haloalkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, cyano group alkyl, halogenated alkoxy alkyl, G 2, or-(CR kR x) v-G 2
R 2a, when occurring each time, be alkyl independently, haloalkyl, alkoxyalkyl, hydroxyalkyl, cyano group alkyl, halogenated alkoxy alkyl, G 2, or-(CR kR x) v-G 2
G 2, when occurring each time, be aryl, heteroaryl, cycloalkyl, cycloalkenyl group, or heterocycle, wherein each G 2Be unsubstituted independently or being selected from following substituting group by 1,2,3,4 or 5 replaces :-G 3,-(CR 2gR 2h) w-G 3, alkyl, thiazolinyl, alkynyl, halogen ,-CN, oxo ,-NO 2,-OR 1b,-OC (O) R 1b,-OC (O) N (R Z4) (R 3b) ,-SR 1b,-S (O) 2R 2b,-S (O) 2N (R Z4) (R 3b) ,-C (O) R 1b,-C (O) OR 1b,-C (O) N (R Z4) (R 3b) ,-N (R Z4) (R 3b) ,-N (R Z4) C (O) R 1b,-N (R Z4) C (O) O (R 1b) ,-N (R Z4) C (O) N (R Z4) (R 3b) ,-(CR 2gR 2h) w-NO 2,-(CR 2gR 2h) w-OR 1b,-(CR 2gR 2h) w-OC (O) R 1b,-(CR 2gR 2h) w-OC (O) N (R Z4) (R 3b) ,-(CR 2gR 2h) w-SR 1b,-(CR 2gR 2h) w-S (O) 2R 2b,-(CR 2gR 2h) wS (O) 2N (R Z4) (R 3b) ,-(CR 2gR 2h) w-C (O) R 1b,-(CR 2gR 2h) w-C (O) OR 1b,-(CR 2gR 2h) w-C (O) N (R Z4) (R 3b) ,-(CR 2gR 2h) w-N (R Z4) (R 3b) ,-(CR 2gR 2h) w-N (R Z4) C (O) R 1b,-(CR 2gR 2h) w-N (R Z4) C (O) O (R 1b) ,-(CR 2gR 2h) w-N (R Z4) C (O) N (R Z4) (R 3b) ,-(CR 2gR 2h) w-CN, and haloalkyl;
G 3, when occurring each time, be monocyclic heterocycles independently, bicyclic heteroaryl, or monocyclic cycloalkyl; Wherein each G that occurs 3Be unsubstituted independently or being selected from following substituting group by 1,2,3 or 4 replaces :-N (R Z4) (R 3b), alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, halo, oxo, CN, and OH;
M, q, t, u, v, and w when occurring each time, are 1,2,3,4 independently of one another, or 5;
N and p when occurring each time, are 2,3,4 independently of one another, or 5;
R 1bAnd R 3b, when occurring each time, be hydrogen independently of one another, alkyl, haloalkyl, monocyclic cycloalkyl, or-(CR 2gR 2h) w-monocyclic cycloalkyl;
R 2b, when occurring each time, be alkyl independently, haloalkyl, monocyclic cycloalkyl, or-(CR 2gR 2h) w-monocyclic cycloalkyl;
R a, R c, R d, R e, R f, R 1g, R 2g, R 2h, R k, and R x, when occurring each time, be hydrogen independently of one another, halogen, alkyl, or haloalkyl;
R 1h, when occurring each time, be hydrogen independently, halogen, alkyl, haloalkyl ,-OR 1b,-N (R Z4) (R 3b) ,-N (R Z4) C (O) R 1b,-N (R Z4) C (O) O (R 1b), or-N (R Z4) S (O) 2R 1b
Each R that occurs bBe hydrogen independently, halogen, alkyl, haloalkyl, or OH;
R Z3And R Z4, when occurring each time, be hydrogen independently of one another, alkyl, or haloalkyl; With
As by R 1b, R 2b, and R 3bExpression, as substituting group or as the monocyclic cycloalkyl of a substituent part, be unsubstituted or be selected from following substituting group by 1,2,3,4,5 or 6 and replace: alkyl, halogen, haloalkyl, hydroxyl, oxo, and alkoxyl group;
Prerequisite is that this compound is not
The 4-methyl-N-[(3Z)-1-phenyl-1,4,5,6-tetrahydrochysene-3H-cyclopenta [c] isothiazole-3-subunit] benzsulfamide;
N-[(3Z)-and 1-cyclohexyl-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit]-the 4-methyl benzenesulfonamide;
The 4-methyl-N-[(3Z)-1-phenyl-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit] benzsulfamide; With
(5Z)-2,4-phenylbenzene isothiazole-5 (2H)-subunit urethanum.
Relate to pharmaceutical composition on the other hand, it comprises one or more described compounds or its medicinal acceptable salt for the treatment of significant quantity, solvate, or the salt of solvate, and one or more medicinal acceptable carriers herein.Such composition can be according to described method afford herein, typically as being used for the treatment of or prevention and cannaboid (CB) receptor subtype CB 2The relevant situation and the part of treatment of conditions scheme.More particularly, described method can be used for the treatment with pain as but be not limited to chronic pain, neuropathic pain, nociceptive pain, osteoarthritis pain (osteoarthritric pain), inflammatory pain, pain caused by cancer, low back pain, postoperative pain and the eye pain; The situation that inflammatory conditions, immune disorders, neurological disorder, immune cancer, dyspnoea, obesity, diabetes, cardiovascular disorder are relevant or be used to provide neuroprotective (neuroprotection).
Further, provide in this article individually or with one or more medicinal acceptable carriers in combination, compound of the present invention or its medicinal acceptable salt, solvate, or the salt of solvate is used for the treatment of above-mentioned disease or situation in manufacturing, be used for the treatment of especially pain as but be not limited to, chronic pain, neuropathic pain, nociceptive pain, osteoarthritis pain (osteoarthritric pain), inflammatory pain, pain caused by cancer, low back pain, purposes in the medicine of postoperative pain and eye pain or its combination.
Further described this compound in this article, contained this compound compositions and by giving the method for this compound or its combination treatment or prevention situation and illness.
These and other target of the present invention has been described in following paragraph.These targets should not be considered to limit scope of the present invention.
Embodiment
Describe in detail.
The compound of formula (I) is disclosed,
Figure 114738DEST_PATH_IMAGE002
R wherein 1, R 2, R 3, R 4With limit in L such as the above summary of the invention He in the following detailed description.Also disclose and contained such compound compositions and with the method for such compound and combination treatment situation and illness.
In various embodiments, The compounds of this invention can have one or more variablees, and it occurs in any substituting group or in described compound or any herein other formula greater than once.The definition that variations per hour at every turn occurs is independent of its definition when another time occurs.In addition, during the stable compound of combination results only in this way, substituent combination just can allow.Stable compound be can be from reaction mixture isolated compound.
A. the definition of term
As using in specification sheets and claims, unless opposite regulations, following term has specified implication:
Term " thiazolinyl " as used in this article is meant by removing containing 2-10 carbon and containing the straight or side chain hydrocarbon chain of at least one carbon-to-carbon double bond of two hydrogen evolution.The representative example of thiazolinyl is including, but not limited to vinyl, 2-propenyl (allyl group), 2-methyl-2-propenyl, 3-butenyl, but-1-ene base, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl isophthalic acid-heptenyl and 3-decene base.
Term " alkoxyl group " is meant the alkyl as defined herein that is connected to parent molecular moiety by Sauerstoffatom as used in this article.The representative example of alkoxyl group is including, but not limited to methoxyl group, oxyethyl group, propoxy-, 2-propoxy-, butoxy, tert.-butoxy, pentyloxy, and hexyloxy.
Term " alkoxyalkyl " is meant the alkoxyl group as defined herein that is connected to parent molecular moiety by alkyl as defined herein as used in this article.The representative example of alkoxyalkyl is including, but not limited to the tert.-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl, and methoxymethyl.
Term " alkyl " is meant the saturated hydrocarbon chain of the straight or side chain that contains 1-10 carbon atom as used in this article.Term " low alkyl group " or " C 1-6Alkyl " be meant the straight or branched-chain hydrocarbon that contains 1-6 carbon atom.Term " C 1-3Alkyl " be meant the straight or branched-chain hydrocarbon that contains 1-3 carbon atom.The representative example of alkyl is including, but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl (1-methyl-propyl), isobutyl-, the tertiary butyl, n-pentyl, 1,1-dimethylpropyl, isopentyl, neo-pentyl, n-hexyl, 3-methyl hexyl, 2,2-dimethyl amyl group, 2,3-dimethyl amyl group, n-heptyl, n-octyl, n-nonyl and positive decyl.
Term " alkylidene group " expression is derived from the divalent group of the straight or branched-chain hydrocarbon of 1-10 carbon atom.The representative example of alkylidene group is including, but not limited to-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH 2CH 2CH 2CH 2-and-CH 2CH (CH3) CH 2-.
Term " alkynyl " is meant the straight or branched-chain hydrocarbon group that contains 2-10 carbon atom and contain at least one carbon-to-carbon triple bond as used in this article.The representative example of alkynyl is including, but not limited to ethynyl (ethynyl), 1-proyl, 2-propynyl, 3-butynyl, valerylene base and ethyl acetylene base.
Term " aryl " is meant phenyl or bicyclic aryl as used in this article.Bicyclic aryl is naphthyl (comprising naphthalene-1-yl), or is fused to the phenyl of monocyclic cycloalkyl, or is fused to the phenyl of monocycle cycloalkenyl group.The representative example of aryl is including, but not limited to dihydro indenyl, indenyl, naphthyl, dihydro naphthyl and tetralyl.Bicyclic aryl is connected to parent molecular moiety by any carbon atom contained in the dicyclo ring system.Aryl can be unsubstituted or substituted.
Term " cyano group " is meant-the CN group as used in this article.
As used in this article, term " cyano group alkyl " is meant the cyano group as defined herein that is connected to parent molecular moiety by alkyl as defined herein.The representative example of cyano group alkyl is including, but not limited to the cyanogen methyl, 2-cyanoethyl and 3-cyano group propyl group.
Term " cycloalkyl " or " naphthenic hydrocarbon " are meant monocycle as used in this article, dicyclo, or three rings, or volution cycloalkyl.Monocyclic cycloalkyl is the carbocyclic ring ring system that contains 3-8 carbon atom, zero heteroatoms and zero pair key.The example of monocycle ring system comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Term " C3-6 cycloalkyl " is meant and contains 3 to 6 carbon atoms as used in this article, the monocyclic cycloalkyl of zero heteroatoms and zero pair key.The example of C3-6 cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.Bicyclic cycloalkyl is the monocyclic cycloalkyl that is fused to the monocyclic cycloalkyl ring, or the monocycle ring system of bridge joint, and wherein two of the monocycle ring non-adjacent carbon atoms connect by the alkylidene bridge that contains 1,2,3 or 4 carbon atom.The representative example of bicyclic cycloalkyl is including, but not limited to dicyclo [3.1.1] heptyl, dicyclo [2.2.1] heptyl, dicyclo [2.2.2] octyl group (comprising dicyclo [2.2.2] suffering-1-yl), dicyclo [3.2.2] nonyl, dicyclo [3.3.1] nonyl, and dicyclo [4.2.1] nonyl.The example of tricyclic naphthenes base is the bicyclic cycloalkyl that is fused to monocyclic cycloalkyl, or bicyclic cycloalkyl, and two non-adjacent carbon atoms of wherein said ring system connect by an alkylidene bridge to four carbon atom of bicyclic cycloalkyl ring.The representative example of three ring ring systems is including, but not limited to three ring [3.3.1.03,7] nonane (octahydro-2,5-endo-methylene group pentalene (methanopentalene) or diamantane (noradamantane) falls) and three the ring [3.3.1.13,7] decane (diamantane).The example of volution cycloalkyl is the monocyclic cycloalkyl ring, and wherein two substituting groups on the identical carbon atoms of described ring with described carbon atom, form 4-, 5-or 6-unit monocyclic cycloalkyl.The example of volution cycloalkyl is spiral shell [a 2.5] octane.Monocycle, dicyclo, three rings and volution cycloalkyl can be unsubstituted or substituted, and are connected to parent molecular moiety by any commutable atom contained in the described ring system.
Term " cycloalkenyl group " or " cycloolefin " are meant monocycle or dicyclic hydrocarbon ring system as used in this article.The monocycle cycloalkenyl group has 4,5,6,7 or 8 carbon atoms and zero heteroatoms.The tetra-atomic ring cording has 1 two key, five or the six-ring cording have 1 or 2 two key and seven or the octatomic ring cording 1,2 or 3 two key is arranged.The representative example of monocycle cycloalkenyl group is including, but not limited to cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctene base.The dicyclo cycloalkenyl group is the monocycle cycloalkenyl group that is fused to monocyclic cycloalkyl, or is fused to the monocycle cycloalkenyl group of monocycle cycloalkenyl group.Monocycle or dicyclo cyclenes basic ring can comprise 1 or 2 alkylidene bridge, and each comprises 1,2 or 3 carbon atom, and each connects two non-adjacent carbon atoms of described ring system.The representative example of dicyclo cycloalkenyl group is including, but not limited to 4,5,6,7-tetrahydrochysene-3aH-indenes, octahydro naphthyl and 1,6-dihydro-pentalene.Monocycle and dicyclo cycloalkenyl group can be connected to parent molecular moiety by any commutable atom contained in the described ring system, and can be unsubstituted or substituted.
Term " halo " or " halogen " are meant Cl, Br, I as used in this article, or F.
Term " halogenated alkoxy " is meant at least a as defined herein halogen that is connected to parent molecular moiety by alkoxyl group as defined herein as used in this article.The representative example of halogenated alkoxy is including, but not limited to the chlorine methoxyl group, 2-fluorine oxyethyl group, trifluoromethoxy and five fluorine oxyethyl groups.
Term " halogenated alkoxy alkyl " is meant the halogenated alkoxy as defined herein that is connected to parent molecular moiety by alkyl as defined herein as used in this article.The representative example of halogenated alkoxy alkyl is including, but not limited to chloromethane oxygen ylmethyl and trifluoromethoxy methyl.
Term " haloalkyl " is meant that wherein 1,2,3,4,5 or 6 hydrogen atom is by halogen alternate alkyl as defined herein as used in this article.Term " C as used in this article 1-6Haloalkyl " be meant that wherein 1,2,3,4,5 or 6 hydrogen atom is by halogen alternate C as defined herein 1-6Alkyl.The representative example of haloalkyl is including, but not limited to chloromethyl, methyl fluoride, 2-fluoro ethyl, 1,1-two fluoro ethyls, 2,2-two fluoro ethyls, 2,2,2-three chloroethyls, 2,2,2-trifluoroethyl, 2,2,2-three fluoro-1, the 1-dimethyl ethyl, 2-fluoro-1,1-dimethyl ethyl, trifluoromethyl, difluoromethyl, 4-fluoro-4-methyl amyl, 4,4-difluoro amyl group, 4-fluorine butyl, 3-fluoro-3-methyl butyl, 4,4,4-trifluoro butyl, pentafluoroethyl group and 2-chloro-3-fluorine amyl group.
Term " heterocycle " or " heterocyclic " are meant and contain at least one heteroatomic monocycle as used in this article, dicyclo, three rings, or volution ring system.Monocyclic heterocycles be contain at least one be independently selected from O, N and S heteroatomic three-, four-, five-, six-, or seven-membered ring.Three or tetra-atomic ring comprise zero or two keys and a heteroatoms that is selected from O, N and S.Five-ring comprises zero or two keys and 1,2 or 3 heteroatoms that is selected from O, N and S.Six-ring comprises zero, one or two two key and 1,2 or 3 heteroatoms that is selected from O, N and S.Seven-membered ring comprises zero, 1,2 or 3 two key and 1,2 or 3 heteroatoms that is selected from O, N and S.The representative example of monocyclic heterocycles is including, but not limited to azetidinyl (azetidinyl) (comprising azetidine-1-yl), azepan base (azepanyl), ethylenimine base (aziridinyl), Diazesuberane base (diazepanyl), and dihydro-oxazolyls (for example 4,5-dihydro-1,3-oxazole-2-yl), 1,3-dioxane base (comprises 1,3-dioxane-2-yl), 1,3-dioxolane base, dihydro pyranyl (comprises 3,4-dihydro-2H-pyrans-6-yl), 1,3-dithiolane base, 1,3-dithian base, imidazolinyl, imidazolidyl, the isothiazoline base, the isothiazole alkyl, isoxazoline-3-yl, isoxazole alkyl, morpholinyl (comprising morpholine-4-yl), 4,5-dihydro-isoxazole base (comprising 4,5-dihydro-isoxazole-5-yl), dihydro-oxazinyl (for example 5,6-dihydro-4H-1,3-oxazine-2-base) ， oxadiazole quinoline base oxadiazole alkyl oxazolinyl ， oxazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolinyl, pyrazolidyl, pyrrolinyl, pyrrolidyl (comprising tetramethyleneimine-3-base, tetramethyleneimine-2-base, tetramethyleneimine-1-yl), tetrahydrofuran base (comprising tetrahydrofuran (THF)-2-yl), THP trtrahydropyranyl (comprising tetrahydrochysene-2H-pyrans-4-yl), tetrahydro-thienyl, Thiadiazoline base, the thiadiazoles alkyl, thiazolinyl, thiazolidyl, thio-morpholinyl, 1,1-titanium dioxide thio-morpholinyl (thiomorpholine sulfone), thiapyran base and trithian base.Bicyclic heterocycle is the monocyclic heterocycles that is fused to phenyl, or be fused to the monocyclic heterocycles of monocyclic cycloalkyl, or be fused to the monocyclic heterocycles of monocyclic cycloalkenyl group, or be fused to the monocyclic heterocycles of monocyclic heterocycles, or the monocyclic heterocycles ring system of bridge joint, the atom of two non-vicinities of wherein said ring connects by the alkylidene bridge that contains 1,2,3 or 4 carbon atom.The representative example of bicyclic heterocycle is including, but not limited to benzopyranyl, benzo thiapyran base, 2, the 3-dihydro benzo furyl, 2,3-dihydrobenzo thienyl, oxabicyclo [2.2.1] heptyl (comprise oxabicyclo [2.2.1] heptan-2-yl) and 2,3-dihydro-1H-indyl.Spirocyclic heterocyclic is meant monocyclic heterocycles, and wherein two substituting groups on same carbon atom form 4-, 5-or 6-unit monocyclic cycloalkyl, and wherein cycloalkyl is to choose wantonly by 1,2,3,4 or 5 alkyl to replace.An example of spiroheterocyclic is 5-oxaspiro [3, a 4] octane.The tricyclic heterocyclic illustration is the bicyclic heterocycle that is fused to phenyl, or be fused to the bicyclic heterocycle of monocyclic cycloalkyl, or be fused to the bicyclic heterocycle of monocycle cycloalkenyl group, or be fused to the bicyclic heterocycle of monocyclic heterocycles, or bicyclic heterocycle, wherein the atom of two of the dicyclo ring non-vicinities connects by the alkylidene bridge that is made of 1,2,3 or 4 carbon atom.The example of tricyclic heterocyclic is including, but not limited to octahydro-2,5-epoxy pentalene (epoxypentalene), six hydrogen-2H-2,5-endo-methylene group cyclopenta (methanocyclopenta) [b] furans, six hydrogen-1H-1,4-endo-methylene group cyclopenta (methanocyclopenta) [c] furans, azepine-diamantane (admantane) are as 1-aza-tricycle [3.3.1.13,7] decane, and oxa--diamantane such as 2-oxatricyclo [3.3.1.13,7] decane.Monocycle, dicyclo, three rings and Spirocyclic heterocyclic are connected to parent molecular moiety by any carbon atom contained in the described ring or any nitrogen-atoms, and can be unsubstituted or substituted.Heterocycle nuclear nitrogen and sulfur heteroatom can be randomly oxidized and nitrogen-atoms can be randomly by quaternized (quarternized).
Term " heteroaryl " is meant bicyclic heteroaryl or bicyclic heteroaryl as used in this article.Bicyclic heteroaryl is five or six-ring.Five-ring comprises two two keys.Five-ring can comprise a heteroatoms that is selected from O or S; Or 1,2,3 or 4 nitrogen-atoms and randomly oxygen or sulphur atom.Six-ring comprises 3 two keys and 1,2,3 or 4 nitrogen-atoms.The representative example of bicyclic heteroaryl is including, but not limited to furyl (comprising furans-2-yl), imidazolyl ， isoxazolyl, isothiazolyl ， oxadiazole base, 1, the 3-oxazolyl, pyridyl (comprises pyridine-2-base, pyridin-3-yl, pyridin-4-yl), pyridazinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyrryl, tetrazyl, thiadiazolyl group, the 1,3-thiazoles base (comprises 1,3-thiazoles-4-base, 1, the 3-thiazol-2-yl), thienyl (comprising thiophene-2-yl), triazolyl, and triazinyl.Bicyclic heteroaryl is made up of following: the bicyclic heteroaryl that is fused to phenyl, or be fused to the bicyclic heteroaryl of monocyclic cycloalkyl, or be fused to the bicyclic heteroaryl of monocyclic cycloalkenyl group, or be fused to the bicyclic heteroaryl of bicyclic heteroaryl, or be fused to the monocyclic heteroaryl of monocyclic heterocyclic.The representative example of bicyclic heteroaryl includes but not limited to, benzofuryl, benzothienyl benzoxazolyl, benzimidazolyl-, Ben Bing oxadiazole base, 6,7-dihydro-1,3-benzothiazolyl, imidazo [1,2-a] pyridyl, indazolyl, indyl, pseudoindoyl, isoquinolyl, naphthyridinyl, pyridine-imidazole base (pyridoimidazolyl), quinolyl (comprising quinoline-8-yl), thiazole also [5,4-b] pyridine-2-base, thiazole is [5,4-d] pyrimidine-2-base also, with 5,6,7,8-tetrahydroquinoline-5-base.Monocycle and bicyclic heteroaryl can be substituted or unsubstituted and be connected to parent molecular moiety by any carbon atom contained in the described ring system or any nitrogen-atoms.The nitrogen of heteroaryl ring and sulfur heteroatom can be randomly oxidized, and are expected in the scope of the present invention.
Term " heteroatoms " is meant nitrogen, oxygen or sulphur atom as used in this article.
As used in this article term " hydroxyalkyl " be meant at least one as defined herein hydroxyl be connected to parent molecular moiety by alkylidene group as defined herein.The representative example of hydroxyalkyl is including, but not limited to methylol, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxyl amyl group, 2-hydroxy-2-methyl propyl group, 1-hydroxyl-1-methylethyl and 2-ethyl-4-hydroxyl heptyl.
Term " hydroxyl " is meant-the OH group as used in this article.
Term " oxo " expression=O group as used in this article.
B. compound
The compound of formula (I) is aforesaid.
The particular value of the variable group in the compound of formula (I) is as follows.In appropriate circumstances, other values, definition, claim or embodiment that such value can limit in any context are used.
For the compound of formula (I), as in the summary of the invention part, describing R prevailingly 2Be alkyl, thiazolinyl, alkynyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-S (R Zb) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) N (R Z1) (R Z2a) ,-(CR aR b) m-SO 2N (R Z1) (R Z2a) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-SO 2(R Zd) ,-SO 2(R Zd) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1, G wherein 1, R a, R b, m, R Za, R Zb, R Zd, R Z1, R Z2a, and R Z2bBe as described in summary of the invention and the embodiment herein.
In some embodiment of the compound of formula (I), R 2Be alkyl (for example methyl, ethyl, n-propyl, isobutyl-, normal-butyl, n-pentyl etc.), thiazolinyl (for example, allyl group, vinyl, but-1-ene base etc.), alkynyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl (4-fluoro-4-methyl amyl for example, 4,4-difluoro amyl group, 3-fluoro-3-methyl butyl, 4,4,4-trifluoro butyl, 4-fluorine butyl) ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1, G wherein 1, R a, R b, m, R Za, R Zb, R Z1, and R Z2bBe as described in summary of the invention and the embodiment herein.For example, in certain embodiments, m is 1,2,3, or 4.In other embodiments, m is 1,2, or 3.In other embodiments, m is 1 or 2.
In some embodiment of the compound of formula (I), R 2Be alkyl (for example methyl, ethyl, n-propyl, isobutyl-, normal-butyl, n-pentyl etc.), thiazolinyl (for example, allyl group, vinyl, but-1-ene base etc.), alkynyl ,-(CR aR b) m-CN, haloalkyl (4-fluoro-4-methyl amyl for example, 4,4-difluoro amyl group, 3-fluoro-3-methyl butyl, 4,4,4-trifluoro butyl, 4-fluorine butyl) ,-(CR aR b) m-O (R Za), or-(CR aR b) m-G 1, G wherein 1, R a, R b, m, and R Za, be as described in summary of the invention and the embodiment herein.For example, in certain embodiments, m is 1,2,3, or 4.In other embodiments, m is 1,2, or 3.In other embodiments, m is 1 or 2.
In some embodiment of the compound of formula (I), R 2Be alkyl (for example methyl, ethyl, n-propyl, isobutyl-, normal-butyl, n-pentyl etc.), thiazolinyl (for example, allyl group, vinyl, but-1-ene base etc.), alkynyl, or C 1-6Haloalkyl (4-fluoro-4-methyl amyl for example, 4,4-difluoro amyl group, 3-fluoro-3-methyl butyl, 4,4,4-trifluoro butyl, 4-fluorine butyl).
In certain embodiments, R 2Be G 1, G wherein 1Described in summary of the invention.G 1Example including, but not limited to cycloalkyl (for example monocyclic cycloalkyl as but be not limited to cyclopropyl) and heterocycle (for example monocyclic heterocycles as but be not limited to THP trtrahydropyranyl), its each be optional substituted, as describing in the summary of the invention part prevailingly.Optional substituent example is when existing, including, but not limited to alkyl (for example methyl, ethyl), oxo, and haloalkyl.
In certain embodiments, R 2Be-(CR aR b) m-G 1, m wherein, G 1, R a, m, and R bDescribed in summary of the invention.G 1Example including, but not limited to aryl (for example phenyl), cycloalkyl (cyclopropyl for example, cyclobutyl, cyclopentyl, cyclohexyl), and heterocycle (for example 4,5-dihydro-isoxazole base, morpholinyl, 1,3-dioxane base, 1,3-dioxolane base, tetrahydrofuran base), heteroaryl (furyl for example, 1,3-thiazoles base, thienyl), its each be optional substituted, as describing in the summary of the invention part prevailingly.Optional substituent example is when existing, including, but not limited to alkyl (for example methyl, ethyl), haloalkyl, and oxo.R aAnd R bAs in the summary of the invention part, describing prevailingly.R aExample including, but not limited to hydrogen and C 1-6Alkyl (for example methyl, ethyl, sec.-propyl).R bExample including, but not limited to hydrogen, C 1-6Alkyl (for example methyl, ethyl, sec.-propyl), and OH.
In certain embodiments, R 2Be-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N 3,-(CR aR b) m-CN ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) (R Zb), or-(CR aR b) m-C (R Zb)=NO (R Z1), R wherein a, R b, R Z1, R Zb, and m, described in summary of the invention.Each R that occurs a, R b, R Zb, and R Z1For example be hydrogen or C independently 1-6Alkyl (for example methyl, ethyl, sec.-propyl).
In certain embodiments, R 2Be-O (R Za) or-N (R Z1) (R Z2b), R wherein Za, R Z1, and R Z2bDescribed in summary of the invention.R ZaExample including, but not limited to hydrogen, alkyl (C for example 1-6Alkyl as but be not limited to methyl, ethyl, 1-methyl-propyl, sec.-propyl), haloalkyl (for example 4-fluorine butyl) ,-(CR cR d) q-CN and-(CR cR d) q-G 1, R wherein c, R d, q, G 1Described in summary of the invention.G 1, for example, be optional substituted phenyl or optional substituted pyrrolidyl.Each R that occurs cAnd R d, be hydrogen or C independently of one another 1-6Alkyl (for example methyl, ethyl, sec.-propyl).Q is 1 or 2.In certain embodiments, q is 1.R Z1, for example, be hydrogen or C 1-3Alkyl (for example methyl).R Z2b, for example, be-C (O) O (R Zc), R wherein ZcDescribed in summary of the invention.R Zc, for example, be C 1-6Alkyl (for example tertiary butyl).
In certain embodiments, R 2Be-(CR aR b) m-O (R Za) or-(CR aR b) m-N (R Z1) (R Z2b), m wherein, R a, R b, R Za, R Z1, and R Z2bBe as described in summary of the invention and the embodiment herein.In certain embodiments, R ZaBe hydrogen, alkyl (C for example 1-6Alkyl as but be not limited to methyl, ethyl, 1-methyl-propyl, sec.-propyl), haloalkyl (C for example 1-6Haloalkyl as but be not limited to 2,2,2-trifluoroethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls), or-(CR cR d) q-G 1, q wherein, R c, R d, and G 1Be as described in summary of the invention and the embodiment herein.G 1, for example, be optional substituted heterocycle (for example monocyclic heterocycles as but be not limited to tetrahydrofuran (THF)) or optional substituted phenyl.In certain embodiments, each R that occurs a, R c, and R d, for example be hydrogen or C independently 1-6Alkyl (for example methyl, ethyl, sec.-propyl).R b, for example be hydrogen independently when occurring each time, C 1-6Alkyl (for example methyl, ethyl, sec.-propyl), or OH.Q is 1 or 2.In certain embodiments, q is 1.R Z1And R Z2b, for example, be hydrogen or C independently 1-6Alkyl (for example methyl, ethyl, sec.-propyl).
As describing R in the above summary of the invention prevailingly 3Be hydrogen, alkyl, halogen ,-CN ,-G 2, haloalkyl, or-(CR aR b) m-G 2. in certain embodiments, R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces).In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).
As prevailingly described in the summary of the invention, R 4Be alkyl, thiazolinyl, alkynyl ,-(CR aR b) n-CN ,-(CR aR b) n-OH ,-(CR aR b) n-O (alkyl), haloalkyl, G 2, or-(CR aR b) m-G 2In certain embodiments, R 4Be alkyl (C for example 1-6Alkyl as but be not limited to methyl, the tertiary butyl, 1,1-dimethylpropyl), haloalkyl (for example the 2-fluoro-1,1-dimethyl ethyl, 2,2,2-three fluoro-1,1-dimethyl ethyl), or G 2(for example optional substituted C3-6 cycloalkyl as but be not limited to, optional substituted cyclopropyl or optional substituted cyclobutyl, or optional substituted monocyclic heterocycle as but be not limited to optional substituted oxa-cyclobutyl or optional substituted tetrahydrofuran base).In certain embodiments, G 2Be cyclopropyl or cyclobutyl, its each optional by 1 or 2 C 1-3Alkyl (for example methyl) replaces.
Be R 2In described each embodiment, m, if present, described in summary of the invention.For example, in certain embodiments, m is 1,2,3, or 4.In other embodiments, m is 1,2, or 3.In other embodiments, m is 1 or 2.
Described in the summary of the invention, L is C=O as prevailingly, C=S, S (O) 2, or C=NCN.
In certain embodiments, L is C=O.
In certain embodiments, L is C=S.
In certain embodiments, L is S (O) 2
In certain embodiments, L is C=NCN.
As in summary of the invention, describing R prevailingly 1Be alkyl, thiazolinyl, alkynyl ,-(CR aR b) m-OH ,-(CR aR b) m-O (alkyl) ,-(CR aR b) m-CN, haloalkyl, G 1,-NR Z1R Z5, or-OR Z5.
In certain embodiments, R 1Be G 1,-NR Z1R Z5, or-OR Z5, G wherein 1, R Z1, and R Z5Be described in summary of the invention and embodiment herein.
In certain embodiments, R 1Be-OR Z5, R wherein Z5Be as disclosed in summary of the invention.For example, R Z5Be alkyl (for example neo-pentyl), haloalkyl (for example 2,2,2-three chloroethyls), or G 1a, and G 1aDescribed in summary of the invention.For example, G 1aBe optional substituted cycloalkyl as but be not limited to optional substituted adamantyl.
In certain embodiments, R 1Be-NR Z1R Z5, R wherein Z1And R Z5Described in summary of the invention.For example, R Z5Be G 1aOr-(CR aR b) m-C (O) N (R Z1) (R Z1), G wherein 1a, R a, R b, m, and R Z1Described in summary of the invention.For example, each R that occurs aAnd R bBe hydrogen or alkyl (for example methyl, ethyl, the tertiary butyl) independently of one another.R Z1, when occurring each time, be hydrogen or alkyl (for example methyl, ethyl, the tertiary butyl) independently.M for example, is 1 or 2.G 1a, for example, be optional substituted cycloalkyl as but be not limited to optional substituted cyclohexyl.G 1aOptional substituent limiting examples be alkyl, haloalkyl, and oxo.
In certain embodiments, R 1Be G 1, G wherein 1As in summary of the invention, describing prevailingly.In other embodiments, G 1Be aryl (for example phenyl, naphthyl), heteroaryl (for example quinoline-8-yl), heterocycle (for example pyrrolidyl, oxabicyclo [2.2.1] heptyl, dihydro pyranyl), or cycloalkyl (cyclopropyl for example, cyclobutyl, cyclopentyl, cyclohexyl, dicyclo [2.2.2] octyl group, adamantyl, positive adamantyl (noradamantyl)), its each be optional substituted, as describing in summary of the invention neutralization embodiment hereinafter prevailingly.
In certain embodiments, R 1Be G 1, G wherein 1Be phenyl or naphthyl, its each be optional substituted, as what describe in summary of the invention and embodiment hereinafter prevailingly.
In certain embodiments, R 1Be G 1, G wherein 1Be heteroaryl, optional substituted, as described in summary of the invention and the embodiment hereinafter.In certain embodiments, R 1It is optional substituted quinoline-8-base.
In certain embodiments, R 1Be G 1, G wherein 1Be cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, dicyclo [2.2.2] octyl group, adamantyl, positive adamantyl (noradamantyl)), its each be optional substituted, as described in summary of the invention and the embodiment hereinafter.
In certain embodiments, R 1Be G 1, G wherein 1Be heterocycle, optional substituted, described in summary of the invention.In certain embodiments, R 1Be pyrrolidyl, dihydro pyranyl, oxa--adamantyl, or oxabicyclo [2.2.1] heptyl, its each be optional substituted, as described in summary of the invention and the embodiment hereinafter.
In certain embodiments, work as R 1Be G 1The time, G 1Optional substituent example including, but not limited to:
(a). alkyl (for example methyl, ethyl, sec.-propyl),
(b). alkynyl (for example ethynyl),
(c). halogen (F for example, Cl, I),
(d). -CN，
(e). oxo;
(f) .-C (R 1a)=N-O (R 1a), R wherein 1aBe as disclosed in summary of the invention.For example, each R that occurs 1aBe hydrogen or C independently 1-6Alkyl (for example methyl);
(g). L 1-A 1, L wherein 1And A 1Be as disclosed in summary of the invention.For example, L 1Be O and A 1Be R 1a, N (R Z3) (R 1a), or-(CR 1gR 1h) u-A 2, R wherein 1a, R Z3, R 1g, R 1h, u, and A 2Be as disclosed in summary of the invention and the embodiment herein.For example, work as L 1Be O and A 1Be N (R Z3) (R 1a) time, limiting examples comprise following those, R wherein Z3Be hydrogen and R 1aBe alkyl (for example the tertiary butyl, sec.-propyl).For L wherein 1Be O and A 1Be R 1aCompound, R so 1a, for example, be hydrogen, alkyl (C for example 1-6Alkyl as but be not limited to methyl, ethyl), haloalkyl (for example 2,2,2-trifluoroethyl, 2-fluoro ethyl, trifluoromethyl), hydroxyalkyl (for example 2-hydroxy-2-methyl propyl group), or-(CR kR x) v-G 2R wherein k, R x, v, and G 2Be as disclosed in summary of the invention.For example, R k, R xBe that for example, each is hydrogen or C independently 1-3Alkyl (for example methyl).V for example, is 1.G 2, for example, be optional substituted heterocycle (for example optional substituted monocyclic heterocycle as but be not limited to, pyrrolidyl ， oxazolidinyl, piperidyl), or optional substituted heteroaryl (for example optional substituted bicyclic heteroaryl as but be not limited to pyridyl, pyrazinyl).G 2Optional substituent example including, but not limited to C 1-6Alkyl (for example methyl), oxo, halogen, and haloalkyl.For A wherein 1Be-(CR 1gR 1h) u-A 2Those, A so 2, for example, be CON (R Z3) (R 3a) or CN, wherein R Z3And R 3aBe as disclosed in summary of the invention.R 1gAnd R 1hBe, for example, hydrogen.U for example, is 1.CON (R Z3) (R 3a) R Z3And R 3aIncluding, but not limited to hydrogen and C 1-6Alkyl (for example methyl).Other example of compound including, but not limited to following those, R wherein 1Substituting group be L 1-A 1, L wherein 1Be N (R Z3), and A 1Be as disclosed in summary of the invention.Other example of compound including, but not limited to following those, R wherein 1Substituting group be L 1-A 1, L wherein 1Be N (R Z3) and A 1Be R 1a, R wherein Z3And R 1aBe as disclosed in the summary of the invention.For example, R Z3And R 1aBe hydrogen or C independently of one another 1-6Alkyl (for example methyl);
(h) .-S (O) 2R 2a, R wherein 2aBe as disclosed in summary of the invention.For example, R 2aBe C 1-6Alkyl (for example methyl),
(i) .-C (O) R 1a, R wherein 1aBe as disclosed in summary of the invention.For example, R 1aBe hydrogen, C 1-6Alkyl (for example methyl, ethyl), or G 2, G wherein 2Be as disclosed in summary of the invention.For example, G 2Be optional substituted phenyl or optional substituted heterocycle (for example optional substituted azetidinyl, pyrrolidyl).G 2Optional substituent example including, but not limited to alkyl (for example methyl), halogen (F for example, Cl) ,-OR 1b(R for example 1bBe hydrogen or C 1-3And haloalkyl (for example trifluoromethyl) alkyl);
(j) .-C (O) OR 1a, R wherein 1aBe as disclosed in summary of the invention.For example, R 1aBe hydrogen or C 1-6Alkyl (for example methyl, ethyl, the tertiary butyl),
(k) .-C (O) N (R Z3) (R 3a), R wherein Z3And R 3aBe as disclosed in summary of the invention.For example, R Z3Be hydrogen or C 1-6Alkyl (for example methyl).R 3a, for example, be hydrogen, C 1-6Alkyl (for example methyl, ethyl, n-propyl, sec.-propyl), alkynyl (for example Propargyl), alkoxyl group (for example methoxyl group), haloalkyl (for example 2,2,2-trifluoroethyl), hydroxyalkyl (for example 2-hydroxyethyl, 3-hydroxypropyl), alkoxyalkyl (for example 2-methoxy ethyl), G 2, or-(CR kR x) v-G 2R wherein k, R x, v, and G 2Be as disclosed in summary of the invention.For example, R k, R xBe that for example, each is hydrogen or C independently 1-3Alkyl (for example methyl).V for example, is 1.G 2, for example, be phenyl, heteroaryl (for example bicyclic heteroaryl as but be not limited to pyridyl), cycloalkyl (for example monocyclic cycloalkyl as but be not limited to cyclopropyl, cyclobutyl) or heterocycle (for example monocyclic heterocycles as but be not limited to tetrahydrofuran base, pyrrolidyl); Its each be optional substituted, described in summary of the invention, for example, optionally is independently selected from that following substituting group replaces: alkyl, halogen, and haloalkyl;
(l) .-N (R 3a) C (O) R 1a, R wherein 3aAnd R 1aBe as disclosed in summary of the invention.For example, R 3aBe hydrogen or C 1-6Alkyl (for example methyl), and R 1aBe hydrogen, C 1-6Alkyl (for example methyl), or G 2, G wherein 2Be as disclosed in summary of the invention.For example, G 2Be phenyl or heterocycle (for example monocyclic heterocycles as but be not limited to azetidinyl, pyrrolidyl, morpholinyl), its each be optional substituted, as in the summary of the invention and described herein.G 2Optional substituent example including, but not limited to alkyl, halogen, haloalkyl, and OH;
(m). haloalkyl (difluoromethyl for example, 1,1-two fluoro ethyls, methyl fluoride, trifluoromethyl);
(n). N (R 3a) C (O) O (R 1a), R wherein 3aAnd R 1aBe as disclosed in summary of the invention.For example, R 3aBe hydrogen, and R 1aBe C 1-6Alkyl (for example methyl, ethyl, the tertiary butyl);
(o). N (R 3a) C (O) N (R Z3) (R 3a), R wherein 3aAnd R Z3Be as disclosed in summary of the invention.For example, R Z3Be hydrogen or C 1-6Alkyl (for example methyl), and R 3aBe hydrogen, C 1-6Alkyl (for example methyl), hydroxyalkyl (for example 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl), or G 2, G wherein 2Be as disclosed in summary of the invention, for example, G 2It is optional substituted phenyl; With
(p). G 2G wherein 2Be as disclosed in summary of the invention.For example, G 2Be phenyl, heterocycle (for example dihydro-1,3-oxazolyl, dihydro-1,3-oxazinyl), or heteroaryl (for example pyridyl), its each be optional substituted, described in summary of the invention.G 2Optional substituent example including, but not limited to C 1-6Alkyl (for example methyl), and halogen (F for example, Cl), haloalkyl (for example trifluoromethyl), and CN.
Should be understood that in conjunction with above-mentioned embodiment, comprise especially, more particularly and embodiment preferred that the application has expected the compound of formula (I).
Therefore, an aspect relates to the compound of one group of formula (I), wherein R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces); And R 2Be alkyl (for example methyl, ethyl, n-propyl, isobutyl-, normal-butyl, n-pentyl etc.), thiazolinyl (for example, allyl group, vinyl, but-1-ene base etc.), alkynyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl (4-fluoro-4-methyl amyl for example, 4,4-difluoro amyl group, 3-fluoro-3-methyl butyl, 4,4,4-trifluoro butyl, 4-fluorine butyl) ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1, G wherein 1, R Zb, R Z1, R Za, R Z2b, R a, R bAnd m is as describing at summary of the invention with in describing in detail partly prevailingly.For example, in certain embodiments, m is 1,2,3, or 4.In other embodiments, m is 1,2, or 3.In other embodiments, m is 1 or 2.In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).
The compound that relates to one group of formula (I) on the other hand, wherein R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces); And R 2Be alkyl (for example methyl, ethyl, n-propyl, isobutyl-, normal-butyl, n-pentyl etc.), thiazolinyl (for example, allyl group, vinyl, but-1-ene base etc.), alkynyl ,-(CR aR b) m-CN, haloalkyl (4-fluoro-4-methyl amyl for example, 4,4-difluoro amyl group, 3-fluoro-3-methyl butyl, 4,4,4-trifluoro butyl, 4-fluorine butyl) ,-(CR aR b) m-O (R Za), or-(CR aR b) m-G 1, G wherein 1, R a, R b, m, and R Za, as summary of the invention with described in describing in detail partly.For example, in certain embodiments, m is 1,2,3, or 4.In other embodiments, m is 1,2, or 3.In other embodiments, m is 1 or 2.In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).
The compound that relates to one group of formula (I) on the other hand, wherein R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces); And R 2Be alkyl (for example methyl, ethyl, isobutyl-, normal-butyl, n-pentyl etc.), thiazolinyl (for example, allyl group, vinyl, but-1-ene base etc.) or C 1-6Haloalkyl (4-fluoro-4-methyl amyl for example, 4,4-difluoro amyl group, 3-fluoro-3-methyl butyl, 4,4,4-trifluoro butyl, 4-fluorine butyl).In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).
Another aspect relates to the compound of one group of formula (I), wherein R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces); And R 2Be G 1, G wherein 1As summary of the invention with described in describing in detail partly.G 1Example including, but not limited to cycloalkyl (for example monocyclic cycloalkyl as but be not limited to cyclopropyl) and heterocycle (for example monocyclic heterocycles as but be not limited to THP trtrahydropyranyl), its each be optional substituted, as describing in the summary of the invention part prevailingly.Optional substituent example is when existing, including, but not limited to alkyl (for example methyl, ethyl), oxo, and haloalkyl.In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).
Another aspect relates to the compound of one group of formula (I), wherein R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces); And R 2Be-(CR aR b) m-G 1, G wherein 1, R a, m, and R bAs summary of the invention with described in describing in detail partly.G 1Example including, but not limited to aryl (for example phenyl), cycloalkyl (cyclopropyl for example, cyclobutyl, cyclopentyl, cyclohexyl), and heterocycle (for example 4,5-dihydro-isoxazole base, morpholinyl, 1,3-dioxane base, 1,3-dioxolane base, tetrahydrofuran base), heteroaryl (furyl for example, 1,3-thiazoles base, thienyl), its each be optional substituted, as describing in the summary of the invention part prevailingly.Optional substituent example is when existing, including, but not limited to alkyl (for example methyl, ethyl), haloalkyl, and oxo.R aAnd R bAs in the summary of the invention part, describing prevailingly.R aExample including, but not limited to hydrogen and C 1-6Alkyl (for example methyl, ethyl, sec.-propyl).R bExample including, but not limited to hydrogen, C 1-6Alkyl (for example methyl, ethyl, sec.-propyl), and OH.In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).In certain embodiments, m is 1 or 2.
Further the aspect relates to the compound of one group of formula (I), wherein R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces); And R 2Be-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N 3,-(CR aR b) m-CN ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) (R Zb), or-(CR aR b) m-C (R Zb)=NO (R Z1), R wherein Zb, R a, R b, R Z1And described in m such as the summary of the invention.Each R that occurs Zb, R a, R b, and R Z1For example be hydrogen or C independently 1-6Alkyl (for example methyl, ethyl, sec.-propyl).In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).
Further the aspect relates to the compound of one group of formula (I), wherein R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces); And R 2Be-O (R Za) or-N (R Z1) (R Z2b), R wherein Za, R Z1, and R Z2bBe to set forth as summary of the invention with in describing in detail partly.R ZaExample including, but not limited to hydrogen, alkyl (C for example 1-6Alkyl as but be not limited to methyl, ethyl, 1-methyl-propyl, sec.-propyl), haloalkyl (for example 4-fluorine butyl) ,-(CR cR d) q-CN and-(CR cR d) q-G 1, R wherein c, R d, q, and G 1Be to set forth as summary of the invention with in describing in detail partly.G 1, for example, be optional substituted phenyl or optional substituted pyrrolidyl.Each R that occurs cAnd R d, be hydrogen or C independently of one another 1-6Alkyl (for example methyl, ethyl, sec.-propyl).Q is 1 or 2.In certain embodiments, q is 1.R Z1, for example, be hydrogen or C 1-3Alkyl (for example methyl).R Z2b, for example, be-C (O) O (R Zc), R wherein ZcDescribed in summary of the invention.R Zc, for example, be C 1-6Alkyl (for example tertiary butyl).In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).
Still another aspect relates to the compound of one group of formula (I), wherein R 3Be hydrogen, C 1-6Alkyl (for example methyl), haloalkyl, or optional substituted cycloalkyl (for example optional substituted monocyclic cycloalkyl as but be not limited to, optional by 1 or 2 C 1-3The cyclopropyl that alkyl replaces); And R 2Be-(CR aR b) m-O (R Za) or-(CR aR b) m-N (R Z1) (R Z2b), m wherein, R a, R b, R Za, R Z1, and R Z2bBe as described in summary of the invention and the embodiment herein.In certain embodiments, R ZaBe hydrogen, alkyl (C for example 1-6Alkyl as but be not limited to methyl, ethyl, 1-methyl-propyl, sec.-propyl), haloalkyl (C for example 1-6Haloalkyl as but be not limited to 2,2,2-trifluoroethyl, 2-fluoro ethyl, 2,2-two fluoro ethyls), or-(CR cR d) q-G 1, q wherein, R c, R d, and G 1As in the summary of the invention and described in describing in detail partly.G 1, for example, be optional substituted heterocycle (for example monocyclic heterocycles as but be not limited to tetrahydrofuran (THF)) or optional substituted phenyl.In certain embodiments, each R that occurs a, R c, and R d, for example be hydrogen or C independently 1-6Alkyl (for example methyl, ethyl, sec.-propyl).R b, for example be hydrogen independently when occurring each time, C 1-6Alkyl (for example methyl, ethyl, sec.-propyl), or OH.Q is 1 or 2.In certain embodiments, q is 1.R Z1And R Z2b, for example, be hydrogen or C independently 1-6Alkyl (for example methyl, ethyl, sec.-propyl).In certain embodiments, R 3Be hydrogen or C 1-6Alkyl (for example methyl).In certain embodiments, m is 1,2,3, or 4.
The compound of another group formula (I) including, but not limited to following those, R wherein 2And R 3With the atom that they were connected to, formation contains zero or other two keys, zero or one other be selected from O, S, N and N (H) heteroatomic five-, six-or seven-first monocycle ring, each described monocycle ring is unsubstituted independently or is selected from following substituting group (R by 1,2,3,4 or 5 21) replace: oxo, alkyl, thiazolinyl, alkynyl, halogen ,-CN ,-O (R 1a) ,-C (O) OH ,-C (O) O (alkyl) ,-C (O) (R 1a) ,-N (R Z3) (R 3a) ,-N (R 3a) C (O) R 1a,-N (R 3a) C (O) O (R 1a) ,-N (R 3a) C (O) N (R Z3) (R 3a) ,-N (R 3a) S (O) 2(R 2a) ,-N (R 3a) S (O) 2N (R Z3) (R 3a) ,-SO 2(R 2a) ,-C (O) N (R Z3) (R 3a) ,-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN ,-(CR 1gR 1h) u-O (R 1a), and haloalkyl, two adjacent or non-adjacent atoms of each described monocycle ring randomly connect by the alkylidene bridge of 1,2,3 or 4 carbon atom; With two substituting group (R on same carbon atom 21), with described carbon atom, randomly formation contains 0,1 or 2 first monocycle ring of heteroatomic 3-6 that is selected from O, S and N (H).
The compound of another group formula (I) comprise following those, R wherein 2And R 3, with the atom that they were connected to, be formed on and contain the other two keys of zero in the ring, zero or the single six-membered rings ring of a N (H), each described ring is unsubstituted independently or is selected from following substituting group (R by 1,2,3,4 or 5 21) replace: oxo, alkyl, thiazolinyl, alkynyl, halogen ,-CN ,-O (R 1a) ,-C (O) OH ,-C (O) O (alkyl) ,-C (O) (R 1a) ,-N (R Z3) (R 3a) ,-N (R 3a) C (O) R 1a,-N (R 3a) C (O) O (R 1a) ,-N (R 3a) C (O) N (R Z3) (R 3a) ,-N (R 3a) S (O) 2(R 2a) ,-N (R 3a) S (O) 2N (R Z3) (R 3a) ,-SO 2(R 2a) ,-C (O) N (R Z3) (R 3a) ,-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN ,-(CR 1gR 1h) u-O (R 1a), and haloalkyl; With two substituting group (R on same carbon atom 21), with described carbon atom, randomly formation contains 0,1 or 2 first monocycle ring of heteroatomic 3-6 that is selected from O, S and N (H).
Other example of the compound of one group of formula (I) including, but not limited to following those, R wherein 2And R 3, with the atom that they were connected to, form the single six-membered rings ring, as noted before, it has formula (II)
Figure 894475DEST_PATH_IMAGE003
G wherein 3Be non-existent, CH 2, N (H), O, or S; R 21Be to contain G 3Any commutable atom of ring on optional substituting group, and have value as noted before, r is 0,1,2,3,4 or 5, and R 1, R 4And L is prevailingly at summary of the invention with above in the embodiment and described herein.In certain embodiments, G 3Be N (H).G in other embodiments 3Be CH 2R 21Example including, but not limited to alkyl (C for example 1-6Alkyl as but be not limited to methyl, ethyl, sec.-propyl, normal-butyl, n-propyl), haloalkyl (C for example 1-6Haloalkyl as but be not limited to trifluoromethyl) ,-C (O) O (C 1-6Alkyl) ,-C (O) OH, and oxo; With two R on same carbon atom 21, with described carbon atom, randomly form 3-6 unit monocycle ring, randomly contain heteroatoms (one or more), as in summary of the invention, describing prevailingly.In certain embodiments, r is 0,1,2, or 3.In other embodiments, r is 0,1, or 2.
In the formula (I) or compound (II) of as described in the previous paragraph each group, R 1, R 4, L and optional substituting group are when existing, as partly neutralizing in the above-described embodiment and description in this article at summary of the invention prevailingly.
For example, for the formula (I) or the compound (II) of each group as noted before, the example of son group comprise following those, R wherein 1Be G 1,-NR Z1R Z5, or-OR Z5, G wherein 1, R Z1And R Z5Be to set forth as summary of the invention with in describing in detail partly.
The example of the other child group of formula (I) or compound (II) including, but not limited to following those, R wherein 1Be-OR Z5And R Z5Be as disclosed in summary of the invention and detailed description part.For example, R Z5Be alkyl (for example neo-pentyl), haloalkyl (for example 2,2,2-three chloroethyls), or G 1a, and G 1aSet forth as summary of the invention with in describing in detail partly.For example, G 1aBe optional substituted cycloalkyl as but be not limited to optional substituted adamantyl.
Other example of the child group of formula (I) or compound (II) including, but not limited to following those, R wherein 1Be-NR Z1R Z5, and R Z1And R Z5Be to set forth as summary of the invention with in describing in detail partly.For example, R Z5Be G 1aOr-(CR aR b) m-C (O) N (R Z1) (R Z1), G wherein 1a, R a, R b, m, and R Z1Be to set forth as summary of the invention with in describing in detail.For example, each R that occurs aAnd R bBe hydrogen or alkyl (for example methyl, ethyl, sec.-propyl, the tertiary butyl) independently of one another.R Z1, when occurring each time, be hydrogen or alkyl (for example methyl, ethyl, the tertiary butyl) independently.M for example, is 1 or 2.G 1a, for example, be optional substituted cycloalkyl as but be not limited to, optional substituted cyclohexyl is as summary of the invention with describe in detail described in the part.
For the formula (I) or the compound (II) of each group as noted before, the example of son group comprise following those, R wherein 1Be G 1, and G 1As summary of the invention with described in describing in detail partly.For example, G 1Be aryl (for example phenyl, naphthyl), heteroaryl (for example quinoline-8-yl), heterocycle (for example pyrrolidyl, oxabicyclo [2.2.1] heptyl, dihydro pyranyl), or cycloalkyl (cyclopropyl for example, cyclobutyl, cyclopentyl, cyclohexyl, dicyclo [2.2.2] octyl group, adamantyl, positive adamantyl (noradamantyl)), its each be optional substituted, as prevailingly at summary of the invention with describe in detail in the part and describe.
Other example of the other child group of formula (I) or compound (II) comprise following those, R wherein 1Be phenyl or naphthyl, its each be optional substituted, as prevailingly at summary of the invention with describe in detail in the part and describe.
Another other example of the child group of formula (I) or compound (II) including, but not limited to following those, R wherein 1Be heteroaryl (for example quinoline-8-yl), optional substituted, as describing at summary of the invention with in describing in detail partly prevailingly.
Another other example of the child group of formula (I) or compound (II) including, but not limited to following those, R wherein 1Be heterocycle (for example pyrrolidyl, oxabicyclo [2.2.1] heptyl, oxa--adamantyl, dihydro pyranyl), optional substituted, as prevailingly at summary of the invention with describe in detail in the part and describe.
Another other example of the child group of formula (I) or compound (II) including, but not limited to following those, R wherein 1Be cycloalkyl (cyclopropyl for example, cyclobutyl, cyclopentyl, cyclohexyl, dicyclo [2.2.2] octyl group, adamantyl, positive adamantyl (noradamantyl)), optional substituted, as prevailingly at summary of the invention with describe in detail in the part and describe.
In each group and son group of the compound of as described in the previous paragraph formula (I)-(II), L and R 4As partly neutralizing in the above-described embodiment and description in this article at summary of the invention prevailingly.
For example, R 4Be alkyl (C for example 1-6Alkyl as but be not limited to methyl, the tertiary butyl, 1,1-dimethylpropyl), haloalkyl (for example the 2-fluoro-1,1-dimethyl ethyl, 2,2,2-three fluoro-1,1-dimethyl ethyl), or G 2, G wherein 2Described in summary of the invention.For example, G 2Be optional substituted C3-6 cycloalkyl (for example optional substituted cyclopropyl or optional substituted cyclobutyl) or optional substituted monocyclic heterocycle (for example optional substituted oxa-cyclobutyl or optional substituted tetrahydrofuran base).In certain embodiments, G 2Be cyclopropyl or cyclobutyl, its each optional by 1 or 2 C 1-3Alkyl (for example methyl) replaces.
Included herein compound still be following those, R wherein 3Be hydrogen or C 1-6Alkyl, R 4Be alkyl, haloalkyl, or G 2, and G 2As summary of the invention with described in describing in detail partly.
Intention the application also comprises those compounds, wherein R 3Be hydrogen, C 1-6Alkyl, haloalkyl, or optional substituted cycloalkyl; R 2Be alkyl, thiazolinyl, alkynyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1R 1Be G 1,-NR Z1R Z5,-OR Z5R 4Be alkyl (C for example 1-6Alkyl), haloalkyl, or G 2G 1, R Zb, R Za, R Z1, R Z2b, R a, R b, m, R Z5, and G 2As summary of the invention with describe in detail described in the part and any combination of aforesaid L.For example, L is C=O.In certain embodiments, L is C=S.In other embodiments, L is S (O) 2In other embodiments, L is C=NCN.
The application also comprises those compounds, wherein R 3Be hydrogen, C 1-6Alkyl, haloalkyl, or optional substituted cycloalkyl; R 2Be alkyl, thiazolinyl, alkynyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1R 1Be G 1R 4Be alkyl (C for example 1-6Alkyl), haloalkyl, or G 2And G 1, R Zb, R Za, R Z1, R Z2b, R a, R b, m, and G 2As summary of the invention with describe in detail described in the part and any combination of aforesaid L.For example, L is C=O.In certain embodiments, L is C=S.In other embodiments, L is S (O) 2In other embodiments, L is C=NCN.
Other compound of expection comprise following those, R wherein 3Be hydrogen or C 1-6Alkyl; R 2Be alkyl, thiazolinyl, alkynyl ,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) or-(CR aR b) m-G 1R 4Be alkyl (C for example 1-6Alkyl), haloalkyl, or G 2R 1Be optional substituted phenyl or optional substituted naphthyl; R a, R b, m, R Za, G 1, and G 2As summary of the invention with describe in detail described in the part and any combination of aforesaid L.For example, L is C=O.In certain embodiments, L is C=S.In other embodiments, L is S (O) 2In other embodiments, L is C=NCN.
Other compound of expection comprise following those, R wherein 3Be hydrogen or C 1-6Alkyl; R 2Be alkyl, thiazolinyl, alkynyl ,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) or-(CR aR b) m-G 1R 4Be alkyl (C for example 1-6Alkyl), haloalkyl, or G 2R 1It is optional substituted cycloalkyl; R a, R b, m, R Za, G 1, and G 2As summary of the invention with describe in detail described in the part and any combination of aforesaid L.For example, L is C=O.In certain embodiments, L is C=S.In other embodiments, L is S (O) 2In other embodiments, L is C=NCN.
Other compound of intention comprise following those, R wherein 2And R 3, with the carbon atom that they connected, form the monocycle ring, as prevailingly described in the summary of the invention neutralization embodiment hereinbefore.R 1Be G 1,-NR Z1R Z5,-OR Z5And R 4Be alkyl (C for example 1-6Alkyl), haloalkyl, or G 2R Z5, R Z1, G 1, and G 2As summary of the invention with describe in detail described in the part and any combination of aforesaid L.For example, L is C=O.In certain embodiments, L is C=S.In other embodiments, L is S (O) 2In other embodiments, L is C=NCN.
Other compound of intention comprise following those, R wherein 2And R 3, with the carbon atom that they connected, form the monocycle ring, as prevailingly described in the summary of the invention neutralization embodiment hereinbefore.R 1Be G 1And R 4Be alkyl (C for example 1-6Alkyl), haloalkyl, or G 2G 1And G 2As summary of the invention with describe in detail described in the part and any combination of aforesaid L.For example, L is C=O.In certain embodiments, L is C=S.In other embodiments, L is S (O) 2In other embodiments, L is C=NCN.
Other compound of intention comprise following those, R wherein 2And R 3, form the monocycle ring with the carbon atom that they connected, as prevailingly described in the summary of the invention neutralization embodiment hereinbefore, R 1Be optional substituted phenyl or optional substituted naphthyl; And R 4Be alkyl (C for example 1-6Alkyl), haloalkyl, or G 2G 2As summary of the invention with describe in detail described in the part and any combination of aforesaid L.For example, L is C=O.In certain embodiments, L is C=S.In other embodiments, L is S (O) 2In other embodiments, L is C=NCN.
Other compound of intention comprise following those, R wherein 2And R 3, with the carbon atom that they connected, form the monocycle ring, as prevailingly described in the summary of the invention neutralization embodiment hereinbefore, R 1Be optional substituted cycloalkyl, and R 4Be alkyl (C for example 1-6Alkyl), haloalkyl, or G 2(for example C3-6 cycloalkyl); G 2As summary of the invention with describe in detail described in the part and any combination of aforesaid L.For example, L is C=O.In certain embodiments, L is C=S.In other embodiments, L is S (O) 2In other embodiments, L is C=NCN.
Exemplary compound including, but not limited to
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-(1, the 1-dimethyl propyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-cyclobutyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and 4-butyl-2,3-dimethyl isothiazole-5 (2H)-subunit] six hydrogen-2,5-endo-methylene group pentalene (methanopentalene)-3a (1H)-methane amide;
N-[(5Z)-4-butyl-2-(1-methyl cyclobutyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-allyl group-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(3-methyl-4,5-dihydro-isoxazole-5-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyclopropyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(3Z)-and the 1-tertiary butyl-5-propyl group-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(3Z)-and the 1-tertiary butyl-1,4,6, the 7-tetrahydrochysene- 3H-spiral shell [2,1-benzisothiazole-5,2'-[1,3] dioxolane]-the 3-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-methoxy ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-morpholine-4-base ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[2-(5,5-dimethyl-1,3-dioxane-2-yl) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-(2-azido-ethyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[3-(methoxyimino) propyl group] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-(2-aminoethyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[2-(dimethylamino) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-methyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-hydroxyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-cyanoethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2, the 3-dihydroxypropyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(methoxyimino) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1,3-dioxolane-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-hydroxy-2-methyl propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyanogen methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-[(1Z)-the but-1-ene base]-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-ethyl cyclopropyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(methylol) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(methoxymethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(ethoxyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (phenyl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-(azido methyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-cyclobutyl-1-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[cyclobutyl (hydroxyl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-benzyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-cyclobutyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyclobutylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-tetrahydrochysene-2H-pyrans-4-base isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (1,3-thiazoles-2-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,5-dimethoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-fluoro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-methyl benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (thiophene-2-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
4-{ (the 5Z)-2-tertiary butyl-5-[(5-chloro-2-methoxybenzoyl) imino-]-2,5-dihydro isothiazole-4-yl } methyl-butyrate;
4-{ (the 5Z)-2-tertiary butyl-5-[(5-cyano group-2-methoxybenzoyl) imino-]-2,5-dihydro isothiazole-4-yl } methyl-butyrate;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-fluorobenzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(2,2, the 2-trifluoro ethoxy) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(methylsulfonyl) benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (1,3-thiazoles-4-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1,3-thiazoles-4-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
5-amino-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-formyl-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-[(methoxyimino) methyl] benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(formamido group)-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 5-[(oxyimino) methyl]-the 2-methoxy benzamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-the 4-methoxybenzoic acid;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-iodo-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-ethynyl-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethoxy) benzamide;
5-acetyl-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(difluoromethyl)-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(methyl fluoride)-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(tetrahydrofuran (THF)-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-[(1Z)-N-hydroxyl acetimidoyl (hydroxyethanimidoyl)]-the 2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(1,1-two fluoro ethyls)-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(isopropoxy methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-the 4-methoxyl methyl benzoate;
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide;
N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4-methoxyl group isophthaloyl amine;
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-sec.-propyl-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluoro-4-methyl amyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-oxo butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(2,2, the 2-trifluoro ethoxy) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4,4-difluoro amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-fluoro-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluoro-4-methyl amyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-{[(2R)-tetrahydrofuran (THF)-2-ylmethoxy] methyl } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(2-fluorine oxyethyl group) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(2, the 2-difluoroethoxy) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 1-phenylcyclohexane carboxylic acid amides;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-(2-chloro-4-fluorophenyl) cyclohexane carboxamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-oxo-cyclopentane methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-phenyl cyclopentane formamide;
N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide;
N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3,3-difluoro azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide;
(1S, 4R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4,7,7-trimethylammonium-3-oxo-2-oxabicyclo [2.2.1] heptane-1-methane amide;
(1R, 4S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4,7,7-trimethylammonium-3-oxo-2-oxabicyclo [2.2.1] heptane-1-methane amide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) tetramethyleneimine-1-ethyl formate;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) tetramethyleneimine-1-t-butyl formate;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-(3-cyanopyridine-2-yl) tetramethyleneimine-3-methane amide;
4-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) dicyclo [2.2.2] octane-1-methyl-formiate;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-oxo-1-Phenylpyrrolidine-3-methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-N'-cyano group-2-anisole imino-methylamine (carboximidamide);
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-anisole thioformamide;
N-[(3Z)-and the 1-tertiary butyl-5-(trifluoromethyl)-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit]-5-chloro-2-methoxy benzamide;
(3Z)-the 1-tertiary butyl-3-[(5-chloro-2-methoxybenzoyl) imino-]-1,4,6,7-tetrahydrochysene isothiazole also [4,3-c] pyridine-5 ( 3H)-t-butyl formate;
N-[(3Z)-the 1-tertiary butyl-4,5,6,7-tetrahydrochysene isothiazole is [4,3-c] pyridines-3 (1H)-subunit also]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxybenzenesulphoismide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] naphthalene-1-sulphonamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(dimethylamino) naphthalene-1-sulphonamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] the hexanaphthene sulphonamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] benzsulfamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] quinoline-8-sulphonamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3,3-tetramethyl-cyclopropane carboxamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,3-dichlorobenzene sulphonamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] diamantane-1-methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-methoxyl group-5-(trifluoromethyl) phenylimino methylamine (carboximidamide);
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2-dimethyl-4-oxygen-3,4-dihydro-2H-pyrans-6-methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-oxyethyl group-5-(trifluoromethyl) phenylimino methylamine (carboximidamide);
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-N'-cyano group-2-anisole imino-methylamine (carboximidamide);
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano-2-hydroxy-benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-cyano-2-hydroxy-benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-(2,2, the 2-trifluoro ethoxy) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-hydroxybenzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyclopentyl-methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-cyano group butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(2-fluorine oxyethyl group) benzamide;
2-(2-amino-2-oxo oxyethyl group)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 5-chlorobenzamide;
2-(2-amino-2-oxo oxyethyl group)-the N-[(5Z)-2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-the 5-chlorobenzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4,4,4-trifluoro butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-chloro-2-(2-fluorine oxyethyl group) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-oxyethyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-amyl group isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-[2-(dimethylamino)-2-oxo oxyethyl group] benzamide;
N-[(5Z)-4-butyl-2-(2,2,2-three fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-(2-fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(cyano group methoxyl group) benzamide;
N-[(5Z)-4-butyl-2-(2-fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-(benzyloxy)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-2-tertiary butyl-4-hydroxy isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-methyl ethoxy) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-methyl propoxy-) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butoxy) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyano group methoxyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-{[(2S)-5-oxo-pyrrolidine-2-yl] methoxyl group } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-{[(2R)-5-oxo-pyrrolidine-2-yl] methoxyl group } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-3-methyl-2,5-dihydro isothiazole-4-yl] t-butyl carbamate;
N-[(5Z)-the 2-tertiary butyl-4-(1-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-ethoxyethyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-methoxy ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[1-(2,2, the 2-trifluoro ethoxy) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-vinyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-3-hydroxyl-1,2,2-trimethyl cyclopentane formic acid;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-3-hydroxyl-1,2,2-trimethyl cyclopentane formic acid;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate;
(1R, 3S)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-(tetramethyleneimine-1-base carbonyl) cyclopentane formamide;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane ethyl formate;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane ethyl formate;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate;
(1R, 3S)-3-(azetidine-1-base carbonyl)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3-hydroxy azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid;
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, N 1, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3,3-difluoro azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate;
(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine peopentyl ester;
(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine 2,2, the 2-trichloro ethyl ester;
(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine 1-adamantane esters;
N 2-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-N 1, 3-dimethyl-L-valine amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-(4-methylcyclohexyl) urea;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(2S)-and 1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-{[(2S)-1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) phenylimino methylamine (carboximidamide);
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(2S)-and 5-oxo-pyrrolidine-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(4R)-and 2-oxo-1,3-oxazolidine-4-yl] methoxyl group }-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-[(1-methyl piperidine-2-yl) methoxyl group]-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-{[(2S)-and 1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-(pyrazine-2-ylmethoxy)-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-(pyrazine-2-ylmethoxy)-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-(pyridine-2-ylmethoxy)-5-(trifluoromethyl) benzamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-propyl group pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-sec.-propyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclobutyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclopropyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 1-propyl group pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(3-hydroxypropyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-[(2R)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl Urethylane;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl urethanum;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-1,2,2-trimethyl cyclopentane methane amide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-propyl group pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-methoxy ethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(3-hydroxypropyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-3-(azetidine-1-base carbonyl)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-2,2,3-trimethyl cyclopentane methane amide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclobutyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-[(2S)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 1-[(2S)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-1,2,2-trimethyl cyclopentane methane amide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-2,2,3-trimethyl cyclopentane methane amide;
(1R, 3S)-N 3-benzyl-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridine-2-ylmethyl) pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridin-3-yl methyl) pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridin-4-yl methyl) pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-Propargyl pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(2,2, the 2-trifluoroethyl) pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-Propargyl pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(2,2, the 2-trifluoroethyl) pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-methoxyl group-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(5,6-dihydro-4H-1,3-oxazine-2-yl)-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(5,6-dihydro-4H-1,3-oxazine-2-yl)-1,2,2-trimethyl cyclopentane methane amide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] tetramethyleneimine-1-methane amide;
(1R, 3S)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-(morpholine-4-base carbonyl) cyclopentane formamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-tetramethyleneimine-1-basic ring pentane-1, the 3-diformamide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] morpholine-4-methane amide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] benzamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide;
(1S, 3R)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide;
N-[(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] benzamide;
(1R, 3S)-3-(kharophen)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-({ [(2-hydroxyethyl) amino] carbonyl } amino)-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[({[(2S)-and the 2-hydroxypropyl] amino } carbonyl) amino]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[({[(2R)-and the 2-hydroxypropyl] amino } carbonyl) amino]-1,2,2-trimethyl cyclopentane methane amide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl]-3-hydroxy azetidine-1-methane amide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl]-3,3-difluoro azetidine-1-methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-(2-hydroxy-2-methyl propoxy-)-5-(trifluoromethyl) benzamide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] azetidine-1-methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-({ [methyl (phenyl) amino] carbonyl } amino) cyclopentane formamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) diamantane-1-methyl-formiate;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) diamantane-1-formic acid; With
Uncle's 2-[(fourth amino) oxygen base]-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(trifluoromethyl) benzamide.
The application's compound can exist with the form of steric isomer, wherein has asymmetric or chiral centre.These steric isomers are " R " or " S ", depend on the substituent configuration around chiral carbon atom.Term used herein " R " and " S " are the configuration that defines as in the following document: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976,45:13-30.
The application has expected that various steric isomers and its mixture and these are included in the application's the scope especially.Steric isomer comprises enantiomer and non-corresponding isomer and enantiomer or non-corresponding mixture of isomers.The independent steric isomer of the application's compound can perhaps be prepared by preparation racemic mixture, the well-known fractionation of those skilled in the art subsequently by the synthetic preparation of the commercially available starting material that get that contain asymmetric or chiral centre.The example of these method for splitting is for for example: (1) makes mixture of enantiomers be connected with chiral auxiliary(reagent), by recrystallization or chromatography the non-enantiomer mixture that obtains is separated, and discharges the optical purity product from auxiliary agent; Or (2) make the optical antipode mixture directly separate on chiral chromatographic column.
Geometrical isomer may reside in the The compounds of this invention.Expected by around carbon-to-carbon double bond, the two keys of carbon-nitrogen, cycloalkyl, or the geometrical isomer that obtains of the substituent arrangement of heterocyclic group and composition thereof.To be called Z or E configuration around the substituting group of carbon-to-carbon double bond or carbon-nitrogen bond; And will be called cis or transconfiguration around cycloalkyl or heterocyclic substituting group.
Compound disclosed herein can demonstrate tautomerism.
Therefore, the drawn structural formula in this specification sheets may be represented only a kind of in possible tautomer or the stereoisomer form.Should will be appreciated that to comprise any change or stereoisomer form and composition thereof, be not limited in any change or the stereoisomer form that in compound name or drawn structural formula, are adopted.
Compound can with isotropic substance-mark of containing one or more atoms with the atomic mass that is different from atomic mass that occurring in nature exists the most galore or total mass number or total mass number or-form of enrichment exists.Isotropic substance can be radioactive or inactive isotropic substance.The isotropic substance of atom such as hydrogen, carbon, phosphorus, sulphur, fluorine, chlorine and iodine including, but not limited to 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl and 125I.Other the isotopic compound that contains these and/or other atom is in the application's scope.
In another embodiment, the compound of isotropic substance-mark comprise deuterium ( 2H), tritium ( 3H) or 14The C isotropic substance.The compound of isotropic substance-mark can prepare by the well-known general method of those skilled in the art.The compound of such isotropic substance-mark can be expediently replaces cold reagent to carry out that disclosed program prepares in embodiment and the scheme part by the reagent with the isotropic substance-mark that can get easily.In some cases, thereby compound can be with the agent treated of isotropic substance-mark with its isotopic exchange normal atom, for example by deuteric acid such as D 2SO 4/ D 2The effect of O can be used deuterium exchange hydrogen.Except above-mentioned points, for example, relevant program and intermediate disclosed: Lizondo, J et al., Drugs Fut, 21 (11), 1116 (1996) in following document; Brickner, S J et al., J Med Chem, 39 (3), 673 (1996); Mallesham, B et al., Org Lett, 5 (7), 963 (2003); PCT publication WO1997010223, WO2005099353, WO1995007271, WO2006008754; US patent 7538189; 7534814; 7531685; 7528131; 7521421; 7514068; 7511013; With US patent application publication number 20090137457; 20090131485; 20090131363; 20090118238; 20090111840; 20090105338; 20090105307; 20090105147; 20090093422; 20090088416; With 20090082471, described method is incorporated herein by reference at this.
The compound of isotropic substance-mark can be as standard substance so that determine CB in binding analysis 2The effect of part.Contain that isotopic compound has been used for study of pharmacy so that the mechanism of the effect of the parent compound by assessment heterotope-mark and pathways metabolism is studied internal metabolism course (the Blake et al. J. Pharm. Sci. 64 of compound, 3,367-391 (1975)).Aspect design safety, effective medicine, such metabolism research is important, because the activity in vivo compound is given the patient or proves deleterious or carcinogenic (Foster et al. because of the meta-bolites that is produced by parent compound, Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36 (10): 927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).
In addition, contain inactive isotopic medicine,, be called as " heavy medicine " as the deuterate medicine, can be used for the treatment of and CB 2Active relevant disease and situation.The isotopic amount that exists in the compound is brought up to the natural abundance that is higher than it be called as enrichment.The example of the amount of enrichment comprises from about 0.5,1,2,3,4,5,6,7,8,9,10,12,16,21,25,29,33,37,42,46,50,54,58,63,67,71,75,79,84,88,92,96, to about 100mol%.In the Mammals that comprises rodent and dog, be implemented and kept reaching the time of a couple of days to several weeks with the normal atom of heavy isotope replacement about at the most 15%, and observe minimum side effect (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84:770; Thomson J F, Ann. New York Acad. Sci 1960 84:736; Czakja D M et al., Am. J. Physiol. 1961 201:357).With finding not cause toxicity (Blagojevic N et al. in " Dosimetry up to 15%-23% in the acute replacement people of the deuterium body fluid; Treatment Planning for Neutron Capture Therapy ", Zamenhof R, Solares G and Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23:251 (1997)).
The cold labeling of medicine can change its physico-chemical property such as pKa and lipid solvability.If replacing, isotropic substance influenced zone related in the ligand-receptor interaction, these effects and change the drug effect response that can influence drug molecule.Though some in the physicals of the molecule of cold labeling are different from unlabelled molecule those, but chemistry is identical with biological property, an exception is: because the quality of the raising of heavy isotope, any key that relates to heavy isotope and another atom will be better than the identical key between light isotope and this atom.Therefore, will make that in metabolism or Enzymatic transformation position introducing isotropic substance described reaction is slack-off, this changes moving performance of medicine or effectiveness possibly with respect to the heterotope compound.
C. generally synthetic
In the application's scope, comprise described compound when preparing herein by building-up process or by metabolic process.Compound by metabolic process be included in take place in the human or animal body (in the body) those or in ectogenetic process.
Compound can be by the well-known method preparation of various these compounds of preparation.For example, compound, group L wherein, L 1, A 1, m, q, r, u, G 1, G 2, R a, R b, R c, R d, R Z1, R Z3, R Z5, R Z2b, R Za, R 21, R 1, R 1a, R 1g, R 1h, R 2, R 2a, R 3, R 3a, and R 4Have as in the above summary of the invention part and the implication of being set forth in the embodiment herein, unless otherwise mentioned, can as shown in scheme 1-14, come synthetic.
Already used abbreviation is among scheme below describing and the embodiment: AIBN represents Diisopropyl azodicarboxylate, and DAST represents (two (methoxy ethyl) amino sulfur trifluoride; DMAP represents 4-(dimethylamino) pyridine, and DMF represents N, dinethylformamide, and DMSO represents methyl-sulphoxide, and EDCI represents 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride, and EtOH represents ethanol, Et 3N represents triethylamine, Et 2O represents diethyl ether, Et 2Zn represents zinc ethyl, and EtOAc represents ethyl acetate, CHCl 3The expression chloroform, CH 2Cl 2The expression methylene dichloride, HOBt represents the I-hydroxybenzotriazole hydrate, and KOtBu represents potassium tert.-butoxide, and MeCN represents acetonitrile, and MeOH represents methyl alcohol, NMP represents N-methylmorpholine, PdCl 2(PPh 3) 2Two (triphenyl phosphine) palladium chlorides (II) of expression, PdCl 2(dppf) expression [1, two (diphenylphosphino (the diphenylphosphino)) ferrocene of 1'-] dichloro palladium (II), rt represents room temperature, TBAF represents it is tetrabutyl ammonium fluoride, TMSI represents the iodine trimethyl silyl, and TFA represents that trifluoroacetic acid and THF represent tetrahydrofuran (THF).
The compound of general formula (I), wherein L is C=O and R 3Be hydrogen, can use general procedure to prepare as scheme 1 illustrated.
Scheme 1
Figure 362454DEST_PATH_IMAGE004
The isothiazole ylidene compounds of structure (3) can prepare by following manner: solvent as but be not limited to tetrahydrofuran (THF), diethyl ether, acetonitrile, in methylene dichloride or the chloroform, in about 0 ℃ of temperature to about room temperature, the substituted imines of structure (1) and the lsothiocyanates of structure (2) were reacted about 1 to about 24 hours, in pyridine and methyl alcohol or alcoholic acid mixture, handle subsequently with iodine or bromine, and the handling with sodium bicarbonate subsequently when aftertreatment.
The lsothiocyanates of structure (2) can be synthetic by following manner: at solvent such as tetrahydrofuran (THF), in acetone or its mixture, in envrionment temperature, handle formula R with potassium sulfocyanate 1C (O) X 1Carboxylic acid halides, X wherein 1It is halogen.Carboxylic acid halides can be obtained by corresponding acid, and this uses general procedure known to those skilled in the art, for example, by in suitable solvent such as toluene, handles with thionyl chloride in about room temperature to the temperature of the reflux temperature of about solvent for use.
The imines of structure (1) can by randomly in acid as in the presence of the acetate and randomly in the presence of dewatering agent such as sal epsom, in solvent such as methylene dichloride, use formula R 4NH 2Amine handle formula R 2CH 2The aldehyde of CHO obtains.Reaction can be carried out to about 60 ℃ in about room temperature.
Equally, the compound of general formula (II), wherein L is C=O, and G 3Do not exist, or be selected from CR 101R 102, O, S, NC (O) O (alkyl) or N (R 101), and R 101And R 102Be hydrogen independently of one another, alkyl, or haloalkyl, under the condition of those that can be in being similar to scheme 1, the general procedure described in the operational version 2, by the imines of formula (4) (by using formula R 4NH 2Amine handle corresponding ketone preparation) preparation.
Scheme 2
Figure 176826DEST_PATH_IMAGE005
The compound of general formula (I), wherein L is C=O, can synthesize shown in scheme 3.
Scheme 3
The aminoisothiazoles of structure (6) can obtain formula (7) compound with the bromine bromination in solvent such as benzene and/or acetate.In the presence of alkali such as the triethylamine and in solvent such as tetrahydrofuran (THF) or methylene dichloride, the compound formula R of structure (7) 1COX 1The acidylate of carboxylic acid halides obtain the compound of structure (8).Alternatively, this conversion can be by at coupling agent, alkali and randomly the existence of coupling auxiliary agent time use formula R 1The compound of the acid treatment structure (7) of COOH is finished.The example of coupling reagent is including, but not limited to two (2-oxygen-3-oxazolidinyl) inferior phosphonyl chloride (BOPCl), 1,3-dicyclohexylcarbodiimide (DCC), polymkeric substance support 1,3-dicyclohexylcarbodiimide (PS-DCC), O-(7-azepine benzo triazol-1-yl)-N, N, N', N'-tetramethyl-urea hexafluorophosphate (HATU) and O-benzotriazole-1-base-N, N, N', N'-tetramethyl-urea a tetrafluoro borate (TBTU).The example of coupling auxiliary agent includes but not limited to 1-hydroxyl-7-azepine benzotriazole (HOAT) and I-hydroxybenzotriazole hydrate (HOBT).The example of suitable alkali is including, but not limited to organic bases such as N-methylmorpholine or diisopropylethylamine, or mineral alkali such as sodium bicarbonate.Linked reaction can be in about 0 ℃ of extremely about 50 ℃ temperature at solvent such as chloroform, methylene dichloride, and tetrahydrofuran (THF), N carries out in dinethylformamide or its mixture.
(8) with formula R 4X 2Compound, X wherein 2Be halogen, trifluoromethane sulfonic acid root or tosylate, at alkali such as salt of wormwood, sodium hydride, potassium hydroxide or potassium tert.-butoxide exist down and at solvent such as N, dinethylformamide, acetonitrile, the alkylation in tetrahydrofuran (THF) or the acetone obtains the compound of structure (9).(9) with formula R 2ZnX 3Zincon, X wherein 3Be Br or Cl, the organo-metallic coupling in the presence of palladium catalyst such as two (tri-butyl phosphine) palladium (0) obtains the compound of structure (10).This conversion can be carried out to the situation of about 120 ℃ temperature heating at about 50 ℃ in solvent such as N,N-DIMETHYLACETAMIDE.
The compound of general formula (I), wherein L is C=S, can be in solvent such as toluene, to about 80 ℃ temperature, by using the Lawesson agent treated, by the compound of formula (I), wherein L is the C=O preparation in about room temperature.
The compound of general formula (I), wherein L is C=NCN, can use the general procedure described in scheme 4 to prepare.
Scheme 4
Figure 204005DEST_PATH_IMAGE007
The compound of structure (11) can be passed through (a) in solvent such as toluene by the compound of structure (10), in about room temperature to about 80 ℃ temperature, use the Lawesson agent treated and (b) use the product of mercuric acetate (II) and cyanamide (cyanamide) treatment step (a) to obtain.
The compound of general formula (I), wherein R 2Be alkenyl or alkynyl, can functionalised and be corresponding cycloalkyl, heterocycle, heteroaryl, alcohol, acid and acid derivative, this use is similar to the program of known to those skilled in the art those, for example, by [3+2] or [4+2] addition (additions), ozone decomposes (ozonolysis), hydroboration (hydroboration), Cyclopropanated (cyclopropanation), or the like.
Scheme 5
Formula (14) compound, wherein R 11Be alkyl, allyl group or benzyl can be by the compounds of formula (12) and (13), and condition above-mentioned in the operational version 1 prepares.Formula (14) compound, wherein R 11Be alkyl (for example ethyl), can be by in solvent such as methylene dichloride or chloroform, to about 70 ℃ temperature, being converted into formula (15) compound with the trimethyl silyl Iod R in room temperature.Alternatively, formula (14) compound, wherein R 11Be alkyl, ethyl for example can be by being converted into formula (15) compound with alkali such as sodium hydroxide or potassium hydroxide aqueous solution hydrolysis.Work as R 11When being the tertiary butyl, formula (14) compound can be by being converted into (15) with acid as trifluoroacetic acid or hydrochloric acid reaction.Work as R 11When being benzyl, formula (14) compound can by with suitable transition-metal catalyst for example palladium/carbon hydrocracking be (15).
Scheme 6
Figure 478308DEST_PATH_IMAGE009
Use the above-mentioned condition of compound (7) to the conversion of compound (8), formula (15) compound can be converted into formula (16) compound.By alkali as but be not limited to, the existence of triethylamine or diethyl Isopropylamine down and solvent as but be not limited to methylene dichloride, in tetrahydrofuran (THF) or the dimethyl formamide room temperature to about 50 ℃ down and reagent R 1SO 2The Cl reaction, formula (15) compound can be converted into formula (17) compound.
Scheme 7
Figure 471672DEST_PATH_IMAGE010
By alkali as but be not limited to, triethylamine exist down solvent as but be not limited to, ethanol, acetonitrile, in tetrahydrofuran (THF) or the toluene in room temperature to about 100 ℃ temperature, with the reaction of formula (18) compound, formula (15) compound can be converted into formula (19) compound.Alternatively, by midbody compound (20), formula (15) compound can be converted into formula (19) compound.By solvent as but be not limited to THF, dioxane, in the acetonitrile etc. at alkali such as triethylamine, N-methylmorpholine, reacted 8-24 hour with cyanoimino dithiocarbonic acid dimethyl ester (dimethylcyanocarbonimidodithioate) to about 50 ℃ temperature in room temperature under NaH etc. exist, formula (15) compound can be converted into formula (20) compound.Intermediate (20) can 80-100 ℃ at copper carboxylate (as commercially available venus crystals that gets or 2-thiophenic acid copper), the existence of Pd (0) catalyzer/glycol dimethyl ether (or other aprotic solvent) of trialkyl phosphite (for example triethyl-phosphite) and three (dibenzalacetones), two palladiums (0) or other selection is down with boric acid (boronic acid) (HO) 2B-R 1Handled 12-24 hour and obtain formula (19) compound.
Scheme 8
Figure 226002DEST_PATH_IMAGE011
By with acid as trifluoroacetic acid in solvent such as methylene dichloride, react or by with hydrochloric acid reaction, formula (21) compound can be converted into formula (22) compound.The compound of formula (22) can, by various method for transformation well known to those skilled in the art, be converted into formula (23) compound, wherein R 21Be alkyl, thiazolinyl, alkynyl ,-C (O) (R 1a) ,-SO 2(R 2a) ,-C (O) N (R Z3) (R 3a) ,-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN ,-(CR 1gR 1h) u-O (R 1a), and haloalkyl.For example, by well-known reduction amination method, by in the presence of reductive agent such as sodium cyanoborohydride with suitable aldehydes or ketones reagent react, substituent R 21Can be enclosed.The method that in addition well-known is used for (22) are converted into (23) is by using suitable halogenide, tosylate, the alkylating of mesylate or trifluoromethyl sulfonic acid reagent.The R that can enclose in such a way 21The type of group is an alkyl, thiazolinyl, alkynyl ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN ,-(CR 1gR 1h) u-O (R 1a), and haloalkyl.Other R 21Group is as-C (O) (R 1a) ,-SO 2(R 2a) ,-C (O) N (R Z3) (R 3a) and-S (O) 2N (R Z3) (R 3a) can be by using well-known condition of those skilled in the art and suitable carboxylic acid halides, sulfonic acid halide, carbamyl halogen or isocyanate reaction and enclose.
Scheme 9
Figure 900697DEST_PATH_IMAGE012
Transform by standard well known to those skilled in the art is synthetic, formula (24) compound can be converted into formula (25) compound.For example, by with suitable amine R Z1R Z2bNH replaces the corresponding halogenide that is derived from (24), mesylate or tosylate, and (24) can be converted into the amine of formula (25), wherein R Z2bBe hydrogen, alkyl, haloalkyl, G 1Or-(CR cR d) q-G 1By replacing corresponding halogenide with trinitride reagent, mesylate or tosylate, and use the well-known method reduction of those skilled in the art latter subsequently, compound (24) can be converted into primary amine (25) (R Z1And R Z2bEach is hydrogen naturally).Transform by standard is synthetic, comprise and carbonyl compound (that is, reduction amination) alkylogen, carboxylic acid halides, sulfonic acid halide, reactions such as isocyanic ester, compound (25), wherein R Z1And R Z2bEach is hydrogen naturally, can be converted into compound (25), wherein R Z1Or R Z2bNot hydrogen.
By the well-known standard etherification method of those skilled in the art, formula (24) compound can be converted into formula (26) compound.For example, compound (24) can with alkylating agent R Za-X (X=halogen, OMs, OTs etc.) reaction.Alternatively, compound (26) can pass through with suitable pure R Za-OH replaces the corresponding halogenide that is derived from (24), and mesylate or tosylate prepare.
Scheme 10
Figure 424082DEST_PATH_IMAGE013
Solvent as but be not limited to methylene dichloride, toluene, dioxane, or in the dimethyl formamide, about 25 ℃ to about 150 ℃ temperature, the reaction of formula (15) compound and isocyanic ester can obtain formula (27) compound, wherein R Z1Be hydrogen.Alternatively, solvent as but be not limited to methylene dichloride, toluene, dioxane, or in the dimethyl formamide, about 25 ℃ to about 150 ℃ temperature, use formula ClCONR Z1R Z5Urea chloride handle formula (15) compound, can obtain formula (27) compound, wherein R Z1Not hydrogen.
Solvent as but be not limited to methylene dichloride, tetrahydrofuran (THF), or in the dimethyl formamide, alkali as but be not limited to, triethylamine exists down, about 25 ℃ to about 50 ℃ temperature, the reaction of formula (15) compound and chloro-formic ester or fluorofomates can obtain formula (28) compound, wherein R Z5Defined in (I).
Alternatively, use the general procedure shown in scheme 11, can preparation formula (27) compound.
Scheme 11
Figure 853926DEST_PATH_IMAGE014
Solvent as but be not limited in tetrahydrofuran (THF) or the methylene dichloride alkali as but be not limited to, diisopropylethylamine or triethylamine exist down, in about room temperature, the reaction of formula (15) compound and 4-chloroformate nitrophenyl ester (4-nitrophenylcarbonochloridate) obtains intermediate (29).By solvent as but be not limited to tetrahydrofuran (THF), acetonitrile, or in the dimethyl formamide, about 25 ℃ to about 150 ℃ temperature, with formula HNR Z1R Z5The reaction of amine, intermediate (29) can be converted into (27).Can promote this reaction with microwave radiation.
Many other methods that are used to prepare urea are known in the art and are found in, for example, and in the following document: Chem. R eV., 1972,72,457-496; J. Org. Chem., 1994,59,1937-38; Synthesis, 1996,553-76; Angew. Chem. Int. Ed. Engl., 1987,26,894-95; J. Org. Chem., 2003,68,7289-97; J. Org. Chem., 1997,62,4155-58; Tet. Lett., 1995,36,2583-86; Tet. Lett., 1994,35,4055-58; Tet. Lett., 1997,38,5335-38; Angew. Chem. Int. Ed. Engl., 1995,34,2497-2500; Synlett., 1996,507-08; Synlett., 1996,502-03; Tet. Lett., 1983,24,4569-72; Synthesis, 1989,423-425; J. Org. Chem., 1996,61,4175-79; Tet. Lett., 1998,39,7811-14; J. Org. Chem., 1998,63,4802-07; And J. Comb. Chem., 1999,1,163-172.
Method in the operational version 12 can preparation formula (30) and (31) compound.
Scheme 12
Figure 95552DEST_PATH_IMAGE015
Solvent as but be not limited in the hexane at about room temperature (+) dextrocamphoric acid ((1R to about 80 ℃ temperature; 3S)-1; 2; 2-trimethylammonium-1; 3-pentamethylene dioctyl phthalate) can obtain the intermediate double chloride of acid with the phosphorus pentachloride reaction, it is in solvent such as tetrahydrofuran (THF), in the presence of alkali such as triethylamine; can be sequentially and compound (15), pure subsequently HOR 1aReaction, and obtain the mixture of (30) and (31).(30) can separate by silica gel chromatography with the mixture of (31).Use identical condition,, also can carry out above-mentioned operation, and obtain having opposite stereochemical similar product from (-) dextrocamphoric acid.
The method of operational version 13 can be by (30) preparation formula (32) and (33) compound.
Scheme 13
Figure 573937DEST_PATH_IMAGE016
Formula (30) compound, wherein R 1aBe alkyl, can in aqueous alcoholic solvent (for example water-ethanol), to about 80 ℃ temperature, react, and obtain carboxylic acid cpd (32) with alkali metal hydroxide (for example potassium hydroxide) in about room temperature.By solvent (as but be not limited to tetrahydrofuran (THF) or dimethyl formamide) in, at coupling reagent such as N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (EDC), 1,1'-N,N'-carbonyldiimidazole (CDI), two (2-oxygen-3-oxazolidinyl) inferior phosphonyl chloride (BOPCl), 1,3-dicyclohexylcarbodiimide (DCC), polymkeric substance support 1,3-dicyclohexylcarbodiimide (PS-DCC), O-(7-azepine benzo triazol-1-yl)-N, N, N', N'-tetramethyl-urea hexafluorophosphate (HATU), or O-benzotriazole-1-base-N, N, N', under the existence of N'-tetramethyl-urea a tetrafluoro borate (TBTU), exist or do not exist the coupling auxiliary agent as but be not limited to, under the situation of 1-hydroxyl-7-azepine benzotriazole (HOAT) or I-hydroxybenzotriazole hydrate (HOBT), with amine HNR Z3R 3a(or its salt) reaction, formula (32) compound can be converted into formula (33) compound.Reaction usually exist or do not exist alkali as but be not limited to N-methylmorpholine, triethylamine, or carry out under the situation of diisopropylethylamine.Formula (33) compound, wherein R 3aBe hydroxyalkyl, by with Tosyl chloride, N, the reaction of N-dimethyl aminopyridine and triethylamine can be converted into Xiang Ying De oxazoline.Formula (32) compound can react under Curtius-type rearrangement condition well known to those skilled in the art, and obtains corresponding amine according to the selection of reaction conditions, carbamate, urea, or acid amides.
Formula (31) compound, wherein R 1aBe alkyl, but also the method for operational version 13 is reacted, and form corresponding carboxylic acid and acid amides.The carboxylic acid and the amide compound that are derived from (31) like this can further be processed, and as described in the previous paragraph, and according to the selection of compound and reaction conditions, obtain amine, carbamate ， Huo oxazoline.
Some compound of formula (I), wherein R 1Be G 1, G 1Be that phenyl and described phenyl are by group-L 1-A 10Replace, wherein A 10Be A 1Or its chemical derivative or precursor, represent by formula (35).
Scheme 14
Figure 217408DEST_PATH_IMAGE017
Formula (35) compound, L wherein, L 1, R 2, R 3And R 4Defined in (I); A 10Be A 1Or its chemical derivative or precursor, R G1Expression is suc as formula the G that limits in (I) 1Optional substituting group, with z be 0,1,2,3 or 4, can by exist or do not exist alkali as but be not limited to potassium tert.-butoxide, sodium tert-butoxide, or under the situation of triethylamine solvent (as but be not limited to tetrahydrofuran (THF) or dimethyl formamide) under about 0 ℃-150 ℃ temperature with pure HO-A 10Perhaps amine HN (R Z3) (A 10) reaction, by formula (34) compound.Can promote and HN (R with microwave radiation Z3) (A 10) reaction.
Can recognize that the synthesis flow of embodiment part illustrated and specific embodiment are exemplary, should not be construed as limitation of the scope of the invention, the scope of the invention is defined by the claims.All of synthetic method and specific embodiment substitute, improvement and equivalent include in the scope of claim.
The optimized reaction conditions and the reaction times that are used for each one step can be inequality, depend on the substituting group in the reactant of the concrete reactant of use and use.Unless otherwise indicated, solvent, temperature and other reaction conditions can easily be selected by those of ordinary skills.In the embodiment part, provide ad hoc approach.Can for example the solvent in the residue be removed in the usual way and be further purified such as but not limited to crystallization, distillation, extraction, grinding and chromatography, reactant is carried out aftertreatment by method generally known in the art.Unless otherwise indicated, raw material and reagent can be buied, or those skilled in the art can be prepared by commercially available material with method described in the chemical literature.
Normal experiment comprise the order, the not compatible any chemical functional group of protection of appropriate application response condition, reagent and synthetic route with reaction conditions and in method the appropriate point deprotection in the reaction sequence include within the scope of the present invention.Those skilled in the art know suitable blocking group and with the method for this type of suitable blocking group with different substituents protection and deprotection; Their example can be at T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (the 3rd edition), John Wiley ﹠amp; Sons, NY finds in (1999), and the document is attached to herein by reference in full.Can finish the synthetic of compound by being similar to described in above-mentioned synthesis flow and the specific embodiment those method.
If do not have commercially availablely, method that can be by being selected from the standard technique of organic chemistry, be similar to known analog structure technique for synthesizing compounds, or the method that is similar to method and technology described in above-mentioned flow process or the synthetic embodiment part prepares raw material.
When needing the optically active form of compound, can be by implementing one of described method herein, obtain with opticity raw material (for example by the suitable reactions steps preparation of asymmetric introducing), or obtain with the stereoisomer mixture fractionation (for example chromatographic separation, recrystallization or enzyme split) of standard method with compound or intermediate.
Similarly, when needing the pure geometrical isomer of compound, can make raw material with pure geometrical isomer by implementing one of aforesaid method, or with standard method for example chromatographic separation the geometrical isomer mixture fractionation of compound or intermediate is obtained.
Following examples can be used for illustrating purpose and should not think and limit the scope of the invention.
D. embodiment
Embodiment 1
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 1A
N-(tertiary butyl)-N-inferior hexyl amine (hexylideneamine)
At N 2Down at room temperature at room temperature tert-butylamine (5.25 ml, 50.0 mmol) and MgSO 4(2g)/CH 2Cl 2Add hexanal (6.0 ml, 50 mmol) (10ml) at leisure.Become heat release midway by adding reaction, so temporarily use ice bath so that control speed of reaction and avoid solvent or amine are boiled.After interpolation was finished, at room temperature stirring reaction was 2 hours, at N 2Logistics under filtration over celite and with the anhydrous CH of 20ml 2Cl 2Washing.Evaporating solvent, and obtain light yellow liquid.
Figure 552575DEST_PATH_IMAGE018
Embodiment 1B
5-chloro-2-methoxy benzoyl chloride
Gently heat 5-chloro-O-Anisic Acid (11.3 g, 60.56 mmol) and SOCl 2(9 ml, 123.7 mmol)/toluene (20ml), gas is fiercely separated out simultaneously.Gas separate out calm down after, reacting by heating and refluxing 1.5 hours, cooling and at room temperature stir and spend the night.Volatile matter evaporate in a vacuum and all the other materials with O for toluene and evaporation (2 *) and remove excessive SOCl 2And obtaining white solid, it directly takes next step to and does not purify.
Figure 360125DEST_PATH_IMAGE019
Embodiment 1C
5-chloro-2-methoxybenzoyl lsothiocyanates
The product of mix embodiment 1B (about 60 mmol) and KSCN (5.83 g, 60 mmol) and at room temperature stirred 2 hours in anhydrous tetrahydro furan (25mL) and anhydrous propanone (40ml).Reaction is with diethyl ether (100ml) dilution, and filtration over celite and evaporating solvent in a vacuum obtain title compound.
Figure 438939DEST_PATH_IMAGE020
Embodiment 1D
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
To at room temperature at N 2Under product (1.90 g, 12.2 mmol)/tetrahydrofuran (THF) (10ml) of embodiment 1A in add the product (2.30 g, 10.1 mmol) of embodiment 1C.After 1 hour, at room temperature, react and use I 2(2.59 g, 10.2 mmol), methyl alcohol (30ml) and pyridine (3ml) were handled and are stirred 1 hour.Then at saturated NaHCO 3Divide reactant ligand between the/diethyl ether, continue simultaneously to stir and spend the night.Saturated NaHCO is further used in reaction 3The dilution of/diethyl ether separates each layer and water and extracts once more with diethyl ether (2 *).Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.Add toluene/acetonitrile and evaporation 2x and remove excessive pyridine and H 2O.Flash chromatography separates raw product, uses diethyl ether: CH 2Cl 2: hexane (7:3:3) wash-out and obtain the product of the expectation of 2.68g, wherein current downflow on the impurity.This material is dissolved in minimum CH 2Cl 2In, add hexane up to omiting muddy and it being left standstill 4 hours.Collect the white crystal solid and with cold 1:1 CH 2Cl 2: hexane wash and obtain the title compound of 962.78mg.Mother liquor recrystallize and obtain the other title compound of 555mg from methyl alcohol.Second mother liquor is concentrated into drying, is dissolved in minimum CH 2Cl 2Separate with flash chromatography on silica gel, use diethyl ether: CH 2Cl 2: hexane (7:1:3) wash-out and obtain the title compound of other 600mg.
Figure 936917DEST_PATH_IMAGE021
Embodiment 2
N-[(5Z)-4-butyl-2-(1, the 1-dimethyl propyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At 0 ℃ hexanal (0.123 ml, 1.0 mmol) is added drop-wise to uncle's amylamine (0.117 ml, 1.0 mmol)/diethyl ether (1ml) and MgSO 4(240mg).In 1 hour, under agitation make reaction be warming up to room temperature, be cooled to 0 ℃ once more, handle, stirred 1.5 hours, use I then at 0 ℃ with embodiment 1C (230 mg, 1 mmol) 2(250mg) and pyridine (0.17ml) handle and stirring is spent the night under, make to react and be warming up to room temperature.At saturated NaHCO 3In make the reaction quencher and extract with diethyl ether (3 *).Organic phase (the MgSO that is dried 4), filter and evaporating solvent.With 33% ethyl acetate/hexane and subsequently 45% ethyl acetate/hexane be eluted in the title compound that (2 *) flash chromatography on the silica gel provides 22mg.
Embodiment 3
N-[(5Z)-4-butyl-2-cyclobutyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace uncle's amylamine with the ring butylamine, use to prepare title compound as embodiment 2 described programs.
Figure 596885DEST_PATH_IMAGE023
Embodiment 4
N-[(5Z)-and 4-butyl-2,3-dimethyl isothiazole-5 (2H)-subunit] six hydrogen-2,5-endo-methylene group pentalene (methanopentalene)-3a (1H)-methane amide
Embodiment 4A
Six hydrogen-2,5-endo-methylene group pentalene (methanopentalene)-3a (1H)-carbonyl chloride
Diamantane (noradamantane) formic acid (4.99 g, 30.1 mmol) and SOCl fall in heating 3- 2(5 ml, 69 mmol)/toluene (5ml) is separated out beginning to 65 ℃ up to fierce gas.Remove heating bath 5-10 minute and separate out and relax up to gas.Recovery is 65 ℃ of reacting by heating 2 hours once more.Reaction is cooled to room temperature, removes volatile matter in a vacuum and add toluene and evaporation (2 *) and remove excessive SOCl 2Use rough chloride of acid and need not further purification.
Embodiment 4B
N-(4-bromo-3-methyl isothiazole-5-yl) six hydrogen-2,5-endo-methylene group pentalene (methanopentalene)-3a (1H)-methane amide
To at 4-bromo-3-methyl isothiazole-5-amine of 0 ℃ (as J. Chem. Soc. 1963, preparation described in the p 2032) (1.93 g, 10.1 mmol)/tetrahydrofuran (THF) (25mL) and triethylamine (1.7 ml, 12.2 mmol) add embodiment 4A (1.9 g, 10.3 mmol)/tetrahydrofuran (THF) (15mL) solution in the solution at leisure.Make reaction be warming up to room temperature and stirring is spent the night.Reaction is evaporated to drying, at H 2Distribute between the O/ ethyl acetate and with ethyl acetate aqueous layer extracted (2 *) once more.Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.On silica gel, obtain the compound of two acidylates of the title compound of 0.3g and 1.8g with 15% ethyl acetate/hexane wash-out flash chromatography.The latter is heated and refluxed in methyl alcohol 3 hours, cooling, evaporating solvent and obtain the title compound of other 0.99g on silica gel with the separation of 20% ethyl acetate/hexane wash-out flash chromatography.
Figure 479391DEST_PATH_IMAGE024
Embodiment 4C
N-[(5Z)-and 4-bromo-2,3-dimethyl isothiazole-5 (2H)-subunit] six hydrogen-2,5-endo-methylene group pentalene (methanopentalene)-3a (1H)-methane amide
At room temperature stir the product (1.29 g, 3.79 mmol) of embodiment 4B, K 2CO 3(0.85g) and methyl iodide (1.2 ml, 5 equivalents)/acetonitrile (10ml), tetrahydrofuran (THF) (10mL) and CH 2Cl 2Mixture overnight (3ml) is handled with other methyl iodide (1.2mL), be heated to 65 ℃ 3 hours, at room temperature stir then and spend the night.Reaction is evaporation in a vacuum, at H 2O/CH 2Cl 2Between distribute and use CH once more 2Cl 2Aqueous layer extracted (2 *).Organic phase (the MgSO that is dried 4), filter and evaporating solvent.Use the 35-40%EtOAc/ hexane on silica gel, 100% eluent ethyl acetate flash chromatography obtains the title compound of 0.77g subsequently.
Figure 831875DEST_PATH_IMAGE025
Embodiment 4D
N-[(5Z)-and 4-butyl-2,3-dimethyl isothiazole-5 (2H)-subunit] six hydrogen-2,5-endo-methylene group pentalene (methanopentalene)-3a (1H)-methane amide
The product (44 mg, 0.12 mmol) of heating embodiment 4C, two (tri-butyl phosphine) palladium (0) (13 mg, 0.025 mmol) with 0.5M normal-butyl bromination zinc/tetrahydrofuran (THF) (0.38 ml, 0.19 mixture/N,N-DIMETHYLACETAMIDE mmol) (2ml) to 80-100 ℃ 24 hours, the cooling, at H 2Quencher and extract among the O with diethyl ether (3 *).Make the organic phase filtration over celite and make a small amount of emulsion fragmentation and evaporating solvent.On silica gel, separate raw product, and obtain title compound with 15% ethyl acetate/hexane to 25% ethyl acetate/hexane wash-out flash chromatography.
Figure 774423DEST_PATH_IMAGE026
Embodiment 5
N-[(5Z)-4-butyl-2-(1-methyl cyclobutyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
To 1-methyl ring butylamine (454 mg, 5.33 mmol)/dry CH 2Cl 2(1ml) and MgSO 4(250mg) add hexanal (655 μ l, 5.3 mmol) in the solution at leisure.At N 2Following stirring reaction 1 hour filters 0.45 μ m PFTE strainer, with the dry CH of 0.5mL 2Cl 2Washing with the dilution of 2ml tetrahydrofuran (THF), and is handled with embodiment 1C (703 mg, 3.09 mmol) under continuation is stirred.After 1 hour, reaction I 2(750mg), methyl alcohol (5ml) and pyridine (1ml) are handled and are at room temperature continued and stirred 1 hour.Be reflected at saturated NaHCO 3Distribution and stirring are spent the night between/the diethyl ether.Separate each layer and use the diethyl ether aqueous layer extracted once more.Dry (MgSO 4) organic extract that merges, filter and evaporating solvent.Flash chromatography separates raw product on silica gel, uses diethyl ether: CH 2Cl 2: hexane (7:1:3) wash-out and obtain product and a spot of impurity of the expectation of 88.9mg.Used Analogix IT280 instrument to use the SF15-12g post in 20 minutes, use ethyl acetate: hexane (0:100 to 50:50) gradient elution is chromatographic separation product and obtain the title compound of 75mg once more.
Figure 415620DEST_PATH_IMAGE027
Embodiment 6
N-[(5Z)-4-allyl group-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 6A
2-methyl-N-(penta-4-alkene subunit) third-2-amine
At 0 ℃ at N 2Down at leisure to TERTIARY BUTYL AMINE (5.28 ml, 50 mmol)/CH 2Cl 2(10ml) and MgSO 4Add 4-pentenals (pentenal) (4.94 ml, 50 mmol) in (2.1 g).After interpolation is finished,, make it be warming up to room temperature then and stirred 2 hours 0 ℃ of stirring reaction 15 minutes.The reaction filtration over celite is with the anhydrous CH of 20ml 2Cl 2Washing and obtain clarifying light yellow liquid at the envrionment temperature evaporating solvent.
Embodiment 6B
N-[(5Z)-4-allyl group-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 6A, use to prepare title compound as the described program of embodiment 1D.Use Analogix IT280 on the SF40-115g post, use ethyl acetate: hexane (0:100 to 50:50,20 minutes, 50:50 then, 10 minutes) gradient elution obtains the material that comprises some small amount of impurities of 1.1g by the chromatographic purification product.On silica gel, use diethyl ether: CH 2Cl 2: hexane (7:2:3) wash-out is the chromatographic separation product once more.The product that crystallization from diethyl ether/hexane obtained, and obtain title compound.
Figure 308806DEST_PATH_IMAGE029
Embodiment 7
N-[(5Z)-and the 2-tertiary butyl-4-[(3-methyl-4,5-dihydro-isoxazole-5-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
To at N 2Under ethylidenehydroxylamine (95 μ L, 2.43 mmol)/CHCl 3(10ml) add N-chloro-succinimide (323 mg, 2.43 mmol) and pyridine (10 μ L) in the solution.At room temperature after 2 hours, add embodiment 6B (150mg), triethylamine (340 μ L, 2.4 mmol) and continuation reaction subsequently at room temperature stirred 21 hours.Wash reaction mixture with water and distribute.Use CH once more 2Cl 2Aqueous layer extracted and drying (MgSO 4) organic extract that merges, filter and evaporating solvent.Use Analogix IT280 on the SF15-12g post, use ethyl acetate: hexane (0:100 to 100:0,25 minutes) gradient elution chromatography separation raw product and obtain the title compound of 128mg.
Figure 625518DEST_PATH_IMAGE030
Figure 488432DEST_PATH_IMAGE031
Embodiment 8
N-[(5Z)-the 2-tertiary butyl-4-(cyclopropyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
To at N 2Following glycol dimethyl ether (85 μ l, 0.82 mmol)/dry CH at-10 ℃ (EtOH/ ice) 2Cl 2(3ml) the 1.0M solution (0.82mL) of dropping Et2Zn/ heptane in the solution.Add finish after, drip methylene iodide (0.13 ml, 1.6 mmol) and-10 ℃ of stirring reactions 10 minutes.Embodiment 6B (145mg)/CH is used in reaction then 2Cl 2(1ml) handle and make it be warming up to room temperature and stirring spend the night (about 16 hours).At saturated NH 4Make the reaction quencher among the Cl and use EtOAc/Et 2O/CH 2Cl 2Mixture extraction and use Et subsequently once more 2The O extraction.Organic phase (the MgSO that is dried 4), filtration over celite and concentrated.With Analogix IT280 EtOAc: hexane (0:100 to 50:50) gradient elution chromatography is separated raw product and is obtained the title compound of 45mg.
Figure 712740DEST_PATH_IMAGE032
Embodiment 9
N-[(3Z)-and the 1-tertiary butyl-5-propyl group-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit]-5-chloro-2-methoxy benzamide
In TERTIARY BUTYL AMINE (366 mg, 5 mmol)/anhydrous hexane (20ml) solution, add titanium chloride (IV) (133 mg, 0.5 mmol) at 0 ℃.After 5 minutes, remove cooling bath and in once feeding in raw material, add 4-propyl group pimelinketone (140 mg, 1 mmol).Stir the mixture 2 hours of gained in envrionment temperature.Then, the solid of filtering-depositing and wash with anhydrous diethyl ether.Merging filtrate and washing lotion and at concentrating under reduced pressure.Be dissolved in resistates among the THF (20mL) and at room temperature use 5-chloro-2-methoxybenzoyl lsothiocyanates (190 mg, 0.83 mmol) to handle 1 hour.Add iodine (211 mg, 0.83 mmol), add MeOH (10ml) and pyridine (1ml) subsequently.At room temperature stirred the mixture other 2 hours and add saturated sodium bicarbonate solution and ether subsequently.Stirred this mixture 30 minutes, and separated the ether layer and use the extracted with diethyl ether aqueous solution.The combined ether extract is used the salt water washing, uses anhydrous MgSO 4Dry and under reduced pressure concentrated.Also pass through chromatographic purification (hexane-EtOAc1:1), obtain the title compound of 70mg subsequently with toluene and acetonitrile twice evaporation resistates.
Embodiment 10
N-[(3Z)-and the 1-tertiary butyl-1,4,6, the 7-tetrahydrochysene- 3H-spiral shell [2,1-benzisothiazole-5,2'-[1,3] dioxolane]-the 3-subunit]-5-chloro-2-methoxy benzamide
By with 1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-ketone replaces 4-propyl group pimelinketone, prepares title compound according to the operation of embodiment 9.
Figure 58588DEST_PATH_IMAGE034
Embodiment 11
N-[(5Z)-the 2-tertiary butyl-4-(2-methoxy ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 11A
4-(t-butyldimethylsilyloxy base) butyraldehyde
To at-78 ℃ CH 2Cl 2Drip oxalyl chloride (6.83 g, 53.8 mmol) and dry DMSO (8.41 g, 108 mmol) (150ml).After 5 minutes, drip 4-(t-butyldimethylsilyloxy base) fourth-1-alcohol (10 g, 48.9 mmol)/CH 2Cl 2(5ml).Stir this mixture other 30 minutes at-78 ℃, and add Et3N (24.8 g, 245 mmol).In 30 minutes, make mixture be warming up to room temperature then.After stirring 3 hours, add the water of 100ml.Separate each phase, and with the diethyl ether aqueous phase extracted of 100ml three times.The organic phase that merges is used the 1%HCl aqueous solution of 50ml, the water of 50ml, the 5%NaHCO of 50ml successively 3The saturated NaCl solution washing of the aqueous solution and 50ml.Organic layer MgSO 4Drying is under reduced pressure removed and is desolvated, and obtains title compound.
Embodiment 11B
N-(4-(t-butyldimethylsilyloxy base) butylidene)-2-methyl-prop-2-amine
Replace hexanal with embodiment 11A, use to prepare title compound as the described program of embodiment 1A.
Embodiment 11C
N-[(5Z)-the 2-tertiary butyl-4-(the 2-{[tertiary butyl (dimethyl) silyl] the oxygen base } ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace 1A with embodiment 11B, use to prepare title compound as the described program of embodiment 1D.MS?(DCI/NH 4 +)?m/z?483?(M?+?H) +。
Embodiment 11D
N-[(5Z)-the 2-tertiary butyl-4-(2-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
With tetrabutylammonium fluoride (1M is in THF) (14.9 ml, 14.9 mmol) handle product from 11C (6.0 g, 12.4mmol)/THF (10ml).In this mixture of stirring at room 2 hours.Reaction H 2The O dilution, and water extracts with EtOAc (2 *).Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 2.5g (55%).
Figure 674377DEST_PATH_IMAGE035
Embodiment 11E
N-[(5Z)-the 2-tertiary butyl-4-(2-methoxy ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At room temperature product (70 mgs, 0.19 the mmol)/THF (5ml) of NaH (60%) (12 mg, 0.29 mmol) processing from 11D.Stir this mixture 10 minutes, and in this mixture, added methyl iodide (32.3 mg, 0.23 mmol) then.Other 30 minutes of stirring reaction is used H 2O quencher and extract with EtOAc (2 *).Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 59mg (81%).
Figure 702376DEST_PATH_IMAGE036
Embodiment 12
N-[(5Z)-the 2-tertiary butyl-4-(2-morpholine-4-base ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At the 0 ℃ of product from 11D (100 mg, 0.27 mmol)/CH that handles to contain triethylamine (82 mg, 0.81 mmol) with methylsulfonyl chloride (47 mg, 0.41 mmol) 2Cl 2(10ml).At 0 ℃ of stirring this mixture 15 minutes and except that desolvating.Resistates is dissolved among the THF (10ml), and usefulness morpholine (118 mg, 1.36 mmol) and salt of wormwood (75 mg, 0.54 mmol) are handled and were refluxed 12 hours.At Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), obtain the title compound of 62mg (52%) by anti-phase preparation HPLC purification with 40mL/ minute flow velocity.
Figure 883958DEST_PATH_IMAGE037
Embodiment 13
N-[(5Z)-and the 2-tertiary butyl-4-[2-(5,5-dimethyl-1,3-dioxane-2-yl) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 13A
N-(4-(5,5-dimethyl-1,3-dioxane-2-yl) butylidene)-2-methyl-prop-2-amine
Replace hexanal with 4-(5,5-dimethyl-1,3-dioxane-2-yl) butyraldehyde, use to prepare title compound as the described program of embodiment 1A.
Embodiment 13B
N-[(5Z)-and the 2-tertiary butyl-4-[2-(5,5-dimethyl-1,3-dioxane-2-yl) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace 1A with embodiment 13A, use to prepare title compound as the described program of embodiment 1D.
Figure 152260DEST_PATH_IMAGE038
Embodiment 14
N-[(5Z)-4-(2-azido-ethyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At 0 ℃, handle the product from 11D (209 mg, 0.57 the mmol)/CH that contains triethylamine (172 mg, 1.7 mmol) with methylsulfonyl chloride (97 mg, 0.85 mmol) 2Cl 2(20ml).At 0 ℃, stirred this mixture 20 minutes, remove and desolvate, resistates is dissolved in DMF (10ml) and handles with sodiumazide (184 mg, 2.83 mmol).80 ℃ of heated mixt 2 hours, use H 2O dilutes and extracts with EtOAc (2 *).Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 120mg (54%).
Figure 52083DEST_PATH_IMAGE039
Embodiment 15
N-[(5Z)-and the 2-tertiary butyl-4-[3-(methoxyimino) propyl group] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 15A
(Z)-N-(the 2-tertiary butyl-4-(3-oxopropyl) isothiazole-5 (2H)-subunit)-5-chloro-2-methoxy benzamide
With 2N HCl (10ml, 20 mmol) Processing Example 13B (620 mg, 1.33 mmol)/THF (2ml).60 ℃ of heated mixt 12 hours, be cooled to room temperature and with Virahol/CH 2Cl 2(1:3) (2 *) extraction.Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 304mg (60%).
Figure 618193DEST_PATH_IMAGE040
Embodiment 15B
N-[(5Z)-and the 2-tertiary butyl-4-[3-(methoxyimino) propyl group] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Handle product (26 mg, 0.07 mmol)/EtOH (2ml) with O-methyl hydroxylamine hydrochloride (12 mg, 0.14 mmol) and sodium acetate (6 mg, 0.07 mmol) from 15A.In this mixture of stirring at room 1 hour, remove and desolvate and use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) purify by column chromatography, obtain the title compound of 5.5mg (19%).
Figure 919861DEST_PATH_IMAGE041
Embodiment 16
N-[(5Z)-and the 2-tertiary butyl-4-[2-(dimethylamino) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 16A
N-[(5Z)-4-(2-aminoethyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Under hydrogen balloon with the product (70 mg, 0.18 mmol) of Pd/C (10mg) Processing Example 14/EtOH (10ml) 3 hours.Leach Pd/C and wash with EtOH.Concentrated filtrate obtains the title compound of 60mg (91%).
Figure 212259DEST_PATH_IMAGE042
Embodiment 16B
N-[(5Z)-and the 2-tertiary butyl-4-[2-(dimethylamino) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
The product of embodiment 16A (60 mg, 0.16 mmol)/CH 2Cl 2(10ml) handle with paraformaldehyde (60mg) and borine sodium acetate (sodium boroneacetate) (44 mg, 0.16 mmol).In this mixture of stirring at room 12 hours.Use H 2The O dilution, mixture CH 2Cl 2(1 *) extraction.Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.At Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), by anti-phase preparation HPLC purification resistates, obtain the title compound of 13mg (20%) with 40mL/ minute flow velocity.
Figure 599378DEST_PATH_IMAGE043
Embodiment 17
N-[(5Z)-the 2-tertiary butyl-4-methyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 17A
2-methyl-N-propylidene third-2-amine
Replace hexanal with propionic aldehyde, use to prepare title compound as the described program of embodiment 1A.
Embodiment 17B
N-[(5Z)-the 2-tertiary butyl-4-methyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 17A, use to prepare title compound as the described program of embodiment 1D.
Embodiment 18
N-[(5Z)-the 2-tertiary butyl-4-(3-hydroxyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At-40 ℃ of product (125 mg, 0.33 mmol)/THF (20ml) with methyl-magnesium-bromide (3N) (220 μ l, 0.66 mmol) Processing Example 15A.Make reaction mixture be warming up to-15 ℃ 2 hours and use NH 4The Cl quencher.Mixture CH 2Cl 2(2 *) extraction.Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.At Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), by anti-phase preparation HPLC purification resistates, obtain the title compound of 29mg (22%) with 40mL/ minute flow velocity.
Figure 63038DEST_PATH_IMAGE045
Embodiment 19
N-[(5Z)-the 2-tertiary butyl-4-(2-cyanoethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Product (50 mg, 0.13 mmol)/NMP (1ml) with hydroxylamine hydrochloride (18 mg, 0.26 mmol) Processing Example 15A.In microwave reactor (300W, CEM Explorer) 100 ℃ of heated mixt 15 minutes.At Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), by anti-phase preparation HPLC purification crude mixture, obtain title compound with 40mL/ minute flow velocity.
Figure 860093DEST_PATH_IMAGE046
Embodiment 20
N-[(5Z)-the 2-tertiary butyl-4-(2, the 3-dihydroxypropyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Product (160 mg, 0.44 mmol)/acetone (3ml) and water (0.5mL) with 4-methylmorpholine N-oxide compound (154 mg, 1.32 mmol) and perosmic anhydride (6 mg, 0.02 mmol) Processing Example 6B.In this mixture of stirring at room 12 hours, with the quencher of the saturated Na2S2O3 aqueous solution with Virahol/CH 2Cl 2(1:3) extracting twice.Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.At Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), by anti-phase preparation HPLC purification resistates, obtain the title compound of 67mg (38%) with 40mL/ minute flow velocity.
Figure 406612DEST_PATH_IMAGE047
Embodiment 21
N-[(5Z)-and the 2-tertiary butyl-4-[(methoxyimino) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 21A
N-[(5Z)-the 2-tertiary butyl-4-formyl radical isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Product (200 mg, 0.55 mmol)/acetone (6mL) and water (3ml) with perosmic anhydride (5 mg, 0.02 mmol) Processing Example 6B.In this mixture of stirring at room 10 minutes, in this mixture, add sodium periodate (258 mg, 1.2 mmol) by part ground then.Stirring at room reaction 12 hours, with the quencher of the saturated Na2S2O3 aqueous solution with Virahol/CH 2Cl 2(1:3) extracting twice.Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 78mg (40%).
Figure 580104DEST_PATH_IMAGE048
Embodiment 21B
N-[(5Z)-and the 2-tertiary butyl-4-[(methoxyimino) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 15A with embodiment 21A, use to prepare title compound as the described program of embodiment 15B.
Figure 590785DEST_PATH_IMAGE049
Embodiment 22
N-[(5Z)-the 2-tertiary butyl-4-(1,3-dioxolane-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 22A
3-(1,3-dioxolane-2-yl) propionic aldehyde
To 2-(2-brooethyl)-1, the solution of 3-dioxolane (10 g, 55.2 mmol)/THF (50ml) adds the I as initiator of magnesium (1.6 g, 66.3 mmol) and trace 2Stirring at room reaction mixture 2 hours.After being cooled to-78 ℃, kept 2 hours with dry DMF (1.39 g, 66.3 mmol) quencher mixture with at-78 ℃.Using H 2After the O dilution, reaction mixture CH 2Cl 2(2 *) extraction, distillation (45-55 ℃ 8mmhg), obtains the title compound of 2g (28%) subsequently.MS?(DCI/NH 4 +)?m/z?131?(M?+?H) +。
Embodiment 22B
N-(3-(1,3-dioxolane-2-yl) propylidene)-2-methyl-prop-2-amine
Replace hexanal with embodiment 22A, use to prepare title compound as the described program of embodiment 1A.
Embodiment 22C
N-[(5Z)-the 2-tertiary butyl-4-(1,3-dioxolane-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 22B, use to prepare title compound as the described program of embodiment 1D.
Figure 558741DEST_PATH_IMAGE050
Embodiment 23
N-[(5Z)-the 2-tertiary butyl-4-(1-hydroxy-2-methyl propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Product (50 mg, 0.14 mmol)/THF (5ml) of embodiment 21A is cooled to-40 ℃.In solution, drip sec.-propyl bromination magnesium (3M) (94 μ L, 0.28 mmol).Reaction is remained on-40 ℃ 30 minutes, use saturated NH 4The quencher of the Cl aqueous solution, and with EtOAc (2 *) extraction mixture.Merge organic layer, dry (MgSO 4), filter, and evaporating solvent.At Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), by anti-phase preparation HPLC purification resistates, obtain the title compound of 7.8mg (14%) with 40mL/ minute flow velocity.
Figure 858136DEST_PATH_IMAGE051
Embodiment 24
N-[(5Z)-the 2-tertiary butyl-4-(cyanogen methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 24A
4-oxo butyronitrile
Handle 4 with 4-toluene sulfonic acide (200 mg, 1.2 mmol), 4-diethoxy butyronitrile (10 g, 63.6 mmol)/water (100ml) and backflow 2 hours.PH is adjusted to 7 and mixture CH 2Cl 2(6X) extraction.Merge organic layer, dry (MgSO 4), filter, and evaporating solvent, crude product obtained.
Embodiment 24B
4-(tertbutylimido) butyronitrile
Replace hexanal with embodiment 24A, use to prepare title compound as the described program of embodiment 1A.
Embodiment 24C
N-[(5Z)-the 2-tertiary butyl-4-(cyanogen methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 24B, use to prepare title compound as the described program of embodiment 1D.
Figure 569740DEST_PATH_IMAGE052
Figure 434927DEST_PATH_IMAGE053
Embodiment 25
N-[(5Z)-4-[(1Z)-the but-1-ene base]-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 25A
N-((Z)-oneself-3-alkene subunit)-2-methyl-prop-2-amine
Replace hexanal with (Z)-own-3-hexenoic aldehyde, use to prepare title compound as the described program of embodiment 1A.
Embodiment 25B
N-[(5Z)-4-[(1Z)-the but-1-ene base]-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 25A, use to prepare title compound as the described program of embodiment 1D.
Figure 777047DEST_PATH_IMAGE054
Embodiment 26
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide
Embodiment 26A
5-cyano group-O-Anisic Acid methyl esters
With triethylamine (9.1 g, 12.5 ml, 90 mmol) and PdCl 2(dppf) CH 2Cl 2(1.0 g) handles 3-bromo-4-HOMOVERATRONITRILE (10 g, 47 mmol)/MeOH (100ml).100 ℃ under the CO under 60psi heated mixt 4 hours, filter then and concentrated filtrate.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 8.2g (93%).
Embodiment 26B
5-cyano group-O-Anisic Acid
Product (6.1 g, 31.9 mmol) and lithium hydroxide monohydrate (5.36 g, 128 mmol)/THF (100ml) and H at stirring at room embodiment 26A 2The mixture of O (50ml) 3 hours.To react pH regulator to 3 with 3N HCl, and mixture Virahol/CH 2Cl 2(1:3) extracting twice.Merge organic layer, dry (MgSO 4), filter and concentrate, obtain the title compound of 5.6g (99%).
Figure 610191DEST_PATH_IMAGE056
Embodiment 26C
5-cyano group-2-methoxy benzoyl chloride
Replace 5-chloro-O-Anisic Acid with embodiment 26B, use to prepare title compound as the described program of embodiment 1B.
Embodiment 26D
5-cyano group-2-methoxybenzoyl lsothiocyanates
Replace embodiment 1B with embodiment 26C, use to prepare title compound as the described program of embodiment 1C.
Embodiment 26E
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide
Replace embodiment 1C with embodiment 26D, use to prepare title compound as the described program of embodiment 1D.
Figure 595464DEST_PATH_IMAGE057
Embodiment 27
N-[(5Z)-the 2-tertiary butyl-4-(2-ethyl cyclopropyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
To at-10 ℃ CH 2Cl 2(10ml), add zinc ethyl (130 mg, 1.06 mmol) in 2-glycol dimethyl ether (95 mg, the 1.06 mmol) solution with 1.In this solution, drip methylene iodide (565 mg, 2.1 mmol).Add finish after ,-10 ℃ of settled solutions that stir gained 10 minutes.Embodiment 25B (200 mg, 0.53 mmol) solution is added to this reaction mixture, makes it be warming up to room temperature and stirring is spent the night.Use NH 4Cl acetone then makes the reaction quencher and extracts with EtOAc (2 *).Merge organic layer, dry (MgSO 4), filter and evaporating solvent.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 159mg (77%).
Figure 983852DEST_PATH_IMAGE058
Embodiment 28
N-[(5Z)-the 2-tertiary butyl-4-(methoxymethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 28A
N-[(5Z)-the 2-tertiary butyl-4-(methylol) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
-40 ℃ of products (50 mg, 0.14 mmol)/THF (10ml) 1 hour, use saturated NH with sodium borohydride (21 mg, 0.57 mmol) Processing Example 21A 4The Cl quencher with EtOAc (2 *) extraction, is used MgSO 4Drying is filtered and is concentrated, and obtains the title compound of 50mg.
Figure 54576DEST_PATH_IMAGE059
Embodiment 28B
N-[(5Z)-the 2-tertiary butyl-4-(methoxymethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 11D with embodiment 28A, use to prepare title compound as the described program of embodiment 11E.
Figure 107982DEST_PATH_IMAGE060
Embodiment 29
N-[(5Z)-the 2-tertiary butyl-4-(ethoxyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 11D and replace methyl iodide with embodiment 28A, use to prepare title compound as the described program of embodiment 11E with iodoethane.
Figure 366105DEST_PATH_IMAGE062
Embodiment 30
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 30A
The own nitrile of 6-oxo
With heptan-6-alkene nitrile replaces embodiment 6B, uses to prepare title compound as the described program of embodiment 21A.
Embodiment 30B
6-(tertbutylimido) is nitrile
Replace hexanal with embodiment 30A, use to prepare title compound as the described program of embodiment 1A.
Embodiment 30C
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 30B, use to prepare title compound as the described program of embodiment 1D.
Figure 658547DEST_PATH_IMAGE063
Figure 515644DEST_PATH_IMAGE064
Embodiment 31
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (phenyl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace sec.-propyl bromination magnesium with phenyl-magnesium-bromide, use to prepare title compound as embodiment 23 described programs.
Embodiment 32
N-[(5Z)-4-(azido methyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 11D with embodiment 28A, use to prepare title compound as embodiment 14 described programs.
Figure 64754DEST_PATH_IMAGE066
Embodiment 33
N-[(5Z)-the 2-tertiary butyl-4-(2-cyclobutyl-1-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
In (brooethyl) tetramethylene (211 mg, 1.42 mmol)/THF (20ml), add magnesium (41.3 mg, 1.7 mmol) and initiator iodine (10mg).In this mixture of stirring at room 2 hours, be cooled to-40 ℃ and add in embodiment 21A (100 mg, 0.28 mmol)/THF (20ml) solution then.Make mixture be warming up to room temperature, use saturated NH 4Cl aqueous solution quencher and extract with EtOAc (2 *).Merge organic layer, dry (MgSO 4), filter and evaporating solvent.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 63mg (53%).
Figure 708542DEST_PATH_IMAGE068
Embodiment 34
N-[(5Z)-and the 2-tertiary butyl-4-[cyclobutyl (hydroxyl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace (brooethyl) tetramethylene with the bromine tetramethylene, use to prepare title compound as embodiment 33 described programs.
Figure 257335DEST_PATH_IMAGE069
Embodiment 35
N-[(5Z)-4-benzyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Product (20 mg, 0.05 mmol)/TFA (0.5mL) with triethyl-silicane (54 mg, 0.5 mmol) Processing Example 31.60 ℃ of heated mixt 12 hours, evaporating solvent and at Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), with 40mL/ minute flow velocity,, obtain the title compound of 4.8mg (25%) by anti-phase preparation HPLC purification resistates.
Figure 345377DEST_PATH_IMAGE070
Embodiment 36
N-[(5Z)-the 2-tertiary butyl-4-(2-cyclobutyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 36A
O-{1-[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-2,5-dihydro isothiazole-4-yl]-2-cyclobutyl ethyl } O-phenyl thiocarbonic ester
Drip product (32 mg, 0.07 the mmol)/CH of Processing Example 33 with O-phenyl-chloride sulphur manthanoate (carbonochloridothioate) (18 mg, 0.11 mmol) 2Cl 2(5ml) (contain pyridine (17 mg, 0.2 mmol)).In this mixture of stirring at room 1 hour, remove and desolvate and use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate), by column chromatography purification resistates, obtain the title compound of 32mg (81%).MS?(DCI/NH 4 +)?m/z?559?(M?+?H) +。
Embodiment 36B
N-[(5Z)-the 2-tertiary butyl-4-(2-cyclobutyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Directly use stock solution and tributyl first stannane (33.3 mg of the AIBN (12mg (dry toluene of 0.073 mmol/5ml)) of 2ml (0.03 mmol), 0.114 the mmol) product of Processing Example 36A (32 mg, 0.06 mmol), and the heating gained mixture to 85-90 ℃.After 30 minutes, add other tributyl first stannane (33.3 mg, 0.114 mmol) and AIBN stock solution (1ml).Reaction was refluxed other 30 minutes, concentrate in a vacuum and at Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), with 40mL/ minute flow velocity,, obtain the title compound of 13.2mg (57%) by anti-phase preparation HPLC purification resistates.
Figure 612410DEST_PATH_IMAGE071
Embodiment 37
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 37A
O-{1-[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-2,5-dihydro isothiazole-4-yl]-the 2-methyl-propyl } O-phenyl thiocarbonic ester
Replace embodiment 33 with embodiment 23, use to prepare title compound as the described program of embodiment 36A.MS?(DCI/NH 4 +)?m/z?533?(M?+?H) +。
Embodiment 37B
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 36A with embodiment 37A, use to prepare title compound as the described program of embodiment 36B.
Figure 748993DEST_PATH_IMAGE072
Embodiment 38
N-[(5Z)-the 2-tertiary butyl-4-(cyclobutylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 38A
O-{[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-2,5-dihydro isothiazole-4-yl] (cyclobutyl) methyl } O-phenyl thiocarbonic ester
Replace embodiment 33 with embodiment 34, use to prepare title compound as the described program of embodiment 36A.MS?(DCI/NH 4 +)?m/z?545?(M?+?H) +。
Embodiment 38B
N-[(5Z)-the 2-tertiary butyl-4-(cyclobutylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 36A with embodiment 38A, use to prepare title compound as the described program of embodiment 36B.
Figure 152293DEST_PATH_IMAGE073
Embodiment 39
N-[(5Z)-the 2-tertiary butyl-4-tetrahydrochysene-2H-pyrans-4-base isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 39A
2-methyl-N-(2-(tetrahydrochysene-2H-pyrans-4-yl) ethylidene) third-2-amine
Replace hexanal with 2-(tetrahydrochysene-2H-pyrans-4-yl) acetaldehyde, use to prepare title compound as the described program of embodiment 1A.
Embodiment 39B
N-[(5Z)-the 2-tertiary butyl-4-tetrahydrochysene-2H-pyrans-4-base isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 39A, use to prepare title compound as the described program of embodiment 1D.
Figure 411236DEST_PATH_IMAGE074
Embodiment 40
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (1,3-thiazoles-2-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace sec.-propyl bromination magnesium with the thiazol-2-yl lithium, use to prepare title compound as embodiment 23 described programs.
Embodiment 41
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,5-dimethoxy benzamide
At the product (400mg) of stirring at room embodiment 110B, 2,5-dimethoxybenzoic acid (86 mg, 0.47 mmol), EDCI (181 mg, 0.94 mmol), the mixture of HOBt (145 mg, 0.94 mmol) and DMAP (12 mg, 0.1 mmol)/pyridine (10ml) 1 hour.Remove in a vacuum and desolvate, the dilute with water mixture, and extract with EtOAc.Organic extract (the Na that is dried 2SO 4), filter and concentrate.With a spot of EtOAc debris and filtration, obtain the title compound of 36mg.
Figure 105839DEST_PATH_IMAGE076
Embodiment 42
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-fluoro-2-methoxy benzamide
Replace 2 with 5-fluoro-O-Anisic Acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 629225DEST_PATH_IMAGE077
Embodiment 43
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-methyl benzamide
Replace 2 with 2-methoxyl group-5-tolyl acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 996752DEST_PATH_IMAGE078
Embodiment 44
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (thiophene-2-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
In 2-bromothiophene (444 mg, 2.72 mmol)/THF (10ml), drip n-Butyl Lithium (2.5M) (1.09 ml, 2.72 mmol) at-78 ℃.Handle-78 ℃ of stirring reactions 15 minutes and with embodiment 21A (240 mg, 0.68 mmol)/THF (1ml).-78 ℃ of stirring reactions 1 hour, use saturated NH 4Cl aqueous solution quencher and extract with EtOAc (2 *).Merge organic layer, dry (MgSO 4), filter and evaporating solvent.Use Analogix Intelliflash280 (SiO 2, the 0-75% hexane/ethyl acetate), by column chromatography purification resistates, obtain the title compound of 93mg (31%).
Figure 972798DEST_PATH_IMAGE079
Embodiment 45
4-{ (the 5Z)-2-tertiary butyl-5-[(5-chloro-2-methoxybenzoyl) imino-]-2,5-dihydro isothiazole-4-yl } methyl-butyrate
Embodiment 45A
6-(tertbutylimido) methyl caproate
Replace hexanal with 6-oxo methyl caproate, use to prepare title compound as the described program of embodiment 1A.
Embodiment 45B
4-{ (the 5Z)-2-tertiary butyl-5-[(5-chloro-2-methoxybenzoyl) imino-]-2,5-dihydro isothiazole-4-yl } methyl-butyrate
Replace embodiment 1A with embodiment 45A, use to prepare title compound as the described program of embodiment 1D.
Figure 513501DEST_PATH_IMAGE080
Embodiment 46
4-{ (the 5Z)-2-tertiary butyl-5-[(5-cyano group-2-methoxybenzoyl) imino-]-2,5-dihydro isothiazole-4-yl } methyl-butyrate
Replace embodiment 1A with embodiment 45A, and replace embodiment 1C, use to prepare title compound as the described program of embodiment 1D with embodiment 26D.
Figure 156972DEST_PATH_IMAGE081
Embodiment 47
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(2,2, the 2-trifluoro ethoxy) benzamide
Embodiment 47A
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-fluorobenzamide
Replace 2 with 5-chloro-2-fluorobenzoic acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.MS?(DCI/NH 4 +)?m/z?369?(M?+?H) +。
Embodiment 47B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(2,2, the 2-trifluoro ethoxy) benzamide
At the product (101 mg, 0.27 mmol) of stirring at room embodiment 47A, the mixture of trifluoroethanol (33 mg, 0.32 mmol) and potassium tert.-butoxide (2M) (340 μ L, 0.68 mmol)/THF (10ml) 12 hours.Mixture dilute with water and extract with EtOAc.Organic extract (the Na that is dried 2SO 4), filter and concentrate.At Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), flow velocity with 40mL/ minute, by anti-phase preparation HPLC purification resistates, obtain the title compound of 34mg (28%).
Figure 570767DEST_PATH_IMAGE082
Embodiment 48
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(methylsulfonyl) benzamide
Replace 2 with 2-methoxyl group-5-(methylsulfonyl) phenylformic acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 299689DEST_PATH_IMAGE083
Embodiment 49
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (1,3-thiazoles-4-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace the 2-bromothiophene with the 4-bromo thiazole, use to prepare title compound as embodiment 44 described programs.
Figure 378503DEST_PATH_IMAGE084
Embodiment 50
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 50A
3-(furans-2-yl) third-1-alcohol
In 3-(furans-2-yl) propionic acid (1.4 g, 10 mmol)/THF (50ml), drip borane (1M) (20 ml, 20 mmol).In this mixture of stirring at room 12 hours, use the MeOH quencher, and enriched mixture.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate), by the resistates of column chromatography purification gained, obtain the title compound of 1.0g (79%).
Figure 79743DEST_PATH_IMAGE085
Embodiment 50B
3-(furans-2-yl) propionic aldehyde
Cross product (2.0 g, 15.9 mmol)/CH of iodine alkane (Dess-Martin periodinane) (8.1 g, 19.2 mmol) Processing Example 50A with Dai Si-Martin by part ground 2Cl 2(50ml).In this mixture of stirring at room 2 hours, with saturated NaS2O3 quencher, and mixture CH 2Cl 2Extraction.Use saturated NaHCO 3Washing CH 2Cl 2Layer is used MgSO 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate), by the resistates of column chromatography purification gained, obtain the title compound of 1.44g (73%).
Figure 585811DEST_PATH_IMAGE086
Embodiment 50C
N-(3-(furans-2-yl) propylidene)-2-methyl-prop-2-amine
Replace hexanal with embodiment 50B, use to prepare title compound as the described program of embodiment 1A.
Embodiment 50D
[(5Z)-and the 2-tertiary butyl-4-(furans-2-ylmethyl) isothiazole-5 (2H)-subunit] urethanum
Replace embodiment 1A and replace embodiment 1C with embodiment 50C, use to prepare title compound as the described program of embodiment 1D with different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate).
Figure 802028DEST_PATH_IMAGE087
Embodiment 50E
The 2-tertiary butyl-4-(furans-2-ylmethyl) isothiazole-5 (2H)-imines
Product (300mg, 0.97 mmol)/chloroform (20ml) with TMSI (389 mg, 1.95 mmol) Processing Example 50D.65 ℃ of stirred reaction mixtures 12 hours, use CH 2Cl 2Dilution, organism H 2MgSO is used in the O washing 4Drying is filtered and is concentrated, and obtains title compound.MS?(DCI/NH 4 +)?m/z?237?(M?+?H) +。
Embodiment 50F
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 110B and replace 2 with 5-chloro-O-Anisic Acid with embodiment 51E, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 684534DEST_PATH_IMAGE088
Embodiment 51
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide
Replace embodiment 110B and replace 2 with embodiment 26B with embodiment 51E, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 234420DEST_PATH_IMAGE089
Embodiment 52
N-[(5Z)-the 2-tertiary butyl-4-(1,3-thiazoles-4-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 52A
O-{[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-2,5-dihydro isothiazole-4-yl] (1,3-thiazoles-4-yl) methyl } O-phenyl thiocarbonic ester
Replace embodiment 33 with embodiment 49, use to prepare title compound as the described program of embodiment 36A.MS?(DCI/NH 4 +)?m/z?574?(M?+?H) +。
Embodiment 52B
N-[(5Z)-the 2-tertiary butyl-4-(1,3-thiazoles-4-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 36A with embodiment 52A, use to prepare title compound as the described program of embodiment 36B.
Figure 176969DEST_PATH_IMAGE090
Embodiment 53
N-[(5Z)-the 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide
Embodiment 53A
3-(thiophene-2-yl) third-1-alcohol
Replace 3-(furans-2-yl) propionic acid with 3-(thiophene-2-yl) propionic acid, use to prepare title compound as the described program of embodiment 50A.MS?(DCI/NH 4 +)?m/z?143?(M?+?H) +。
Embodiment 53B
3-(thiophene-2-yl) propionic aldehyde
Replace embodiment 50A with embodiment 53A, use to prepare title compound as the described program of embodiment 50B.
Embodiment 53C
2-methyl-N-(3-(thiophene-2-yl) propylidene) third-2-amine
Replace hexanal with embodiment 53B, use to prepare title compound as the described program of embodiment 1A.
Embodiment 53D
[(5Z)-and the 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-subunit] urethanum
Replace embodiment 1A and replace embodiment 1C with embodiment 53C, use to prepare title compound as the described program of embodiment 1D with different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate).MS?(DCI/NH 4 +)?m/z?325?(M?+?H) +。
Embodiment 53E
The 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-imines
Replace embodiment 50D with embodiment 53D, use to prepare title compound as the described program of embodiment 50E.MS?(DCI/NH 4 +)?m/z?253?(M?+?H) +。
Embodiment 53F
N-[(5Z)-the 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide
Replace embodiment 110B and replace 2 with embodiment 26B with embodiment 53D, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 614903DEST_PATH_IMAGE091
Embodiment 54
N-[(5Z)-the 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 110B and replace 2 with 5-chloro-O-Anisic Acid with embodiment 53E, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 35520DEST_PATH_IMAGE092
Embodiment 55
5-amino-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-methoxy benzamide
Embodiment 55A
(3-{[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] formamyl }-the 4-methoxyphenyl) t-butyl carbamate
Replace 2 with 5-(tert-butoxycarbonyl amino)-O-Anisic Acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs by embodiment 110B.MS?(DCI/NH 4 +)?m/z?462?(M?+?H) +。
Embodiment 55B
5-amino-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-methoxy benzamide
, remove and desolvate and use saturated NaHCO with the product (71mg, 0.15 mmol) of TFA (1ml) Processing Example 55A 10 minutes in room temperature 3Aqueous solution treating mixture and extract with EtOAc (2 *).Organic layer MgSO 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 51mg (92%).
Figure 445773DEST_PATH_IMAGE093
Embodiment 56
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-formyl-2-methoxy benzamide
Embodiment 56A
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-formyl-2-hydroxybenzamide
Replace 2 with 5-formyl-2 hydroxybenzoic acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs by embodiment 110B.MS?(DCI/NH 4 +)?m/z?361?(M?+?H) +。
Embodiment 56B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-formyl-2-methoxy benzamide
Mixture with methyl iodide (165 mg, 1.17 mmol) Processing Example 56A (350 mg, 0.97 mmol) and cesium carbonate (375 mg, 1.94 mmol)/DMF (20ml).In this mixture of stirring at room 2 hours, use H 2O dilutes and extracts with EtOAc (2 *).Organic layer MgSO 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 246mg (68%).
Embodiment 57
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-[(methoxyimino) methyl] benzamide
Replace embodiment 15A with embodiment 56B, use to prepare title compound as the described program of embodiment 15B.
Figure 218874DEST_PATH_IMAGE095
Embodiment 58
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(formamido group)-2-methoxy benzamide
Replace embodiment 110B and replace 2 with formic acid with embodiment 55B, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Embodiment 59
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 5-[(oxyimino) methyl]-the 2-methoxy benzamide
Replace embodiment 15A and replace O-methyl hydroxylamine hydrochloride with embodiment 56B, use to prepare title compound as the described program of embodiment 15B with hydroxylamine hydrochloride.
Figure 973520DEST_PATH_IMAGE097
Embodiment 60
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-the 4-methoxybenzoic acid
At room temperature dropping sodium aqueous solution (6M) (85 μ L) in the stirred solution of perhydrit (223 mg, 2.4 mmol) and embodiment 56B (100 mg, 0.267 mmol)/MeOH (5ml).65 ℃ of heated mixt 2 hours, use the HCl acidifying, and use CH then 2Cl 2/ Virahol (3:1) extraction.Organic layer MgSO 4Drying is filtered and is concentrated.At Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), flow velocity with 40mL/ minute, by the resistates of anti-phase preparation HPLC purification gained, obtain the title compound of 26mg (25%).
Figure 257871DEST_PATH_IMAGE098
Embodiment 61
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-iodo-2-methoxy benzamide
Replace 2 with 5-iodo-O-Anisic Acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs by embodiment 110B.
Figure 670398DEST_PATH_IMAGE099
Embodiment 62
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-ethynyl-2-methoxy benzamide
Embodiment 62A
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-[(trimethyl silyl) ethynyl] benzamide
At the product (330 mg, 0.7 mmol) of 50 ℃ of heating embodiment 61, ethynyl trimethyl silyl (206 mg, 2.1 mmol), PdCl 2(PPh 3) 2(49 mg, 0.07 mmol), the mixture of triethylamine (201 mg, 2.1 mmol) and CuI (33 mg, 0.18 mmol)/DMF (5ml) 16 hours is used H 2O dilutes and extracts with EtOAc (2 *).Organic layer MgSO 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 300mg (97%).MS?(DCI/NH 4 +)?m/z?443?(M?+?H) +。
Embodiment 62B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-ethynyl-2-methoxy benzamide
With product (300 mg, 0.68 mmol)/THF (10ml) of TBAF (1M) (1.7 ml, 1.7 mmol) Processing Example 62A,, use H stirring at room 1 hour 2O dilutes and extracts with EtOAc (2 *).Organic layer MgSO 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 183mg (73%).
Figure 370501DEST_PATH_IMAGE100
Embodiment 63
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethoxy) benzamide
Replace 2 with 2-methoxyl group-5-(trifluoromethoxy) phenylformic acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs by embodiment 110B.
Figure 552083DEST_PATH_IMAGE101
Embodiment 64
5-acetyl-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-methoxy benzamide
Embodiment 64A
5-acetyl-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-hydroxybenzamide
Replace 2 with 5-acetyl-2 hydroxybenzoic acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs by embodiment 110B.MS?(DCI/NH 4 +)?m/z?375?(M?+?H) +。
Embodiment 64B
5-acetyl-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-methoxy benzamide
Replace embodiment 56A with embodiment 64A, use to prepare title compound as the described program of embodiment 56B.
Embodiment 65
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(difluoromethyl)-2-methoxy benzamide
The product of embodiment 56B (140 mg, 0.37 mmol) is dissolved in CH 2Cl 2(4ml), handle catalyzed reaction with DAST (121 mg, 0.75 mmol) and a MeOH.In this mixture of stirring at room 12 hours, use saturated NaHCO 3Aqueous solution quencher and use CH 2Cl 2(2 *) extraction.The organic layer MgSO that merges 4Drying is filtered and is concentrated.On Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters), use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), with 40mL/ minute flow velocity,, obtain title compound by anti-phase preparation HPLC purification resistates.
Figure 907158DEST_PATH_IMAGE103
Embodiment 66
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(methyl fluoride)-2-methoxy benzamide
Embodiment 66A
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(methylol)-2-methoxy benzamide
Replace embodiment 21A with embodiment 56B, use to prepare title compound as the described program of embodiment 28A.MS?(DCI/NH 4 +)?m/z?377?(M?+?H) +。
Embodiment 66B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(methyl fluoride)-2-methoxy benzamide
With product (120 mgs, 0.32 the mmol)/CH of two (methoxy ethyl) amino sulfur trifluoride (106 mg, 0.48 mmol) processing at-78 ℃ embodiment 66A 2Cl 2(10ml).Reaction is remained on-78 ℃ 1 hour, use saturated NaHCO 3Aqueous solution quencher and use CH 2Cl 2(2 *) extraction.The organic layer MgSO that merges 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 56mg (46%).
Figure 551898DEST_PATH_IMAGE104
Embodiment 67
N-[(5Z)-the 2-tertiary butyl-4-(tetrahydrofuran (THF)-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 67A
3-(tetrahydrofuran (THF)-2-yl) propionic acid
Handle (E)-3-(furans-2-yl) vinylformic acid (10 g, 72.4 mmol) with Pd/C (1g)/MeOH (100ml).60 ℃ under 60psi at H 2Following heated mixt 12 hours.After leaching catalyzer, concentrated filtrate obtains the title compound of 9.8g (93%).
Figure 587987DEST_PATH_IMAGE105
Embodiment 67B
3-(tetrahydrofuran (THF)-2-yl) third-1-alcohol
Replace 3-(furans-2-yl) propionic acid with embodiment 67A, use to prepare title compound as the described program of embodiment 50A.
Figure 214140DEST_PATH_IMAGE106
Embodiment 67C
3-(tetrahydrofuran (THF)-2-yl) propionic aldehyde
Replace embodiment 50A with embodiment 67B, use to prepare title compound as the described program of embodiment 50B.
Embodiment 67D
2-methyl-N-(3-(tetrahydrofuran (THF)-2-yl) propylidene) third-2-amine
Replace hexanal with embodiment 67C, use to prepare title compound as the described program of embodiment 1A.
Embodiment 67E
N-[(5Z)-the 2-tertiary butyl-4-(tetrahydrofuran (THF)-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 67D, use to prepare title compound as the described program of embodiment 1D.
Embodiment 68
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-[(1Z)-N-hydroxyl acetimidoyl (hydroxyethanimidoyl)]-the 2-methoxy benzamide
Replace embodiment 15A and replace O-methyl hydroxylamine hydrochloride with embodiment 64B, use to prepare title compound as the described program of embodiment 15B with hydroxylamine hydrochloride.
Embodiment 69
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(1,1-two fluoro ethyls)-2-methoxy benzamide
Product (50 mg, 0.13 mmol) with two (methoxy ethyl) amino sulfur trifluoride (57 mg, 0.26 mmol) Processing Example 64B.85 ℃ of reacting by heating 16 hours, use saturated NaHCO 3Aqueous solution quencher and use CH 2Cl 2(2 *) extraction.The organic layer MgSO that merges 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 12.1mg (23%).
Figure 64918DEST_PATH_IMAGE109
Embodiment 70
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide
Replace embodiment 110B and replace 2 with 2-fluoro-3-(trifluoromethyl) phenylformic acid with embodiment 50E, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Embodiment 71
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Replace embodiment 110B and replace 2 with 2-methoxyl group-5-(trifluoromethyl) phenylformic acid with embodiment 50E, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Embodiment 72
N-[(5Z)-the 2-tertiary butyl-4-(isopropoxy methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
With product (50 mg, 0.14 mmol)/dioxane (5ml) of NaH (60%) (7 mg, 0.17 mmol) Processing Example 28A, handle stirring at room 10 minutes and with isopropyl mesylate (78 mg, 0.56 mmol).85 ℃ of reacting by heating 12 hours, use H 2The O quencher is with EtOAc (2 *) extraction mixture.The organic layer MgSO that merges 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 5.2mg (9%).
Figure 581985DEST_PATH_IMAGE112
Embodiment 73
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide
Replace 2 with 2-fluoro-3-(trifluoromethyl) phenylformic acid, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 592666DEST_PATH_IMAGE113
Embodiment 74
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-the 4-methoxyl methyl benzoate
In the 20ml pressure bottle, the product of embodiment 61 (199 mg, 0.42 mmol)/MeOH (5ml) is added to PdCl 2(dppf) CH 2Cl 2(Heraeus) (15.4 mg, 0.02 mmol) and Et3N (117 μ L, 0.84 mmol).With CO (60psi) pressurised mixt, and 100 ℃ of stirrings 16 hours.Remove and to desolvate and at Waters Symmetry C8 post (25mmX100mm, 7 μ m particle diameters) on, use 10% to 100% acetonitrile: the gradient of 0.1% trifluoroacetic acid aqueous solution, in 8 minutes (10 minute working time), flow velocity with 40mL/ minute, by the resistates of anti-phase preparation HPLC purification gained, obtain the title compound of 15mg (9%).
Figure 560622DEST_PATH_IMAGE114
Embodiment 75
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 75A
6-oxo enanthaldehyde
Replace embodiment 6B with 1-methyl cyclohexane-1-alkene, use to prepare title compound as the described program of embodiment 21A.
Embodiment 75B
7-(tertbutylimido) heptan-2-ketone
Replace hexanal with embodiment 75A, use to prepare title compound as the described program of embodiment 1A.
Embodiment 75C
[(5Z)-and the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit] urethanum
Replace embodiment 1A and replace embodiment 1C with embodiment 75B, use to prepare title compound as the described program of embodiment 1D with different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate).MS?(DCI/NH 4 +)?m/z?313?(M?+?H) +。
Embodiment 75D
5-(the 2-tertiary butyl-5-imino--2,5-dihydro isothiazole-4-yl) penta-2-ketone
Replace embodiment 110A with embodiment 75C, use to prepare title compound as the described program of embodiment 110B.MS?(DCI/NH 4 +)?m/z?241?(M?+?H) +。
Embodiment 75E
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 110B with embodiment 75D, use to prepare title compound as embodiment 41 described programs.
Figure 860016DEST_PATH_IMAGE115
Embodiment 76
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Replace embodiment 110B and replace 5-chloro-O-Anisic Acid with embodiment 75D, use to prepare title compound as embodiment 41 described programs with 2-methoxyl group-5-(trifluoromethyl) phenylformic acid.
Figure 306041DEST_PATH_IMAGE116
Figure 436808DEST_PATH_IMAGE117
Embodiment 77
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide
Replace embodiment 110B and replace 5-chloro-O-Anisic Acid with embodiment 75D, use to prepare title compound as embodiment 41 described programs with 2-fluoro-3-(trifluoromethyl) phenylformic acid.
Figure 575665DEST_PATH_IMAGE118
Embodiment 78
N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4-methoxyl group isophthaloyl amine
Product (110 mg, 0.3 mmol) with the vitriol oil (1ml) Processing Example 26E.40 ℃ of heated mixt 1 hour, use H 2The O dilution extracts with saturated Na2CO3 neutralization with EtOAc (2 *).The organic layer MgSO that merges 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 107mg (93%).
Embodiment 79
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide
In the suspension of Cerium II Chloride (III) (86 mg, 0.35 mmol)/THF (3ml), add product (100 mg, 0.23 mmol)/THF (0.5mL) of embodiment 77.In this mixture of stirring at room 1 hour.Said mixture is cooled to-40 ℃ and dropping methyl-magnesium-bromide (41.6 mg, 0.348 mmol).-40 ℃ of stirring reactions 40 minutes, use saturated NH 4Cl aqueous solution quencher and use CH 2Cl 2(2 *) extraction.The organic layer MgSO that merges 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 57mg (55%).
Embodiment 80
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 77 with embodiment 75E, use to prepare title compound as embodiment 79 described programs.
Figure 597345DEST_PATH_IMAGE121
Embodiment 81
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Replace embodiment 77 with embodiment 76, use to prepare title compound as embodiment 79 described programs.
Embodiment 82
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-sec.-propyl-2-methoxy benzamide
Embodiment 82A
5-sec.-propyl-O-Anisic Acid
5-sec.-propyl-2-methoxybenzaldehyde (2.8 g, 15.7 mmol) is dissolved in the acetone (40ml).In this solution, add thionamic acid (2.29 g, 23.57 mmol) and Textone (1.71 g, 18.85 mmol)/water (40ml).In the flask that opens wide in this mixture of stirring at room 12 hours.Remove acetone and mixture Et 2The O extraction.Organic layer MgSO 4Drying is filtered and is concentrated, and obtains title compound.MS?(DCI/NH 4 +)?m/z?212?(M?+?NH 4) +。
Embodiment 82B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-sec.-propyl-2-methoxy benzamide
Replace 2 with embodiment 82A, the 5-dimethoxybenzoic acid uses to prepare title compound as embodiment 41 described programs.
Figure 915511DEST_PATH_IMAGE123
Embodiment 83
N-[(5Z)-the 2-tertiary butyl-4-(4-fluoro-4-methyl amyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At-78 ℃ of product (50 mg, 0.12 mmol)/CH with DAST (38 mg, 0.24 mmol) Processing Example 80 2Cl 2(4ml).Stir this mixture 1.5 hours at-78 ℃, use saturated NaHCO 3Aqueous solution quencher and use CH 2Cl 2(2 *) extraction.The organic layer MgSO that merges 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 29mg (58%).
Figure 968918DEST_PATH_IMAGE124
Embodiment 84
N-[(5Z)-the 2-tertiary butyl-4-(3-oxo butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 84A
5-oxo hexanal
Replace embodiment 6B with 1-methyl ring penta-1-alkene, use to prepare title compound as the described program of embodiment 21A.
Embodiment 84B
6-(tertbutylimido) oneself-2-ketone
Replace hexanal with embodiment 84A, use to prepare title compound as the described program of embodiment 1A.
Embodiment 84C
[(5Z)-and the 2-tertiary butyl-4-(3-oxo butyl) isothiazole-5 (2H)-subunit] urethanum
Replace embodiment 1A and replace embodiment 1C with embodiment 84B, use to prepare title compound as the described program of embodiment 1D with different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate).
Figure 808698DEST_PATH_IMAGE125
Embodiment 84D
4-(the 2-tertiary butyl-5-imino--2,5-dihydro isothiazole-4-yl) fourth-2-ketone
Replace embodiment 110A with embodiment 84C, use to prepare title compound as the described program of embodiment 110B.MS?(DCI/NH 4 +)?m/z?227?(M?+?H) +。
Embodiment 84E
N-[(5Z)-the 2-tertiary butyl-4-(3-oxo butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 110B with embodiment 84D, use to prepare title compound as embodiment 41 described programs.
Figure 367986DEST_PATH_IMAGE126
Embodiment 85
N-[(5Z)-and the 2-tertiary butyl-4-[(2,2, the 2-trifluoro ethoxy) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 85A
[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-2,5-dihydro isothiazole-4-yl] methylmethanesulfonate
At 0 ℃ of product (300 mg, 0.85 mmol)/CH with methylsulfonyl chloride (145 mg, 1.27 mmol) Processing Example 28A 2Cl 2(10ml) (contain triethylamine (257 mg, 2.54 mmol)).Stirred this mixture 30 minutes at 0 ℃, dilute with water and use CH 2Cl 2(2 *) extraction.The organic layer MgSO that merges 4Drying is filtered and is concentrated, and obtains title compound.
Embodiment 85B
N-[(5Z)-and the 2-tertiary butyl-4-[(2,2, the 2-trifluoro ethoxy) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Handle 2,2,2 tfifluoroethyl alcohol (48 mg, 0.48 mmol)/DMF (2ml) and THF (2.0mL) with sodium hydride (23 mg, 0.58 mmol).Stirring at room reaction 10 minutes, handle with embodiment 85A (80 mg, 0.19 mmol)/THF (0.5mL), 85 ℃ of heating 1.5 hours, use H 2O dilutes and extracts with EtOAc (2 *).The organic layer MgSO that merges 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-50% hexane/ethyl acetate) and by column chromatography purification resistates, obtain the title compound of 24mg (29%).
Figure 660427DEST_PATH_IMAGE127
Embodiment 86
N-[(5Z)-the 2-tertiary butyl-4-(4,4-difluoro amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 64B with embodiment 75E, use to prepare title compound as embodiment 69 described programs.
Figure 517525DEST_PATH_IMAGE128
Embodiment 87
N-[(5Z)-the 2-tertiary butyl-4-(3-fluoro-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 87A
N-[(5Z)-the 2-tertiary butyl-4-(3-hydroxy-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 75E with embodiment 84E, use to prepare title compound as embodiment 79 described programs.MS?(DCI/NH 4 +)?m/z?411?(M?+?H) +。
Embodiment 87B
N-[(5Z)-the 2-tertiary butyl-4-(3-fluoro-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 80 with embodiment 87A, use to prepare title compound as embodiment 83 described programs.
Figure 211811DEST_PATH_IMAGE129
Embodiment 88
N-[(5Z)-the 2-tertiary butyl-4-(4-fluoro-4-methyl amyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Replace embodiment 80 with embodiment 81, use to prepare title compound as embodiment 83 described programs.
Figure 66635DEST_PATH_IMAGE130
Embodiment 89
N-[(5Z)-the 2-tertiary butyl-4-{[(2R)-tetrahydrofuran (THF)-2-ylmethoxy] methyl } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace 2,2,2 tfifluoroethyl alcohol with (R)-(tetrahydrofuran (THF)-2-yl) methyl alcohol, use as the described program of embodiment 85B and obtain title compound by embodiment 85A.
Figure 111951DEST_PATH_IMAGE131
Figure 507160DEST_PATH_IMAGE132
Embodiment 90
N-[(5Z)-and the 2-tertiary butyl-4-[(2-fluorine oxyethyl group) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace 2,2,2 tfifluoroethyl alcohol with the 2-fluoroethanol, use as the described program of embodiment 85B and obtain title compound by embodiment 85A.
Figure 55953DEST_PATH_IMAGE133
Embodiment 91
N-[(5Z)-and the 2-tertiary butyl-4-[(2, the 2-difluoroethoxy) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
With 2, the 2-difluoroethanol replaces 2,2,2 tfifluoroethyl alcohol, uses as the described program of embodiment 85B and obtains title compound by embodiment 85A.
Figure 81678DEST_PATH_IMAGE134
Embodiment 92
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate
Embodiment 92A
[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] urethanum
In the 100mL round-bottomed flask that contains molecular sieve (10 g), in hexanal (Aldrich, 20.0 g, 200 mmol)/acetonitrile (20ml) solution, add pure TERTIARY BUTYL AMINE (Aldrich, 16.1 g, 220 mmol).At room temperature stir this mixture overnight.Remove solid and come concentrated liquid to obtain rough imines, light yellow oil by vacuum filtration by frit by rotatory evaporator.Rough imines is dissolved in anhydrous tetrahydro furan (200ml) and (contains pyridine (Aldrich, 15.8 g, 200 mmol)) in and drip different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate) (Aldrich, 15.7 g, 120 mmol).At room temperature stir the yellow mixture 1 hour of gained.Add anhydrous methanol (100ml) and iodine (Aldrich, 30.5 g, 120 mmol) and form brown slurries.In this mixture of stirring at room 2 hours.By adding the excessive iodine of solid Sodium Pyrosulfite quencher up to the mixture yellowing.Add saturated sodium bicarbonate aqueous solution and in this mixture of stirring at room 15 minutes.Mixture extracts with methylene dichloride (3X75mL).The organic extract that the merges (MgSO that is dried 4), filter, and by the concentrated brown oil that obtains of rotatory evaporator.(silica gel: the 25-95% ethyl acetate/hexane) purified product obtains the title compound of 31.6g (56%) by flash chromatography.
Figure 348712DEST_PATH_IMAGE135
Embodiment 92B
The 2-tertiary butyl-4-butyl isothiazole-5 (2H)-imines
In the 250mL round-bottomed flask that contains magnetic stirring bar, add product (7.11 g, 25.0 mmol) and the chloroform (100ml) of embodiment 92A.Add pure iodine trimethyl silyl (Aldrich, 6.25 g, 31.1 mmol).Connect and have the reflux exchanger of nitrogen inlet and apply heating jacket.Heating yellow reaction mixture to 60 ℃ and stir and spend the night.After being cooled to room temperature, add saturated sodium bicarbonate aqueous solution.Separate organic layer and with methylene dichloride (2 * 50mL) aqueous layer extracted.The organic layer that the merges (MgSO that is dried 4), filter, and by the concentrated yellow semisolid that obtains of rotatory evaporator.(silica gel: the 30-90% ethyl acetate/hexane) purified product obtains title compound by flash chromatography.LC-MS?(ESI+)?m/z?213?(M+H) +。
Embodiment 92C
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate
In the 20mL scintillation vial that contains magnetic stirring bar, add the product (637 mg, 3.00 mmol) of embodiment 92B, racemize 3-(methoxycarbonyl)-1,2,2-trimethyl cyclopentane formic acid (Maybridge, 771 mg, 3.60 mmol), and 2-(1H-benzo [d] [1,2,3] triazol-1-yl)-1,1,3,3-tetramethyl-isourea a tetrafluoro borate (TBTU, Bachem, 1.16 g, 3.60 mmol).Add anhydrous acetonitrile (acetontirile) and (8ml) form white slurries.(Aldrich, 1.09 g 10.8mmol) form brown solution to add pure triethylamine via syringe.Reacting by heating flask to 60 ℃ and mixing 2 hours in wobbler piece (shaker block).Remove volatile matter by rotatory evaporator and obtain brown oil.(silica gel: the 2-20% ethyl acetate/hexane) purified product obtains title compound by flash chromatography.
Figure 282032DEST_PATH_IMAGE136
Embodiment 93
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate
Use is described in product and the racemize 3-(methoxycarbonyl)-2,2 of the method Processing Example 92B among the embodiment 92C, and 3-trimethyl cyclopentane formic acid (Maybridge) obtains title compound.
Embodiment 94
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 1-phenylcyclohexane carboxylic acid amides
Use is described in product and the 1-Santosol 360 formic acid (Aldrich) of the method Processing Example 92B among the embodiment 92C, obtains title compound.
Figure 413117DEST_PATH_IMAGE138
Embodiment 95
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-(2-chloro-4-fluorophenyl) cyclohexane carboxamide
Use is described in product and (the 2-chloro-4-fluorophenyl) naphthenic acid (Acros) of the method Processing Example 92B among the embodiment 92C, obtains title compound.
Figure 901867DEST_PATH_IMAGE139
Embodiment 96
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid
In the 20mL scintillation vial that contains magnetic stirring bar, add product (102 mg, 0.250 mmol) and the potassium hydroxide (84 mg, 1.50 mmol) of embodiment 92C.Add ethanol (1ml) and water (0.25 mL).Heat this scintillation vial to 60 ℃ and reaction mixed 24 hours.After being cooled to room temperature, be adjusted to about 1 by adding 1N hydrochloric acid pH.Mixture extracts with methylene dichloride (3X10mL).The organic extract that the merges (MgSO that is dried 4), filter, and concentrate by rotatory evaporator, obtain the brown solid.Product is recrystallize from ethyl acetate/hexane, obtains the title compound of 74mg (75%).
Figure 904458DEST_PATH_IMAGE140
Embodiment 97
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-oxo-cyclopentane methane amide
Use is described in product and the 3-oxo-cyclopentane formic acid (Aldrich) of the method Processing Example 92B among the embodiment 92C, obtains title compound.
Figure 648683DEST_PATH_IMAGE141
Embodiment 98
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-phenyl cyclopentane formamide
Use is described in product and the 1-phenyl cyclopentane-carboxylic acid (Aldrich) of the method Processing Example 92B among the embodiment 92C, obtains title compound.
Figure 812949DEST_PATH_IMAGE142
Embodiment 99
N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide
In the 20mL scintillation vial, add the product (118 mg, 0.300 mmol) of embodiment 96, Dimethylammonium chloride (Aldrich, 36.7 mg, 0.450 mmol), and 2-(1H-benzo [d] [1,2,3] triazol-1-yl)-1,1,3,3-tetramethyl-isourea a tetrafluoro borate (TBTU, Bachem, 144 mg, 0.450 mmol).Add anhydrous second eyeball (3ml) and form yellow slurry.Add pure triethylamine (Aldrich, 182 mg, 1.80 mmol) and form brown solution.At 25 ℃ of stirring reactions 24 hours in wobbler piece (shaker block).Remove volatile matter by rotatory evaporator and obtain brown oil.By flash chromatography (silica gel: the 10-45% ethyl acetate/hexane) purified product.Product is recrystallize from hexane, obtains the title compound of 67.0mg (53%).
Figure 54574DEST_PATH_IMAGE143
Embodiment 100
N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide
Use is described in the product and the methylamine hydrochloride (Aldrich) of the method Processing Example 96 among the embodiment 99, obtains title compound.
Figure 595277DEST_PATH_IMAGE144
Embodiment 101
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3,3-difluoro azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide
Use is described in the product and 3 of the method Processing Example 96 among the embodiment 99,3-difluoro azetidine hydrochloride (Oakwood)), obtain title compound.
Figure 511597DEST_PATH_IMAGE146
Embodiment 102
(1S, 4R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4,7,7-trimethylammonium-3-oxo-2-oxabicyclo [2.2.1] heptane-1-methane amide
In the 20mL scintillation vial that contains magnetic stirring bar, add the product (327 mg, 1.75 mmol) of embodiment 92B and (1S)-(-)-camphor acyl chlorides (Aldrich, 474 mg, 2.19 mmol) and anhydrous tetrahydro furan (12mL).Add triethylamine (797 mg, 7.88 mmol) and at room temperature stir the yellow slurry 24 hours of gained via syringe.Remove volatile matter by rotatory evaporator and obtain brown oil.(silica gel: the 20-80% ethyl acetate/hexane) purified product obtains the title compound of 527mg (77%) by flash chromatography.
Figure 974940DEST_PATH_IMAGE147
Embodiment 103
(1R, 4S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4,7,7-trimethylammonium-3-oxo-2-oxabicyclo [2.2.1] heptane-1-methane amide
Use is described in the product of the method Processing Example 92B among the embodiment 102 and (1R)-(+)-camphor acyl chlorides (Fluka), obtains title compound.
Figure 319333DEST_PATH_IMAGE148
Embodiment 104
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) tetramethyleneimine-1-ethyl formate
Embodiment 104A
3-{[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] formamyl } tetramethyleneimine-1-t-butyl formate
Use is described in product and 1-(tertbutyloxycarbonyl) tetramethyleneimine-3-formic acid (Aldrich) of the method Processing Example 92B among the embodiment 92C, obtains title compound.MS?(ESI+)?m/z?410?(M+H) +。
Embodiment 104B
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] tetramethyleneimine-3-methane amide
In the 20mL scintillation vial that contains magnetic stirring bar, add the product (143 mg, 0.350 mmol) of embodiment 104A, anhydrous methylene chloride (5ml), and trifluoroacetic acid (200 mg, 1.75 mmol).At room temperature stirred pale yellow solution 4 hours.PH value by adding saturated sodium bicarbonate aqueous solution conditioned reaction mixture is to about 9.Mixture extracts with methylene dichloride (3X10mL).The organic extract that the merges (MgSO that is dried 4), filter, and concentrate by rotatory evaporator, obtain title compound.Do not having to use crude product to be used for next step under the situation of purifying.MS?(ESI+)?m/z?310?(M+H) +。
Embodiment 104C
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) tetramethyleneimine-1-ethyl formate
Use is described in product and the Vinyl chloroformate (Aldrich) of the method Processing Example 104B among the embodiment 102, obtains title compound.
Figure 895939DEST_PATH_IMAGE149
Embodiment 105
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid
Use is described in the product of the method Processing Example 93 among the embodiment 96, obtains title compound.
Embodiment 106
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) tetramethyleneimine-1-t-butyl formate
Use is described in product and 1-(tertbutyloxycarbonyl) tetramethyleneimine-3-formic acid (Aldrich) of the method Processing Example 92B among the embodiment 92C, obtains title compound.
Figure 618225DEST_PATH_IMAGE151
Embodiment 107
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-(3-cyanopyridine-2-yl) tetramethyleneimine-3-methane amide
In the 20mL scintillation vial, add the product (54.2 mg, 0.175 mmol) of embodiment 104B, 2-fluorine cigarette nitrile (Aldrich, 32.1 mg, 0.263 mmol) and anhydrous second eyeball (2ml).Add pure triethylamine (53.1 mg, 0.525 mmol).Reacting by heating mixture to 60 ℃ and mixing 24 hours in the wobbler piece (shaker block) of heating.After being cooled to room temperature, remove volatile matter by rotatory evaporator.(silica gel: the 20-65% ethyl acetate/hexane) purified product obtains the title compound of 54.6mg (76%) by flash chromatography.
Figure 703992DEST_PATH_IMAGE152
Embodiment 108
4-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) dicyclo [2.2.2] octane-1-methyl-formiate
Use is described in product and 4-(methoxycarbonyl) dicyclo [2.2.2] octane-1-formic acid (Oakwood) of the method Processing Example 92B among the embodiment 92C, obtains title compound.
Figure 56476DEST_PATH_IMAGE153
Embodiment 109
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-oxo-1-Phenylpyrrolidine-3-methane amide
Use is described in product and the 5-oxo-1-Phenylpyrrolidine-3-formic acid (Princeton Bio) of the method Processing Example 92B among the embodiment 92C, obtains title compound.
Embodiment 110
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-N'-cyano group-2-anisole imino-methylamine (carboximidamide)
Embodiment 110A
[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] urethanum
To at room temperature at N 2Under embodiment 1A (4.2 g, 27 mmol)/THF (100ml) solution in add different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate) (3.55 g, 27 mmol).Stirred reaction mixture 1 hour and interpolation iodine (6.8 g, 27 mmol), MeOH (100ml) and pyridine (10ml).Stirred reaction mixture 2 hours.Pour reaction mixture into saturated NaHCO 3/ Et 2O and stirring 30 minutes.Add other saturated NaHCO 3And Et 2O and separation organic layer.Use Et 2The organism of O (2 *) aqueous layer extracted and the merging (MgSO that is dried 4) and concentrate in a vacuum.Add toluene and acetonitrile and evaporation and remove and anhydrate and pyridine.Use the 0-100%EtOAc/ hexane to obtain the title compound of 5.2g, yellow solid by flash chromatography purification crude compound as elutriant.
Figure 171380DEST_PATH_IMAGE155
Embodiment 110B
The 2-tertiary butyl-4-butyl isothiazole-5 (2H)-imines
With TMSI (2.65 ml, 19.5 mmol) Processing Example 110A (3.95 g, 13.89 mmol)/chloroform (35mL) solution.65 ℃ of stirred reaction mixtures 8 hours, be cooled to room temperature, water quencher and at CH 2Cl 2With saturated NaHCO 3Between extraction, dry (MgSO 4) and concentrate and obtain title compound (2.45g, 83% yield).
Figure 795259DEST_PATH_IMAGE156
Embodiment 110C
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyanoimino methyl thiocarbamate
With Et3N (0.98 g, 9.71 mmol) Processing Example 110B (2.06g, 9.71 mmol) stirred 12 hours with the mixture of cyanoimino dithiocarbonic acid dimethyl ester (dimethyl cyanocarbonimidodithioate) (1.36 g, 9.3 mmol)/THF (35mL) with at 45 ℃.Enriched mixture under reduced pressure, and by chromatography (the purification resistates of hexane-EtOAc1:1) obtains 1.65g, the title compound of (55% yield).
Embodiment 110D
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-N'-cyano group-2-anisole imino-methylamine (carboximidamide)
To embodiment 110C (0.67 g, 2.15mol), 2-methoxyl group-5-chlorophenylboronic acid (1.046 g, 5.6 mmol), venus crystals (I) (0.794 g, 6.47 mmol)/add three (dibenzalacetone) two palladiums (0) 0.289 g, 0.315 mmol in the mixture of glycol dimethyl ether (35mL)) and triethyl-phosphite (0.170 mg, 1.0 mmol) and mixture was refluxed 16 hours.Mixture under reduced pressure concentrates and chromatographic separation resistates (hexane-EtOAc1:1), obtain the title compound of 550mg (62% yield) then.
Figure 115699DEST_PATH_IMAGE158
Embodiment 111
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-anisole thioformamide
In embodiment 1D (380mg, 1 mmol)/toluene (25ml) solution, add P 2S 5(220mg, 1 mmol) and in 82 ℃ of reacting by heating mixtures 75 minutes under reduced pressure concentrates and by the column chromatography (SiO that purifies 2, the 0-25%EtOAc/ hexane), and obtain title compound (0.14 g, 34% yield).
Figure 40930DEST_PATH_IMAGE159
Embodiment 112
N-[(3Z)-and the 1-tertiary butyl-5-(trifluoromethyl)-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit]-5-chloro-2-methoxy benzamide
Replace 4-propyl group pimelinketone with 4-(trifluoromethyl) pimelinketone, use to prepare title compound as embodiment 9 described programs.
Figure 468500DEST_PATH_IMAGE160
Embodiment 113
(3Z)-the 1-tertiary butyl-3-[(5-chloro-2-methoxybenzoyl) imino-]-1,4,6,7-tetrahydrochysene isothiazole also [4,3-c] pyridine-5 ( 3H)-t-butyl formate
Replace 4-propyl group pimelinketone with the commercially available 4-oxo-piperidine that gets-1-t-butyl formate, use to prepare title compound as embodiment 9 described programs.
Embodiment 114
N-[(3Z)-the 1-tertiary butyl-4,5,6,7-tetrahydrochysene isothiazole is [4,3-c] pyridines-3 (1H)-subunit also]-5-chloro-2-methoxy benzamide
With TFA (1.5mL) Processing Example 113 (800 mg, 1.66 mmol)/CH 2Cl 2(10ml) and at room temperature stirred reaction mixture is 24 hours.Concentrated reaction mixture and under reduced pressure at saturated NaHCO 3Distribute resistates between the/EtOAc, the organism (MgSO that is dried 4), filter and evaporating solvent.Raw product flash chromatography on silica gel separates, with 0-20% methyl alcohol/CH 2Cl 2Wash-out and obtain the title compound of 600mg.
Figure 79927DEST_PATH_IMAGE162
Embodiment 115
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxybenzenesulphoismide
(0.193ml is 1.4mmol) with commercially available 5-chloro-2-anisole-1-SULPHURYL CHLORIDE (334 mg, 1.4 mmol) Processing Example 110B (294 mg, 1.4 the mmol)/CH that gets with triethylamine 2Cl 2(20ml).At room temperature stirred reaction mixture is 18 hours, at CH 2Cl 2With saturated NaHCO 3Between distribute dry (MgSO 4) and concentrate.Obtain title compound (320 mg, 55%) with the 0-60%EtOAc/ hexane by flash chromatography purification resistates.
Figure 226875DEST_PATH_IMAGE163
Embodiment 116
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] naphthalene-1-sulphonamide
Replace 5-chloro-2-anisole-1-SULPHURYL CHLORIDE with naphthalene-1-SULPHURYL CHLORIDE, use to prepare title compound as embodiment 115 described programs.
Figure 458136DEST_PATH_IMAGE164
Embodiment 117
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(dimethylamino) naphthalene-1-sulphonamide
Replace 5-chloro-2-anisole-1-SULPHURYL CHLORIDE with 5-(dimethylamino) naphthalene-1-SULPHURYL CHLORIDE, use to prepare title compound as embodiment 115 described programs.
Figure 639718DEST_PATH_IMAGE165
Embodiment 118
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] the hexanaphthene sulphonamide
Replace 5-chloro-2-anisole-1-SULPHURYL CHLORIDE with the hexanaphthene SULPHURYL CHLORIDE, use the program that is described among the embodiment 115, the preparation title compound.
Figure 94971DEST_PATH_IMAGE166
Embodiment 119
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] benzsulfamide
Replace 5-chloro-2-anisole-1-SULPHURYL CHLORIDE with benzene sulfonyl chloride, use to prepare title compound as embodiment 115 described programs.
Figure 932477DEST_PATH_IMAGE167
Embodiment 120
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] quinoline-8-sulphonamide
Replace 5-chloro-2-anisole-1-SULPHURYL CHLORIDE with quinoline-8-SULPHURYL CHLORIDE, use to prepare title compound as embodiment 115 described programs.
Embodiment 121
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3,3-tetramethyl-cyclopropane carboxamide
With 2,2,3,3-tetramethyl-cyclopropanecarbonyl chloride replaces 5-chloro-2-anisole-1-SULPHURYL CHLORIDE, uses to prepare title compound as embodiment 115 described programs.
Figure 534676DEST_PATH_IMAGE169
Embodiment 122
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,3-dichlorobenzene sulphonamide
With 2,3-dichlorobenzene-1-SULPHURYL CHLORIDE replaces 5-chloro-2-anisole-1-SULPHURYL CHLORIDE, uses to prepare title compound as embodiment 115 described programs.
Figure 160830DEST_PATH_IMAGE170
Embodiment 123
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] diamantane-1-methane amide
Replace 5-chloro-2-anisole-1-SULPHURYL CHLORIDE with 1-diamantane carbonyl chloride, use to prepare title compound as embodiment 115 described programs.
Figure 360998DEST_PATH_IMAGE171
Embodiment 124
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-methoxyl group-5-(trifluoromethyl) phenylimino methylamine (carboximidamide)
Replace 2-methoxyl group-5-chlorophenylboronic acid with 2-methoxyl group-5-trifluoromethyl phenyl boronic acid, use to prepare title compound as the described program of embodiment 110D.
Figure 730799DEST_PATH_IMAGE172
Embodiment 125
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2-dimethyl-4-oxygen-3,4-dihydro-2H-pyrans-6-methane amide
With 2,2-dimethyl-4-oxygen-3,4-dihydro-2H-pyrans-6-carbonyl chloride replace 5-chloro-2-anisole-1-SULPHURYL CHLORIDE, use to prepare title compound as embodiment 115 described programs.
Figure 886974DEST_PATH_IMAGE173
Embodiment 126
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-oxyethyl group-5-(trifluoromethyl) phenylimino methylamine (carboximidamide)
Replace 2-methoxyl group-5-chlorophenylboronic acid with 2-oxyethyl group-5-trifluoromethyl phenyl boronic acid, use to prepare title compound as the described program of embodiment 110D.
Figure 684029DEST_PATH_IMAGE174
Embodiment 127
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
To embodiment 110B (1.0 g, 4.7 mmol)/add 2-methoxyl group-5-(trifluoromethyl) phenylformic acid (1.1 g, 5.2 mmol, JRD Fluorochemicals Ltd) in THF (50ml) solution, N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride (1.0 g, 5.2 mmol, Aldrich), I-hydroxybenzotriazole (0.8 g, 5.2 mmol, Aldrich) and triethylamine (2.0 ml, 14.3 mmol, Aldrich).Stirred this mixture 12 hours at 60 ℃.Then reaction mixture is cooled to room temperature, uses 1M NaHCO 3The aqueous solution (50ml) dilutes and (2 * 50mL) extract with ethyl acetate.The organic extract that the merges (Na that is dried 2SO 4), filter and concentrate.Use Analogix Intelliflash280 (SiO 2, the 0-50% ethyl acetate/hexane) and by column chromatography purification resistates, obtain the title compound of 1.23g (63%).
Figure 496127DEST_PATH_IMAGE175
Embodiment 128
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-N'-cyano group-2-anisole imino-methylamine (carboximidamide)
Embodiment 128A
[(5Z)-and the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit] urethanum
Use is described in the method Processing Example 30A among the embodiment 110A, 2-methyl-prop-2-amine (Aldrich), different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate) (Aldrich) and iodine (EMD chemicals) obtains title compound.MS?(ESI +)?m/z?296?(M+H) +。
Embodiment 128B
4-(the 2-tertiary butyl-5-imino--2,5-dihydro isothiazole-4-yl) butyronitrile
Use is described in method Processing Example 128A and the iodine trimethyl silyl (Aldrich) among the embodiment 110B, obtains title compound.MS?(ESI +)?m/z?224?(M+H) +。
Embodiment 128C
5-chloro-2-anisole imino-acid ethyl ester (ethyl 5-chloro-2-methoxybenzimidate) hydrochloride
0 ℃ with HCl gas bubbling 5-chloro-2-HOMOVERATRONITRILE (9.3 g, 0.056mol, Maybridge) and ethanol (16.2 ml, 0.28mol)/CH 2Cl 2Cooling solution (40ml) 30 minutes.Reaction mixture is placed in the refrigerator 5 days.Concentrated reaction mixture and grind and remove unreacted starting material then with diethyl ether.The drying under reduced pressure throw out, the title compound of acquisition 7.1g (51%).MS?(ESI +)?m/z?214?(M+H) +。
Embodiment 128D
5-chloro-N-cyano group-2-anisole imino-acid ethyl ester (ethyl 5-chloro-N-cyano-2-methoxybenzimidate)
5-chloro-2-anisole imino-acid ethyl ester (ethyl 5-chloro-2-methoxybenzimidate) (1.3 g, 6.2 mmol, obtain in the bicarbonate aqueous solution of embodiment 128C washing back)/MeCN (2ml) solution is added to biphosphate sodium-hydrate (3.4 g, 24.7 mmol), sodium phosphate dibasic heptahydrate (3.3 g, 12.4 mmol) and cyanamide (cyanamide) (0.52 g, 12.4 mmol)/water (20ml) solution.At room temperature stirred reaction mixture spends the night and uses methylene dichloride (3 * 15mL) extractions subsequently.The organic extract that the merges (Na that is dried 2SO 4), filter and concentrate.Resistates comprises about 30% starting material.Handle resistates again and order about the title compound that 1.32g (90%) was finished and obtained in reaction with the reagent of half amount.MS?(ESI +)?m/z?239?(M+H) +。
Embodiment 128E
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-N'-cyano group-2-anisole imino-methylamine (carboximidamide)
At 80 ℃ of heating embodiment 128B (0.2 g, 0.9 mmol, raw product) in the 20ml scintillation vial, embodiment 128D (0.25 g, 1.0 mmol), and the mixture of triethylamine (0.25 ml, 1.8 mmol)/ethanol (1ml) 2 hours.Reaction mixture concentrates and uses subsequently saturated NaHCO to room temperature 3(10ml) dilution.With ethyl acetate (3 * 15mL) aqueous layer extracted.The organic extract that the merges (Na that is dried 2SO 4), filter and concentrate.Use Analogix Intelliflash280 (SiO 2, the 0-50% ethyl acetate/dichloromethane) and by column chromatography purification resistates, obtain the title compound of 115mg (15%).
Figure 404040DEST_PATH_IMAGE176
Embodiment 129
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano-2-hydroxy-benzamide
Obtain title compound by embodiment 130B as by product.
Figure 414722DEST_PATH_IMAGE177
Embodiment 130
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) benzamide
Embodiment 130A
5-cyano group-2-(2,2, the 2-trifluoro ethoxy) phenylformic acid
In the 40ml sealed vial to acetone (20ml), 5-cyano-2-hydroxy-methyl benzoate (2.0 g, 11.3 mmol, Astatech) drip trifluoromethanesulfonic acid 2,2 and in the backflow mixture of salt of wormwood (3.1 g, 22.6 mmol), the 2-trifluoro ethyl ester (3.9 g, 16.9 mmol, TCI).Under refluxing, stir this mixture overnight and then at concentrating under reduced pressure.Resistates is dissolved in water (50ml) and the methylene dichloride (50ml).Separate each layer and with methylene dichloride (3X50mL) aqueous layer extracted.The organic extract that the merges (Na that is dried 2SO 4), filter and concentrate, obtain rough 5-cyano group-2-(2,2, the 2-trifluoro ethoxy) methyl benzoate of 1.8g, with its be suspended in methanol (1:1,100mL) in and with the aqueous solution (2.8 ml, the 13.9 mmol) processing of 5N sodium hydroxide.After 16 hours, reaction mixture is concentrated and uses subsequently washed with dichloromethane 40 ℃ of stirrings.With the 2N HCl aqueous solution, water layer is acidified to pH about 2 comes precipitated product.Throw out is filtered and drying under reduced pressure, obtains the title compound of 1.1g and the product mixtures of unreacted 5-cyano-2-hydroxy-phenylformic acid (5:2 ratio).MS?(ESI +)?m/z?263?(M+NH 4) +。
Embodiment 130B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) benzamide
Use is described in the method Processing Example 130A among the embodiment 127, embodiment 110B, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 320361DEST_PATH_IMAGE178
Embodiment 131
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) benzamide
Use is described in the method Processing Example 128B among the embodiment 127, embodiment 130A, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 416493DEST_PATH_IMAGE179
Embodiment 132
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-cyano-2-hydroxy-benzamide
By product as embodiment 131 obtains title compound.
Figure 128097DEST_PATH_IMAGE180
Embodiment 133
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-(2,2, the 2-trifluoro ethoxy) benzamide
Embodiment 133A
5-chloro-2-(2,2, the 2-trifluoro ethoxy) phenylformic acid
Handle commercially available getting according to the method for embodiment 130A, 5-chloro-2 hydroxybenzoic acid methyl esters (Maybridge), salt of wormwood, trifluoromethanesulfonic acid 2,2,2-trifluoro ethyl ester (TCI) and sodium hydroxide obtains title compound.MS?(ESI +)?m/z?253?(M-H) +。
Embodiment 133B
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-(2,2, the 2-trifluoro ethoxy) benzamide
Use is described in the method Processing Example 128B among the embodiment 127, embodiment 133A, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 258864DEST_PATH_IMAGE181
Embodiment 134
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Use is described in the method Processing Example 128B among the embodiment 127,2-methoxyl group-5-(trifluoromethyl) phenylformic acid (JRD fluorochemicals), N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 600984DEST_PATH_IMAGE182
Embodiment 135
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-hydroxybenzamide
Use is described in the method Processing Example 110B among the embodiment 127,5-chloro-2 hydroxybenzoic acid (Aldrich), N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 918832DEST_PATH_IMAGE183
Embodiment 136
N-[(5Z)-the 2-tertiary butyl-4-(cyclopentyl-methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 136A
3-cyclopentyl propionic aldehyde
To at-78 ℃ CH 2Cl 2Drip (100ml) oxalyl chloride (4.1 ml, 46.8 mmol, Aldrich) and anhydrous DMSO (5.5 ml, 78.0 mmol, Aldrich).After 5 minutes, add 3-cyclopentyl third-1-alcohol (5.0 g, 39.0 mmol, Aldrich)/CH of 5ml 2Cl 2Stir other 0.5 hour of this mixture and add triethylamine (27.2 ml, 195.0 mmol) at-78 ℃.In 0.5 hour, make mixture be warming up to room temperature then.After stirring 3 hours, add the water of 100ml.Separate each phase and with diethyl ether (3 * 100mL) aqueous phase extracted.The organic extract that merges is used the 1%HCl aqueous solution of 50ml, the water of 50ml, the 5%NaHCO of 50ml successively 3The saturated NaCl solution washing of the aqueous solution and 50ml.Organic layer (the MgSO that is dried 4), filter and concentrate and obtain the title compound of 4.1g (83%).MS?(ESI +)?m/z?144?(M+NH 4) +。
Embodiment 136B
N-[(5Z)-the 2-tertiary butyl-4-(cyclopentyl-methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Use is described in the method Processing Example 136A among the embodiment 110A, 2-methyl-prop-2-amine (Aldrich), and embodiment 1C and iodine obtain title compound.
Embodiment 137
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 137A
2, the 2-dimethyl-own nitrile of 6-oxo
To trimethylamine oxide (1.5 g, 19.6 mmol, Aldrich)/suspension of DMSO (10mL) adds 6-bromo-2, the 2-dimethyl nitrile (0.84 ml, 4.9 mmol, Aldrich).At room temperature stir spend the night after, water (10ml) quencher reaction mixture and with hexane (4 * 10mL) extract.The organic extract that merges washs with salt solution (20ml), and dry (NaSO4) filters and concentrate, and obtains the title compound of 0.65g (80% is pure).MS?(ESI +)?m/z?157?(M+NH 4) +。
Embodiment 137B
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Use is described in the method Processing Example 137A among the embodiment 110A, 2-methyl-prop-2-amine (Aldrich), and embodiment 1C and iodine obtain title compound.
Figure 419401DEST_PATH_IMAGE185
Embodiment 138
N-[(5Z)-the 2-tertiary butyl-4-(4-cyano group butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 138A
7-oxo heptonitrile
The method that use is described among the embodiment 137A is handled 7-bromine heptonitrile and trimethylamine oxide, obtains title compound.MS?(ESI +)?m/z?143?(M+NH 4) +。
Embodiment 138B
N-[(5Z)-the 2-tertiary butyl-4-(4-cyano group butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Use is described in the method Processing Example 138A among the embodiment 110A, 2-methyl-prop-2-amine (Aldrich), and embodiment 1C and iodine obtain title compound.
Embodiment 139
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(2-fluorine oxyethyl group) benzamide
Embodiment 139A
5-chloro-2-(2-fluorine oxyethyl group) phenylformic acid
The method that use is described in the following document obtains title compound by 5-chloro-2 hydroxybenzoic acid (Aldrich): Journal of Labelled Compounds ﹠amp; Radiopharmaceuticals (2001), 44 (2), 127-139.MS?(ESI +)?m/z?236?(M+NH 4) +。
Embodiment 139B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(2-fluorine oxyethyl group) benzamide
Use is described in the method Processing Example 139A among the embodiment 127, embodiment 110B, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 737567DEST_PATH_IMAGE187
Embodiment 140
2-(2-amino-2-oxo oxyethyl group)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 5-chlorobenzamide
Embodiment 140A
2-(2-amino-2-oxo oxyethyl group)-5-chloro-benzoic acid
The method described according to embodiment 130A is handled commercially available getting, 5-chloro-2 hydroxybenzoic acid methyl esters (Maybridge), and salt of wormwood, 2-chloromethyl cyanide (Aldrich) and sodium hydroxide obtain title compound.MS?(ESI +)?m/z?248?(M+H 2O) +。
Embodiment 140B
2-(2-amino-2-oxo oxyethyl group)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 5-chlorobenzamide
Use is described in the method Processing Example 140A among the embodiment 127, embodiment 110B, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 790973DEST_PATH_IMAGE188
Embodiment 141
2-(2-amino-2-oxo oxyethyl group)-the N-[(5Z)-2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-the 5-chlorobenzamide
Use is described in the method Processing Example 140A among the embodiment 127, embodiment 128B, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 568437DEST_PATH_IMAGE189
Embodiment 142
N-[(5Z)-the 2-tertiary butyl-4-(4,4,4-trifluoro butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 142A
6,6,6-trifluoro hexanal
The method that use is described among the embodiment 137A is handled the commercially available 6-bromo-1,1 that gets, and 1-trifluoro hexane (Oakwood) and trimethylamine oxide obtain title compound.MS?(ESI +)?m/z?154?(M+NH 4-H 2O) +。
Embodiment 142B
N-[(5Z)-the 2-tertiary butyl-4-(4,4,4-trifluoro butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Use is described in the method Processing Example 142A among the embodiment 110A, 2-methyl-prop-2-amine (Aldrich), and embodiment 1C and iodine obtain title compound.
Figure 49096DEST_PATH_IMAGE190
Embodiment 143
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Embodiment 143A
The 4-methyl pentanal
The method that use is described among the embodiment 136A is handled the commercially available 4-methylpent-1-alcohol that gets, oxalyl chloride, and DMSO, and triethylamine obtain title compound.MS?(ESI +)?m/z?100?(M+NH 4-H 2O) +。
Embodiment 143B
[(5Z)-and the 2-tertiary butyl-4-(2-methyl-propyl) isothiazole-5 (2H)-subunit] urethanum
Use is described in the method Processing Example 143A among the embodiment 110A, 2-methyl-prop-2-amine (Aldrich), different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate) (Aldrich) and iodine (EMD chemicals) obtains title compound.MS?(ESI +)?m/z?285?(M+H) +。
Embodiment 143C
The 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-imines
Use is described in method Processing Example 143B and the iodine trimethyl silyl (Aldrich) among the embodiment 110B, obtains title compound.MS?(ESI +)?m/z?213?(M+H) +。
Embodiment 143D
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Use is described in the method Processing Example 143C among the embodiment 127,2-methoxyl group-5-(trifluoromethyl) phenylformic acid (JRD fluorochemicals), N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 607117DEST_PATH_IMAGE191
Embodiment 144
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-chloro-2-(2-fluorine oxyethyl group) benzamide
Use is described in the method Processing Example 143C among the embodiment 127, embodiment 139A, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 198635DEST_PATH_IMAGE192
Embodiment 145
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide
Use is described in the method Processing Example 143C among the embodiment 127, embodiment 26B, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 231270DEST_PATH_IMAGE193
Embodiment 146
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-oxyethyl group-5-(trifluoromethyl) benzamide
Embodiment 146A
2-fluoro-5-(trifluoromethyl) ethyl benzoate
In 2-fluoro-5-(trifluoromethyl) Benzoyl chloride (5.0 g, 22.0 mmol)/THF (25mL) solution, add Et3N (3.1 ml, 22.0 mmol) EtOH (1.3 ml, 22.0 mmol) subsequently.Stirred this mixture 1 hour and used saturated NH in envrionment temperature 4The Cl aqueous solution (10ml) quencher.Separate each layer and with the organic layer anhydrous Na of 3 * 10mL EtOAc aqueous layer extracted and merging 2SO 4Drying is filtered and at concentrating under reduced pressure.By column chromatography (SiO 2, the purification rough material of 60% hexane/EtOAc) and obtain title compound (4.8 g, 20.3 mmol, 92% yield).
Figure 882831DEST_PATH_IMAGE194
Embodiment 146B
2-oxyethyl group-5-(trifluoromethyl) ethyl benzoate
In EtOH (2.5 ml, 42.7 mmol)/25mlTHF, add KOt-Bu (4.6 g, 40.6 mmol).Stirred the mixture 20 minutes in envrionment temperature, add embodiment 146A/25mL THF by sleeve pipe then.Stirred the mixture 1 hour in envrionment temperature, use saturated NH then 4The quencher of the Cl aqueous solution.Separate each layer, with 3 * 10mL EtOAc aqueous layer extracted.The organic layer Na that merges 2SO 4Drying is filtered and at concentrating under reduced pressure.By column chromatography purification (SiO 2, 60% hexane/EtOAc, 100%EtOAc then) and obtain title compound.MS?(DCI/NH 3)?m/z?263?(M+H) +。
Embodiment 146C
2-oxyethyl group-5-(trifluoromethyl) phenylformic acid
In embodiment 146B (1.63 g, 6.2 mmol)/EtOH (50ml) solution, add the 40%KOH aqueous solution (5.81 g, 31.1 mmol).Stirred the mixture 1 hour, then partial concentration under reduced pressure.This material dilutes and this solution 10%HCl acidified aqueous solution with 20mL EtOAc.Separate each layer and with EtOAc (3X20mL) aqueous layer extracted.The organic layer Na that merges 2SO 4Drying is filtered and is obtained title compound (1.39 g, 5.94 mmol, 95% yield) at concentrating under reduced pressure.MS?(DCI/NH 3)?m/z?252?(M+NH 4) +。
Embodiment 146D
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-oxyethyl group-5-(trifluoromethyl) benzamide
Use is described in the method Processing Example 143C among the embodiment 127, embodiment 146C, and N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Embodiment 147
N-[(5Z)-the 2-tertiary butyl-4-amyl group isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
The method that use is described among the embodiment 110A is handled the commercially available enanthaldehyde that gets (Aldrich), 2-methyl-prop-2-amine (Aldrich), and embodiment 1C and iodine obtain title compound.
Figure 995461DEST_PATH_IMAGE196
Embodiment 148
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 148A
6-fluorine hexanal
Use is described in method among the embodiment 137A and handles commercially available getting, and 1-bromo-6-fluorine hexane (Narchem) and trimethylamine oxide obtain title compound.MS?(ESI +)?m/z?136?(M+NH 4) +。
Embodiment 148B
[(5Z)-and the 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-subunit] urethanum
Use is described in the method Processing Example 148A among the embodiment 110A, 2-methyl-prop-2-amine (Aldrich), and different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate) (Aldrich) and iodine obtains title compound.MS?(ESI +)?m/z?303?(M+H) +。
Embodiment 148C
The 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-imines
Use is described in method Processing Example 148B and the iodine trimethyl silyl (Aldrich) among the embodiment 110B, obtains title compound.MS?(ESI +)?m/z?231?(M+H) +。
Embodiment 148D
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Use is described in the method Processing Example 148C among the embodiment 127,5-chloro-O-Anisic Acid (Aldrich), N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Embodiment 149
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Use is described in the method Processing Example 148C among the embodiment 127,2-methoxyl group-5-(trifluoromethyl) phenylformic acid (JRD Fluorochemicals Ltd), N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 632295DEST_PATH_IMAGE198
Embodiment 150
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-[2-(dimethylamino)-2-oxo oxyethyl group] benzamide
To propione (10ml), and dropping 2-chloro-N,N-dimethylacetamide in the mixture of salt of wormwood (0.28 g, 2.0 mmol) and embodiment 135 (0.25 g, 0.7 mmol) (0.25 g, 2.0 mmol, Fluka).After refluxing 36 hours, reaction mixture is used saturated NaHCO to room temperature 3(10ml) quencher and extract with ethyl acetate (3X20mL).The organic extract that the merges (Na that is dried 2SO 4), filter and concentrate.Use Analogix Intelliflash280 (SiO 2, the 0-50% ethyl acetate/dichloromethane) and by column chromatography purification resistates, obtain the title compound of 50mg (16%).
Figure 899329DEST_PATH_IMAGE199
Figure 301491DEST_PATH_IMAGE200
Embodiment 151
N-[(5Z)-4-butyl-2-(2,2,2-three fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 151A
[(5Z)-and 4-butyl-2-(2,2,2-three fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit] urethanum
The method that use is described among the embodiment 110A is handled the commercially available hexanal that gets (Aldrich), 1,1,1-three fluoro-2-methyl-prop-2-amine (Chemcollect), different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate) (Aldrich) and iodine obtains title compound.MS?(ESI +)?m/z?339?(M+H) +。
Embodiment 151B
4-butyl-2-(1,1,1-three fluoro-2-methyl-prop-2-yls) isothiazole-5 (2H)-imines
Use is described in method Processing Example 151A and the iodine trimethyl silyl (Aldrich) among the embodiment 110B, obtains title compound.MS?(ESI +)?m/z?267?(M+H) +。
Embodiment 151C
N-[(5Z)-4-butyl-2-(2,2,2-three fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Use is described in the method Processing Example 151B among the embodiment 127,5-chloro-O-Anisic Acid (Aldrich), N-(3-dimethylaminopropyl)-N-ethyl carbodiimide (ethylcarbodimide) hydrochloride, I-hydroxybenzotriazole and triethylamine obtain title compound.
Figure 970370DEST_PATH_IMAGE201
Embodiment 152
N-[(5Z)-4-butyl-2-(2-fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
Embodiment 152A
1-fluoro-N-inferior hexyl-2-methyl-prop-2-amine
At 0 ℃ to 1-fluoro-2-methyl-prop-2-amine hydrochlorate (ABCR) (2 g, 15.7 mmol), anhydrous magnesium sulfate (3.77 g, 31.4 mmol) and salt of wormwood (2.17 g, 15.68 mmol)/suspension of methylene dichloride (100ml) drips hexanal (1.93 ml, 15.7 mmol).At room temperature stirred reaction mixture is 10 hours, filters then and concentrates, and obtains title compound, light yellow liquid.
Embodiment 152B
[(5Z)-and 4-butyl-2-(2-fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit] urethanum
Use is described in the method Processing Example 152A among the embodiment 1D, and different sulphur cyanato-formic acid O-ethyl ester (O-ethyl carbonisothiocyanatidate) (Aldrich) and iodine obtains title compound.Use Analogix Intelliflash280 (SiO 2, the 0-50% ethyl acetate/hexane), by the column chromatography purified product, obtain title compound.MS?(ESI+)?m/z?303?(M+?H) +。
Embodiment 152C
4-butyl-2-(1-fluoro-2-methyl-prop-2-yl) isothiazole-5 (2H)-imines
Use is described in method Processing Example 152B and the iodine trimethyl silyl (Aldrich) among the embodiment 110B, obtains title compound.MS?(ESI +)?m/z?231?(M+H) +。
Embodiment 152D
N-[(5Z)-4-butyl-2-(2-fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide
In embodiment 152C (0.46 g, 2.0 mmol)/THF (10ml) solution, add 2-methoxyl group-5-(trifluoromethyl) Benzoyl chloride (0.52 g, 2.2 mmol, JRD Fluorochemicals Ltd) and triethylamine (0.84 ml, 6.0 mmol).After 14 hours, reaction mixture is used saturated NaHCO to room temperature 60 ℃ of stirrings 3(10ml) quencher and extract with ethyl acetate (3X20mL).The organic extract that the merges (Na that is dried 2SO 4), filter and concentrate.Use Analogix Intelliflash280 (SiO 2, the 0-50% ethyl acetate/dichloromethane) and by column chromatography purification resistates, obtain the title compound of 75mg.
Figure 963734DEST_PATH_IMAGE202
Embodiment 153
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(cyano group methoxyl group) benzamide
(1:1 4mL) adds sodium hydride (39.2 mg, 0.98 mmol) and 2-bromoacetonitrile (65 μ L, 0.98 mmol) in the solution to embodiment 135 (300 mg, 0.82 mmol)/THF/DMF.Spend the night 40 ℃ of stirring reactions 4 hours with 80 ℃ of stirrings.Reaction mixture is used saturated NaHCO to room temperature 3(10ml) quencher and extract with ethyl acetate (3X20mL).The organic extract that the merges (Na that is dried 2SO 4), filter and concentrate.Use Analogix Intelliflash280 (SiO 2, the 0-50% ethyl acetate/dichloromethane) and by column chromatography purification resistates, obtain the title compound of 15mg.
Figure 921326DEST_PATH_IMAGE203
Embodiment 154
N-[(5Z)-4-butyl-2-(2-fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 1A with embodiment 152A, use to prepare title compound as the described program of embodiment 1D.Use Analogix Intelliflash280 (SiO 2, gradient 0-50% ethyl acetate/hexane), by the column chromatography purified product, and obtain title compound.
Figure 923917DEST_PATH_IMAGE204
Embodiment 155
N-[(5Z)-4-(benzyloxy)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
By replacing 4-propyl group pimelinketone with 2-(benzyloxy) acetaldehyde, prepare title compound according to the operation of embodiment 9.
Figure 447302DEST_PATH_IMAGE205
Embodiment 156
N-[(5Z)-the 2-tertiary butyl-4-(1-methyl ethoxy) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 156A
N-[(5Z)-2-tertiary butyl-4-hydroxy isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At 0 ℃ with trifluoromethanesulfonic acid (1741 mg, 11.6 mmol) Processing Example 155 (500 mg, 1.16 mmol)/anhydrous CH 2Cl 2(20ml) solution is 1 hour.Add the saturated solution of sodium bicarbonate and separate organic layer, use anhydrous MgSO 4Dry and at concentrating under reduced pressure, obtain the rough material of 400mg, it directly uses and not purification in ensuing reaction.
Figure 611567DEST_PATH_IMAGE206
Embodiment 156B
N-[(5Z)-the 2-tertiary butyl-4-(1-methyl ethoxy) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At the product (70 mg, 0.2 mmol) of 50 ℃ of whipping steps 1, the mixture of 2-iodopropane (85 mg, 0,5 mmol) and salt of wormwood (42 mg, 0.3 mmol)/DMF (10ml) 12 hours.Pour into mixture in the water then and use ethyl acetate extraction.Acetic ester layer water, MgSO is used in the salt water washing 4Dry and under reduced pressure concentrated.By chromatographic purification resistates (hexane EtOAc1:1), obtain the title compound of 49mg.
Figure 56455DEST_PATH_IMAGE207
Figure 597157DEST_PATH_IMAGE208
Embodiment 157
N-[(5Z)-the 2-tertiary butyl-4-(1-methyl propoxy-) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
By replacing 2-iodopropane to prepare title compound according to the operation of embodiment 156B with sec.-butyl iodide.
Figure 975049DEST_PATH_IMAGE209
Embodiment 158
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butoxy) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
By replacing 2-iodopropane to prepare title compound according to the operation of embodiment 156B with 1-bromo-4-fluorine butane.
Figure 575795DEST_PATH_IMAGE210
Embodiment 159
N-[(5Z)-the 2-tertiary butyl-4-(cyano group methoxyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
By replacing 2-iodopropane to prepare title compound according to the operation of embodiment 156B with the 2-bromoacetonitrile.
Figure 976820DEST_PATH_IMAGE211
Embodiment 160
N-[(5Z)-the 2-tertiary butyl-4-{[(2S)-5-oxo-pyrrolidine-2-yl] methoxyl group } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
By replacing 2-iodopropane to prepare title compound according to the operation of embodiment 156B with (S)-4-toluenesulphonic acids (5-oxygen tetramethyleneimine-2-yl) methyl esters.
Figure 321214DEST_PATH_IMAGE212
Embodiment 161
N-[(5Z)-the 2-tertiary butyl-4-{[(2R)-5-oxo-pyrrolidine-2-yl] methoxyl group } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
By replacing 2-iodopropane to prepare title compound according to the operation of embodiment 156B with (R)-4-toluenesulphonic acids (5-oxygen tetramethyleneimine-2-yl) methyl esters.
Embodiment 162
[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-3-methyl-2,5-dihydro isothiazole-4-yl] t-butyl carbamate
Embodiment 162A
(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-3-methyl-2,5-dihydro isothiazole-4-ethyl formate
To ethyl 3-oxobutanoate (1.3 g, 10 mmol) and 2-methyl-prop-2-amine (0.73 g, 10 mmol)/add anhydrous magnesium sulfate (3.0 g, 25 mmol) and Montmorillonite (polynite) K10 (3.0 g, 10 mmol) in toluene (15mL) solution.Stir the mixture 14 hours of gained and be cooled to room temperature then at 45 ℃.Mixture dilutes with anhydrous diethyl ether, filters and washs with ether.Merging filtrate and washing lotion and at concentrating under reduced pressure.Resistates is dissolved among the THF (60ml), adds 5-chloro-2-methoxybenzoyl lsothiocyanates (2.16 g, 9.5 mmol) and stirred this mixture 2 hours in envrionment temperature.Add iodine (2.4 g, 9.5 mmol) and add MeOH (100ml) and pyridine (10ml) subsequently.At room temperature make the mixture standing over night and use the saturated solution of ethyl acetate and sodium bicarbonate to handle subsequently other 1 hour.Separate each layer and use the ethyl acetate extraction water layer.Merge extract, use the salt water washing, use MgSO 4Dry and under reduced pressure concentrated.Obtain the title compound of 2.8g with hexane-ether (1:1) abrasive solid.
Figure 403888DEST_PATH_IMAGE214
Embodiment 162B
(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-3-methyl-2,5-dihydro isothiazole-4-formic acid
In product (1.45 g, 3.5 the mmol)/dioxane (7.5mL) of embodiment 162A and ethanol (15mL) solution, add 1N NaOH (5 ml, 5 mmol) and in this mixture of stirring at room 16 hours.Add the 1N NaOH (2.5 ml, 2.5 mmol) of another part and continue other 9 hours of reaction.Add water (15mL) and remove organism in decompression.Solution is acidified to pH 4 and solid is filtered, and washes the title compound that obtains 1.2g with drying under reduced pressure with water.
Figure 354526DEST_PATH_IMAGE215
Embodiment 162C
[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-3-methyl-2,5-dihydro isothiazole-4-yl] t-butyl carbamate
Make embodiment 162B (784 mg at 80 ℃, 2 mmol), the mixture of triethylamine (0.57 ml, 4.1 mmol) and diphenylphosphine acylazide thing (diphenyl phosphorazidate) (1.13 g, 4.1 mmol)/dioxane (10ml) refluxed 3 hours.Add the trimethyl carbinol (30ml), continue other 8 hours of 80 ℃ of heating.Mixture is cooled to room temperature and under reduced pressure concentrates.Add water and extract mixture with EtOAc.Acetic ester layer 10%NaHCO 3, salt water washing and under reduced pressure concentrated.Chromatography (EtOAc-MeOH 9:1) obtains the product of 10mg.
Figure 237031DEST_PATH_IMAGE216
Embodiment 163
N-[(5Z)-the 2-tertiary butyl-4-(1-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
At-40 ℃ of product (450 mg, 1.28 mmol)/THF (20ml) that drip Processing Example 21A with methyl-magnesium-bromide (0.85 ml, 2.55 mmol).-40 ℃ of stirring reactions 1.5 hours, use saturated NH 4Cl quencher and with EtOAc (2 *) extraction mixture.Merge organic layer, use MgSO 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 10-80% ethyl acetate/hexane) and by column chromatography purification resistates, obtain the title compound of 220mg (47%).
Figure 589515DEST_PATH_IMAGE217
Embodiment 164
N-[(5Z)-the 2-tertiary butyl-4-(1-ethoxyethyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 11D and replace methyl iodide with embodiment 163, use to prepare title compound as the described program of embodiment 11E with iodoethane.
Figure 469747DEST_PATH_IMAGE218
Embodiment 165
N-[(5Z)-the 2-tertiary butyl-4-(1-methoxy ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Replace embodiment 11D with embodiment 163, use to prepare title compound as the described program of embodiment 11E.
Figure 907681DEST_PATH_IMAGE219
Embodiment 166
N-[(5Z)-and the 2-tertiary butyl-4-[1-(2,2, the 2-trifluoro ethoxy) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Embodiment 166A
Methylsulfonic acid 1-[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-2,5-dihydro isothiazole-4-yl] ethyl ester
Product (220 mg, 0.6 mmol)/CH with embodiment 163 2Cl 2(20ml) and the mixture of triethylamine (181 mg, 1.8 mmol) be cooled to 0 ℃ and drip to handle with methylsulfonyl chloride (102 mg, 0.9 mmol).0 ℃ of stirring reaction 30 minutes, pour in the water and mixture CH 2Cl 2(2 *) extraction.Merge organic layer, use MgSO 4Drying is filtered and is concentrated, and obtains title compound (234 mg, 88%).MS?(DCI/NH 3)?m/z?383?(M-Ms+15) +。
Embodiment 166B
N-[(5Z)-and the 2-tertiary butyl-4-[1-(2,2, the 2-trifluoro ethoxy) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
Handle 2,2,2 tfifluoroethyl alcohol (39.3 mg, 0.39 mmol)/THF (2ml) with NaH (60%) (19 mg, 0.47 mmol).Stirring at room reaction 20 minutes.In said mixture, add embodiment 166A (117 mg, 0.262 mmol)/THF (1ml).80 ℃ of heated mixt 12 hours, pour in the water and with EtOAc (2 *) extraction mixture.Merge organic layer, use MgSO 4Drying is filtered and is concentrated.Use Analogix Intelliflash280 (SiO 2, the 0-80% ethyl acetate/hexane) and by column chromatography purification resistates, obtain the title compound of 11mg (9%).
Embodiment 167
N-[(5Z)-the 2-tertiary butyl-4-vinyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide
In the reaction of preparation embodiment 166B (18 mg, 20%), obtain title compound as by product.
Figure 145076DEST_PATH_IMAGE221
Embodiment 168
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-3-hydroxyl-1,2,2-trimethyl cyclopentane formic acid
The mixture to 60 of the heating product (50.0 mg, 0.127 mmol) of embodiment 102 and potassium hydroxide (71.5 mg, 1.27 mmol)/ethanol (1ml) and water (0.2mL) ℃ 24 hours.After being cooled to envrionment temperature, adding 1N HCl (aq) and regulate pH to about 1.The mixture ethyl acetate extraction.Extract (the MgSO that is dried 4), filter, and by the concentrated white solid that obtains of rotatory evaporator.Obtain the title compound of 39.2mg (75%) by the re-crystallizing in ethyl acetate solid.
Embodiment 169
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-3-hydroxyl-1,2,2-trimethyl cyclopentane formic acid
Use is described in the product (200 mg, 0.509 mmol) of the method Processing Example 103 among the embodiment 168, obtains title compound.
Figure 183756DEST_PATH_IMAGE223
Embodiment 170
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate
The mixture of heating (+)-dextrocamphoric acid (Aldrich, 2.00 g, 10.0 mmol) and phosphorus pentachloride (Aldrich, 4.16 g, 20.0 mmol)/hexane (75ml) is to refluxing and stirring 24 hours.After being cooled to envrionment temperature, obtain light yellow oil by the rotatory evaporator concentrated reaction mixture.Rough two chloride of acid (474 mg, 2.00 mmol) are added to the product (425 mg, 2.00 mmol) of embodiment 92B and the mixture of triethylamine (1.01 g, 10.0 mmol)/anhydrous tetrahydro furan (12mL).Stirred this mixture 2 hours.Add the mixture overnight of anhydrous methanol (10ml) and stirring gained.Obtain brown oil by the rotatory evaporator enriched mixture.Flash chromatography (silica gel, 5-25% ethyl acetate/hexane) obtains the title compound of 343mg (42%).
Figure 611326DEST_PATH_IMAGE224
Figure 938402DEST_PATH_IMAGE225
Embodiment 171
(1R, 3S)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product of the method Processing Example 92B among the embodiment 170 and (+) dextrocamphoric acid (Aldrich), and difference is that to be used to catch the methyl alcohol of intermediate saturated with ammonia solution rather than methyl alcohol, obtains title compound.
Figure 957174DEST_PATH_IMAGE226
Embodiment 172
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-(tetramethyleneimine-1-base carbonyl) cyclopentane formamide
Embodiment 172A
(1R, 3S)-1,2,2-trimethylammonium-3-(tetramethyleneimine-1-carbonyl) cyclopentane-carboxylic acid
Grind (+)-dextrocamphoric acid (Aldrich, 2.00 g, 10.0 mmol) by mortar and pestle, toluene sulfonyl chloride (Aldrich, 1.14 g, 6.00 mmol), and salt of wormwood (6.22 g, 45.0 mmol) 1 hour.Concentrate by rotatory evaporator with washed with dichloromethane viscosity slurry and flushing thing and to obtain intermediate acid anhydrides, white solid.At room temperature mix this rough acid anhydrides (356 mg, 1.00 mmol), tetramethyleneimine (Aldrich 356 mg, 5.00 mmol) and anhydrous second eyeball 24 hours.By adding 1N hydrochloric acid the pH value of mixture is adjusted to about 1 and the mixture dichloromethane extraction.Extract (the MgSO that is dried 4), filter, and concentrate the title compound that obtains 238mg (94%) by rotatory evaporator.
Embodiment 172B
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-(tetramethyleneimine-1-base carbonyl) cyclopentane formamide
Use is described in method Processing Example 172A among the embodiment 92C and the product of embodiment 92B, obtains title compound.
Figure 448329DEST_PATH_IMAGE227
Embodiment 173
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid
Use is described in the product of the method Processing Example 177 among the embodiment 96, obtains title compound.MS?(ESI+)?m/z?395?(M+H) +。
Embodiment 174
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid
Use is described in the product of the method Processing Example 186 among the embodiment 96, obtains title compound.MS?(ESI+)?m/z?395?(M+H) +。
Embodiment 175
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane ethyl formate
The mixture of heating (+)-dextrocamphoric acid (Aldrich, 2.00 g, 10.0 mmol) and phosphorus pentachloride (Aldrich, 4.16 g, 20.0 mmol)/hexane (75ml) is to refluxing and stirring 24 hours.After being cooled to envrionment temperature, obtain light yellow oil by the rotatory evaporator concentrated reaction mixture.Rough two chloride of acid (356 mg, 1.50 mmol) are added to the product (319 mg, 1.50 mmol) of embodiment 92B and the mixture of triethylamine (455 g, 4.50 mmol)/anhydrous tetrahydro furan (12mL).Stirred this mixture 2 hours.Add the mixture overnight of dehydrated alcohol (20ml) and stirring gained.Obtain brown oil by the rotatory evaporator enriched mixture.Flash chromatography (silica gel, 5-25% ethyl acetate/hexane) obtains the title compound of 327mg (52%).
Figure 476328DEST_PATH_IMAGE228
Figure 657911DEST_PATH_IMAGE229
Embodiment 176
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane ethyl formate
Use is described in product and (-) dextrocamphoric acid (Aldrich) of the method Processing Example 92B among the embodiment 175, obtains title compound.
Figure 113163DEST_PATH_IMAGE230
Embodiment 177
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate
The mixture of heating (+)-dextrocamphoric acid (Aldrich, 2.00 g, 10.0 mmol) and phosphorus pentachloride (Aldrich, 4.16 g, 20.0 mmol)/hexane (75ml) is to refluxing and stirring 24 hours.After being cooled to envrionment temperature, obtain light yellow oil by the rotatory evaporator concentrated reaction mixture.Rough two chloride of acid (474 mg, 2.00 mmol) are added to the product (425 mg, 2.00 mmol) of embodiment 92B and the mixture of triethylamine (1.01 g, 10.0 mmol)/anhydrous tetrahydro furan (12mL).Stirred this mixture 2 hours.Add the mixture overnight of anhydrous methanol (10ml) and stirring gained.Obtain brown oil by the rotatory evaporator enriched mixture.Flash chromatography (silica gel, 5-25% ethyl acetate/hexane) obtains the title compound of 331mg (41%).
Figure 944809DEST_PATH_IMAGE231
Embodiment 178
(1R, 3S)-3-(azetidine-1-base carbonyl)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide
At room temperature with solid N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (EDC) (Aldrich, 216 mg, 1.12 mmol), the product of embodiment 173 (296 mg, 0.750 mmol), hydroxybenzotriazole (Aldrich, 152 mg, 1.12 mmol), azetidine hydrochloride (Aldrich, 105 mg, 1.12 mmol), triethylamine (Aldrich, 152 mg, 1.50 mmol) with anhydrous N, dinethylformamide (4ml) is mixed together.Add water and come quencher and mixture dichloromethane extraction.Extract concentrates with dried over sodium sulfate and by rotatory evaporator and obtains brown oil.Flash chromatography (silica gel: the 20-75% ethyl acetate/hexane) obtain the title compound of 189mg (58%).
Figure 510920DEST_PATH_IMAGE232
Embodiment 179
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide
Use is described in the product and the Dimethylammonium chloride (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 812588DEST_PATH_IMAGE233
Embodiment 180
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3-hydroxy azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide
Use is described in the product and the 3-hydroxy azetidine hydrochloride (Oakwood) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 376425DEST_PATH_IMAGE234
Embodiment 181
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid
Use is described in the product of the method Processing Example 170 among the embodiment 96, obtains title compound.MS?(ESI+)?m/z?395?(M+H) +。
Embodiment 182
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, 1,2,2-tetramethyl-ring pentane-1,3-diformamide tetramethyl-ring pentane-1,3-diformamide
Use is described in the product and the methylamine hydrochloride (Aldrich) of the method Processing Example 181 among the embodiment 178, obtains title compound.
Embodiment 183
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, N 1, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide
Use is described in the product and the Dimethylammonium chloride (Aldrich) of the method Processing Example 181 among the embodiment 178, obtains title compound.
Figure 867766DEST_PATH_IMAGE236
Embodiment 184
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide
Use is described in the product and the methylamine hydrochloride (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 227203DEST_PATH_IMAGE237
Figure 24258DEST_PATH_IMAGE238
Embodiment 185
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3,3-difluoro azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide
Use is described in the product and 3 of the method Processing Example 173 among the embodiment 178, and 3-difluoro azetidine hydrochloride (Oakwood) obtains title compound.
Figure 633094DEST_PATH_IMAGE239
Embodiment 186
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate
The mixture of heating (-)-dextrocamphoric acid (Aldrich, 2.00 g, 10.0 mmol) and phosphorus pentachloride (Aldrich, 4.16 g, 20.0 mmol)/hexane (75ml) is to refluxing and stirring 24 hours.After being cooled to envrionment temperature, obtain light yellow oil by the rotatory evaporator concentrated reaction mixture.Rough two chloride of acid (474 mg, 2.00 mmol) are added to the product (425 mg, 2.00 mmol) of embodiment 92B and the mixture of triethylamine (1.01 g, 10.0 mmol)/anhydrous tetrahydro furan (12mL).Stirred this mixture 2 hours.Add the mixture overnight of anhydrous methanol (10ml) and stirring gained.Obtain brown oil by the rotatory evaporator enriched mixture.Flash chromatography (silica gel, 5-25% ethyl acetate/hexane) obtains the title compound of 212mg (26%).
Figure 541007DEST_PATH_IMAGE240
Embodiment 187
(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine peopentyl ester
At room temperature stir embodiment 110B (0.106 g, 0.5 mmol), triethylamine (0.073 ml, 0.5 mmol), with the mixture of chloroformic acid peopentyl ester (neopentyl carbonochloridate) (0.074 ml, 0.5 mmol)/methylene dichloride (10ml) 18 hours.Concentrated reaction mixture in a vacuum.(0-100% ethyl acetate/hexane) purified by the gradient flash chromatography and obtained title compound (145 mg, 89% yield) on silica gel.
Figure 489371DEST_PATH_IMAGE241
Embodiment 188
(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine 2,2, the 2-trichloro ethyl ester
By chloroformic acid 2,2,2-trichloro ethyl ester (2,2,2-trichloroethyl cabonochloridate) and embodiment 110B prepare title compound (117 mg, 16% yield) as embodiment 187 described programs in use.
Figure 457327DEST_PATH_IMAGE242
Embodiment 189
(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine 1-adamantane esters
Use and prepare title compound (187 mg, 79% yield) by fluorine formic acid 1-diamantane ester (1-adamantane carbonofluoridate) and embodiment 110B as embodiment 187 described programs.
Figure 553459DEST_PATH_IMAGE243
Embodiment 190
N 2-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-N 1, 3-dimethyl-L-valine amide
Embodiment 190A
[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] carboxylamine 4-nitrophenyl ester
Mixture with triethylamine (0.78 g, 7.7 mmol) Processing Example 110B (1.48 g, 7 mmol) and 4-chloroformate nitrophenyl ester (4-nitrophenylcarbonochloridate) (1.41 g, 7 mmol)/methylene dichloride.At room temperature stirred reaction mixture is 18 hours, uses CH 2Cl 2The dilution and wash with water, use MgSO 4Dry and concentrated in a vacuum.Obtain title compound (1.8 g, 68% yield) by flash chromatography purification (0-50% ethyl acetate/hexane).
Embodiment 190B
N 2-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-N 1, 3-dimethyl-L-valine amide
With commercially available (the S)-2-amino-N that gets, 3,3-trimethylammonium butyramide (115 mg, 0.79 mmol) Processing Example 190A (120 mg, 0.3 mmol)/acetonitrile (5ml).Reacting by heating mixture and 100 ℃ of microwave radiations 60 minutes and concentrate in a vacuum then.Obtain title compound (105 mg, 86% yield) by flash chromatography purification (50 to 100% ethyl acetate/hexane).
Figure 468326DEST_PATH_IMAGE244
Embodiment 191
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-(4-methylcyclohexyl) urea
The program that use is described among the embodiment 190B prepares title compound (105 mg, 86% yield) by 4-methyl cyclohexane alkanamine and embodiment 190A.
Figure 333514DEST_PATH_IMAGE245
Embodiment 192
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(2S)-and 1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide
Embodiment 192A
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-fluoro-5-(trifluoromethyl) benzamide
With triethylamine (2.63 ml, 18.8 mmol) and commercially available 2-fluoro-5-(trifluoromethyl) Benzoyl chloride (2.13 g, 9.4 mmol) Processing Example 110B (2 g, 9.42 the mmol)/CH that gets 2Cl 2(20ml).At room temperature stirred reaction mixture is 18 hours, at CH 2Cl 2With saturated NaHCO 3Between distribute dry (MgSO 4) and concentrate.Use the 0-60%EtOAc/ hexane by the flash chromatography resistates of purifying, obtain title compound (2.83 g, 74%).MS?(DCI/NH 3)?m/z?403?(M+H) +。
Embodiment 192B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(2S)-and 1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide
In (S)-(1-methylpyrrolidin-2-yl) methyl alcohol (0.23 ml, 2 mmol)/tetrahydrofuran (THF) (3ml), add 1M potassium tert.-butoxide/THF (2 ml, 2 mmol) and stirred this mixture 10 minutes.Add embodiment 192A (402 mg, 1 mmol) and stirred the mixture 24 hours in envrionment temperature.With EtOAc diluted mixture thing, use NH 4The Cl aqueous solution, water, MgSO is used in the salt water washing 4Dry and remove and desolvate.By silica gel chromatography (0-20%MeOH/CH 2Cl 2(0.1% NH 4OH)) purified product obtains title compound (263 mg, 53% yield).
Figure 472371DEST_PATH_IMAGE246
Embodiment 193
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-{[(2S)-1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) phenylimino methylamine (carboximidamide)
Embodiment 193A
To embodiment 110C (500 mg, 1.61 mmol), 2-fluoro-5-(trifluoromethyl) phenyl-boron dihydroxide (871 mg, 2.6 mmol), venus crystals (I) (0.592 g, 4.83 mmol)/add three (dibenzalacetones), two palladiums (0) (0.22 g, 0.15 mmol) and triethyl phosphate (0.132 ml, 0.47 mmol) and mixture was refluxed 16 hours in the mixture of DME (35mL).Mixture under reduced pressure concentrates then and (hexane: EtOAc, 1:1) chromatographic separation resistates obtain title compound (200 mg, 29% yield) on silica gel.MS?(DCI/NH 3)?m/z?427?(M+H) +。
Embodiment 193B
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-{[(2S)-1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) phenylimino methylamine (carboximidamide)
Replace embodiment 192A with embodiment 193A, use the program that is described among the embodiment 192B, the preparation title compound.
Figure 55799DEST_PATH_IMAGE247
Embodiment 194
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(2S)-and 5-oxo-pyrrolidine-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide
Use and prepare title compound (225 mg, 45% yield) by (S)-5-(methylol)-pyrrolidin-2-one and embodiment 192A as the described program of embodiment 192B.
Figure 369417DEST_PATH_IMAGE249
Embodiment 195
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(4R)-and 2-oxo-1,3-oxazolidine-4-yl] methoxyl group }-5-(trifluoromethyl) benzamide
Use and prepare title compound (45 mg, 10% yield) by (R)-4-hydroxyl methyl oxazolidinone and embodiment 192A as the described program of embodiment 192B.
Figure 679175DEST_PATH_IMAGE250
Embodiment 196
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-[(1-methyl piperidine-2-yl) methoxyl group]-5-(trifluoromethyl) benzamide
Use as the described program of embodiment 192B and prepare title compound (310 mg, 81% yield) by (1-methyl piperidine)-2-base methyl alcohol and embodiment 192A.
Figure 749900DEST_PATH_IMAGE251
Embodiment 197
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-{[(2S)-and 1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide
Embodiment 197A
N-[(5Z)-the 2-tertiary butyl-4-(2-methyl-propyl) isothiazole-5 (2H)-subunit]-2-fluoro-5-(trifluoromethyl) benzamide
With triethylamine (2.63 ml, 18.8 mmol) and commercially available 2-fluoro-5-(trifluoromethyl) Benzoyl chloride (2.13 g, 9.4 mmol) Processing Example 143C (2 g, 9.42 the mmol)/CH that gets 2Cl 2(20ml).At room temperature stirred reaction mixture is 18 hours, at CH 2Cl 2With saturated NaHCO 3Between distribute dry (MgSO 4) and concentrate.Use the 0-60%EtOAc/ hexane by the flash chromatography resistates of purifying, obtain title compound (3.1 g, 82% yield).MS?(DCI/NH 3)?m/z?403?(M+H) +。
Embodiment 197B
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-{[(2S)-and 1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide
Replace embodiment 192A to use with embodiment 197A and prepare title compound (290 mg, 78% yield) as the described program of embodiment 192B.
Figure 580769DEST_PATH_IMAGE253
Embodiment 198
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-(pyrazine-2-ylmethoxy)-5-(trifluoromethyl) benzamide
Use and prepare title compound (70 mg, 19% yield) by pyrazine-2-base-methyl alcohol and embodiment 192A as the described program of embodiment 192B.
Figure 61429DEST_PATH_IMAGE254
Embodiment 199
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-(pyrazine-2-ylmethoxy)-5-(trifluoromethyl) benzamide
Use and prepare title compound (225 mg, 61% yield) by pyrazine-2-base-methyl alcohol and embodiment 197A as the described program of embodiment 192B.
Figure 822712DEST_PATH_IMAGE255
Embodiment 200
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-(pyridine-2-ylmethoxy)-5-(trifluoromethyl) benzamide
Use as the described program of embodiment 192B and prepare title compound (313 mg, 64% yield) by pyridine-2-base methyl alcohol and embodiment 197A.
Embodiment 201
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product and the ethylamine hydrochloride (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 108517DEST_PATH_IMAGE257
Embodiment 202
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-propyl group pentamethylene-1, the 3-diformamide
Use is described in the product and the propylamin hydrochloride (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 25657DEST_PATH_IMAGE258
Embodiment 203
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product and the ethanolamine hydrochloric salt (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 8657DEST_PATH_IMAGE259
Embodiment 204
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate
Use is described in product and (-)-dextrocamphoric acid (Aldrich) of the method Processing Example 92B among the embodiment 170, obtains title compound.
Figure 403866DEST_PATH_IMAGE260
Embodiment 205
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid
Use is described in the product of the method Processing Example 204 among the embodiment 96, obtains title compound.MS?(ESI+)?m/z?395?(M+H) +。
Embodiment 206
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-sec.-propyl-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product and the Isopropylamine (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 218238DEST_PATH_IMAGE261
Embodiment 207
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclobutyl-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product and the ring butylamine hydrochloride (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 40701DEST_PATH_IMAGE262
Embodiment 208
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclopropyl-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product and the cyclopropylamine hydrochloride (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Figure 245417DEST_PATH_IMAGE263
Figure 444317DEST_PATH_IMAGE264
Embodiment 209
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, 1,2,2-tetramethyl-ring pentane-1,3-diformamide
Use is described in the product and the methylamine hydrochloride (Aldrich) of the method Processing Example 205 among the embodiment 178, obtains title compound.
Figure 113196DEST_PATH_IMAGE265
Embodiment 210
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product and the ethylamine hydrochloride (Aldrich) of the method Processing Example 205 among the embodiment 178, obtains title compound.
Embodiment 211
(1S, 3R)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 1-propyl group pentamethylene-1, the 3-diformamide
Use is described in the product and the propylamin hydrochloride (Aldrich) of the method Processing Example 205 among the embodiment 178, obtains title compound.
Figure 64152DEST_PATH_IMAGE267
Figure 801163DEST_PATH_IMAGE268
Embodiment 212
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product and the ethanolamine hydrochloric salt (Aldrich) of the method Processing Example 205 among the embodiment 178, obtains title compound.
Figure 324549DEST_PATH_IMAGE269
Embodiment 213
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(3-hydroxypropyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide
Use is described in the product and the Propanolamine (Aldrich) of the method Processing Example 173 among the embodiment 178, obtains title compound.
Embodiment 214
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-[(2R)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide
Use is described in the product of the method Processing Example 173 among the embodiment 178 and (R)-(tetrahydrofuran (THF)-2-yl) methylamine (Aldrich), obtains title compound.
Figure 349771DEST_PATH_IMAGE272
Embodiment 215
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl Urethylane
In the 100mL round-bottomed flask that contains magnetic stirring bar, add embodiment 173 (1.18 g, 3.00 mmol), diphenylphosphine acylazide thing (Aldrich, 90.8 mg, 3.30 mmol) dry toluene (45mL) and triethylamine (Aldrich, 1.25 ml, 9.00 mmol).Heated mixt is to refluxing 4 hours under nitrogen atmosphere.After the cooling, remove volatile matter by rotatory evaporator and obtain clarified liq.Rough intermediate (235 mg, 0.600 mmol) is dissolved in the anhydrous methanol and stirs this mixture overnight.Remove volatile matter by rotatory evaporator and obtain shallow brown oil.Flash chromatography (silica gel, 25-75% ethyl acetate/hexane) obtains the title compound of 86mg (34%).
Embodiment 216
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl urethanum
Replace methyl alcohol as preparation title compound as described in the embodiment 215 with ethanol.
Figure 266091DEST_PATH_IMAGE274
Embodiment 217
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-1,2,2-trimethyl cyclopentane methane amide
In the 20mL scintillation vial that contains magnetic stirring bar, add embodiment 203 (219 mg, 0.500 mmol), the crystal (Aldrich) of solid toluene sulfonyl chloride (Aldrich, 105 mg, 0.550 mmol) and dimethyl aminopyridine.Add anhydrous tetrahydro furan and form colourless solution and interpolation triethylamine (Aldrich, 0.139 ml, 1.00 mmol).At room temperature stirred reaction mixture spends the night.Adding water (10ml) and mixture extracts with methylene dichloride (3X10mL).The organic extract dried over sodium sulfate that merges is filtered, and by the concentrated viscous solid that obtains of rotatory evaporator.Flash chromatography (silica gel, 40-100% ethyl acetate/hexane) obtains the title compound of 134mg (64%).
Figure 995013DEST_PATH_IMAGE275
Embodiment 218
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide
As Processing Example 174 and methylamine hydrochloride (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 73827DEST_PATH_IMAGE276
Embodiment 219
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-propyl group pentamethylene-1, the 3-diformamide
As Processing Example 174 and propylamin hydrochloride (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 571804DEST_PATH_IMAGE277
Embodiment 220
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-methoxy ethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide
As Processing Example 174 and 2-methoxyethyl amine (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 546714DEST_PATH_IMAGE278
Embodiment 221
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(3-hydroxypropyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide
As Processing Example 174 and 3-amino third-1-alcohol (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 497352DEST_PATH_IMAGE279
Embodiment 222
(1S, 3R)-3-(azetidine-1-base carbonyl)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 174 and azetidine hydrochloride (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 379858DEST_PATH_IMAGE280
Embodiment 223
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide
As Processing Example 174 and Dimethylammonium chloride (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 929744DEST_PATH_IMAGE281
Embodiment 224
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-2,2,3-trimethyl cyclopentane methane amide
As Processing Example 212 as described in the embodiment 217, toluene sulfonyl chloride (Aldrich), and triethylamine (Aldrich) obtain title compound.
Embodiment 225
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclobutyl-1,2,2-trimethyl cyclopentane-1,3-diformamide
As Processing Example 174 and amino tetramethylene hydrochloride (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 310227DEST_PATH_IMAGE283
Embodiment 226
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-[(2S)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide
As Processing Example as described in the embodiment 178 173 and (S)-(tetrahydrofuran (THF)-2-yl) methylamine (Aldrich), obtain title compound.
Figure 730844DEST_PATH_IMAGE284
Embodiment 227
(1S, 3R)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 1-[(2S)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide
As Processing Example as described in the embodiment 178 205 and (S)-(tetrahydrofuran (THF)-2-yl) methylamine (Aldrich), obtain title compound.
Figure 141097DEST_PATH_IMAGE285
Embodiment 228
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide
As Processing Example 174 and 2-monoethanolamine hydrochloride (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 254547DEST_PATH_IMAGE286
Embodiment 229
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide
As Processing Example 181 and ethylamine hydrochloride (Aldrich) as described in the embodiment 178, obtain title compound.
Embodiment 230
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide
As Processing Example 181 and 2-monoethanolamine hydrochloride (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 404085DEST_PATH_IMAGE288
Embodiment 231
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 228 as described in the embodiment 217, toluene sulfonyl chloride (Aldrich), and triethylamine (Aldrich) obtain title compound.
Figure 668844DEST_PATH_IMAGE289
Embodiment 232
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-2,2,3-trimethyl cyclopentane methane amide
As Processing Example 230 as described in the embodiment 217, toluene sulfonyl chloride (Aldrich), and triethylamine (Aldrich) obtain title compound.
Figure 953195DEST_PATH_IMAGE290
Figure 365722DEST_PATH_IMAGE291
Embodiment 233
(1R, 3S)-N 3-benzyl-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane-1,3-diformamide
As Processing Example 173 and benzylamine (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 393721DEST_PATH_IMAGE292
Embodiment 234
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridine-2-ylmethyl) pentamethylene-1, the 3-diformamide
As Processing Example 173 and 2-aminomethyl pyridine (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 653932DEST_PATH_IMAGE293
Embodiment 235
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridin-3-yl methyl) pentamethylene-1, the 3-diformamide
As Processing Example 173 and 3-aminomethyl pyridine (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 843605DEST_PATH_IMAGE294
Embodiment 236
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridin-4-yl methyl) pentamethylene-1, the 3-diformamide
As Processing Example 173 and 4-aminomethyl pyridine (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 247221DEST_PATH_IMAGE296
Embodiment 237
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-Propargyl pentamethylene-1, the 3-diformamide
As Processing Example 173 and propargyl amine hydrochlorate (Aldrich) as described in the embodiment 178, obtain title compound.
Embodiment 238
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(2,2, the 2-trifluoroethyl) pentamethylene-1, the 3-diformamide
As Processing Example 173 and 2,2 as described in the embodiment 178,2-trifluoro ethylamine hydrochloride (Aldrich) obtains title compound.
Figure 909464DEST_PATH_IMAGE298
Embodiment 239
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-Propargyl pentamethylene-1, the 3-diformamide
As Processing Example 174 and propargyl amine hydrochlorate (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 296583DEST_PATH_IMAGE299
Embodiment 240
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(2,2, the 2-trifluoroethyl) pentamethylene-1, the 3-diformamide
As Processing Example 174 and 2,2 as described in the embodiment 178,2-trifluoro ethylamine hydrochloride (Aldrich) obtains title compound.
Embodiment 241
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-methoxyl group-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide
As Processing Example 173 and N as described in the embodiment 178, O-dimethyl hydroxyl amine hydrochlorate (Aldrich) obtains title compound.
Figure 760242DEST_PATH_IMAGE301
Embodiment 242
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(5,6-dihydro-4H-1,3-oxazine-2-yl)-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 221 as described in the embodiment 217, toluene sulfonyl chloride (Aldrich), and triethylamine (Aldrich) obtain title compound.
Embodiment 243
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(5,6-dihydro-4H-1,3-oxazine-2-yl)-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 213 as described in the embodiment 217, toluene sulfonyl chloride (Aldrich), and triethylamine (Aldrich) obtain title compound.
Figure 166133DEST_PATH_IMAGE303
Embodiment 244
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] tetramethyleneimine-1-methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and tetramethyleneimine (Aldrich) obtain title compound.
Figure 277308DEST_PATH_IMAGE304
Embodiment 245
(1R, 3S)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and ammonium hydroxide (Aldrich) obtain title compound.
Figure 287990DEST_PATH_IMAGE305
Embodiment 246
(1R, 3S)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3-trimethyl cyclopentane methane amide
As Processing Example 205 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and ammonium hydroxide (Aldrich) obtain title compound.
Figure 255946DEST_PATH_IMAGE306
Embodiment 247
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide
As Processing Example 205 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and methylamine hydrochloride (Aldrich) obtain title compound.
Figure 555340DEST_PATH_IMAGE307
Embodiment 248
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-(morpholine-4-base carbonyl) cyclopentane formamide
As Processing Example 173 and morpholine (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 266944DEST_PATH_IMAGE308
Embodiment 249
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-tetramethyleneimine-1-basic ring pentane-1, the 3-diformamide
As Processing Example 173 and tetramethyleneimine-1-amine hydrochlorate (Aldrich) as described in the embodiment 178, obtain title compound.
Figure 132132DEST_PATH_IMAGE309
Embodiment 250
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] morpholine-4-methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and morpholine (Aldrich) obtain title compound.
Figure 270989DEST_PATH_IMAGE310
Embodiment 251
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] benzamide
In the 100mL round-bottomed flask that contains magnetic stirring bar, add embodiment 173 (1.18 g, 3.00 mmol), diphenyl phosphate azide (Aldrich, 908 mg, 3.30 mmol), and dry toluene (45mL).Add pure triethylamine (Aldrich, 0.418 ml, 3.00 mmol) and form pale yellow solution.Heated mixt refluxes under nitrogen atmosphere and stirred 8 hours.After the cooling, add mixture methylene dichloride (3 * 25mL) extractions of water (30ml) and gained.The organic extract Sodium Persulfate and the filtration that merge.Remove volatile matter by rotatory evaporator.Flash chromatography (silica gel, 5-50% ethyl acetate/hexane) obtains isocyanic ester, colourless oil.
In the 20-mL bottle, add isocyanic ester (98 mg, 0.25 mmol) and anhydrous tetrahydro furan (3ml).Bottle cools off in ice bath and drips phenyl-magnesium-bromide (Aldrich, 1.00M, in tetrahydrofuran (THF), 0.500 ml, 0.500 mmol) solution.After interpolation, make mixture be warming up to room temperature and stirring is spent the night.Add water (10ml) carefully.Mixture extracts with methylene dichloride (3X10mL).The organic extract dried over sodium sulfate that merges is filtered, and by the concentrated brown oil that obtains of rotatory evaporator.Flash chromatography (silica gel, 30-90% ethyl acetate/hexane) obtains the title compound of 43mg (36%).
Figure 57680DEST_PATH_IMAGE311
Embodiment 252
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and methylamine hydrochloride (Aldrich) obtain title compound.
Figure 307395DEST_PATH_IMAGE312
Embodiment 253
(1S, 3R)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 174 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and ammonium hydroxide (Aldrich) obtain title compound.
Figure 292669DEST_PATH_IMAGE313
Embodiment 254
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide
As Processing Example 174 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and methylamine hydrochloride (Aldrich) obtain title compound.
Figure 751780DEST_PATH_IMAGE315
Embodiment 255
N-[(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] benzamide
As Processing Example 174 as described in the embodiment 251, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and phenyl-magnesium-bromide (Aldrich) obtain title compound.
Figure 805187DEST_PATH_IMAGE316
Embodiment 256
(1R, 3S)-3-(kharophen)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 173 as described in the embodiment 251, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and lithium methide (Aldrich) obtain title compound.
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Figure 125627DEST_PATH_IMAGE318
Embodiment 257
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-({ [(2-hydroxyethyl) amino] carbonyl } amino)-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich) and 2-monoethanolamine (Aldrich) obtain title compound.
Figure 355751DEST_PATH_IMAGE319
Embodiment 258
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[({[(2S)-and the 2-hydroxypropyl] amino } carbonyl) amino]-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich) and (the S)-amino propan-2-ol (Aldrich) of 1-obtains title compound.
Figure 212849DEST_PATH_IMAGE320
Embodiment 259
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[({[(2R)-and the 2-hydroxypropyl] amino } carbonyl) amino]-1,2,2-trimethyl cyclopentane methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich) and (the R)-amino propan-2-ol (Aldrich) of 1-obtains title compound.
Figure 761959DEST_PATH_IMAGE322
Embodiment 260
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl]-3-hydroxy azetidine-1-methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich) and 3-hydroxy azetidine hydrochloride (Oakwood) obtain title compound.
Figure 807275DEST_PATH_IMAGE323
Embodiment 261
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl]-3,3-difluoro azetidine-1-methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich) and 3,3-difluoro azetidine hydrochloride (Oakwood) obtains title compound.
Figure 202484DEST_PATH_IMAGE324
Embodiment 262
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-(2-hydroxy-2-methyl propoxy-)-5-(trifluoromethyl) benzamide
With NaH (60% dispersion) (44.7 mg, 1.12 mmol) Processing Example 192A (150 mg, 0.37 mmol)/THF (5ml) with stirred 10 minutes.In this mixture, add 2-methylpropane-1,2-glycol (101 mg, 1.12 mmol).At room temperature stirred reaction mixture is 2 hours.Adding water (10ml) and mixture extracts with methylene dichloride (3X10mL).The organic extract dried over sodium sulfate that merges is filtered, and concentrates.Obtain the title compound of 61mg (35%) by flash chromatography purification (silica gel, 40-100% ethyl acetate/hexane).
Figure 751277DEST_PATH_IMAGE325
Embodiment 263
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] azetidine-1-methane amide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich) and azetidine hydrochloride (Aldrich) obtain title compound.
Figure 777002DEST_PATH_IMAGE326
Embodiment 264
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-({ [methyl (phenyl) amino] carbonyl } amino) cyclopentane formamide
As Processing Example 173 as described in the embodiment 215, diphenylphosphine acylazide thing (Aldrich), triethylamine (Aldrich), and methylphenylamine (Aldrich) obtain title compound.
Embodiment 265
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) diamantane-1-methyl-formiate
In the 250mL round-bottomed flask that contains magnetic stirring bar, add 1, and the 3-adamantane acid (Aldrich, 2.02 g, 9.00mol), phosphorus pentachloride (3.75 g, 18.0 mmol), and hexane (75ml).Heated mixt refluxes under nitrogen atmosphere and reflux and spend the night.After the cooling, remove volatile matter, obtain diacid chloride by solids removed by filtration with by rotatory evaporator.
In the 20mL bottle that contains magnetic stirring bar, add rough diacid chloride (392 mg, 1.50 mmol) and anhydrous tetrahydro furan (10ml).Drip embodiment 92B (212 mg, 1.00 mmol) and triethylamine (0.836 ml, 6.00 mmol)/anhydrous tetrahydrofuran solution at leisure and form dark orange slurries.In this mixture of stirring at room 4 hours.Add methyl alcohol (10ml) and stirred this mixture other 4 hours.The mixture that adds water (15mL) and gained extracts with methylene dichloride (3X10mL).The organic extract dried over sodium sulfate that merges is filtered, and concentrates by rotatory evaporator and obtains brown oil.Flash chromatography (silica gel, 5-25% ethyl acetate/hexane) obtains the title compound of 119mg (27%).
Figure 242936DEST_PATH_IMAGE328
Embodiment 266
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) diamantane-1-formic acid
As Processing Example 265 as described in the embodiment 96, obtain title compound.MS?(ESI +)?m/z?419?(M+H) +。
Embodiment 267
Uncle's 2-[(fourth amino) oxygen base]-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(trifluoromethyl) benzamide
With NaH (60% dispersion) (42 mg, 1.04 mmol) Processing Example 192A (210 mg, 0.52 mmol)/THF (5ml).After 10 minutes, mixture is cooled to 0 ℃ and interpolation N-tertiary butyl oxyamine (93 mg, 1.04 mmol).Make mixture be warming up to room temperature and stirred 4 hours.Adding water (10ml) and mixture extracts with methylene dichloride (3X10mL).The organic extract dried over sodium sulfate that merges is filtered, and concentrates.Obtain the title compound of 42mg (17%) by flash chromatography (silica gel, 40-100% ethyl acetate/hexane) purification resistates.
Figure 646235DEST_PATH_IMAGE329
E. biological data
(i) in vitro method--CB 2And CB 1Radioligand-binding assay:
With described CB herein 1And CB 2Radioligand-binding assay is determined with respect to CB 1Acceptor, The compounds of this invention and CB 2The bonded selectivity.
Allow stably express people CB 2The HEK293 cell growth of acceptor covers individual layer up to forming.Temporarily, with cell harvesting, in the presence of proteinase inhibitor, at TE damping fluid (50 mM Tris-HCl, 1 mM MgCl 2With 1 mM EDTA) middle polytron (polytron) vibrations 2 X 10 seconds of using, carry out homogenize, then by 45, centrifugal 20 minutes of 000Xg.Final peplomer material is being laid in damping fluid (50 mM Tris-HCl, 1 mM MgCl 2, 1 mM EDTA and 10% sucrose) in homogenize again, down freezing standby at-78 ℃.By at analysis buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2With the 0.5 mg/mL BSA of fatty acids not, pH 7.4) in (protein concn is 5 μ g/ holes, for people CB with film preparation 2) add to deep-well plates each hole (comprise ([ 3H] CP-55,940 (120 Ci/mmol are by the commercially available non-selective CB agonists that get of Tocris)), cause saturated association reaction.After 30 ℃ of cultivations in 90 minutes, by the cold analysis buffer of adding 300 μ l/ holes association reaction is stopped, filter by UniFilter-96 GF/C filter plate (pre-soaking is 2 hours in 1 mg/mL BSA) fast vacuum subsequently.In TopCount, carry out the active counting of combination with Microscint-20.With from 12 kinds of concentration of 0.01-8 nM [ 3H] CP-55,940 carry out saturation experiments.With 0.5 nM [ 3H] CP-55,940 and the experiment that is at war with of the displaced ligands that is selected from 5 kinds of concentration of 0.01nM to 10 μ M.(Tocris, Ellisville MO), are used to estimate non-specific binding to add the unlabelled CP 55,940 of 10 μ M.
Allow stably express rat CB 2The HEK293 cell growth of acceptor covers individual layer up to forming.Temporarily, with cell harvesting, in the presence of proteinase inhibitor, at TE damping fluid (50 mM Tris-HCl, 1 mM MgCl 2With 1 mM EDTA) middle polytron (polytron) vibrations 2 X 10 seconds of using, carry out homogenize, then by 45, centrifugal 20 minutes of 000Xg.Final peplomer material is being laid in damping fluid (50 mM Tris-HCl, 1 mM MgCl 2, 1 mM EDTA and 10% sucrose) in homogenize again, down freezing standby at-78 ℃.By at analysis buffer (50 mM Tris, 2.5 mM EDTA, 5 mM MgCl 2With the 0.5 mg/mL BSA of fatty acids not, pH 7.4) in film preparation (for rat CB 2, protein concentration is 20 μ g/ holes) add to deep-well plates each hole (comprise [ 3H] CP-55,940 (120 Ci/mmol are by the commercially available non-selective CB agonists that get of Tocris)), cause saturated association reaction.After 30 ℃ of cultivations in 45 minutes, by the cold analysis buffer of adding 300 μ l/ holes association reaction is stopped, filter by UniFilter-96 GF/C filter plate (pre-soaking is 2 hours in 1 mg/mL BSA) fast vacuum subsequently.In TopCount, carry out the active counting of combination with Microscint-20.With from 12 kinds of concentration of 0.01-8 nM [ 3H] CP-55,940 carry out saturation experiments.With 0.5 nM [ 3H] CP-55,940 and the experiment that is at war with of the displaced ligands that is selected from 5 kinds of concentration of 0.01nM to 10 μ M.(Tocris, Ellisville MO), are used to estimate non-specific binding to add the unlabelled CP 55,940 of 10 μ M.
HEK293 people CB 1Film is available from Perkin Elmer.Contain by film (8-12 μ g/ hole) is added [ 3H] and CP 55,940 (120 Ci/mmol, Perkin Elmer, Boston, MA) and analysis buffer (50 mM Tris, 2.5 mM EDTA, the 5 mM MgCl of enough volumes 2With the 0.5 mg/mL BSA of fatty acids not, pH 7.4) (West Chester PA) to cumulative volume 250 μ L, causes combination for Scienceware 96-hole depth orifice plate, VWR in each hole.Cultivate back (keeping 90 minutes) at 30 ℃, make combination termination by the cold analysis buffer that adds 300 μ L/ holes, by UniFilter-96 GF/C filter plate (Perkin Elmer, Boston, MA) (pre-soaking is at least 3 hours in 0.3% PEI) fast vacuum filters (FilterMate Cell Harvester, Perkin Elmer, Boston, MA), then with cold analysis buffer washing 5 times.In TopCount, (all come from Perkin Elmer, Boston MA) carries out the active counting of combination with Microscint-20.With 1 nM [ 3H] CP-55, the experiment that is at war with of the displaced ligands of 940 and 5 concentration (1nM to 10 μ M).(Tocris, Ellisville MO), are used to estimate non-specific binding to add the unlabelled CP 55,940 of 10 μ M.Find the compound tested with CB 2About 10 times-Yue 1000 times Ki and CB of receptors bind 1Receptors bind.These results show that some compound of being tested is than CB 1Preferential and the CB of acceptor 2In conjunction with, be CB therefore 2The selective ligands of acceptor.
CB 2And CB 1The cyclase functional analysis:
According to supplier's rules, (Fremont, HitHunter TM cAMP assay kit CA) carries out the cyclase functional analysis from DiscoveRx in use.Temporarily, (Invitrogen, Carlsbad CA) separate expression CB to use the cell dissociation damping fluid 2Or CB 1The HEK cell of acceptor (rat or people), in 96 orifice plates with 10,000 cells/well with its dispersion and place in suspension, analyze then.Forskolin (rat CB at fixed concentration 2Be 18 μ M and rat CB 1Be 37 μ M) existence under be supplemented with the Dulbescco phosphate-buffered saline (Invitrogen of bovine serum albumin, Carlsbad, CA) in (0.01% final concn) with test ligand and/or 10 μ M CP 55 of variable concentrations, the 940-positive control was 37 ℃ of culturing cell suspension 20 minutes.By adding the molten damping fluid termination reaction of born of the same parents and detecting fluorescence according to program according to the specification sheets of manufacturers.Use is calculated the EC50 value from the dose-response curve match of the S shape of Prism (GraphPad).In described cyclase is analyzed, than rat CB 1Receptor activation rat CB 2Aspect, the compound of being tested be about 100 times to approximately 10,000 times effectively.
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Ii) data in the body:
Animal
Use bull Sprague-Dawley rat (the 250-300g body weight, Charles River Laboratories, Portage, MI).Institutional Animal Care and Use Committee (IACUC) approval animal by Abbott Laboratories is handled and experimental program.For all operation techniques, animal is maintained (4% induces, and 2% keeps) under the halothane anesthesia, perioperatively is sterilized cutting part with 10% polyvidone-iodine solution.
The otch model of postoperative pain
With Brennan etc., 1996, Pain, program described in 64,493 produces the skin incision model of postoperative pain.(nose cone) sends isoflurane with all rat anesthesias by nose cone.Behind the sterilizing operation, right back nail-press is opened.The toe face of left back pawl is put into the aseptic plastic drape by the hole.Preparation is by the skin of rear solid end toe face and the 1-cm longitudinal cut of manadesma, and this otch extends to toe from calcaneal near side (ns) 0.5 cm of distance, and sole of the foot flesh is lifted, and longitudinally cuts, and keeps the muscle origin or beginning and keeps the insertion point complete.Use two mattress suture lines (5-0 nylon) with skin closure then.After the operation, allow animal recover then 2 hours, at this moment, press commentary valency tactile allodynia.For estimating anti-nociceptive effect, behind the incision of skin 90 minutes, give animal vehicle or test compounds by i.p., give behind the compound to estimate in 30 minutes tactile allodynia.
As Chaplan, S.R., F.W. Bach, J.W. Porgrel, J.M. Chung and T.L. Yaksh, 1994, the quantitative evaluation of tactile allodynia in the rat pawl, J. Neurosci. Methods, described in 53,55, use the von Frey long filament (Stoelting of calibration, Wood Dale IL), measures tactile allodynia.Rat is put into inverted independent plastics cage (20 x, 12.5 x, 20 cm), and this plastics cage is positioned at the top of suspension wire grid, allows rat adaptive testing case 20 minutes.The opening that von Frey long filament is passed through the gauze plate from the bottom of cage directly vertically arrives the interior zone of otch 1-3 mm (direct neighbor), keeps about 8 seconds in this position then, so that enough reactive force causes long filament slight curving.The positivity reaction comprises that rear solid end is stimulated back withdrawal suddenly, or has just removed the post-stimulatory behavior of shrinking.With about (up-down) method (as described in following document, Dixon, W.J., 1980, experimental observation result's Validity Analysis, Ann. Rev. Pharmacol. Toxicol., 20,441) measure 50% withdrawal threshold values.
In the otch model of postoperative pain under less than about 300 micromoles/kg, for example, under less than about 50 micromoles/kg, than the salt solution vehicle, the compound exhibits of some test goes out the statistically evident variation of pawl withdrawal aspect latent period in the otch model of postoperative pain.
The spinal nerves ligation model of neuropathic pain:
Use the program that is described at first in the following document to produce the neuropathic pain model (SNL model) that the spinal nerves ligation is brought out: Kim, S.H. and J.M. Chung, 1992, An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat, Pain, 50,355.Be adjacent to that backbone separates the left L5 of rat with the L6 spinal nerves and away from DRG with 5-0 silk suture (silk suture) ligation securely, note avoiding damaging the L4 spinal nerves.Make false rat experience identical process, but not ligation nerve.Before estimating tactile allodynia, allow all animals recover at least 1 week, but be no more than for 3 weeks.
As Chaplan, S.R., F.W. Bach, J.W. Porgrel, J.M. Chung and T.L. Yaksh, 1994, the quantitative evaluation of tactile allodynia in the rat pawl, J. Neurosci. Methods, described in 53,55, use the von Frey long filament (Stoelting of calibration, Wood Dale IL), measures tactile allodynia.Rat is put into inverted independent plastic containers (20 x, 12.5 x, 20 cm), and these plastic containers are positioned at the top of suspension wire grid, allow rat adaptive testing case 20 minutes.Make vertical setting of toe face of von Frey long filament and the rear solid end of selection, keep about 8 seconds in this position then, so that enough reactive forces cause long filament slight curving.The positivity reaction comprises that rear solid end is stimulated back withdrawal suddenly, or has just removed the post-stimulatory behavior of shrinking.With about (up-down) method (as described in following document, Dixon, W.J., 1980, experimental observation result's Validity Analysis, Ann. Rev. Pharmacol. Toxicol., 20,441) measure 50% withdrawal threshold values.Have only baseline threshold values mark to be used for this research, get rid of the animal that shows movement defect less than the rat of 4.25 g.Also in several control groups, estimate the tactile allodynia threshold values, comprise offside pawl not test (N.T.), false operation and animal infusion of saline and nerve injury rat.
Under less than about 50 micromoles/kg, than the salt solution vehicle, representational compound exhibits goes out the statistically evident variation of pawl withdrawal aspect latent period in the spinal nerves ligation model of neuropathic pain.
The insecondary mechanical hypersensitivity that capsaicine brings out:
Allow rat adapt to research department's environment 1 hour.With they temporary transient constraints, be injected to right back pawl center then, capsaicine is given with 10 μ g/10 μ L vehicle (10% ethanol and 2-hydroxypropyl cyclodextrin) by (intraplantar) in the sufficient sole of the foot.Give capsaicine after 180 minutes, (Joshi etc. 2006, and Neuroscience 143,587-596) measuring the Secondary cases mechanical hyperalgesia away from the heel portion of injection site.Preceding 30 minutes of test (after giving capsaicine 150 minutes), injection (i.p.) compound.
Measure tactile allodynia as mentioned above.
Under less than about 300 micromoles/kg, for example, under less than about 50 micromoles/kg, than the salt solution vehicle, the compound exhibits of some test goes out the statistically evident variation of pawl withdrawal aspect latent period in the capsaicine model in the capsaicine model.
The knee joint osteoarthritis pain model that MIA-brings out
Use the 26G pin under slight isoflurane anesthesia, in rat, to cause one-sided knee joint osteoarthritis in the right knee joint cavity by (i.a.) in sodium iodoacetate (MIA, the isotonic saline solution that 3mg/0.05mL the is aseptic) simple joint is expelled to.Select the dosage (3mg/i.a. injection) of MIA based on the result who obtains in the preliminary study, wherein under this dosage, observe best pain behavior.(Columbus Instruments, Columbus put on the pain behavior evaluation that maximum compression on the hind leg strain gauge arrangement is carried out the hind leg clamping force by record in OH) in the commercially available clamping force measuring system that gets.To each animal, be maximum hind leg accumulative total force of compression (CFmax) (gram force)/kg body weight with the clamping force data conversion.Behind i.a. injection MIA 20 days, measure the analgesic effect of test compounds.Vehicle control group for each compound of being tested is designated as 0%, yet the group that is used as experiment first of age-matched is designated as 100% (normally).Then, the effect % that represents each dosage group with the % that turns back to normality than the group that is used as experiment first.Compound gives by oral (p.o.) or intraperitoneal (i.p.).Usually, any time in oral back between about 1 hour to about 5 hours, carry out the evaluation of the analgesic effect of test compounds.Usually, any time after i.p. gives between about 0.5 hour to about 2 hours, carry out the evaluation of the analgesic effect of test compounds.The selection of preferred time point of analgesic effect that is used for measuring test compounds is based on the consideration of test compounds at the independent pharmacokinetic properties of rat.Known or provided the time point of higher plasma concentration of test compounds to be preferable over known by expectation or provided those of lower concentration by expectation.Behind the single dosage or after repeating quantitatively to give test compounds, the frequency that wherein quantitatively gives is every day 1 to 2 time, can carry out the evaluation of the analgesic effect of test compounds.The time length that such repetition quantitatively gives every day can continue any time greater than 1 day.The typical duration that multiple quantitatively gives every day is about 5 days-Yue 12 days.
Give the back in the MIA of osteoarthritis pain model at single dosage, under less than about 300 micromoles/kg, for example, under less than about 50 micromoles/kg, than the salt solution vehicle, the compound exhibits of test goes out the statistically evident variation of hind leg clamping force intensity aspect.After repeating every day to give 5 to 12 days in the MIA of osteoarthritis pain model less than about 30 micromoles/kg, than the salt solution vehicle, some compound exhibits goes out the statistically evident variation of hind leg clamping force intensity aspect.
F. use the method for compound
A kind of embodiment provides the method for treatment pain in the Mammals of the such treatment of needs (comprising the people) (for example, chronic pain, inflammatory pain, postoperative pain, neuropathic pain, nociceptive pain, cancer pain, low back pain, eye pain).This method comprises, separately or with one or more medicinal acceptable carriers jointly, one or more that give Mammals treatment significant quantity are compound as described herein, or the salt of its medicinal acceptable salt, solvate or solvate.This method comprises that further the form with single dosage gives compound of the present invention.This method also is included in a couple of days, several weeks, several months or longer time and repeats or give for a long time described compound herein.In certain embodiments, this method comprises, separately or with one or more medicinal acceptable carriers jointly, give one or more compounds as described herein of Mammals treatment significant quantity or the salt of its medicinal acceptable salt, solvate or solvate, and one or more NSAID (non-steroidal anti-inflammatory drug) (NSAID) or other anodyne (Paracetamol for example, or its combination opioid).
Another embodiment provides sanatory method in the Mammals of this such treatment of needs, and described illness is selected from inflammatory diseases, Immunological diseases, neurological disorder, immune cancer, dyspnoea and cardiovascular disorder.This method comprises, separately or with one or more medicinal acceptable carriers associatings, give one or more the described compounds of Mammals treatment significant quantity or the salt of its medicinal acceptable salt, solvate or solvate herein.
Another embodiment relates to the method that neuroprotective (neuroprotection) is provided in the Mammals of the such treatment of needs.These methods comprise, separately or with one or more medicinal acceptable carriers associatings, give one or more the described compounds of Mammals treatment significant quantity or the salt of its medicinal acceptable salt, solvate or solvate herein.
Another embodiment provides by repeating in a couple of days, several weeks or several months or the secular salt that gives this compound or its medicinal acceptable salt, solvate or solvate, or its pharmaceutical composition improves herein the curative effect of described compound or the method for effectiveness.
Except that contained herein data, some serial evidences are supported CB 2The viewpoint that acceptor works in analgesia.HU-308 is the highly selective CB that identifies first 2In the agonist one, it in rat formalin constant pain model, cause anti-nociception reaction (Hanus, L. etc., Proc. Nat. Acad. Sci., 1999,96,14228-14233).CB 2Selective cannabinoid part AM-1241 the acute pain animal model of burning (Malan, T. P etc., Pain, 2001,93,239-245; Ibrahim, M. M. etc., Proc. Nat. Acad. Sci., 2005,102 (8), 3093-3098), constant pain animal model (Hohmann, A. G. etc., J. Pharmacol. Exp. Ther., 2004,308,446-453), inflammatory pain animal model (Nackley, A. G. etc., Neuroscience, 2003,119,747-757; Quartilho, A. etc., Anesthesiology, 2003,99,955-60) with neuropathic pain animal model (Ibrahim, M. M. etc., Proc. Nat. Acad. Sci., 2003,100,10529-10533) the strong analgesia effectiveness of middle demonstration.CB 2Selectivity partial agonist GW405833 is called L768242 again, it is effective (Valenzano, K. J. etc., Neuropharmacology in the rodent model of neuropathic, otch and chronic and acute inflammation pain, 2005,48,658-672 and Clayton, N. etc., Pain, 2002,96,253-260).
CB 2There are the potentiality with opium sample shortage (sparing) effect in conditioning agent.Existing morphine and non-selective CB agonist △ 9The record of the synergic antalgic effect the between-THC (Cichewicz, D. L., Life Sci. 2004,74,1317-1324).Therefore, when with low dosage morphine or other opioid coupling, CB 2Part has additivity or synergic antalgic effect, provides to reduce harmful OPIOIDS incident for example tolerance, constipation and respiration inhibition but do not lose the strategy that analgesia is renderd a service.
CB 2Acceptor is present in tissue relevant with immunologic function and cell type, CB 2Receptor mrna by human B cell, natural killer cell, monocyte, neutrophilic leukocyte and T cell expressing (Galiegue etc., Eur. J. Biochem., 1995,232,54-61).To rejecting CB 2The research prompting of mouse, CB 2Acceptor have regulate immune effect (Buckley, N. E. etc., Eur. J. Pharmacol. 2000,396,141-149).Although the growth of immunocyte and differentiation and wild-type animal is similar in the animal of rejecting, at rejecting CB 2There is not △ in the mouse of acceptor 9The immunosuppressive action of-THC, thus CB is provided 2Acceptor relates to immunoregulatory evidence.Equally, selectivity CB 2Conditioning agent can be used for treating autoimmune disorder, includes but not limited to multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, type i diabetes, irritable bowel syndrome, psoriatic, psoriatic arthritis and hepatitis; And immune correlated disease, include but not limited to tissue rejection in the organ transplantation, non-intertropica stomatitis allergic diarrhoea (celiaca), asthma, chronic obstructive disease of lung, pulmonary emphysema, bronchitis, adult respiratory distress syndrome, transformation reactions, allergic rhinitis, dermatitis and xerodermosteosis.
It is believed that microgliacyte is the immunocyte of central nervous system (CNS), wherein they are controlled immunoreactive starting and carry out.The CB that on microgliacyte, expresses 2Acceptor depends on inflammatory states, finds the CB in the microgliacyte of contacted antigenic, propagation and migration 2Level is than the height (Carlisle, S. J. etc., Int. Immunopharmacol., 2002,2,69) of dormancy or complete activated microgliacyte.Neural inflammation causes the multiple change of microgliacyte form, has CB 2Neural inflammation takes place in the rise of other element of acceptor and Endocannabinoids system-in several neurodegenerative diseases, and observes and induce microgliacyte CB 2Acceptor (Carrier, E. J. etc., Current Drug Targets-CNS ﹠amp; Neurological Disorders, 2005,4,657-665).Therefore, CB 2Part can be used for treating clinically neural inflammation.
Multiple sclerosis is common immune-mediated CNS disease, and wherein the ability of neurone conduction impulsion is impaired by demyelinization and axon infringement.As the demyelinization of generation as a result of chronic inflammatory diseases, finally cause to predict variation and various clinical symptom that worsen with age growth usually.These comprise painful muscle spasm, tremble, ataxia, motor weakness, sphincter dysfunction and language performance difficulty (Pertwee, R. G., Pharmacol. Ther. 2002,95,165-174).During experimental autoimmunization encephalomyelitis (EAE), CB 2Acceptor quilt rise on the activated microgliacyte (Maresz, K. etc., J. Neurochem. 2005,95,437-445).CB 2Receptor activation stop inflammatory cell for example leukocyte recruitment in CNS (Ni, X. etc., Multiple Sclerosis, 2004,10,158-164), (Arevalo-Martin, A. shield in experimental carrying out property demyelinization; Deng, J. Neurosci., 2003,23 (7), 2511-2516), this effect is the developing key feature of multiple sclerosis.Therefore, CB 2Receptor modulators can be provided for the uniqueness treatment of demyelinating disease.
Presenile dementia is a chronic neurodegenerative disease, and this disease is modal senile dementia form.Current research is found, CB 2Raised in the neuritis plaque relevant with microgliacyte of expression of receptor in presenile dementia patient brain (Benito, C. etc., J. Neurosci., 2003,23 (35), 11136-11141).External, use CB 2Agonist JWH-133 handles, and the microgliacyte of amyloid-beta-bring out is activated and the neurotoxicity inefficacy, and this type of effect can be by CB 2(J. Neurosci. 2005,25 (8), 1904-1913) for Ramirez, B. G. etc. in antagonist SR144528 blocking-up.CB 2Conditioning agent can have anti-inflammatory and neuroprotective dual function, therefore has the clinical application that treatment develops relevant neural inflammation with presenile dementia and neuroprotective is provided.
In people's inflammatory bowel tissue, observe the epithelium CB of increase 2The expression of receptor level (Wright, K. etc., Gastroenterology, 2005,129,437-453).After in rat, bringing out the endogenous cytotoxic inflammation, CB 2Receptor activation set up again the transhipment of normal stomach (Mathison, R. etc., Br. J. Pharmacol. 2004,142,1247-1254).CB in people's colon epithelial cell system 2Receptor activation can suppress TNF-α inductive interleukin-8 (IL-8) discharge (Ihenetu, K. etc., Eur. J. Pharmacol. 2003,458,207-215).In inflammatory bowel, the chemokine that discharges by epithelial cell for example neutrophilia chemoattracting cytoking IL-8 raised (Warhurst, A. C. etc., Gut, 1998,42,208-213).Therefore, give CB 2Receptor modulators may be represented the novel method of treatment inflammation and intestines and stomach disease, and the intestines and stomach disease includes but not limited to inflammatory bowel, irritable bowel syndrome, secretory diarrhea, ulcerative colitis, Crohn disease and gastroesophageal reflux disease (GERD).
As reaction to chronic hepatic injury, hepatic fibrosis takes place, finally cause liver cirrhosis, owing to the complication of following of serious portal hypertension, liver failure and hepatocellular carcinoma, this sclerosis is great worldwide health problem (Lotersztajn, S. etc., Annu. Rev. Pharmacol. Toxicol., 2005,45,605-628).Although in normal people's liver, can not detect CB 2Acceptor, but CB 2Acceptor is expressed in sclerosis patient's liver biopsy samples.Activated CB in the liver myofibroblast of cultivating 2Acceptor produce effective anti-fiber have an effect (Julien, B. etc., Gastroenterology, 2005,128,742-755).In addition, give tetracol phenixin for a long time after, with respect to wild-type mice, reject CB 2The hepatic fibrosis that take place to worsen of mouse.Give CB 2Receptor modulators can be represented the peculiar methods of treatment hepatic fibrosis.
Cough is the main and lasting symptom of multiple inflammatory lung disease, this type of tuberculosis comprise asthma, chronic obstructive disease of lung, virus infection and pulmonary fibrosis (Patel, H. J. etc., Brit. J. Pharmacol., 2003,140,261-268).Current research provides neurogenicity CB 2Acceptor is present in the evidence of air flue, proves CB 2The effect of receptor activation in cough suppresses (Patel, H. J. etc., Brit. J. Pharmacol., 2003,140,261-268 and Yoshihara, S. etc., Am. J. Respir. Crit. Care Med., 2004,170,941-946).Exogenous and Endocannabinoids part passes through CB 2Acceptor suppresses the C-fiber and activates, and reduces neurogenicity Inflammatory response (Yoshihara, S. etc., J. Pharmacol. Sci. 2005,98 (1), 77-82 in airway tissue; Yoshihara, S. etc., Allergy and Immunology, 2005,138,80-87).Therefore, CB 2Selective modulator can have the purposes as cough medicine treatment pneumonia, chronic cough and various air flue inflammatory diseasess, and the air flue inflammatory diseases includes but not limited to asthma, chronic obstructive disease of lung and pulmonary fibrosis.
Inherited genetic factors has material impact to bone density, CB 2Acceptor gene relevant with people's osteoporosis (Karsak, M. etc., Human Molecular Genetics, 2005,14 (22), 3389-3396).Osteoclast and scleroblast mainly are responsible for keeping bone structure and function by the process that is called reconstruction, this reconstruction relate to bone absorption again and synthetic (Boyle, W. J. etc., Nature, 2003,423,337-342).Detect CB on osteoclast and the skeletonization precursor cell 2Expression of receptor gives mouse CB 2Behind the agonist, cause the dose-dependently bone forming increase (Grotenhermen, F. and Muller-Vahl, K., Expert Opin. Pharmacother., 2003,4 (12), 2367-2371).Comprise CB 2Selectivity inverse agonist SR144528 shows that at interior cannaboid inverse agonist the bone that inhibition osteoclast activity and upset oophorectomize are brought out runs off in mouse, this mouse is postmenopausal osteoporosis disease model (Ralston, S. H. etc., Nature Medicine, 2005,11,774-779).Therefore, CB 2Conditioning agent can be used for treatment and preventing osteoporosis disease, osteoarthritis and osteopathy.
Atherosclerosis is a chronic inflammatory disease, is the major cause of heart disease and stroke.In people and mouse atherosclerotic plaque, detect CB 2Acceptor.After rejecting the mouse low dosage THC of apo E, show the atherosclerotic lesions development, and these effects are by CB 2Selective antagonist SR144528 inhibition (Steffens, S. etc., Nature, 2005,434,782-786).Therefore, to CB 2The activated compound of acceptor can be used for the treatment of atherosclerosis clinically.
CB 2Acceptor is expressed on immune cancer cells, target CB 2Transferring dies can set up the novel method for the treatment of the immunity system cancer to acceptor to induce.Selectivity CB 2Agonist induction glioblastoma disappear (Sanchez, C. etc., Cancer Res., 2001,61,5784-5789), skin carcinoma (Casanova, M. L. etc., J. Clin. Invest., 2003,111,43-50) and lymphoma (McKallip, R. J. etc., Blood, 2002,15 (2), 637-634).Therefore, CB 2Conditioning agent can have the purposes as the anticarcinogen of anti-immunogenic tumour.
CB 2The receptor activation proof can be protected heart to prevent ischemic and pour into deleterious effect (Lepicier, P. etc., Brit. J. Pharm. 2003,139,805-815 again; Bouchard, J.-F. etc., Life Sci. 2003,72,1859-1870; Filippo, C. D. etc., J. Leukoc. Biol. 2004,75,453-459).Therefore, CB 2Conditioning agent can have the purposes of treatment or preventing cardiovascular disease and myocardial infarction development.
Can change the actual dose level of the activeconstituents in medicinal compositions, so that obtain effectively to reach amount, composition and the mode of administration of particular patient desired therapeutic reactive activity compound.The dosage level of selecting will depend on the severity of the activity, route of administration, treatment time of particular compound, the illness of being treated and the patient's that treated situation and medical history.Yet what those skilled in the art grasped is to be lower than the dosage that obtains beginning compound under the desired level of desired therapeutic effect and little by little to improve dosage up to having obtained desired effects.In the treatment of some medical condition, may need the repetition or secular the giving of described compound herein so that realize the desired therapeutic response." repeat or secular giving " is meant in a couple of days, several weeks, several months or longer time every day (that is every day) or (that is, is not every day) off and on and give The compounds of this invention.Especially, the treatment of long-term pain condition can need such repetition or the secular The compounds of this invention that gives.The compounds of this invention can become more effective when repetition or secular giving, and the treatment effective dose can be lower than the treatment effective dose that gives from single when making repetition or secular giving.
Described herein compound can also give with the form of pharmaceutical composition, and it comprises compound of interest and one or more medicinal acceptable carriers.Phrase " treatment significant quantity " is meant and is used for rational benefit/danger of being applicable to any therapeutic treatment compound than sanatory sufficient amount.Yet, should will be appreciated that total every day of the usage of compound and composition will be decided by the attending doctor in the scope of medical science judgement reliably.For any specific patient, the effective dosage level of specific treatment will depend on multiple factor, comprise the illness of being treated and the severity of illness; The activity of employed specific compound; Employed specific composition; Patient's age, body weight, general health state, sex and diet; Administration time/number of times, the discharge rate of route of administration and employed specific compound; The time length of treatment; With employed specific compound combination or the medicine that uses simultaneously; With the well-known similar factor of medical field.What for example, those skilled in the art grasped is to be lower than the dosage that obtains beginning compound under the desired level of desired therapeutic effect and little by little to improve dosage up to having obtained desired effects.
Compound can be individually, perhaps with one or more other described herein compounds jointly, perhaps give with one or more other medicinal medicaments associatings (being co-administered).For example, one or more compounds, or the salt of its medicinal acceptable salt, solvate or solvate, can give with following the associating: one or more anodyne (Paracetamol for example, opioid such as morphine), or one or more NSAID (non-steroidal anti-inflammatory drug) (NSAID), or its combination.The limiting examples of NSAID includes but not limited to Asprin, diclofenac, diflunisal (diflusinal), R-ETODOLAC, fenbufen, fenoprofen, flufenisal, flurbiprofen, Ibuprofen BP/EP, indomethacin, Ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, Naproxen Base, nimesulide, nitro flurbiprofen (nitroflurbiprofen), olsalazine, Taisho), Phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin and zomepirac.In certain embodiments, NSAID (non-steroidal anti-inflammatory drug) (NSAID) is an Ibuprofen BP/EP.Combination therapy comprises the single pharmaceutical dosage formulation that comprises one or more described compounds and one or more other medicinal medicaments herein, and gives compound of the present invention and each other medicinal medicament with its own independent pharmaceutical dosage formulation form.For example, a kind of compound and one or more other medicinal medicaments can give the patient as tablet or capsular form together with the single oral dosage composition of each activeconstituents with fixed ratio; Perhaps each medicament can give with the form of independent oral dosage preparation.
Under the situation of using independent dosage particles, described herein compound and one or more other medicinal medicaments can be in the substantially the same times (for example simultaneously) or in that the stagger time (for example sequentially) gives dividually.
Total per daily dose of the compound of administration of human or other animal is about 0.01 mg/kg body weight-Yue 100 mg/kg body weight.More preferred dose can be about 0.03 mg/kg body weight-Yue 30 mg/kg body weight.If desired, effectively per daily dose can be divided into a plurality of dosage that are used for the administration purpose.Therefore, single dosage composition can contain the approximate number of this type of amount or its composition per daily dose.Certainly effectively per daily dose can change along with the time length of treatment.
G. medicinal compositions
Pharmaceutical composition also is provided in this article, and it comprises the salt of described compound or its medicinal acceptable salt, solvate or solvate herein.
Pharmaceutical composition is provided on the other hand, it comprises one or more described compounds herein, or the salt of its medicinal acceptable salt, solvate or solvate, with one or more medicinal acceptable carriers, individually or with one or more anodynes (for example Paracetamol) associatings, perhaps with one or more NSAID (non-steroidal anti-inflammatory drug) (NSAID) associatings, perhaps its combination.
But in through port, rectum, parenteral, the brain pond, intravaginal, intraperitoneal, part (by powder, ointment or drops), contain clothes or oral cavity or nasal spray administration of human and other Mammals medicinal compositions.Term " parenteral " is meant mode of administration as used in this article, and this pattern comprises intravenously, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and intra-articular injection and infusion.
The pharmaceutical adjunct of nontoxic inert solid, semisolid or liquid filling agent, thinner, capsule formed material or any kind represented in term " medicinal acceptable carrier " as used in this article.Some examples that can be used as the material of medicinal acceptable carrier are that sugar is such as but not limited to lactose, dextrose plus saccharose; Starch is such as but not limited to W-Gum and yam starch; Mierocrystalline cellulose and derivative thereof are such as but not limited to Xylo-Mucine, ethyl cellulose and cellulose acetate; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Talcum powder; Vehicle is such as but not limited to theobroma oil and suppository wax; Oil is such as but not limited to peanut oil, oleum gossypii seminis, Thistle oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; Glycol is propylene glycol for example; Ester is such as but not limited to ethyl oleate and Laurate ethyl; Agar; Buffer reagent is such as but not limited to magnesium hydroxide and aluminium hydroxide; Alginic acid; Apirogen water; Isotonic saline solution; Ringer's solution; Ethanol and phosphate buffered saline buffer; And other nontoxic compatibility lubricant also can add composition with tinting material, releasing agent, Drug coating, sweeting agent, correctives and spices, sanitas and antioxidant according to preparation teacher's judgement such as but not limited to sodium lauryl sulphate and Magnesium Stearate.
The medicinal compositions that is used for parenteral injection contains medicinal acceptable sterilized water or non-aqueous solution, dispersion, suspension or emulsion and is used to face the sterilized powder that forms aseptic parenteral solution or dispersion once more with preceding.The example of suitable water and nonaqueous carrier, thinner, solvent or solvent comprises water, ethanol, polyvalent alcohol (for example glycerine, propylene glycol, polyoxyethylene glycol etc.), vegetables oil (for example sweet oil), injection organic ester (for example ethyl oleate) and suitable mixture thereof.For example can be by using for example Yelkin TTS of coating material; In the situation of dispersion,, keep suitable flowability by keeping the granularity that needs and passing through to use tensio-active agent.
These compositions also can contain auxiliary agent for example sanitas, wetting agent, emulsifying agent and dispersion agent.Can guarantee to stop microbial process by introducing various antibiotic and anti-mycotic agent, these antibiotic and anti-mycotic agent are for example Ni Baijin ester class, trichloro-butyl alcohol, phenol Sorbic Acid etc.Also may need to add isotonic agent for example sugar, sodium-chlor etc.Reagent that can be by introducing delayed absorption is aluminum monostearate and gelatin for example, obtains prolonging the injectable drug form of absorption.
In some cases, be the effect of prolong drug, need slow down absorption subcutaneous or the intramuscularly medicine.Can finish this effect by the crystallization of use poorly water-soluble or the liquid suspension of amorphous material.Drug absorption speed then depends on its dissolution rate, and dissolution rate can be depending on grain size and crystal formation.Perhaps, by with medicine dissolution or be suspended in the oily solvent, finish administered parenterally form delayed absorption.
By for example form the micro-capsule skeleton of medicine, preparation injection depot formulations form in polylactide-poly-glycollide at biodegradable polymers.According to the character of the concrete polymkeric substance of the ratio of medicine and polymkeric substance and use, may command drug releasing rate.The example of other biodegradable polymers comprises poly-(ortho ester) and poly-(acid anhydrides).Also can be by pharmaceutical pack being embedded in the liposome or micro emulsion compatible preparation bank injection formulations with bodily tissue.
For example can hold back filter and filter, or sterilant be mixed the aseptic solid composite form, aseptic solid composite can be dissolved in or be scattered in sterilized water or other aseptic injection medium, injection formulations is sterilized by facing with preceding by bacterium.
Be used for peroral administration solid dosage and comprise capsule, tablet, pill, powder and granule.In this type of solid dosage, can with the medicinal acceptable vehicle of active compound and at least a inertia or carrier for example Trisodium Citrate or secondary calcium phosphate mix, and/or mix: a) for example starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid of weighting agent or supplement with following component; B) for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic of tackiness agent; C) wetting Agent for Printing Inks glycerine for example; D) for example agar-agar, lime carbonate, potato or tapioca (flour), alginic acid, some silicate and yellow soda ash of disintegrating agent; E) solution retarding agent paraffin for example; F) absorption enhancer quaternary ammonium compound for example; G) for example hexadecanol and Zerol of wetting agent; H) for example talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and composition thereof of lubricant for example kaolin and wilkinite and i of absorption agent).Under the situation of capsule, tablet and pill, formulation also can contain buffer reagent.
Also available examples of such carriers such as lactose or lactose and high molecular weight polyethylene glycol etc., the solids composition with similar type in soft hard-filled gelatin capsule is made weighting agent.
Other Drug coating that available Drug coating and shell are for example known in enteric coating and the formulation art, the solid dosage of preparation tablet, dragee, capsule, pill and granule.They can be chosen wantonly and contain opalizer, also can be to make their only release of active ingredients, or preferentially in certain part release of enteron aisle, choose the composition that discharges by the slowly-releasing mode wantonly.The example of spendable embedding composition comprises polymkeric substance and wax.
Active compound also can be the microencapsulation form, if suitable one or more above-mentioned carriers that contains.
Be used for peroral administration liquid dosage form and comprise medicinal acceptable emulsion, solution, suspension, syrup and elixir.Remove the active ingredient beyond the region of objective existence, liquid dosage form also can contain inert diluent commonly used in this area for example water or other solvent; Solubilizing agent and emulsifying agent be the fatty acid ester and composition thereof of ethanol, Virahol, ethyl-carbonate, ethyl acetate, phenylcarbinol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (especially Oleum Gossypii semen, Peanut oil, Semen Maydis oil, Wheat germ oils, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and anhydro sorbitol for example.
Except that inert diluent, oral compositions also can contain auxiliary agent for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and spices.
Remove the active ingredient beyond the region of objective existence, but the suspension for example different hard ester alcohol of ethoxylation, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminium hydroxide, wilkinite, agar-agar, tragacanth and composition thereof partially of suspending agent-containing also.
The composition that is used for rectum or vagina administration is preferably suppository, can be by for example cocoa ester, polyoxyethylene glycol or suppository wax are mixed with suitable non-irritating one or more carriers with compound, prepare this suppository, examples of such carriers at room temperature is a solid, but under body temperature liquid, therefore in rectum or vaginal canal, melt release of active compounds.
Also can the liposome form give The compounds of this invention.Such as known in the art, liposome is obtained by phosphatide or other lipid matter usually.Form liposome by single chamber or the crystallization of multicell hydration liquid that is dispersed in the water medium.Can use any nontoxic physiologically acceptable and metabolizable lipid that can form liposome.Except that one or more compound of interest, the present composition of liposome form also can contain stablizer, sanitas, vehicle etc.Preferred lipid is natural and synthetic phosphatide and the phosphatidylcholine (Yelkin TTS) that uses separately or together.
The method of known formation liposome in this area.Referring to, Prescott for example, Ed., Methods in Cell Biology, XIV volume, Academic Press, New York, N.Y. (l976), the 33rd page and following or the like.
The formulation that is used for topical administration comprises powder, sprays, ointment and inhalation.Can under aseptic condition, active compound be mixed with the sanitas of medicinal acceptable carrier and any needs, the buffer reagent that may need or propellent.Also consider ophthalmic preparation, eye ointment, powder and solution.
Compound can be used by the form of inorganic or the medicinal acceptable salt of organic acid deutero-.Phrase " medicinal acceptable salt " is illustrated in and is applicable in the reliable medical judgment scope with the tissue of people and rudimentary animal and contacts no inappropriate toxicity, pungency, anaphylaxis etc., and with rational interests/risk than those salt that match.
Know medicinal acceptable salt in this area.For example, S. M. Berge etc. describe medicinal acceptable salt in detail in (J. Pharmaceutical Sciences, 1977,66:1 and following or the like).Can be during the last separation of compound and purifying in-situ preparing salt, or by making free alkali functional group and appropriate organic reaction preparation salt separately.Representational acid salt includes but not limited to acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, 2-isethionate (isothionate), lactic acid salt, malate, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, right-tosylate and undecylate.Also available this type of reagent such as elementary alkyl halide are such as but not limited to muriate, bromide and the iodide of methyl, ethyl, propyl group and butyl; Sulfuric acid dialkyl such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide is such as but not limited to muriate, bromide and the iodide of decyl, dodecyl, tetradecyl and octadecyl; Arylalkyl halogenide such as benzyl and styroyl bromination thing and other, alkaline nitrogen-containing group is quaternized.Thereby obtain water or oil soluble or dispersed product.The example that can be used for forming the acid of medicinal acceptable acid salt comprises this type of mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid; With this type of organic acid such as acetate, fumaric acid, toxilic acid, 4-toluene sulfonic acide, succsinic acid and citric acid.
Can be by making the part that contains carboxylic acid and oxyhydroxide, carbonate or the supercarbonate reaction of suitable alkali such as but not limited to medicinal acceptable metallic cation, or with ammonia or organic primary, second month in a season or reactive tertiary amine, during the last separation and purifying of compound, the in-situ preparing base addition salt.Medicinal acceptable salt includes but not limited to based on basic metal or alkaline-earth metal such as but not limited to cationic salts of lithium, sodium, potassium, calcium, magnesium and aluminium etc., with nontoxic season ammonia and amine cationic salts, comprise ammonium, tetramethylammonium, Tetrylammonium, methylamine, dimethylamine, Trimethylamine 99, triethylamine, diethylamine, ethamine etc.Other the representative organic amine that can be used for forming base addition salt comprises quadrol, thanomin, diethanolamine, piperidines, piperazine etc.
Term " medicinal acceptable prodrugs " or " prodrug " representative is applicable to the tissue of people and rudimentary animal in reliable medical judgment scope and contacts as used in this article, no inappropriate toxicity, pungency, anaphylaxis etc., and with rational interests/risk than matching and those prodrugs of compounds effective in their intended purpose.
What consider herein is by synthetic method or by the prodrug compound that forms of bio-transformation in vivo.
Compound can exist non-solventization and solvation form, comprises for example semihydrate of hydrated form.Generally speaking, for purpose of the present invention, contain medicinal acceptable solvent for example the solvation form of water and ethanol etc. be equal to the non-solvent form.

Claims (24)

1. the compound of formula (I)
Or its medicinal acceptable salt, solvate, prodrug, or combination, wherein
L is C=O, C=S, S (O) 2, or C=NCN;
R 1Be alkyl, thiazolinyl, alkynyl ,-(CR aR b) m-OH ,-(CR aR b) m-O (alkyl) ,-(CR aR b) m-CN, haloalkyl, G 1,-NR Z1R Z5, or-OR Z5
R Z5Be alkyl, haloalkyl, G 1a,-(CR aR b) m-G 1a,-(CR aR b) n-OR Z1,-(CR aR b) n-N (R Z1) (R Z1) ,-(CR aR b) m-C (O) O (R Z1) ,-(CR aR b) m-C (O) R Z1,-(CR aR b) m-C (O) N (R Z1) (R Z1) ,-(CR aR b) m-S (O) 2R Z1,-(CR aR b) m-S (O) 2N (R Z1) (R Z1), or-(CR aR b) m-CN;
R 2Be alkyl, thiazolinyl, alkynyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-S (R Zb) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) N (R Z1) (R Z2a) ,-(CR aR b) m-SO 2N (R Z1) (R Z2a) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-SO 2(R Zd) ,-SO 2(R Zd) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1
R 3Be hydrogen, alkyl, halogen ,-CN ,-G 2, haloalkyl, or-(CR aR b) m-G 2
R 4Be alkyl, thiazolinyl, alkynyl ,-(CR aR b) n-CN ,-(CR aR b) n-OH ,-(CR aR b) n-O (alkyl), haloalkyl, G 2, or-(CR aR b) m-G 2Or
R 2And R 3, or R 3And R 4With the atom that they were connected to, formation contains zero or other two keys, zero or one other be selected from O, S, N and N (H) heteroatomic five-, six-or seven-first monocycle ring, each described monocycle ring is unsubstituted independently or is selected from following substituting group (R by 1,2,3,4 or 5 21) replace: oxo, alkyl, thiazolinyl, alkynyl, halogen ,-CN ,-O (R 1a) ,-C (O) OH ,-C (O) O (alkyl) ,-C (O) (R 1a) ,-N (R Z3) (R 3a) ,-N (R 3a) C (O) R 1a,-N (R 3a) C (O) O (R 1a) ,-N (R 3a) C (O) N (R Z3) (R 3a) ,-N (R 3a) S (O) 2(R 2a) ,-N (R 3a) S (O) 2N (R Z3) (R 3a) ,-SO 2(R 2a) ,-C (O) N (R Z3) (R 3a) ,-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN ,-(CR 1gR 1h) u-O (R 1a), and haloalkyl; Two the adjacent or non-adjacent atoms of each randomly connect by the alkylidene bridge of 1,2,3 or 4 carbon atom in the described monocycle ring; With two substituting group (R on same carbon atom 21), with described carbon atom, randomly formation contains 0,1 or 2 first monocycle ring of heteroatomic 3-6 that is selected from O, S and N (H);
R Za, when occurring each time, be hydrogen independently, alkyl, haloalkyl ,-(CR cR d) p-O (alkyl), G 1,-(CR cR d) q-CN, or-(CR cR d) q-G 1
R Zb, when occurring each time, be hydrogen independently, alkyl, haloalkyl, G 1, or-(CR cR d) q-G 1
R Z1, when occurring each time, be hydrogen independently, alkyl, or haloalkyl;
R Z2a, when occurring each time, be hydrogen independently, alkyl, haloalkyl, G 1, or-(CR cR d) q-G 1, or
R Z2b, when occurring each time, be hydrogen independently, alkyl, haloalkyl, G 1,-C (O) R Zc,-C (O) OR Zc,-C (O) N (R Z1) (R Zc) ,-S (O) 2R Zd,-S (O) 2N (R Z1) (R Zc), or-(CR cR d) q-G 1,
R Zc, when occurring each time, be hydrogen independently, alkyl, haloalkyl, G 1, or-(CR eR f) t-G 1
R Zd, when occurring each time, be alkyl independently, haloalkyl, G 1, or-(CR eR f) t-G 1
G 1And G 1a, when occurring each time, be aryl independently of one another, heteroaryl, cycloalkyl, cycloalkenyl group, or heterocycle, wherein each G 1And G 1aBe unsubstituted independently or being selected from following substituting group by 1,2,3,4 or 5 replaces: alkyl, thiazolinyl, alkynyl, alkoxyl group thiazolinyl, hydroxyl thiazolinyl, halogen ,-CN, oxo ,-G 2,-NO 2,-C (R 1a)=N-O (R 1a) ,-OC (O) R 1a,-OC (O) N (R Z3) (R 3a) ,-SR 1a,-S (O) 2R 2a,-S (O) 2N (R Z3) (R 3a) ,-C (O) R 1a,-C (O) OR 1a,-C (O) N (R Z3) (R 3a) ,-L 1-A 1,-N (R 3a) C (O) R 1a,-N (R 3a) S (O) 2R 2a,-N (R 3a) C (O) O (R 1a) ,-N (R 3a) C (O) N (R Z3) (R 3a) ,-(CR 1gR 1h) u-NO 2,-(CR 1gR 1h) u-OR 1a,-(CR 1gR 1h) u-OC (O) R 1a,-(CR 1gR 1h) u-OC (O) N (R Z3) (R 3a) ,-(CR 1gR 1h) u-SR 1a,-(CR 1gR 1h) u-S (O) 2R 2a,-(CR 1gR 1h) u-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-C (O) R 1a,-(CR 1gR 1h) u-C (O) OR 1a,-(CR 1gR 1h) u-C (O) N (R Z3) (R 3a) ,-(CR 1gR 1h) u-N (R Z3) (R 3a) ,-(CR 1gR 1h) u-N (R 3a) C (O) R 1a,-(CR 1gR 1h) u-N (R 3a) S (O) 2R 2a,-(CR 1gR 1h) u-N (R 3a) C (O) O (R 1a) ,-(CR 1gR 1h) u-N (R 3a) C (O) N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN, and haloalkyl;
A 1Be R 1a,-(CR 1gR 1h) u-A 2,-N (R Z3) C (O) R 1a,-N (R Z3) C (O) OR 2a,-N (R Z3) (R 1a), or-N=C (R Z3) (R 1a);
A 2Be-C (O) R 1a,-S (O) 2R 2a, CON (R Z3) (R 3a), CSN (R Z3) (R 3a) ,-SO 2N (R Z3) (R 3a) ,-CN ,-C (=NOR 1a) R 1a,-N (R 3a) C (O) R 1a,-N (R 3a) C (O) OR 2a,-N (R 3a) S (O) 2R 2a,-N (R 3a) C (O) N (R Z3) (R 3a) ,-N (R 3a) S (O) 2N (R Z3) (R 3a), or-L 2-R Z6
R Z6Be alkoxyalkyl, hydroxyalkyl, cyano group alkyl, halogenated alkoxy alkyl, G 2, or-(CR kR x) v-G 2
L 1And L 2Be O or N (R independently of one another Z3);
R 1aAnd R 3a, when occurring each time, be hydrogen independently of one another, alkyl, alkynyl, haloalkyl, alkoxyl group, alkoxyalkyl, hydroxyalkyl, cyano group alkyl, halogenated alkoxy alkyl, G 2, or-(CR kR x) v-G 2
R 2a, when occurring each time, be alkyl independently, haloalkyl, alkoxyalkyl, hydroxyalkyl, cyano group alkyl, halogenated alkoxy alkyl, G 2, or-(CR kR x) v-G 2
G 2, when occurring each time, be aryl, heteroaryl, cycloalkyl, cycloalkenyl group, or heterocycle, wherein each G 2Be unsubstituted independently or being selected from following substituting group by 1,2,3,4 or 5 replaces :-G 3,-(CR 2gR 2h) w-G 3, alkyl, thiazolinyl, alkynyl, halogen ,-CN, oxo ,-NO 2,-OR 1b,-OC (O) R 1b,-OC (O) N (R Z4) (R 3b) ,-SR 1b,-S (O) 2R 2b,-S (O) 2N (R Z4) (R 3b) ,-C (O) R 1b,-C (O) OR 1b,-C (O) N (R Z4) (R 3b) ,-N (R Z4) (R 3b) ,-N (R Z4) C (O) R 1b,-N (R Z4) C (O) O (R 1b) ,-N (R Z4) C (O) N (R Z4) (R 3b) ,-(CR 2gR 2h) w-NO 2,-(CR 2gR 2h) w-OR 1b,-(CR 2gR 2h) w-OC (O) R 1b,-(CR 2gR 2h) w-OC (O) N (R Z4) (R 3b) ,-(CR 2gR 2h) w-SR 1b,-(CR 2gR 2h) w-S (O) 2R 2b,-(CR 2gR 2h) wS (O) 2N (R Z4) (R 3b) ,-(CR 2gR 2h) w-C (O) R 1b,-(CR 2gR 2h) w-C (O) OR 1b,-(CR 2gR 2h) w-C (O) N (R Z4) (R 3b) ,-(CR 2gR 2h) w-N (R Z4) (R 3b) ,-(CR 2gR 2h) w-N (R Z4) C (O) R 1b,-(CR 2gR 2h) w-N (R Z4) C (O) O (R 1b) ,-(CR 2gR 2h) w-N (R Z4) C (O) N (R Z4) (R 3b) ,-(CR 2gR 2h) w-CN, and haloalkyl;
G 3, when occurring each time, be monocyclic heterocycles independently, bicyclic heteroaryl, or monocyclic cycloalkyl; Wherein each G that occurs 3Be unsubstituted independently or being selected from following substituting group by 1,2,3 or 4 replaces :-N (R Z4) (R 3b), alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, halo, oxo, CN, and OH;
M, q, t, u, v, and w when occurring each time, are 1,2,3,4 independently of one another, or 5;
N and p when occurring each time, are 2,3,4 independently of one another, or 5;
R 1bAnd R 3b, when occurring each time, be hydrogen independently of one another, alkyl, haloalkyl, monocyclic cycloalkyl, or-(CR 2gR 2h) w-monocyclic cycloalkyl;
R 2b, when occurring each time, be alkyl independently, haloalkyl, monocyclic cycloalkyl, or-(CR 2gR 2h) w-monocyclic cycloalkyl;
R a, R c, R d, R e, R f, R 1g, R 2g, R 2h, R k, and R x, when occurring each time, be hydrogen independently of one another, halogen, alkyl, or haloalkyl;
R 1h, when occurring each time, be hydrogen independently of one another, halogen, alkyl, haloalkyl ,-OR 1b,-N (R Z4) (R 3b) ,-N (R Z4) C (O) R 1b,-N (R Z4) C (O) O (R 1b), or-N (R Z4) S (O) 2R 1b
Each R that occurs bBe hydrogen independently, halogen, alkyl, haloalkyl, or OH;
R Z3And R Z4, when occurring each time, be hydrogen independently of one another, alkyl, or haloalkyl; With
As by R 1b, R 2b, and R 3bThe monocyclic cycloalkyl as a substituting group or a substituent part of expression is unsubstituted or is selected from following substituting group by 1,2,3,4,5 or 6 and replaces: alkyl, halogen, haloalkyl, hydroxyl, oxo, and alkoxyl group;
Prerequisite is that this compound is not
The 4-methyl-N-[(3Z)-1-phenyl-1,4,5,6-tetrahydrochysene-3H-cyclopenta [c] isothiazole-3-subunit] benzsulfamide;
N-[(3Z)-and 1-cyclohexyl-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit]-the 4-methyl benzenesulfonamide;
The 4-methyl-N-[(3Z)-1-phenyl-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit] benzsulfamide; With
(5Z)-2,4-phenylbenzene isothiazole-5 (2H)-subunit urethanum.
2. according to compound or its medicinal acceptable salt or solvate, the wherein R of claim 1 1Be G 1,-NR Z1R Z5, or-OR Z5
3. according to compound or its medicinal acceptable salt or solvate, the wherein R of claim 1 2Be alkyl, alkynyl, thiazolinyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1
4. according to compound or its medicinal acceptable salt of claim 1, solvate, or the salt of solvate, wherein R 3Be hydrogen or C 1-6Alkyl, and R 4Be alkyl, haloalkyl, or G 2
5. according to compound or its medicinal acceptable salt of claim 1, solvate, or the salt of solvate, wherein
R 3Be hydrogen, C 1-6Alkyl, haloalkyl, or optional substituted cycloalkyl; With
R 2Be alkyl, thiazolinyl, alkynyl, G 1,-C (R Zb)=NO (R Z1) ,-O (R Za) ,-N (R Z1) (R Z2b) ,-(CR aR b) m-N 3,-(CR aR b) m-CN, haloalkyl ,-(CR aR b) m-O (R Za) ,-(CR aR b) m-C (O) O (R Zb) ,-(CR aR b) m-C (O) (R Zb) ,-(CR aR b) m-C (R Zb)=NO (R Z1) ,-(CR aR b) m-N (R Z1) (R Z2b), or-(CR aR b) m-G 1
6. according to compound or its medicinal acceptable salt of claim 5, solvate, or the salt of solvate, wherein
R 1Be G 1,-NR Z1R Z5, or-OR Z5
7. according to compound or its medicinal acceptable salt of claim 6, solvate, or the salt of solvate, wherein R 4Be alkyl, haloalkyl, or G 2
8. according to compound or its medicinal acceptable salt of claim 7, solvate, or the salt of solvate, wherein R 1Be G 1
9. according to compound or its medicinal acceptable salt of claim 7, solvate, or the salt of solvate, wherein L is C=O.
10. according to compound or its medicinal acceptable salt of claim 7, solvate, or the salt of solvate, wherein L is S (O) 2
11. according to compound or its medicinal acceptable salt of claim 7, solvate, or the salt of solvate, wherein L is C=S.
12. according to compound or its medicinal acceptable salt of claim 7, solvate, or the salt of solvate, wherein L is C=NCN.
13. according to compound or its medicinal acceptable salt of claim 1, solvate, or the salt of solvate, wherein R 2And R 3With the atom that they were connected to, formation contains zero or other two keys, zero or one be selected from O, S, N, and N's (H) is heteroatomic five-, six-or seven-first monocycle ring, each described monocycle ring is unsubstituted independently or is selected from following substituting group (R by 1,2,3,4 or 5 21) replace: oxo, alkyl, thiazolinyl, alkynyl, halogen ,-CN ,-O (R 1a) ,-C (O) OH ,-C (O) O (alkyl) ,-C (O) (R 1a) ,-N (R Z3) (R 3a) ,-N (R 3a) C (O) R 1a,-N (R 3a) C (O) O (R 1a) ,-N (R 3a) C (O) N (R Z3) (R 3a) ,-N (R 3a) S (O) 2(R 2a) ,-N (R 3a) S (O) 2N (R Z3) (R 3a) ,-SO 2(R 2a) ,-C (O) N (R Z3) (R 3a) ,-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN ,-(CR 1gR 1h) u-O (R 1a), and haloalkyl, two the adjacent or non-adjacent atoms of each randomly connect by the alkylidene bridge of 1,2,3 or 4 carbon atom in the described monocycle ring; With two substituting group (R on same carbon atom 21), with described carbon atom, randomly formation contains 0,1 or 2 first monocycle ring of heteroatomic 3-6 that is selected from O, S and N (H).
14. according to compound or its medicinal acceptable salt of claim 13, solvate, or the salt of solvate, wherein
R 1Be G 1,-NR Z1R Z5, or-OR Z5With
R 4Be alkyl, haloalkyl, or G 2
15. according to compound or its medicinal acceptable salt of claim 14, solvate, or the salt of solvate, wherein R 1Be G 1
16. according to compound or its medicinal acceptable salt of claim 14, solvate, or the salt of solvate, wherein L is C (O).
17. according to the compound of claim 1, it has formula (II)
Figure 35412DEST_PATH_IMAGE002
Or its medicinal acceptable salt, solvate, or the salt of solvate, wherein
G 3Be CH 2Or N (H);
R 21Be to contain G 3Any commutable atom of ring on optional substituting group and be oxo, alkyl, thiazolinyl, alkynyl, halogen ,-CN ,-O (R 1a) ,-C (O) OH ,-C (O) O (alkyl) ,-C (O) (R 1a) ,-N (R Z3) (R 3a) ,-N (R 3a) C (O) R 1a,-N (R 3a) C (O) O (R 1a) ,-N (R 3a) C (O) N (R Z3) (R 3a) ,-N (R 3a) S (O) 2(R 2a) ,-N (R 3a) S (O) 2N (R Z3) (R 3a) ,-SO 2(R 2a) ,-C (O) N (R Z3) (R 3a) ,-S (O) 2N (R Z3) (R 3a) ,-(CR 1gR 1h) u-G 2,-(CR 1gR 1h) u-CN ,-(CR 1gR 1h) u-O (R 1a), or haloalkyl; Two substituting group (R on same carbon atom 21), with described carbon atom, randomly form and contain 0,1 or 2 and be selected from O, S, or the heteroatomic 3-6 unit monocycle ring of N (H);
R is 0,1,2,3,4 or 5; With
R 1, L, and R 4Described in claim 1.
18. according to compound or its medicinal acceptable salt of claim 17, solvate, or the salt of solvate, wherein R 1Be G 1,-NR Z1R Z5, or-OR Z5With
R 4Be alkyl, haloalkyl, or G 2
19. according to compound or its medicinal acceptable salt of claim 18, solvate, or the salt of solvate, wherein R 1Be G 1
20. according to compound or its medicinal acceptable salt of claim 18, solvate, or the salt of solvate, wherein L is C (O).
21. according to the compound of the formula (I) of claim 1, it is selected from:
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-(1, the 1-dimethyl propyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-cyclobutyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and 4-butyl-2,3-dimethyl isothiazole-5 (2H)-subunit] six hydrogen-2,5-endo-methylene group pentalene (methanopentalene)-3a (1H)-methane amide;
N-[(5Z)-4-butyl-2-(1-methyl cyclobutyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-allyl group-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(3-methyl-4,5-dihydro-isoxazole-5-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyclopropyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(3Z)-and the 1-tertiary butyl-5-propyl group-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(3Z)-and the 1-tertiary butyl-1,4,6,7-tetrahydrochysene-3H-spiral shell [2,1-benzisothiazole-5,2'-[1,3] dioxolane]-the 3-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-methoxy ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-morpholine-4-base ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[2-(5,5-dimethyl-1,3-dioxane-2-yl) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-(2-azido-ethyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[3-(methoxyimino) propyl group] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-(2-aminoethyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[2-(dimethylamino) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-methyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-hydroxyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-cyanoethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2, the 3-dihydroxypropyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(methoxyimino) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1,3-dioxolane-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-hydroxy-2-methyl propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyanogen methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-[(1Z)-the but-1-ene base]-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-ethyl cyclopropyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(methylol) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(methoxymethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(ethoxyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (phenyl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-(azido methyl)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-cyclobutyl-1-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[cyclobutyl (hydroxyl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-benzyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-cyclobutyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyclobutylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-tetrahydrochysene-2H-pyrans-4-base isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (1,3-thiazoles-2-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,5-dimethoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-fluoro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-methyl benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (thiophene-2-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
4-{ (the 5Z)-2-tertiary butyl-5-[(5-chloro-2-methoxybenzoyl) imino-]-2,5-dihydro isothiazole-4-yl } methyl-butyrate;
4-{ (the 5Z)-2-tertiary butyl-5-[(5-cyano group-2-methoxybenzoyl) imino-]-2,5-dihydro isothiazole-4-yl } methyl-butyrate;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-fluorobenzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(2,2, the 2-trifluoro ethoxy) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(methylsulfonyl) benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[hydroxyl (1,3-thiazoles-4-yl) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1,3-thiazoles-4-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(thiophene-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
5-amino-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-formyl-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-[(methoxyimino) methyl] benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(formamido group)-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 5-[(oxyimino) methyl]-the 2-methoxy benzamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-the 4-methoxybenzoic acid;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-iodo-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-ethynyl-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethoxy) benzamide;
5-acetyl-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(difluoromethyl)-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(methyl fluoride)-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(tetrahydrofuran (THF)-2-ylmethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-[(1Z)-N-hydroxyl acetimidoyl (hydroxyethanimidoyl)]-the 2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(1,1-two fluoro ethyls)-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(2-furyl methyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(isopropoxy methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-the 4-methoxyl methyl benzoate;
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-oxo amyl group) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide;
N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4-methoxyl group isophthaloyl amine;
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-2-fluoro-3-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-hydroxy-4-methyl amyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-sec.-propyl-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluoro-4-methyl amyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-oxo butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(2,2, the 2-trifluoro ethoxy) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4,4-difluoro amyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-fluoro-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluoro-4-methyl amyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-{[(2R)-tetrahydrofuran (THF)-2-ylmethoxy] methyl } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(2-fluorine oxyethyl group) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[(2, the 2-difluoroethoxy) methyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 1-phenylcyclohexane carboxylic acid amides;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-(2-chloro-4-fluorophenyl) cyclohexane carboxamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-oxo-cyclopentane methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-phenyl cyclopentane formamide;
N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide;
N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3,3-difluoro azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide;
(1S, 4R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4,7,7-trimethylammonium-3-oxo-2-oxabicyclo [2.2.1] heptane-1-methane amide;
(1R, 4S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-4,7,7-trimethylammonium-3-oxo-2-oxabicyclo [2.2.1] heptane-1-methane amide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) tetramethyleneimine-1-ethyl formate;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) tetramethyleneimine-1-t-butyl formate;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1-(3-cyanopyridine-2-yl) tetramethyleneimine-3-methane amide;
4-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) dicyclo [2.2.2] octane-1-methyl-formiate;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-oxo-1-Phenylpyrrolidine-3-methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-N'-cyano group-2-anisole imino-methylamine (carboximidamide);
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-anisole thioformamide;
N-[(3Z)-and the 1-tertiary butyl-5-(trifluoromethyl)-4,5,6,7-tetrahydrochysene-2,1-benzisothiazole-3 (1H)-subunit]-5-chloro-2-methoxy benzamide;
(3Z)-and the 1-tertiary butyl-3-[(5-chloro-2-methoxybenzoyl) imino-]-1,4,6,7-tetrahydrochysene isothiazole is [4,3-c] pyridines-5 (3H)-t-butyl formate also;
N-[(3Z)-the 1-tertiary butyl-4,5,6,7-tetrahydrochysene isothiazole is [4,3-c] pyridines-3 (1H)-subunit also]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxybenzenesulphoismide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] naphthalene-1-sulphonamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(dimethylamino) naphthalene-1-sulphonamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] the hexanaphthene sulphonamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] benzsulfamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] quinoline-8-sulphonamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3,3-tetramethyl-cyclopropane carboxamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,3-dichlorobenzene sulphonamide;
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] diamantane-1-methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-methoxyl group-5-(trifluoromethyl) phenylimino methylamine (carboximidamide);
N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2-dimethyl-4-oxo-3,4-dihydro-2H-pyrans-6-methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-oxyethyl group-5-(trifluoromethyl) phenylimino methylamine (carboximidamide);
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-N'-cyano group-2-anisole imino-methylamine (carboximidamide);
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano-2-hydroxy-benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-cyano group-2-(2,2, the 2-trifluoro ethoxy) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-cyano-2-hydroxy-benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-(2,2, the 2-trifluoro ethoxy) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-hydroxybenzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyclopentyl-methyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(3-cyano group-3-methyl butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-cyano group butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(2-fluorine oxyethyl group) benzamide;
2-(2-amino-2-oxo oxyethyl group)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-the 5-chlorobenzamide;
2-(2-amino-2-oxo oxyethyl group)-the N-[(5Z)-2-tertiary butyl-4-(3-cyano group propyl group) isothiazole-5 (2H)-subunit]-the 5-chlorobenzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4,4,4-trifluoro butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-chloro-2-(2-fluorine oxyethyl group) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-5-cyano group-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-oxyethyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-amyl group isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-[2-(dimethylamino)-2-oxo oxyethyl group] benzamide;
N-[(5Z)-4-butyl-2-(2,2,2-three fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-butyl-2-(2-fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-2-methoxyl group-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-(cyano group methoxyl group) benzamide;
N-[(5Z)-4-butyl-2-(2-fluoro-1,1-dimethyl ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-4-(benzyloxy)-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-2-tertiary butyl-4-hydroxy isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-methyl ethoxy) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-methyl propoxy-) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(4-fluorine butoxy) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(cyano group methoxyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-{[(2S)-5-oxo-pyrrolidine-2-yl] methoxyl group } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-{[(2R)-5-oxo-pyrrolidine-2-yl] methoxyl group } isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
[(5Z)-and the 2-tertiary butyl-5-{[(5-chloro-2-methoxyphenyl) carbonyl] imino-}-3-methyl-2,5-dihydro isothiazole-4-yl] t-butyl carbamate;
N-[(5Z)-the 2-tertiary butyl-4-(1-hydroxyethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-ethoxyethyl group) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-(1-methoxy ethyl) isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-and the 2-tertiary butyl-4-[1-(2,2, the 2-trifluoro ethoxy) ethyl] isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
N-[(5Z)-the 2-tertiary butyl-4-vinyl isothiazole-5 (2H)-subunit]-5-chloro-2-methoxy benzamide;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-3-hydroxyl-1,2,2-trimethyl cyclopentane formic acid;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-3-hydroxyl-1,2,2-trimethyl cyclopentane formic acid;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate;
(1R, 3S)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-(tetramethyleneimine-1-base carbonyl) cyclopentane formamide;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane formic acid;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane ethyl formate;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane ethyl formate;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate;
(1R, 3S)-3-(azetidine-1-base carbonyl)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3-hydroxy azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid;
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, N 1, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[(3,3-difluoro azetidine-1-yl) carbonyl]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethyl cyclopentane methyl-formiate;
(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine peopentyl ester;
(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine 2,2, the 2-trichloro ethyl ester;
(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit carboxylamine 1-adamantane esters;
N 2-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-N 1, 3-dimethyl-L-valine amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-(4-methylcyclohexyl) urea;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(2S)-and 1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N'-cyano group-2-{[(2S)-1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) phenylimino methylamine (carboximidamide);
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(2S)-and 5-oxo-pyrrolidine-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-{[(4R)-and 2-oxo-1,3-oxazolidine-4-yl] methoxyl group }-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-[(1-methyl piperidine-2-yl) methoxyl group]-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-{[(2S)-and 1-methylpyrrolidin-2-yl] methoxyl group }-5-(trifluoromethyl) benzamide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-(pyrazine-2-ylmethoxy)-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-(pyrazine-2-ylmethoxy)-5-(trifluoromethyl) benzamide;
N-[(5Z)-the 2-tertiary butyl-4-isobutyl-isothiazole-5 (2H)-subunit]-2-(pyridine-2-ylmethoxy)-5-(trifluoromethyl) benzamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-propyl group pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane methyl-formiate;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-1,2,2-trimethyl cyclopentane formic acid;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-sec.-propyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclobutyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclopropyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 1-propyl group pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(3-hydroxypropyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-[(2R)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl Urethylane;
(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl urethanum;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-1,2,2-trimethyl cyclopentane methane amide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-propyl group pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-methoxy ethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(3-hydroxypropyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-3-(azetidine-1-base carbonyl)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3, N 3, 1,2,2-pentamethyl-pentamethylene-1,3-diformamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-2,2,3-trimethyl cyclopentane methane amide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-cyclobutyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-[(2S)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 3-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 1-[(2S)-and tetrahydrofuran (THF)-2-ylmethyl] pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-ethyl-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 3-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 1-(2-hydroxyethyl)-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-1,2,2-trimethyl cyclopentane methane amide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(4,5-dihydro-1,3-oxazole-2-yl)-2,2,3-trimethyl cyclopentane methane amide;
(1R, 3S)-N 3-benzyl-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane-1,3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridine-2-ylmethyl) pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridin-3-yl methyl) pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(pyridin-4-yl methyl) pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-Propargyl pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(2,2, the 2-trifluoroethyl) pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-Propargyl pentamethylene-1, the 3-diformamide;
(1S, 3R)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-(2,2, the 2-trifluoroethyl) pentamethylene-1, the 3-diformamide;
(1R, 3S)-N 1-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-N 3-methoxyl group-N 3, 1,2,2-tetramethyl-ring pentane-1,3-diformamide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(5,6-dihydro-4H-1,3-oxazine-2-yl)-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-(5,6-dihydro-4H-1,3-oxazine-2-yl)-1,2,2-trimethyl cyclopentane methane amide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] tetramethyleneimine-1-methane amide;
(1R, 3S)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2,2,3-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-(morpholine-4-base carbonyl) cyclopentane formamide;
(1R, 3S)-N 1-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-N 3-tetramethyleneimine-1-basic ring pentane-1, the 3-diformamide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] morpholine-4-methane amide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] benzamide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide;
(1S, 3R)-the 3-[(aminocarbonyl) amino]-N-[(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1S, 3R)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-{[(methylamino) carbonyl] amino } cyclopentane formamide;
N-[(1R, 3S)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] benzamide;
(1R, 3S)-3-(kharophen)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-({ [(2-hydroxyethyl) amino] carbonyl } amino)-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[({[(2S)-and the 2-hydroxypropyl] amino } carbonyl) amino]-1,2,2-trimethyl cyclopentane methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-3-[({[(2R)-and the 2-hydroxypropyl] amino } carbonyl) amino]-1,2,2-trimethyl cyclopentane methane amide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl]-3-hydroxy azetidine-1-methane amide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl]-3,3-difluoro azetidine-1-methane amide;
N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-2-(2-hydroxy-2-methyl propoxy-)-5-(trifluoromethyl) benzamide;
N-[(1S, 3R)-3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl)-2,2,3-trimethylammonium cyclopentyl] azetidine-1-methane amide;
(1R, 3S)-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-1,2,2-trimethylammonium-3-({ [methyl (phenyl) amino] carbonyl } amino) cyclopentane formamide;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) diamantane-1-methyl-formiate;
3-([(5Z)-and 4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit] amino } carbonyl) diamantane-1-formic acid; With
Uncle's 2-[(fourth amino) oxygen base]-N-[(5Z)-4-butyl-2-tertiary butyl isothiazole-5 (2H)-subunit]-5-(trifluoromethyl) benzamide; Or
Its medicinal acceptable salt, solvate, or the salt of solvate.
22. a pharmaceutical composition, it comprises compound or its medicinal acceptable salt of the formula according to claim 1 (I) for the treatment of significant quantity, solvate, or the salt of solvate, and medicinal acceptable carrier.
23. the method for a treatment pain in the Mammals of the such treatment of needs comprises giving the compound that this Mammals is treated the formula according to claim 1 (I) of significant quantity, or its medicinal acceptable salt, solvate, or the salt of solvate.
24. method of in the Mammals of the such treatment of needs, treating the illness that is selected from inflammatory conditions, immune disorders, neurological disorder, immune cancer, dyspnoea and cardiovascular disorder, the compound that comprises the formula according to claim 1 (I) that gives this Mammals treatment significant quantity, or its medicinal acceptable salt, solvate, or the salt of solvate.
CN2009801536988A 2008-11-04 2009-11-04 1,2 -thiazol yl derivatives as cannabinoid receptor ligands Pending CN102272111A (en)

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