CN101611018A - Heterocyclic sulfonamide with Edg-I antagonistic activity - Google Patents
Heterocyclic sulfonamide with Edg-I antagonistic activity Download PDFInfo
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- CN101611018A CN101611018A CNA2007800495750A CN200780049575A CN101611018A CN 101611018 A CN101611018 A CN 101611018A CN A2007800495750 A CNA2007800495750 A CN A2007800495750A CN 200780049575 A CN200780049575 A CN 200780049575A CN 101611018 A CN101611018 A CN 101611018A
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Abstract
The present invention relates to have structural formula (I), (Ia) and (Ib) compound or its drug acceptable salt, they have the Edg-1 antagonistic activity and therefore can be used for its antitumour activity and therefore be used for the treatment of the method for human or animal body.The invention still further relates to the method that is used to make described chemical compound, comprise that their pharmaceutical composition is used for warm-blooded animal at the manufacturing medicine with them, as the purposes in the philtrum generation antitumous effect.
Description
Edg (endothelium mutant gene) acceptor belongs to the very relevant lipid activation G-protein coupled receptor of a class.Edg-1, Edg-3, Edg-5, Edg-6, and Edg-8 (being also referred to as S1P1, S1P3, S1P2, S1P4, and S1P5) be confirmed as C18-Sphingosine 1-phosphate (SIP) specific acceptor.Edg-2, Edg-4, and Edg-7 (also being called LPA1 respectively, LP A2 and LP A3) be Ultrapole L (LPA) specific acceptor.In SIP acceptor abnormal shape, Edg-1, Edg-3 and Edg-5 by wide expression, are confined to central nervous system and the expression of Edg-6 is confined to the expression of Lymphoid tissue and thrombocyte and Edg-8 significantly in various tissues.
The Edg acceptor is responsible for signal transduction and is considered to comprising the cell development, hyperplasia, and maintenance, migration, variation plays an important role in the cell processes of plastics and apoptosis.Some Edg acceptor with blood vessel again or remove the disease form the matchmaker relevant-for example, the disease that causes by the glasses neovascularization, especially retinopathy (diabetic retinopathy, the xanthelasma sex change relevant) with the age; Psoriasis; With hemangioblastoma as " strawberry mark ".The Edg acceptor also with various inflammatory diseases, as sacroiliitis, rheumatoid disease sacroiliitis especially, the arteriosclerosis of artery arteriosclerosis and appearance after transplanting, endometriosis or chronic asthma; With, especially, tumor disease or lymphocytes interactions, for example, and transplant rejection, autoimmune disease, inflammatory disease, it is relevant with cancer to catch.The change of Edg receptor active influences the pathology and/or the symptomology of these diseases.Therefore, the molecule useful as therapeutics of altered self Edg receptor active is used for the treatment of these diseases.Therefore, the invention provides the have structural formula compound of (I):
Ring A is carbocyclic ring or heterocyclic radical; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
6Group replace;
R
1Be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, diazanyl, urea groups, N, N-two (C
1-3Alkyl) urea groups, alkyloyl C.6, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical, heterocyclic radical; R wherein
1Can be by one or more R on the carbon
7Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
8Group replace;
N is 0-5; R wherein
1Value can be identical or different;
R
2Be selected from C
16Alkyl, C
2-6Alkenyl or C
2-6Alkynyl, carbocylic radical, and heterocyclic radical; R wherein
2Can be by one or more R on the carbon
9Replace; If wherein described heterocyclic radical comprises the NH part, nitrogen can be optionally selected from R so
19Group replace;
R
3Be selected from hydrogen, C
1-6Alkyl, C
2-6Alkenyl or C
2-6Alkynyl, carbocylic radical, heterocyclic radical; R wherein
3Can be by one or more R on the carbon
11Replace; If wherein described heterocyclic radical comprises the NH part, nitrogen can be optionally selected from R so
20Group replace;
Or, in addition, R
2And R
3Can form C with the carbon that they connected
3-6The carbocyclic ring ring;
R
4Be selected from C
1-6Alkyl or carbocyclic ring; R wherein
4Can be by one or more R on the carbon
10Replace;
Ring D is fused on the have structural formula imidazoles of (I) and is 5-7 unit ring; If wherein described ring comprises-the NH-part, nitrogen can be optionally selected from R so
14Group replace;
R
5Be on carbon substituting group and be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N-(C
1-6Alkyl) amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, heterocyclic radical carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical, or two R
5Can form 5 to 8-unit's carbocyclic ring or heterocyclic rings with the carbon atom of the ring D that they connected; R wherein
5Can be by one or more R on the carbon
15Replace; If wherein described heterocyclic radical or heterocyclic ring comprise-the NH-part, nitrogen can optionally be selected from R by group so
1
M is 0-5; R wherein
5Value can be identical or different;
R
7, R
9, R
11And R
15Be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
16Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical; R wherein
7, R
9, R
11And R
15Can be independently on the carbon by one or more R
17Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
18Group replace;
R
6, R
8, R
13, R
14, R
16, R
18, R
19And R
20Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyl oxygen base carbonyl, benzoyl and phenyl sulfonyl;
R
10Be selected from halo, nitro, hydroxyl, amino, carboxyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical; R wherein
10Can be by one or more R on the carbon
12Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
13Group replace;
R
12And R
17Be selected from halo, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methyl sulfo-, ethylenebis dithiocarbamate, methyl sulfinyl, ethylsulfinyl-1 base, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
Or its drug acceptable salt; Prerequisite is, this compound is not the phenyl methyl of 4-methyl-N-[(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)] benzsulfamide.
In another embodiment, The compounds of this invention relates to structural formula (I) compound, A wherein, D, R
1, R
2, R
3, R
4, R
5, m and n definition are as structural formula (I) and its drug acceptable salt, and prerequisite is R
4It or not difluoromethyl.
In another embodiment, The compounds of this invention relates to the have structural formula compound of (Ia)
R wherein
3Be hydrogen and A, D, R
1, R
2, R
4, R
5, m and n definition are as structural formula (I) and its drug acceptable salt.
In another embodiment, The compounds of this invention relates to the have structural formula compound of (Ia), wherein R
3Be hydrogen and A, D, R
1, R
2, R
4, R
5, m and n definition are as structural formula (I) and its drug acceptable salt, and prerequisite is R
4It or not difluoromethyl.
In another embodiment, The compounds of this invention relates to the have structural formula compound of (Ib)
R wherein
3Be hydrogen and A, D, R
1, R
2, R
4, R
5, m and n definition are as structural formula (I) and its drug acceptable salt.
In another embodiment, The compounds of this invention relates to the have structural formula compound of (Ib), wherein R
3Be hydrogen and A, D, R
1, R
2, R
4, R
5, m and n definition are as structural formula (I) and its drug acceptable salt, and prerequisite is R
4It or not difluoromethyl.
In another embodiment,, The compounds of this invention relates to and has arbitrary structural formula (I), (Ia) and compound (Ib) wherein
Ring A is carbocyclic ring or heterocyclic radical; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
6Group replace;
R
1Be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N～(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical, heterocyclic radical; R wherein
1Can be by one or more R on the carbon
7Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
8Group replace;
N is 0-5; R wherein
1Value can be identical or different;
R
2Be selected from C
1-6Alkyl, C
2-6Alkenyl or C
2-6Alkynyl, carbocylic radical, and heterocyclic radical; R wherein
2Can be by one or more R on the carbon
9Replace; If wherein described heterocyclic radical comprises the NH part, nitrogen can be optionally selected from R so
19Group replace;
R
3Be selected from hydrogen, C
1-6Alkyl, C
2-6Alkenyl or C
2-6Alkynyl, carbocylic radical, heterocyclic radical; R wherein
3Can be by one or more R on the carbon
11Replace; If wherein described heterocyclic radical comprises the NH part, nitrogen can be optionally selected from R so
20Group replace;
R
4Be selected from C
1-6Alkyl or carbocyclic ring; R wherein
4Can be by one or more R on the carbon
10Replace;
Ring D is fused on the have structural formula imidazoles of (I) and is 5-7 unit ring; If wherein described ring comprises-the NH-part, nitrogen can be optionally selected from R so
14Group replace;
R
5Be on carbon substituting group and be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, heterocyclic radical carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical, or two R
5Can form 5 to 8-unit's carbocyclic ring or heterocyclic rings with the carbon atom of the ring D that they connected; R wherein
5Can be by one or more R on the carbon
15Replace; If wherein described heterocyclic radical or heterocyclic ring comprise-the NH-part, nitrogen can be optionally selected from R so
16Group replace;
M is 0-5; R wherein
5Value can be identical or different;
R
7, R
9, R
11And R
15Be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical; R wherein
7, R
9, R
11And R
15Can be independently on the carbon by one or more R
17Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
18Group replace;
R
6, R
8, R
13, R
14, R
16, R
18, R
19And R
20Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyl oxygen base carbonyl, benzoyl and phenyl sulfonyl;
R
10Be selected from halo, nitro, hydroxyl, amino, carboxyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical; R wherein
10Can be by one or more R on the carbon
12Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
13Group replace;
R
12And R
17Be selected from halo, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methyl sulfo-, ethylenebis dithiocarbamate, methyl sulfinyl, ethylsulfinyl-1 base, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethyl methyl acyl group, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
Or its drug acceptable salt; Prerequisite is, this compound is not the phenyl methyl of 4-methyl-N-[(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)] benzsulfamide.
In this specification sheets, term " alkyl " comprises direct sum branched chain alkyl group but each alkyl group is mentioned that as " propyl group " be concrete for the straight chain type only.For example, " C
1-6Alkyl " and " C
1-4Alkyl " comprises methyl, ethyl, propyl group, sec.-propyl and t-butyl.But to mentioning of each alkyl group, and mentioning to each branched chain alkyl group as ' sec.-propyl ' be concrete only to the branched chain type as ' propyl group ' be concrete only for the straight chain type.Similar convention is applicable to other groups.If dispensable substituting group is selected from " one or more " group, to be exemplified be to comprise all substituting groups that are selected from a kind of regulation group or the substituting group that is selected from two or more regulation groups in this definition so.
" heterocyclic radical " is comprise 4-12 atom saturated, fractional saturation or unsaturated, and list or dicyclo ring, wherein at least one atom is selected from nitrogen, sulphur or oxygen, unless otherwise prescribed, can be by carbon or nitrogen, wherein-CH
2-group can optionally be replaced by-C (O)-and, theheterocyclic nitrogen atom can optionally have C
1-6Alkyl group and formation quaternary compound or ring nitrogen and/or sulphur atom can be optionally oxidized to form N-oxide compound and or S-oxide compound.The embodiment and the suitable value of term " heterocyclic radical " are morpholinoes, piperidyl, pyridyl, pyranyl, pyrryl, isothiazolyl, indyl, quinolyl, thienyl, 1,3-benzo dioxy amyl group, thiadiazolyl group, piperazinyl, thiazolidyl, pyrrolidyl, thiomorpholine generation, pyrrolinyl, high piperazinyl, 3,5-two oxa-piperidyls, THP trtrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl ， isoxazolyl, N-methylpyrrole base, 4-pyridone, 1-isoquinolone, 2-Pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide compound.Other the value that is applicable to " heterocyclic radical " comprises 3,4-dihydro-1,4-oxazinyl; 2,3-dihydro-1,4-Ben Bing dioxin base; 2,1,3-diazosulfide base; Pyrazolyl.In one aspect of the invention, " heterocyclic radical " is comprise 5 or 6 atoms saturated, fractional saturation or unsaturated, and list or dicyclo ring, wherein at least one atom is selected from nitrogen, sulphur or oxygen, unless otherwise prescribed, it can be carbon or nitrogen keyed jointing ,-CH
2-group can optionally be replaced by-C (O)-and the epithio atom can be optionally oxidized to form the S-oxide compound.
" carbocyclic ring " is comprise 3-12 atom saturated, fractional saturation or unsaturated, list or bicyclic carbocyclic; Wherein-CH
2-group can optionally be replaced by-C (O)-.Especially " carbocyclic ring " is the dicyclo ring that comprises single cyclic rings of 5 or 6 atoms or comprise 9 or 10 atoms.The value that is applicable to " carbocyclic ring " comprises cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralyl, indanyl or 1-oxo indanyl.
" C
3-6The carbocyclic ring ring " be comprise a 3-6 carbon atom saturated mono ring-type carbocyclic ring wherein-CH
2-group can optionally be replaced by-C (O)-.Be applicable to " C
3-6The carbocyclic ring ring " value comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.For " ring D is fused to and has structural formula (I), on the imidazoles of structural formula (Ia) or structural formula (Ib) and be 5-7 unit ring ", described ring comprise imidazoles carbon-to-carbon double bond and, except described pair of key, comprise 3-5 by the single or doubly linked C of being selected from, N, other annular atomses of O or S.The suitable embodiment that is fused to the ring D on the have structural formula imidazoles of (I) comprises the 1H-benzimidazolyl-, 1H-imidazoles [4,5-b] pyridyl, 1H-imidazoles [4,5-c] pyridyl, 3H-imidazoles [4,5-c] pyridyl, 3H-imidazoles [4,5-b] pyridyl, 5H-imidazoles [4,5-c] pyridazinyl and 7H-purine radicals.
Two R
5(m=2) can form 5 to 8-unit's carbocyclic ring or heterocyclic rings with the carbon of the ring D that they connected.The example of these rings comprises alkyl dioxin or two Oxolan basic rings.
" C
1-6Alkyloyl oxygen base " an example be acetoxyl group." C
1-6Alkoxy carbonyl " example comprise methoxycarbonyl, ethoxy carbonyl, n-and t-butoxy carbonyl." C
1-6Alkoxyl group " example comprise methoxyl group, oxyethyl group and propoxy-." C
1-6Alkanoylamino " example comprise formamido group, kharophen and propionyl amino." C
1-6Alkyl S (O), wherein a is 0 to 2 " example comprise the methyl sulfo-, ethylenebis dithiocarbamate, methyl sulfinyl, ethylsulfinyl-1 base, methylsulfonyl and ethylsulfonyl." C
1-6Alkyloyl " example comprise propionyl and ethanoyl." N-(C
1-6Alkyl) amino " example comprise methylamino and ethylamino." N, N-(C
1-6Alkyl)
2Amino " example comprise two N-methylaminos, the amino and N-ethyl-N-methylamino of two (N-ethyls)." C
2-6Alkenyl " example be vinyl, allyl group and 1-propenyl." C
2-6Alkynyl " example be ethynyl, 1-proyl and 2-propynyl." N-(C
1-6Alkyl) sulfamyl " example be N-(methyl) sulfamyl and N-(ethyl) sulfamyl." N, N-(C
1-6Alkyl)
2Sulfamyl " example be N, N-(dimethyl) sulfamyl and N-(methyl)-N-(ethyl) sulfamyl." N-(C
1-6Alkyl) formamyl " example be methylamino carbonyl and ethylamino carbonyl." N, N-(C
1-6Alkyl)
2Formamyl " example be dimethylamino carbonyl and methylethyl aminocarboxyl." C
1-6Alkyl sulfonyl-amino " example comprise methyl sulphonyl amino, sec.-propyl sulfuryl amino and t-butyl sulfuryl amino." C
1-6Alkyl sulphonyl " example comprise methyl sulphonyl, sec.-propyl alkylsulfonyl and t-butyl alkylsulfonyl.
Has structural formula (I), some compounds of structural formula (Ia) or structural formula (Ib) can have chiral centre and/or geometrical isomer center (E-and Z-isomer), will be exemplified with the present invention is to comprise all these optics, diastereomer and the geometrical isomer with Edg-1 antagonistic activity.
What the present invention relates to have the Edg-1 antagonistic activity has structural formula (I), any and all tautomeric forms of the compound of structural formula (Ia) or structural formula (Ib).
It is also understood that to have structural formula (I), some compound of structural formula (Ia) or structural formula (Ib) can solvation and not the solvation form as, for example, hydrated form exists.It is to comprise all these the solvation forms with Edg-1 antagonistic activity that the present invention will be exemplified.
The particular value of variable group is as follows.These values can be as required and above and following defined any definition, and claim or embodiment are used together.Ring A is a carbocyclic ring.
Ring A is a heterocyclic radical; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
6Group replace.
Ring A is a pyrazolyl, imidazolyl, 3,4-dihydro-2H-1, the 4-benzoxazinyl, pyrryl, furyl, pyridyl, thiazolyl ， isoxazolyl, 3,4-dihydro-2H-1, the 4-benzoxazinyl, 1,3-benzo dioxy amyl group, 2,1,3-diazosulfide, quinolyl or thienyl, wherein said pyrazolyl, imidazolyl, 3,4-dihydro-2H-1,4-benzoxazinyl or pyrryl can be gone up if necessary in N and be selected from R
6Group replace.
Ring A is a pyrazolyl, imidazolyl, 3,4-dihydro-2H-1,4-benzoxazinyl, pyrryl, furyl, pyridyl, thiazolyl ， isoxazolyl, 3,4-dihydro-2H-1,4-benzoxazine, 1,3-benzo dioxy amyl group, 2,1,3-diazosulfide, quinolyl, thienyl, cyclopropyl, cyclopentyl or cyclohexyl, wherein said pyrazolyl, imidazolyl, 3,4-dihydro-2H-1,4-benzoxazinyl or pyrryl can be gone up if necessary in N and be selected from R
6Group replace.
R
6Be C
1-3Alkyl.
Ring A is an aryl.
Ring A is a phenyl.
Ring A is a phenyl, pyridyl or pyrimidyl.
Ring A is a phenyl, pyridyl, pyrimidyl or pyrryl.
Ring A is a phenyl, pyridyl, pyrimidyl or N-methylpyrrole base.Ring A is C
3-6Cycloalkyl.
Ring A is a cyclopropyl, cyclopentyl, cyclohexyl.
R
1Be halo, cyano group, C
1-3Alkanoylamino, C
1-3Alkyl or C
1-3Alkoxy carbonyl.
R
1Be halo, cyano group, formamyl, or C
1-3Alkyl.
R
1Be halo, cyano group, formamyl, or methyl.R
1Be halo, cyano group, formamyl, C
1-3Alkoxyl group or C
2-6Alkenyl.
R
1Be halo or cyano group.
R
1It is halo.
R
1Be bromine, chlorine or fluorine.
R
1Be chlorine.
N is 0-3.
N is 1.
N is 2.
Ring A is a phenyl, R
1Being selected from halo or cyano group and n is 1 or 2.
R
2Be C
1-6Alkyl.
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein:
R
9It is carbocyclic ring.
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein:
R
9Be carbocylic radical, R wherein
9Can be independently on the carbon by one or more R
17Replace; Wherein:
R
17It is halo.
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein:
R
9It is carbocyclic ring; R wherein
9Can be independently on the carbon by one or more R
17Replace; Wherein:
R
17It is fluorine.
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein:
R
9It is heterocyclic radical.
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein:
R
9It is pyridyl.
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein:
R
9Be heterocyclic radical, R wherein
9Can be independently on the carbon by one or more R
17Replace; If wherein described heterocyclic radical comprises the NH part, nitrogen can be optionally selected from R so
19Group replace.
R
2It is methyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein:
R
9It is phenyl.R
2It is methyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein:
R
9Be by one or more R on the carbon
17The phenyl that replaces.
R
2It is methyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; Wherein: R
9The phenyl that to be phenyl replaced by one or more halos on the carbon.
R
2Be methyl, ethyl, sec.-propyl, or isobutyl-; R wherein
2Can be independently on the carbon by one or more R
9Replace.
R
2Be methyl, ethyl, sec.-propyl, isobutyl-or benzyl.
R
2It is methyl.
R
3Be hydrogen.
R
3Be C
1-6Alkyl.
R
3It is methyl.
R
2And R
3Form C with the carbon that they connected
3-6The carbocyclic ring ring.
R
2And R
3Form cyclopropyl or cyclobutyl ring with the carbon that they connected.
R
4Be selected from C
1-6Alkyl; R wherein
4Can be by one or more R on the carbon
10Replace.
R
4Be selected from methyl, ethyl, propyl group or isobutyl-; R wherein
4Can be by one or more R on the carbon
10Replace; Wherein:
R
10It is cyclopropyl.
R
4Be selected from methyl, cyclopropyl methyl, ethyl, propyl group, isobutyl-or C
3-6Cycloalkyl.
R
4Be C
3-6Cycloalkyl; R wherein
4Can be by one or more R on the carbon
10Replace.
R
4It is cyclopropyl.
R
4It is ethyl.
R
4It or not difluoromethyl.
Be fused to and have structural formula (I), ring D formation 1H-benzoglyoxaline or 3H-imidazoles [4,5-b] pyridine on the imidazoles of structural formula (Ia) or structural formula (Ib).
Be fused to and have structural formula (I), ring D formation 1-H-benzoglyoxaline or 3H-imidazoles [4,5-c] pyridine on the imidazoles of structural formula (Ia) or structural formula (Ib).Be fused to and have structural formula (I), ring D on the imidazoles of structural formula (Ia) or structural formula (Ib) forms 1H-benzoglyoxaline, 1H-imidazoles [4,5-b] pyridyl, 1H-imidazoles [4,5-c] pyridyl, 3H-imidazoles [4,5-c] pyridyl, 3H-imidazoles [4,5-b] pyridyl, 5H-imidazoles [4,5-c] pyridazinyl and 7H-purine radicals.
Be fused to and have structural formula (I), ring D formation 1-H-imidazoles [4,5-c] pyridine or hydrazine-3H-imidazoles [4,5-c] pyridines (2: 1) on the imidazoles of structural formula (Ia) or structural formula (Ib).Be fused to and have structural formula (I), the ring D formation 1-H-benzoglyoxaline on the imidazoles of structural formula (Ia) or structural formula (Ib), 3H-imidazoles [4,5-b] pyridine, 1H-imidazoles [4,5-c] pyridine or hydrazine-3H-imidazoles [4,5-c] pyridines (2: 1).
R
5Be on carbon substituting group and be independently selected from halo, carboxyl, formamyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, heterocyclic radical carbonyl, carbocyclic ring or heterocyclic radical, or two R
5Can form 5 to 8-unit's carbocyclic ring or heterocyclic rings with the carbon atom of the ring D that they connected; R wherein
5Can be by one or more R on the carbon
15Replace; If wherein described heterocyclic radical or heterocyclic ring comprise-the NH-part, nitrogen can be optionally selected from R so
16Group replace;
R
5Be halo, methyl, trifluoromethyl, N-methylmorpholine generation, methoxyl group, trifluoromethoxy, ethoxy carbonyl, hydroxymethyl, difluoromethyl, carboxyl, formamyl, N, N-(C
1-6Alkyl)
2Formamyl, N-morpholino carbonyl, N, N-dimethylaminomethyl, N-morpholino methyl, methoxycarbonyl, methyl mercapto, methyl sulphonyl, pyridyl and cyclopropyl.
R
5Be halo, C
1-6Alkyl, C
ι-6Alkoxyl group or C
3-6Cycloalkyl, wherein R
5Can be by one or more R on the carbon
15Replace.
R
5Be halo, C
1-6Alkyl, C
1-6Alkoxyl group or C
3-6Cycloalkyl, wherein R
5Can on carbon, be replaced by one or more halos.
R
5Be C
1-6Alkyl, C
1-6Alkoxyl group or C
3-6Cycloalkyl, wherein R
5Can on carbon, be replaced by one or more halos.
R
5Be halo, C
1-6Alkyl or C
1-6Alkoxyl group.
R
5Be trifluoromethyl, methoxyl group or cyclopropyl.
R
5It is halo.
R
5Be chlorine or fluorine.
R
5Be that halo and m are 1.
R
5Be that halo and m are 2.
R
5Be C
1-6Alkyl.
R
5Be C
1-6Alkyl, wherein R
5Can on carbon, be replaced by halo.
R
5It is trifluoromethyl.
R
5Be C
1-6Alkoxyl group.
R
5It is methoxyl group.
M is 0,1 or 2.
M is 0,1,2 or 3.
M is 0.
M is 1.
M is 2.
M is 3.
In another aspect of this invention, provide to have structural formula (I), the compound (as mentioned above) of structural formula (Ia) or structural formula (Ib), wherein:
Ring A is carbocyclic ring or heterocyclic radical, if wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
6Group replace;
R
1Be halo, cyano group, formamyl, C
1-6Alkoxyl group, C
1-6Alky or C
2-6Alkynyl;
N is 0,1 or 2;
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9
R
3Be hydrogen or C
1-6Alkyl; Or R
2And R
3Form cyclopropyl or cyclobutyl ring with the carbon that they connected;
R
4Be selected from C
1-6Alkyl or C
3-6Cycloalkyl; R wherein
4Can be by one or more R on the carbon
10Replace;
Be fused to and have structural formula (I), the ring D formation 1H-benzoglyoxaline on the imidazoles of structural formula (Ia) or structural formula (Ib), 3H-imidazoles [4,5-b] pyridine or 1H-imidazoles [4,5-c] pyridine;
R
5Be halo, C
1-6Alkyl, C
3-6Cycloalkyl or C
1-6Alkoxyl group, wherein C
1-6Alkyl is replaced by halo on carbon; With
M is 0,1 or 2;
Or its drug acceptable salt.
In another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is carbocyclic ring or heterocyclic radical, if wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
6Group replace;
R
6Be C
1-3Alkyl; R
1Be halo, cyano group, formamyl, C
1-6Alkoxyl group or C
1-6Alkyl;
N is 1 or 2;
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace;
R
3Be hydrogen; R
4Be selected from C
1-6Alkyl, wherein R
4Can be by one or more R on the carbon
10Replace;
Be fused to and have structural formula (I), the ring D formation 1H-benzoglyoxaline on the imidazoles of structural formula (Ia) or structural formula (Ib), 3H-imidazoles [4,5-b] pyridine or 1H-imidazoles [4,5-c] pyridine;
R
5Be halo, C
1-6Alkyl, C
3-6Cycloalkyl or C
1-6Alkoxyl group, wherein C
1-6Alkyl is replaced by halo on carbon; With
M is 0,1 or 2;
R
9And R
10Definition is as structural formula (I);
Or its drug acceptable salt.
In another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is carbocyclic ring or heterocyclic radical;
R
1Be halo, cyano group, formamyl or C
1-6Alkoxyl group;
N is 1 or 2;
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace;
R
3Be hydrogen or C
1-6Alkyl; Or R
2And R
3Form cyclopropyl or cyclobutyl ring with the carbon that they connected;
R
4Be selected from C
1-6Alkyl or C
3-6Cycloalkyl; R wherein
4Can be by one or more R on the carbon;
Be fused to and have structural formula (I), the ring D formation 1H-benzoglyoxaline on the imidazoles of structural formula (Ia) or structural formula (Ib), 3H-imidazoles [4,5-b] pyridine, 1H-imidazoles [4,5-c] pyridine or hydrazine-3H-imidazoles [4,5-c] pyridines (2: 1);
R
5Be halo, C
1-6Alkyl or C
ι-6Alkoxyl group, wherein C
1-6Alkyl is replaced by halo on carbon; With
M is 0,1 or 2;
Or its drug acceptable salt.
In another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is carbocyclic ring or heterocyclic radical; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
6Group replace;
R
1Be halo, cyano group, formamyl, C
1-6Alkyl, C
2-6Alkynyl or C
1-6Alkoxyl group;
N is 1 or 2;
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace;
R
3Be hydrogen or C
1-6Alkyl; Or R
2And R
3Form cyclopropyl or cyclobutyl ring with the carbon that they connected;
R
4Be selected from C
1-6Alkyl or C
3-6Cycloalkyl; R wherein
4Can be by one or more R on the carbon
1
Be fused to and have structural formula (I), the ring D formation 1H-benzoglyoxaline on the imidazoles of structural formula (Ia) or structural formula (Ib), 3H-imidazoles [4,5-b] pyridine or 1H-imidazoles [4,5-c] pyridine;
R
5Be halo, C
1-6Alkyl or C
1-6Alkoxyl group, wherein C
1-6Alkyl is replaced by halo on carbon; With
M is 0,1 or 2;
Or its drug acceptable salt.
In another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is selected from phenyl, cyclopropyl, cyclopentyl, cyclohexyl, pyrazolyl, imidazolyl, furyl, pyridyl, 1,3-thiazoles base ， isoxazolyl, thienyl, pyrryl, 3,4-dihydro-2H-1, the 4-benzoxazinyl, 2,3-dihydro-1,4-Ben Bing dioxin base, 2,1,3-diazosulfide base, quinolyl, dihydro naphthyl, pyrimidyl, pyridyl-N-oxide compound, or 6-oxo-1,6-dihydropyridine base, wherein said pyrazolyl, imidazolyl, pyrryl and 3,4-dihydro-2H-1, the 4-benzoxazinyl can be selected from R on nitrogen
6Group replace;
R
1Be selected from halo, nitro, cyano group, amino, formamyl, C
1-6Alkyl, C
2-6Alkynyl C
1-6Alkoxyl group, diazanyl, urea groups, N, N-two (C
1-3Alkyl) urea groups, C
1-6Alkanoylamino, C
1-6Alkyl S (O), wherein a is 0 to 2, carbocylic radical, heterocyclic radical; R wherein
1Can be by one or more R on the carbon
7Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
8Group replace;
N is 0,1,2 or 3;
R
2Be selected from methyl, ethyl, sec.-propyl, isobutyl-, phenyl methyl, 4-fluorophenyl methyl and pyridylmethyl;
R
3Be hydrogen or methyl; Or R
2And R
3Form cyclopropyl or cyclobutyl ring with the carbon that they connected;
R
4Be selected from methyl, ethyl, propyl group, cyclopropyl, cyclopropyl methyl, isobutyl-and 2,2,2-trifluoroethyl;
Be fused to and have structural formula (I), the ring D formation 1H-benzoglyoxaline on the imidazoles of structural formula (Ia) or structural formula (Ib), 3H-imidazoles [4,5-b] pyridine, 1H-imidazoles [4,5-c] pyridine, 1H-imidazoles [4,5-b] pyridine, 3H-imidazoles [4,5-c] pyridine or 5H-imidazoles [4,5-c] pyridazinyl;
R
5Be selected from chlorine, bromine, fluorine, methyl, isobutyl-, hydroxymethyl, difluoromethyl, trifluoromethyl, morpholinyl-4-methyl, N, the N-dimethylaminomethyl, cyclopropyl, methoxyl group, trifluoromethoxy, carboxyl, ethyl carboxyl, methyl carboxyl, formamyl, N, N-formyl-dimethylamino, morpholinyl carbonyl, 3-pyridyl, the 4-pyridyl, the methyl sulfo-, methyl sulphonyl is replaced by halo on carbon; With
M is 0,1 or 2;
If or m=2, two R
5Common dioxin base or the dioxy amyl group ring of forming;
Or its drug acceptable salt.
Therefore in another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein: ring A is a carbocyclic ring;
R
1It is halo;
N is 1;
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace;
R
3Be hydrogen or C
1-6Alkyl;
R
4Be selected from C
1-6Alkyl or C
3-6Cycloalkyl; R wherein
4Can be by one or more R on the carbon
10Replace;
Be fused to and have structural formula (I), the ring D formation 1H-benzoglyoxaline on the imidazoles of structural formula (Ia) or structural formula (Ib), 3H-imidazoles [4,5-b] pyridine, 1H-imidazoles [4,5-c] pyridine or hydrazine-3H-imidazoles [4,5-c] pyridines (2: 1);
R
5Be halo, C
1-6Alkyl or C
1-6Alkoxyl group, the wherein C that is replaced by halo on the carbon
1-6Alkyl;
M is 0,1 or 2;
R
9Be carbocyclic ring or heterocyclic radical; With
R
10It is carbocyclic ring;
Or its drug acceptable salt.
In another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is a carbocyclic ring;
R
1It is halo;
N is 1;
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace;
R
3Be hydrogen or C
1-6Alkyl;
R
4Be selected from C
1-6Alkyl or C
3-6Cycloalkyl; R wherein
4Can be by one or more R on the carbon
10Replace;
Be fused to and have structural formula (I), ring D on the imidazoles of structural formula (Ia) or structural formula (Ib) forms the 1H-benzoglyoxaline, 3H-imidazoles [4,5-b] pyridyl, 1H-imidazoles [4,5-c] pyridyl, hydrazine-3H-imidazoles [4,5-c] pyridyl (2: 1), 5H-imidazoles [4,5-c] pyridazinyl or 7H-purine radicals;
R
5Be halo, C
1-6Alkyl or C
1-6Alkoxyl group, wherein C
1-6Alkyl is replaced or two R by halo on carbon
5Can form 5 to 8-unit's carbocyclic ring or heterocyclic rings with the carbon atom of the ring D that they connected; Wherein 5 to 8-unit's rings can be by one or more R on the carbon
15Replace; If wherein described heterocyclic ring comprises-the NH-part, nitrogen can be optionally selected from R so
16Group replace;
M is 0,1 or 2;
R
9Be carbocyclic ring or heterocyclic radical; With
R
10It is carbocyclic ring;
Or its drug acceptable salt.
Therefore in another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is a carbocyclic ring;
R
1It is halo;
N is 1;
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace; R
3Be hydrogen;
R
4Be selected from C
1-6Alkyl; R wherein
4Can be by one or more R on the carbon
10Replace;
Be fused to and have structural formula (I), ring D on the imidazoles of structural formula (Ia) or structural formula (Ib) forms the 1-H-benzimidazolyl-, 3H-imidazoles [4,5-b] pyridyl, 1H-imidazoles [4,5-c] pyridyl, hydrazine-3H-imidazoles [4,5-c] pyridyl (2: 1), 5H-imidazoles [4,5-c] pyridazinyl and 7H-purine radicals;
R
5Be halo or C
1-6Alkyl, wherein C
1-6Alkyl is replaced by halo on carbon.
M is 0,1 or 2;
R
9Be carbocyclic ring or heterocyclic radical; With
R
10It is carbocyclic ring;
Or its drug acceptable salt.
In another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is a carbocyclic ring;
R
1Be halo or cyano group; N is 1;
R
2Be C
1-6Alkyl; R wherein
2Can be independently on the carbon by one or more R
9Replace;
R
3Be hydrogen;
R
4Be selected from C
1-6Alkyl; R wherein
4Can be by one or more R on the carbon
10Replace;
Be fused to and have structural formula (I), ring D on the imidazoles of structural formula (Ia) or structural formula (Ib) forms the 1-H-benzimidazolyl-, 3H-imidazoles [4,5-b] pyridyl, 1H-imidazoles [4,5-c] pyridyl, hydrazine-3H-imidazoles [4,5-c] pyridyl (2: 1), 5H-imidazoles [4,5-c] pyridazinyl and 7H-purine radicals;
R
5Be halo or C
1-6Alkyl, wherein C
1-6Alkyl is replaced by halo on carbon;
M is 0,1 or 2;
R
9Be carbocyclic ring or heterocyclic radical; With
R
10It is carbocyclic ring;
Or its drug acceptable salt.
Therefore in another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is a phenyl;
R
1Be chlorine; N is 1;
R
2Be methyl, ethyl, sec.-propyl, or isobutyl-; R wherein
2Can be independently on the carbon by one or more R
9Replace;
R
3Be hydrogen;
R
4Be selected from methyl, cyclopropyl methyl, ethyl, propyl group or isobutyl-;
Be fused to and have structural formula (I), ring D formation 1-H-benzoglyoxaline or 3H-imidazoles [4,5-b] pyridine on the imidazoles of structural formula (Ia) or structural formula (Ib), 1H-imidazoles [4,5-c] pyridine or hydrazine-3H-imidazoles [4,5-c] pyridines (2: 1);
R
9It is carbocyclic ring; With
M is 0;
Or its drug acceptable salt.
Therefore in another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is a phenyl;
R
1Be chlorine, cyano group or fluorine;
N is 0 or 1;
R
2Be methyl, ethyl, sec.-propyl, or isobutyl-;
R
3Be hydrogen;
R
4Be selected from methyl, cyclopropyl methyl, ethyl, propyl group or isobutyl-;
Be fused to and have structural formula (I), ring D formation 1H-benzoglyoxaline or 3H-imidazoles [4,5-b] pyridine on the imidazoles of structural formula (Ia) or structural formula (Ib), 1H-imidazoles [4,5-c] pyridine or hydrazine-3H-imidazoles [4,5-c] pyridines (2: 1); With
M is 0;
Or its drug acceptable salt.
Therefore in another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is a phenyl, pyrimidyl or pyridyl;
R
1Be chlorine, fluorine, cyano group, formamyl, or;
N is 0 or 1;
R
2It is methyl;
R
3Be hydrogen or methyl;
R
4Be selected from methyl, cyclopropyl methyl, ethyl, propyl group or isobutyl-;
Be fused to and have structural formula (I), ring D formation 1-H-benzoglyoxaline or 3H-imidazoles [4,5-b] pyridine on the imidazoles of structural formula (Ia) or structural formula (Ib), 1H-imidazoles [4,5-c] pyridine or hydrazine-3H-imidazoles [4,5-c] pyridines (2: 1); With
M is 0;
Or its drug acceptable salt.
In another aspect of this invention, provide to have structural formula (I), the compound of structural formula (Ia) or structural formula (Ib) (as mentioned above), wherein:
Ring A is phenyl or pyridyl;
R
1Be halo, cyano group, formamyl or C
1-6Alkyl;
N is 1 or 2;
R
2It is methyl;
R
3Be hydrogen;
R
4It is ethyl;
Be fused to and have structural formula (I), the ring D formation 1H-benzoglyoxaline on the imidazoles of structural formula (Ia) or structural formula (Ib), 3H-imidazoles [4,5-b] pyridine, 1H-imidazoles [4,5-c] pyridine or 1H-imidazoles [4,5-b] pyridine;
R
5Be trifluoromethyl, methoxyl group or cyclopropyl; With
M is 1;
Or its drug acceptable salt.
In another aspect of this invention, the preferred compound of the present invention is arbitrary example or its drug acceptable salt.
Another embodiment of the present invention relates to embodiment 145,148, and 149,150,151,152,158,160,161,173,174,180 and 183 compound or its drug acceptable salt.
Another aspect of the present invention provides a kind of method that preparation has compound or the drug acceptable salt or the interior hydrolyzable ester of its body of structural formula (I) that is used for, and this method (variable group definition such as structural formula (I) wherein unless otherwise prescribed) comprising:
Method a) will have the compound of structural formula (II):
With the amine with structural formula (III):
The reaction and then if desired:
I) structural formula (I) compound is changed into another structural formula (I) compound;
Ii) remove any blocking group;
Iii) form drug acceptable salt.
L is a displaceable group, and the value that is applicable to L for example is, halo is chlorine or bromine for example.More than Fan Ying special reaction condition is as follows.
Method a) has that structural formula (II) and compound (III) can next reacts in the existence of suitable solvent such as DCM and alkali such as triethylamine.Reaction may need heat condition.
Compound with structural formula (II) is commercially available, or they be in the document known or they can prepare by methods known in the art.
Compound with structural formula (III) can prepare according to scheme 1:
Scheme 1
Compound with structural formula (III) also can prepare according to scheme 2:
Scheme 2
Compound with structural formula (2b) also can prepare according to scheme 2a:
Compound with structural formula (III) also can prepare according to scheme 3:
Scheme 3
Compound with structural formula (III) also can prepare according to scheme 4:
Scheme 4
Some that is appreciated that various ring substituents in the The compounds of this invention can be introduced or generate by conventional functional group modification immediately before or after aforesaid method by the substitution reaction of standard aromatics, and these are included in the method for the present invention.These reactions and modification comprise, for example, utilize the substituting group of aromatics substitution reaction to introduce substituent reduction, substituent alkylation and substituent oxidation.The reagent and the reaction conditions that are used for these steps are that chemical field is known.The object lesson of aromatics substitution reaction comprises and uses concentrated nitric acid and introduce nitryl group, uses, and for example, carboxylic acid halides and Lewis acid (as aluminum chloride) are under Friedel Crafts condition and introduce carboxyl groups; Use alkylogen and Lewis acid (as aluminum chloride) under Friedel Crafts condition and introduce alkyl group; With introducing halogen foundation group.The object lesson of modification comprises by for example, and catalytic hydrogenation is used nickel catalyzator or with iron processing and nitryl group is reduced into amino group under heating in the presence of the spirit of salt; Alkylthio is oxidized to alkyl sulfinyl or alkyl sulphonyl.
Be further appreciated that in reactions more as herein described, may need/protect ideally any sensitive group in the compound.Need or wish the situation of protection and be applicable to that the method for protection is that those skilled in the art are known.The GPF (General Protection False group can use (illustration referring to T.W.Green, the blocking group in the organic synthesis, John Wiley and Sons, 1991) according to standard practice.Therefore, if reactant comprises group such as amino, carboxyl or hydroxyl, may be in the reaction of mentioned some of this paper blocking group.
The blocking group that is applicable to amino or alkylamino group is; for example; carboxyl groups, for example alkyloyl group such as ethanoyl, alkoxycarbonyl groups; methoxycarbonyl for example; ethoxy carbonyl or t-butoxy carbonyl group, aryl methoxy carbonyl group, for example benzyl oxygen base carbonyl; or aroyl group, for example benzoyl.The inevitable basis of protective condition of going that is used for above blocking group changes the selection of blocking group.Therefore, for example, carboxyl groups such as alkyloyl or alkoxycarbonyl groups or aroyl group can be for example, by with suitable alkali such as alkali metal hydroxide, lithium hydroxide for example, sodium hydroxide or ammoniacal liquor are separated and are removed.In addition; carboxyl groups such as t-butoxy carbonyl group can for example pass through with suitable acid such as spirit of salt; sulfuric acid; sulfuric acid or phosphoric acid or trifluoroacetic acid are handled and are removed and aryl methoxy carbonyl group such as benzyl oxygen base carbonyl group can pass through hydrogenation on palladium on catalyzer such as the carbon, or by with Lewis acid for example the processing of three (trifluoroacetic acid) boron remove.Other blocking groups that are applicable to the primary amino group are for example, can pass through to use alkanamine, for example dimethylamino propylamine, or the phthalyl group of removing with the hydrazine processing.The blocking group that is applicable to oh group is, for example, and carboxyl groups, for example alkyloyl group such as ethanoyl, aroyl group, for example benzoyl, or arylmethyl group, for example benzyl.The inevitable basis of protective condition of going that is used for above blocking group changes the selection of blocking group.Therefore, for example, carboxyl groups such as alkyloyl or or the aroyl group can be for example, by with suitable alkali such as alkali metal hydroxide, lithium hydroxide for example, sodium hydroxide or ammoniacal liquor are separated and are removed.In addition arylmethyl group such as benzyl group can, for example, by in that catalyzer such as palladium-hydrogenation is removed on-carbon.
The blocking group that is applicable to carboxylic group is; for example; esterified group for example by removing with alkali such as sodium hydroxide hydrolysis; for example methyl or ethyl group; or for example can be for example by using acid; for example organic acid such as trifluoroacetic acid are handled and the t-butyl group of removal, or the benzyl group that for example can for example remove by palladium hydrogenation on catalyzer such as carbon.Blocking group can use the routine techniques that chemical field knows and removes in any suitable stage of synthetic.
The compounds of this invention can be oral, without enteron aisle, and the oral cavity, vagina, rectum sucks, sucks, the hypogloeeis, intramuscular, subcutaneous, the part, in the nose, intraperitoneal, intrathoracic, intravenously, epidural, in the sheath, the interior and administration of brain by being expelled to the joint.
Dosage depends on route of administration, severity of disease, other factors that patient's age and body weight and attending doctor are considered when each mode of determining to be best suited for given patient and dosage level usually.
The significant quantity that is used for the treatment of the The compounds of this invention of infection is to be enough to have symptom ground to alleviate warm blooded animal, and especially people's infection symptoms slows down progression of infection, or reduces the amount of the possibility that patient with infection symptoms worsens.
For by compound pharmaceutical composition of the present invention, inertia, drug acceptable carrier can be solid or liquid.The solid form preparation comprises powder, tablet, but dispersible granule, capsule, cachet and suppository.Solid carrier can be that one or more can be used as thinner, flavouring agent, solvating agent, lubricant, suspension agent, binding agent, or the material of tablet disintegrant; It also can be an encapsulating material.
In powder, carrier is a kind of and segmentation active ingredient blended finely-divided solid.In tablet, active ingredient and the carrier with necessary bonding properties are according to suitable mixed and be pressed into required shape and size.
In order to prepare suppository composition, the mixture of low melt wax such as glycerin fatty acid ester and theobroma oil at first is melted and activeconstituents is passed through, and for example, stirs and disperses wherein.The fusion homogeneous mixture is introduced in the mould of stock size subsequently and cools off and solidify.
Suitable carriers comprises magnesiumcarbonate, Magnesium Stearate, talcum, lactose, sugar, pectin, dextrin, starch, tragacanth, methylcellulose gum, sodium carboxy methyl cellulose, low melt wax, theobroma oil, and analogue.
Some compounds of the present invention can form salt and these salt also within the scope of the invention with various inorganic and organic bronsted lowry acids and bases bronsted lowries.The example of these acid salt comprises acetate, adipate, ascorbate salt, benzoate, benzene sulfonate, supercarbonate, hydrosulfate, butyrates, camphorate, camsilate, choline, Citrate trianion, cyclohexyl-n-sulfonate, diethylenediamine, ethane sulfonate, fumarate, glutaminate, oxyacetate, Hemisulphate, 2-hydroxyethyl sulfonate, enanthate, hexanoate, hydrochloride, hydrobromide, hydriodide, hydroxymaleic acid salt, lactic acid salt, malate, maleate, methane sulfonates, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulphate, phenylacetic acid salt, phosphoric acid salt, diphosphate, picrate, Pivalate, propionic salt, quinine hydrochlorate, salicylate, stearate, succinate, sulfamate, sulfonate, vitriol, tartrate, tosylate (p-tosylate), trifluoroacetate, and undecylate.Alkali salt comprises ammonium salt, an alkali metal salt such as sodium, lithium and sylvite, alkaline earth salt such as aluminium, calcium and magnesium salts, with the salt such as the dicyclohexyl amine salt of organic bases, N-methyl D-glycosamine and with amino acid such as arginine, Methionin, the salt of ornithine etc.In addition, alkaline nitrogen-containing group can be with following reagent seasonization: low alkyl group halogen, and as methyl, ethyl, propyl group and butyl halogenide; Dialkyl sulfate such as dimethyl, diethyl, dibutyl; Diamyl vitriol; Long-chain halogenide such as decyl, lauryl, nutmeg base and stearyl halogen; Aralkyl halogen such as bromotoluene etc.Non-toxicity physiological acceptable salt is preferred, but other salt also can, as be used for the isolated or purified product.Salt can be by conventional methods, as by with the product of free alkali form and one or more normal suitable acid in insoluble therein solvent of this salt or medium, or in solvent such as water, react removal or lyophilize or on suitable ion exchange resin, be exchanged for another negatively charged ion by the negatively charged ion that will have salt now and form in a vacuum subsequently.In order to have structural formula (I), compound or its drug acceptable salt of structural formula (Ia) or structural formula (Ib) are used for Mammals, comprise people's treatment (comprising prophylactic treatment), usually it are mixed with pharmaceutical composition according to the standard drug practice.
Except The compounds of this invention, pharmaceutical composition of the present invention also can comprise one or more medicaments that has value in one or more mentioned disease patient's condition of treatment this paper, or is total to administration (simultaneously or sequentially) with them.
The term composition means the prescription that comprises active ingredient or drug acceptable salt and drug acceptable carrier.For example, the present invention can for example be made into tablet by manner known in the art, capsule, moisture or oily solution, suspension, emulsion, cream, ointment, gel, nasal spray, suppository, divided powder or aerosol that is used to suck or sprays, with the form that is used for using aseptic moisture or oily solution or the suspension or the aseptic emulsion of (comprising intravenously, intramuscular or immersion) without enteron aisle.
The liquid form composition comprises solution, suspension, and emulsion.The sterilized water of active compound or water propylene glycol solution can be mentioned as an example that is applicable to without the liquid preparation of enterally administering.Liquid composition also can be formulated into solution in moisture polyglycol solution.The aqueous solution that is used for oral administration can be by adding suitable tinting material with solubilization of active ingredient in water neutralization as required, flavouring agent, stablizer and thickening material and prepare.The aq suspension that is used to orally use can be by will segmenting active ingredient and viscous material such as natural synthetical glue, and resin, methylcellulose gum, known other suspension agents in sodium carboxy methyl cellulose and formula of medicine field are dispersed in together in the water and make.
Pharmaceutical composition can be at unit dosage form.In these forms, composition is divided into the dosage unit of the active ingredient that comprises appropriate amount.Unit dosage form can be a packaged preparation, and described packing comprises the preparation of discrete magnitude, for example, and parcel tablet, capsule and the powder in bottle or ampoule.Unit dosage form also can be a capsule, cachet, or tablet self, or it can be any of these packaged form of suitable number.
According to a further aspect in the invention, provide defined above in the method for treatment human or animal body, use have structural formula (I) or compound (Ia) or its drug acceptable salt.
We have found that the defined compound of the present invention, or its drug acceptable salt are the effective antitumor agent, its performance it is believed that and is derived from its Edg-1 antagonist performance.Therefore, The compounds of this invention expection can be used for treating Edg-1 institute separately or the disease or the medical condition of part media, and promptly this compound is used in generation Edg-1 antagonist action in the warm-blooded animal that needs this treatment.
Therefore, The compounds of this invention provides a kind of method that is used for the treatment of cancer, and it is characterized in that the antagonist action of Edg-1, and promptly this compound can be used for producing separately or part is the antitumous effect of media with the antagonist action of Edg-1.
Therefore The compounds of this invention provides that a kind of to be used for the treatment of various can be to it is characterized in that any unusually, and non-required or pathological angiogenesis generates, for example the method for the disease of the associated angiogenesis of the relevant vasculogenesis of tumour.This compound can be used for producing separately or partly thinks the antitumous effect of the antagonistic action media of Edg-1.
This compound of the present invention is expected at the activity that has wide region in the disease of associated angiogenesis, includes, but not limited to non-solid tumour such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and solid tumour and smoulder as melanoma nonsmall-cell lung cancer, glioma therebetween, liver cell (liver) cancer, glioblastoma, thyroid carcinoma, bile duct, bone, stomach, brain/CNS, head and neck, liver, stomach, prostate gland, chest, kidney, testis, ovary, skin, uterine cervix, lung, muscle, neurone, oesophagus, bladder, lung, uterus, vulva, uterine endometrium, kidney, colorectum, pancreas, pleura/peritonaeum, sialisterium and epidermis shape tumour.
The many non-superfluous sick disease that excessive angiogenic growth also can be used for treating owing to The compounds of this invention.These non-superfluous angiogenic generate diseases associated and comprise: arteriosclerosis, vascular tumor, hemangioendothelioma, hemangiofibroma, blood vessel distortion (as rendu-Osler-Weber disease disease (HHT), or the Osier-Weber syndromes), knurl, pyogenic granuloma, excessive natural on-off cycles of hair growth, Kaposis ' sarcoma, keloid, allergy oedema, psoriasis, dysfunction metrostaxis, follicular cyst, ovary is super to stimulate, and endometriosis is breathed painful, ascites, dialysis patient's peritonaeum sclerosis, the adhesivity that is derived from abdominal operation forms, obesity, rheumatoid disease sacroiliitis, synovitis, osteomyelitis, pannus growth, spur, bloodthirsty joint, and inflammation and course of infection (as hepatitis, pneumonia, glomerulonephritis), asthma, nasal polyp, liver regeneration becomes, pulmonary hypertension, prematureness retinopathy, diabetic retinopathy, the xanthelasma sex change relevant with the age, white matter is softening, neovascular glaucoma, cornea grafting neovascularization, trachoma, thyroiditis, Tiroidina increases and the lymphocytic hyperplasia illness.
Therefore according to this aspect of the present invention, provide as this paper is defined above to have structural formula (I), compound or its drug acceptable salt of structural formula (Ia) or structural formula (Ib) as medicine.
According to a further aspect in the invention, the structural formula (I) that has defined above is provided, the compound of structural formula (Ia) or structural formula (Ib) or its drug acceptable salt purposes in making medicine, described medicine are used for producing the Edg-1 antagonist action warm-blooded animal such as people.
According to this aspect the present invention of the present invention, the structural formula (I) that has defined above is provided, the compound of structural formula (Ia) or structural formula (Ib) or its drug acceptable salt purposes in making medicine, described medicine is used for producing antitumous effect warm-blooded animal such as people.
According to another characteristics of the present invention, the structural formula (I) that has defined above is provided, the pathological angiogenesis that the compound of structural formula (Ia) or structural formula (Ib) or its drug acceptable salt purposes in making medicine, described medicament are used for the treatment of warm-blooded animal such as people generates disease, thrombosis, cardiac infarction, coronary heart disease, arteriosclerosis, tumour, osteoporosis, inflammation or infection.
Another feature of this aspect according to the present invention, a kind of warm-blooded animal that is used in this treatment of needs is provided, produce the method for Edg-1 antagonist action as philtrum, comprise to described animals administer significant quantity defined above and have structural formula (I), compound or its drug acceptable salt of structural formula (Ia) or structural formula (Ib).
Another feature of this aspect according to the present invention, a kind of warm-blooded animal that is used in this treatment of needs is provided, produce the method for antitumous effect as philtrum, comprise to described animals administer significant quantity defined above and have structural formula (I), compound or its drug acceptable salt of structural formula (Ia) or structural formula (Ib).
Another feature of this aspect according to the present invention, a kind of warm-blooded animal at this treatment of needs is provided, has generated disease, thrombosis in the treatment pathological angiogenesis as human, cardiac infarction, coronary heart disease, arteriosclerosis, tumour, osteoporosis, the method of inflammation or infection comprises to described animals administer significant quantity defined above having structural formula (I), compound or its drug acceptable salt of structural formula (Ia) or structural formula (Ib).
In another aspect of this invention, a kind of pharmaceutical composition that is used at warm-blooded animal such as people's generation Edg-1 antagonist action is provided, comprise this paper defined compound in the past with structural formula (I), or its drug acceptable salt, and the medicine that combines can be accepted diluent or carrier.
In another aspect of this invention, a kind of pharmaceutical composition that is used at warm-blooded animal such as people's generation antitumous effect is provided, comprise this paper defined compound in the past with structural formula (I), or its drug acceptable salt, and the medicine that combines can be accepted diluent or carrier.
In another aspect of this invention, provide the pathological angiogenesis that is used for the treatment of warm-blooded animal such as people to generate disease, thrombosis, cardiac infarction, coronary heart disease, arteriosclerosis, tumour, osteoporosis, the pharmaceutical composition of inflammation or infection, comprise this paper defined compound in the past with structural formula (I), or its drug acceptable salt, and the medicine that combines can be accepted diluent or carrier.
Anticancer therapy defined herein can be used as unique treatment and uses and maybe can comprise, except The compounds of this invention, and conventional surgical or radiation treatment or chemotherapy.These chemotherapies can comprise the antineoplastic agent of one or more following kinds:
1. for example be used for the anti-hyperplasia of medical science oncology/anti-superfluous crude drug thing and its combination, as alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Antimetabolite (for example antifolate such as fluorine pyrimidine such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methotrexate, cytarabin and hydroxyurea); Antitumor antibiotics (for example anthracycline such as Dx, bleomycin, Dx, daunomycin, epirubicin, idarubicin, Mitomycin-C, dactinomycin and Plicamycin); Antimitotic agent (for example vinca alkaloids such as vincristine(VCR), vinealeucoblastine(VLB), vindesine and vinorelbine and Taxan such as taxol and taxotere); With local isomerase inhibitors (for example sufficient leaf thiophene former times such as Etoposide and teniposide, amsacrine and Mei Xin and camptothecine);
2. cytostatics such as estrogen antagonist (tamoxifen for example, toremifene, raloxifene, droloxifene and iodoxyfene), the downward conditioning agent of estrogen receptor (for example fulvestrant), androgen antagonist (bicalutamide for example, flutamide, Nilutamide and cyproterone acetate), lhrh antagonist or LHRH agonist (for example goserelin, Leuprolide and buserelin), progestogen (for example acetate megestrol), the inhibitor such as the finasteride of aromatase inhibitor (for example Anastrozole, letrozole, vorozole and Exemestane) and 5;
3. the anticancer reagent (for example inhibitor of metalloprotein enzyme inhibitors such as Marimastat and urokinase plasminogen activator function of receptors) of invading;
4. the inhibitor of somatomedin function, for example these inhibitor comprise growth factor antibodies, growth factor receptor antibody (for example anti-erbb
2Antibody Herceptin [Herceptin
TM] and anti-erbb
1Antibody Erbitux (cetuximab) [C
225]), the Acacia transferase inhibitors, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, epidermal growth factor subclass inhibitor (EGFR class tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib for example for example, AZD 1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (Tarceva, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), for example platelet-derived somatomedin class inhibitor and for example pHGF class inhibitor;
5. anti-angiogenic agent is as those of the effect that suppresses vascular endothelial growth factor, (anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF [Avastin for example
TM], compound for example is disclosed in International Patent Application WO 97/22596, WO 97/30035, those of WO 97/32856 and WO 98/13354) and those (for example linomide, the inhibitor and the angiostatin of beta 2 integrin alpha v β 3 functions) by other mechanism work;
6. vascular lesion such as Combretastatin (Combretastatin) A4 and be disclosed in International Patent Application WO 99/02166, WO 00/40529, and WO 00/41669, and WO 01/92224, the compound of WO 02/04434 and WO 02/08213;
7. antisense therapy for example relates to those of the above target of enumerating, as ISIS 2503, and anti-ras antisense;
8. gene therapy scheme, comprise for example be used for substituting aberrant gene as unusual P
53Or unusual BRCA1 or BRCA2, the GDEPT enzyme prodrug of the gene targeting (treatment) scheme is as using the cytosine(Cyt) deaminase, those of thymidine kinase or bacterium nitroreductase enzyme and be used to increase the scheme of patient to the patience of chemotherapy or radiation treatment such as the treatment of many drug resistance genes; With
9. immunotherapy scheme, comprise scheme in the external and body of the immunogenetics that for example is used to increase the patient tumors cell, as cytokine such as interleukin-22, the transfection of interleukin 4 or granulocyte-big phage colony stimulating factor, be used to reduce the scheme that the T-cell does not have variability, use the scheme of transfection immunocyte such as cytokine-transfection dentritic cell, use the scheme of cytokine-system of transfection tumor cell and the scheme of use anti-id AB.
These combination therapys can utilize each treatment component the time, order or dosing and realizing separately.These combined prods adopt The compounds of this invention and the other drug-promoting agent in its approved dosage range in above-mentioned dosage range.
Biological activity
Below analyze and can be used for measuring the effect of The compounds of this invention as the SlP1/Edgl inhibitor.
I. cell in vitro base receptor activation analysis-Transfluor analyzes
This cell based analysis is designed to assess the small molecules antagonist and suppresses GPCR S1P1 activatory ability in the presence of its similar part S1P.Analyze the initial technology of developing and having by Molecular Dev at present by NorakBiosciences (Xsira medicine) of using.Adopt people's osteogenesis sarcoma (U2OS) clone and following beta-inhibited protein white matter (arrestin)/egfp (GFP) structure that is called Edg-1 Transfluor U2OS WT Clone#37 of overexpression Edg-1/SlP1 acceptor.
Use high-content screening scheme (Cellomics Arrayscan), receptor active is measured by the localization again that assessment β-SlP of arrestin GFP response Edg-1 stimulates.Particularly, making sheet and in 384 well plastic bottom titer plate (BD Falcon) under the density of Edg-1Transfluor U2OS WT Clone#37 cell 6250 cells in 40 μ L media of every well at 37 degrees centigrade/5%CO
2Following overnight incubation.Before screening, with compound dissolution extremely final material concentration 10mM in 100% methyl-sulphoxide (DMSO).Compound series is subsequently comprising use Tecan Genesis instrument dilution in the Edg-1 Transfluor cell growth medium of 30%DMSO under the 30X ultimate density.These 30X plates used Edg-1 Transfluor growth medium to be diluted to the 6X ultimate density subsequently before dosing immediately.Cell uses the 6X diluted chemical compound or the 6%DMSO dosage of 10 μ L/ wells subsequently and at room temperature cultivated in advance 15 minutes.Cell plate use the 6X SlPEdg-1 Transfluor growth medium administration of 10 μ L/ wells, subsequently at 37 degrees centigrade/5%CO
2Under cultivated 45 minutes.The ultimate density of DMSO in well is 1%, compound be 1X (3 times, 9 IC
50Dilution begins under 100 μ M ultimate densities) and 375nM or 750nM S IP part.Cell plate are subsequently by directly adding 5% formaldehyde of 50 μ L/ wells and at room temperature cultivating in the dark and fixed in 30 minutes in 1X Dulbecco ' s phosphate buffered saline (PBS) (DPBS).Remove laking agent and alternative 1X DPBS, then cell is at room temperature used in the dark the Hoechst 33342 (molecule probe) of 10 μ g/mL ultimate densities to dye 15 minutes with 50 μ L/ wells.Get on decontaminant and use BioTek ExL405 plate washer to substitute 1X DPBS of slave plate with 50 μ L/ wells.Plate is sealed subsequently and on Cellomics Arrayscan, uses the analysis of GPCR signalling algorithm.EC
50Value is used IDBS ActivityBase computed in software subsequently.
II. cell in vitro base receptor activation analysis-Transfluor analyzes
This cell-Ji analyzes and is designed to assess the small molecules antagonist suppresses GPCR SlP1 in the presence of its similar part SlP activatory ability.Analyze the initial technology of developing and having by Molecular Dev (MDS analytical technology) at present by NorakBioscience (Xsira medicine) of using.Adopt people's osteogenesis sarcoma (U2OS) clone and following β-arrestin/ egfp (GFP) structure that is called Edg-1 Transfluor U2OS WT Clone#37 of overexpression Edg-1/SlP1 acceptor.
Use high-content screening scheme (Molecular Devices ImageExpress), receptor active is measured by the localization again that assessment β-SlP of arrestin GFP response Edg-1 stimulates.Particularly, making sheet and in 384 well plastic bottom titer plate (BD Falcon) under the density of Edg-1 Transfluor U2OS WT Clone#37 cell 6250 cells in 44 μ L media of every well at 37 degrees centigrade/5%CO
2Following overnight incubation.Before screening, with compound dissolution extremely final material concentration 10mM in 100% methyl-sulphoxide (DMSO).Compound series is subsequently comprising use BioMek instrument dilution in the Edg-1 Transfluor cell growth medium of 6%DMSO under the 10X ultimate density.Cell uses 6 μ L/ well 10X diluted chemical compounds or 6%DMSO dosage subsequently and at room temperature cultivated in advance 15 minutes.Cell plate use the 6X SlPEdg-1 Transfluor growth medium administration of 10 μ L/ wells, subsequently at 37 degrees centigrade/5%CO
2Under cultivated 45 minutes.The ultimate density of DMSO in well is 1%, compound be 1X (3 times, 9 IC
50Dilution begins under 3 μ M ultimate densities) and the 750nMSIP part.Cell plate are subsequently by directly adding 50 μ L/ well 5% formaldehyde and at room temperature cultivating in the dark and fixed in 30 minutes in 1X Dulbecco ' s phosphate buffered saline (PBS) (DPBS).Remove laking agent and alternative 1X DPBS, then cell is at room temperature used in the dark the Hoechst 33342 (molecule probe) of 10 μ g/mL ultimate densities to dye 15 minutes with 50 μ L/ wells.Get on decontaminant and use BioTek ExL405 plate washer to substitute 1X DPBS of slave plate with 50 μ L/ wells.Plate is sealed subsequently and on Molecular Dev ImageXpress, uses the analysis of GPCR signalling algorithm.EC
50Value is used IDBS ActivityBase computed in software subsequently.
The compounds of this invention generally has EC
50Value＜100 μ M are if test in arbitrary above-mentioned two kinds of analyses.For example, the compound of embodiment 18 has the EC of 0.896 μ M
50Value; The compound of embodiment 19 has the EC of 10.3 μ M
50Value; Has the EC of 5.15 μ M with the compound of embodiment 21
50Value.If detection limit is 33 μ M, the enantiomer of the compound of embodiment 102,4-chloro-N-[(1S)-1-(1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] benzsulfamide, in analyzing, these do not have any activity of surveying.
Should be appreciated that structural formula (I) compound with chiral centre is when being split as each enantiomer, generally only a kind of enantiomer has activity in above-mentioned analysis.
The percentage inhibiting value also uses IDBS ActivityBase computed in software and provides at each embodiment in following experiment chapters and sections, except embodiment 1,55,70,101,111,135,163,175 and 184. are suppressed at the down embodiment 91 of record of 1 μ M except %, are recorded in the metering % inhibition down of the most close 3.5 μ M.
In most of the cases, compound is initial by maximum concentration 100 μ M (ultimate density in well) beginning administration.Obtain the dose-response curve of accurate match carefully, make maximum concentration be reduced to 10 μ M or lower in some cases.Therefore, the difference of compound absolute concentration reflects the difference of the maximum concentration of corresponding dilution series.Therefore, the compound that is listed in 3.70 μ M begins titration from maximum concentration 100 μ M, and the compound of classifying 3.50 μ M as carries out titration from the compound that maximum concentration 10 μ M begin titration and classify 3.30 μ M as maximum concentration.The embodiment 91 that classifies 1 μ M as carries out titration with 3.50 μ M as maximum concentration.
Embodiment
The present invention is existing to be described by following indefiniteness example, wherein, unless have described in addition:
(i) temperature is with a degree centigrade expression; Operate in room temperature or envrionment temperature, that is, under 18-25 degree centigrade temperature, carry out;
(ii) organic solution is dry on anhydrous sodium sulphate; Solvent evaporation uses rotatory evaporator decompression (600-4000 pascal; 4.5-30mmHg) under under the highest 60 degrees centigrade bath temperature, carry out;
(iii) in general, be only to provide for the purpose of illustration in TLC and reaction times after the reaction process;
(iv) final product has gratifying proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;
(v) productive rate only provide for the purpose of illustration and must not be the process exploitation by carefulness obtain those; More if desired material repeats preparation;
If (vii) provide, the NMR data are mainly to diagnose the δ value form of proton, provide with the relative ppm number as the tetramethylsilane (TMS) of internal standard, use deuterium methyl-sulphoxide (DMSO-d under 400MHz
6) measure as solvent, unless refer else;
(vii) chemical symbol has its conventional implication; Use SI unit and symbol;
(viii) the solvent ratio is with volume: volume (v/v) provides; With
(ix) mass spectrum uses 70 electron-volts electron energy to use the probe that directly exposes to carry out under chemi-ionization (CI) pattern; Wherein said ionization is subjected to electron bombardment (EI), fast atom bombardment (FAB) or electron spray(ES) (ESP) influence; Provide the value of m/z; The ion of general only record indication matrix amount; Unless with have describedly in addition, the mass ion of being quoted is (M/Z);
(x) if a certain synthetic be described to and be described in before embodiment similar, so used amount is and is used for the suitable mmole ratio of embodiment before this; With
(xi) use hereinafter to be referred as:
The THF tetrahydrofuran (THF);
BOC tertiary butyl oxygen base carbonyl;
DMF N, dinethylformamide;
The EtOAc ethyl acetate;
The RT room temperature;
The DCM methylene dichloride
The DMSO dimethyl sulfoxide (DMSO)
AcOH acetate
The IBCF isobutyl chlorocarbonate
PyBOP benzotriazole-1-base-oxygen base-three-pyridyl-phosphorus hexafluorophosphate
The LAH lithium aluminium hydride
The TEA triethylamine; With
The DIEA diisopropylethylamine
The DIBAL diisobutyl aluminium hydride
DAST diethylamino sulfur trifluoride
NaBH (OAC)
3Sodium triacetoxy borohydride
(DPPF) PdC
12The two phenenyl phosphinyl Palladous chloride
(PPh
3)
4Pd tetra-triphenylphosphine palladium (0)
The CDI carbonyl dimidazoles
HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urine
Hexafluorophosphate
The SFC supercritical fluid chromatography
Lawesson ' s reagent has the not phosphine sulfuration of p-p-methoxy-phenyl sulfo-of following structure
The thing dimer:
Embodiment 1
4-chloro-N-[(1R)-and 1-(ethyl of 1-ethyl-1H-benzimidazolyl-2 radicals-yl)] benzsulfamide
[(1R)-and 1-(ethyl of 1-ethyl-1H-benzimidazolyl-2 radicals-yl)] amine (intermediate 1; 0.700g, 3.70mmol) and Et
3(1.70mL 12.2mmol) is dissolved among the DCM (30mL) N.Be cooled to after 0 degree centigrade, dripping 4-chlorobenzene sulfonyl chloride (0.820g, 3.88mmol) solution in DCM (5mL) and reaction mixture stirred spend the night under RT.Reaction mixture with DCM (70mL) dilution and water (3 * 10mL) and salt solution (10mL) wash.Organic layer is dry in a vacuum and concentrated, obtains the dark-brown semi-solid residue, uses silica gel and CHCl by the flash distillation column chromatography
3/ MeOH (98: 2) and purifying obtains product as lilac solid (1.30g, 97% productive rate).1H?NMR(300MHz，CDCl
3)δ7.64-7.57(m，3H)，7.26-7.16(m，5H)，6.18(d，J＝8.3Hz，1H)，4.85-4.75(m，1H)，4.24-3.99(m，2H)，1.56(d，J＝6.9Hz，3H)，1.35(t，J＝7.1Hz，3H)。M/Z＝363
The compound of embodiment 2-182 is by step similar to Example 1 preparation, wherein use suitable SULPHURYL CHLORIDE (referring to number of pages 17) with structural formula (II) (be commercially available, except according to following preparation and in table 7, provide be used for embodiment 105-109, Exs.114,127,140,148,151,155,160,161,172,173,177, those of 181) and in table 1, be expressed as the suitable intermediate amine (referring to 17 pages) of INT with structural formula (III), but embodiment 68-78, embodiment 8095,101,102,106,111,128,129,133,134,141,149,152,158,163,164,165,167,168,169,170,171,178 and 182 use at the synthesis path of table 1 end description synthetic by the embodiment that lists in table 1.Embodiment 187 is by following the suitable intermediate amine with structural formula (III) (referring to the 17 pages) preparation of describing after the table 1 closely.The step that is used to prepare intermediate sees Table 1.
Table 1
By using 40% methyl alcohol, the mapping of 0.1% dimethyl amine on normal phase chirality HPLC (chirality pak AD-H, 250 * 21mm, 5 μ) splits and generates embodiment 101 by embodiment 12.Embodiment 102 uses 50% hexane by embodiment 13 similarly, and 50% (1: 1) ethanol: methyl alcohol, 0.1%DIEA generates as properties-correcting agent.Embodiment 88 also can be by embodiment 88 the mapping of racemize type split and generate.The raceme of embodiment 88 prepares by being similar to embodiment 88 described methods as commercially available starting raw material by using Boc-DL-Ala-OH.Mapping splits at normal phase chirality HPLC (chirality pak AD-H, 250 * 21-mm, 5 μ) upward uses 30% Virahol to carry out as properties-correcting agent.Embodiment 173 and 174 is by generating in the mapping fractionation of carrying out its its corresponding raceme after synthetic as described below.Embodiment 179-181 is by supercritical fluid chromatography [SFC] (methyl alcohol/CO
2) separate and mainly to be rich in its respective mixtures of required isomer and to generate.Embodiment 183 and 184 splits by mapping and is generated by described its raceme of method synthetic.
Embodiment 68:
4-chloro-N-{1-[1-ethyl-6-(hydroxymethyl)-1H-benzimidazolyl-2 radicals-yl] ethyl } benzsulfamide:
To comprise thick 2-(1-{[(4-chloro-phenyl-) alkylsulfonyl]-amino ethyl)-1-ethyl-1H-benzoglyoxaline-6-carboxylic acid ethyl ester (embodiment 67,250mL circular base flask 12.5mmol) find time and backfill with N2 (3x).Add anhydrous THF (30mL), and gained solution is cooled to 0 degree centigrade.(1.0M solution is in THF to drip DIBAL; 50mL, 50mmol).After 0 degree centigrade of following 1.5h, add other DIBAL (14mL, 14mmol).Gained solution at room temperature stirs and spends the night.Moisture MeOH cancellation (stopping to discharge until gas) is used in reaction carefully, and with the biphasic mixture layering.Water layer extracts (2x) with EtOAc and extracts, and with the organism H that merges
2The O washing, salt water washing, dry (MgSO
4), filter and concentrate.Crude product is by silica gel chromatography (gradient elution; Rf=0.27 in 100%EtOAc) and purifying obtains colourless to light yellow solid (3.32g, 68%).
Above step application in embodiment 76, is obtained embodiment 78.
Embodiment 69:
4-chloro-N-{1-[6-(difluoromethyl)-1-ethyl-1H-benzimidazolyl-2 radicals-yl] ethyl benzsulfamide embodiment 69 in two steps by embodiment 68 preparation:
Step 1:4-chloro-N-[1-(ethyl of 1-ethyl-6-formyl radical-1H-benzimidazolyl-2 radicals-yl)] benzsulfamide:
The 100mL round-bottomed flask is equipped with 4-chloro-N-{1-[1-ethyl-6-(hydroxymethyl)-1H-benzimidazolyl-2 radicals-yl] ethyl } (embodiment 68, and 1.18g is 3.00mmol) with activation MnO for benzsulfamide
2(85%; 1.56g, 15.3mmol).Adding acetone (15mL) and suspension at room temperature stirred through weekend.Mixture is passed through Celite pad by suction strainer, and with filter cake acetone thorough washing.Filtrate is concentrated, provide title compound as foam materials (1.18g, 100%).M/Z＝391。1H?NMR(CDCl
3)δppm1.46(t，J＝7.33Hz，3H)1.66(d，7＝6.82Hz，3H)4.15-4.26(m，1H)4.31(m，1H)4.89(m，1H)6.35(m，1H)7.11-7.21(m，2H)7.63(m，2H)7.73(m，1H)7.83(m，1H)7.90(m，1H)10.08(s，1H)。
Step 2:
4-chloro-N-{1-[6-(difluoromethyl)-1-ethyl-1H-benzimidazolyl-2 radicals-yl] ethyl } benzsulfamide
The 50mL round-bottomed flask be equipped with 4-chloro-N-[1-(ethyl of 1-ethyl-6-formyl radical-1H-benzimidazolyl-2 radicals-yl)] benzsulfamide (derive from step 1,232mg, 0.59mmol) and CHCl
3(4mL).Add the new DAST that steams (180 μ L, 1.36mmol), and with gained solution 60 degrees centigrade of following heated overnight.During cooling, reaction mixture is at CH
2Cl
2And H
2Distribute between the O.Water layer CH
2Cl
2Extract, and with the organism salt water washing that merges, dry (MgSO
4), filter and concentrate.Crude product is by silica gel chromatography (gradient elution; The Rf=0.26 among the EtOAc) and purifying obtains orange oil at 50: 50 hexanes:.From CH
2Cl
2Crystallization in the/hexane provides product as light yellow solid (34mg, 14%).
Embodiment 70
2-(1-{[(4-chloro-phenyl-) sulfuryl amino } ethyl)-1-ethyl-1H-benzoglyoxaline-6-carboxylic acid
The 250mL round-bottomed flask is equipped with 2-(1-{[(4-chloro-phenyl-) alkylsulfonyl]-amino } ethyl)-(embodiment 67, and 1.76g is 4.04mmol) with diox (10mL) for 1-ethyl-1H-benzoglyoxaline-6-carboxylic acid ethyl ester.(732mg is 18.3mmol) at H to add NaOH
2Solution among the O (6mL), and with mixture heating up to 50 degree centigrade.After 5h, reaction is cooled and uses H
2O (20mL) dilution.Drip dense HCl (～3mL), colorless solid precipitation is separated by suction filtration, uses H
2O washs and in the air dry air, obtains title compound (1.14g, 69%).M/Z＝407。1H?NMR?δppm1.30(t，J＝7.20Hz，3H)1.38(d，J＝6.82Hz，3H)4.28-4.38(m，2H)4.82-4.91(m，1H)7.42(m，2H)7.55(m，1H)7.68(m，2H)7.78(m，1H)8.08(m，1H)8.62(m，1H)12.79(s，1H)。
Prepare embodiment 71-73 by embodiment 70:
Embodiment 71-73 is prepared by the general step of following general introduction by embodiment 70.The developmental tube of being furnished with stirring rod is equipped with 2-(1-{[(4-chloro-phenyl-) alkylsulfonyl]-amino-ethyl)-(embodiment 70,0.33mmol) and PyBOP (0.37mmol) for 1-ethyl-1H-benzoglyoxaline-6-carboxylic acid.Add diisopropylethylamine (70 μ L, 0.39mmol) and CH
2Cl
2(1.0mL), and with solution at room temperature stir 30min.Add required amine (～2 equivalent) and mixture subsequently and at room temperature stir 2h.Reaction H
2O (10mL) dilutes and uses CH
2Cl
2(2x) extract.With the organism salt water washing that merges, dry (MgSO
4), filter and concentrate.(0.1%TFA/ of 5-95% in MeCN is at H by reversed-phase HPLC for crude amide
20.1%TFA among the O; Atlantis 19 * 100 posts; 10min moves) and purifying.
This step application in embodiment 76, is obtained embodiment 77.
Preparation embodiment 74 and 75:
Embodiment 74 and 75 by general method described below with suitable amine with 4-chloro-N-[1-(ethyl of 1-ethyl-6-formyl radical-1H-benzimidazolyl-2 radicals-yl)] benzsulfamide (generating in the step 1 of above embodiment 69) reduction amination prepares:
Be used for reduction amination with preparation embodiment 74 and 75 general step: the 25mL round-bottomed flask be equipped with 4-chloro-N-[1-(ethyl of 1-ethyl-6-formyl radical-1H-benzimidazolyl-2 radicals-yl)] (embodiment 69 for benzsulfamide; 1 equivalent); corresponding amine (1.5 equivalent), and THF (～4mL/mmol aldehyde).Add NaBH (OAc)
3(2 equivalent) and reaction are at room temperature stirred and are spent the night.Be reflected at EtOAc and H
2Distribute between the O and water layer further extracts with EtOAc.With the organism salt water washing that merges, dry (MgSO
4), filter and concentrate.Crude product is by reversed-phase HPLC and purifying obtains required compound as its tfa salt.
Embodiment 80
4-chloro-N-(1-[1-ethyl-6-(methyl sulphonyl)-1H-benzimidazolyl-2 radicals-yl] ethyl) benzsulfamide
With 4-chloro-N-{1-[1-ethyl-6-(methyl sulfo-)-1H-benzimidazolyl-2 radicals-yl] ethyl } (embodiment 79, and 659mg, 250mL round-bottomed flask 1.61mmol) comprise the processing with MeOH (10mL) for benzsulfamide.Solution is cooled to 0 degree centigrade, and adds ozone (2.25g, 7.32mmol oxygenant) and H subsequently
2O.Mixture is warmed to room temperature.After 4 hours, reaction H
2O (40mL) dilution and mixture CH
2Cl
2Extract (2x).With the organism salt water washing that merges, dry (MgSO
4), filter and concentrate.Crude product is by silica gel chromatography (gradient elution; The Rf=0.29 among the EtOAc) and purifying obtains colorless solid (459mg, 64%) at 25: 75 hexanes:.
Embodiment 95:
4-chloro-N-[1-(1-ethyl-4-methoxyl group-1H-imidazoles [4,5-c
1Pyridine-2-yl) ethyl] benzsulfamide
4-chloro-N-[1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] (embodiment 94, and 20mg) solution in MeOH (1mL) is handled with 20 molar equivalent sodium methylates for benzsulfamide.Gained solution backflow 5h.Reaction mixture concentrates and obtains thickness glue, and purifying obtains 4-chloro-N-[1-(1-ethyl-4-methoxyl group-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl on reversed-phase HPLC] benzsulfamide.
Embodiment 96:
4-chloro-N-{1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethyl } benzsulfamide
Embodiment 96 is prepared in 7 steps by commercially available 2-amino-2-malonamide nitrile:
Step 1:
5-amino-1-ethyl-1H-imidazoles-4-methane amide
To 2-amino-2-malonamide nitrile (10g) at CH
3Solution among the CN adds orthoformic acid triethyl ester ester and reflux 2h.In cooling solution, add ethamine (61mL, 2M is in THF).Solution is stirred and spends the night.Form throw out and collection, obtain required product, 5-amino-1-ethyl-1H-imidazoles-4-methane amide is as solid (Hg).M/Z?154。
Step 2:9-ethyl-2-(trifluoromethyl)-1,9-dihydro-6H-purine-6-one:
Add Trifluoroacetic Acid Ethyl Ester (15.44mL) to the solution of 5-amino-1-ethyl-1H-imidazoles-4-methane amide (2g) in EtOH (71mL), add sodium ethylate subsequently.Reaction mixture is heated and refluxed 24 hours.Crude mixture extracts with the saturated aqueous ammonium chloride dilution with EtOAc.Organic layer is concentrated and is directly used in next step.M/Z?232。
Step 3:6-chloro-9-ethyl-2-(trifluoromethyl)-9H-purine
5-amino-1-ethyl-1H-imidazoles-4-methane amide (about 2g) is at POCl
3Solution (10mL) is heated to reflux and spends the night.Reaction mixture is concentrated and uses the silica chromatogram purification under vacuum, obtain 6-chloro-9-ethyl-2-(trifluoromethyl)-9H-purine as solid.M/Z?250。
Step 4:1-[6-chloro-9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethyl ketone
Under-78 degrees centigrade, add LDA 90.7mL, 1.8M), add N-methoxyl group-N-methylacetamide (252.8uL) then with stirring 35min to the solution of 6-chloro-9-ethyl-2-(trifluoromethyl)-9H-purine (200mg) in THF.After stirring 0.5h, reaction water cancellation and extract with EtOAc.Organic layer is concentrated.Mixture uses the silica chromatogram purification, obtains 1-[6-chloro-9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethyl ketone.M/z?292。
Step 5:1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethanol
To 1-[6-chloro-9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] the solution adding triethylamine of ethyl ketone (50mg) in EtOAc (1mL), add palladium on the carbon (50mg) subsequently.Reaction mixture is at H
2(1atm) place 5h down.Reaction mixture filtration over celite pad and concentrated obtains 1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethanol (40mg).M/Z?260。
Step 6:[(4-chloro-phenyl-) alkylsulfonyl] and 1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethyl } the carboxylamine tertiary butyl ester
To 1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] the solution adding triphenylphosphine of ethanol (30mg) in THF (1mL), [(4-chloro-phenyl-) alkylsulfonyl] carboxylamine tertiary butyl ester (100mg) and azo-2-carboxylic acid's diisopropyl ester (70ul).Reaction is stirred and is spent the night.Reaction mixture is concentrated and uses the silica column purification, obtains [(4-chloro-phenyl-) alkylsulfonyl] { 1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethyl } carboxylamine tertiary butyl ester.M/Z?533。
Step 7:
4-chloro-N-{1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethyl } benzsulfamide
The solution of [(4-chloro-phenyl-) alkylsulfonyl] { 1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethyl } carboxylamine tertiary butyl ester in MeOH is handled with HCl (4mL, 4N is in the Zai diox).Reaction mixture stir 48h and be concentrated and on reversed-phase HPLC purifying, obtain 4-chloro-N-{1-[9-ethyl-2-(trifluoromethyl)-9H-purine-8-yl] ethyl benzsulfamide (20mg).
Embodiment 97,98,103,104 and 144 by the represented method of following examples 97 directly by corresponding amide starting raw material (SM2)
2Ab, 2ac, 2e ' and 2ad and suitable commercially available SULPHURYL CHLORIDE generate.Embodiment 103 and 144 is by supercritical fluid chromatography (MeOH/CO
2) split enantiomer and generate.Embodiment 104 is generated by 2e ' and suitable commercially available SULPHURYL CHLORIDE similarly, and just reaction at room temperature but not carry out in the microwave of the following stated and required product is separated to generate required product from unreacted starting raw material by column chromatography.
Embodiment 97:
4-chloro-N-[(1R)-and 1-(6-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] benzsulfamide:
Step 1:(2R)-and N-(6-chloro-4-ethylamino-pyridin-3-yl)-2-[(4-chloro-phenyl-) sulfuryl amino] propionic acid amide
In anhydrous MeOH (20mL), add tertiary butyl N-[(1R)-1-[(6-chloro-4-ethylamino-pyridin-3-yl) formamyl] ethyl] carbamate (SM 2ab, 1.3g, 3.8mmol) and the HCl in the Zai diox (20mL, 4M solution).Be reflected at rt and keep 1h down.Concentrate and remove solvent.In resistates, add DCM (15mL) and mixture and be cooled to-15 degrees centigrade.Add the p-chlorobenzene sulfonyl chloride (0.8g, 3.9mmol) and Et
3N (1.5mL, 11.4mmol).Reaction is warmed to rt 1h.Adding entry (10mL) afterwards, (2 * 15mL) extract, dry (Na with DCM
2SO
4) and concentrate, product is collected into solid (1.1g, 60% productive rate).M/Z?416。
Step 2:
4-chloro-N-[(1R)-and 1-(6-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] benzsulfamide:
In being furnished with the microwave tube of magnetic stirring bar, place (2R)-N-(6-chloro-4-ethylamino-pyridin-3-yl)-2-[(4-chloro-phenyl-) sulfuryl amino] propionic acid amide (0.3g, 0.72mmol) and add AcOH (5mL).Reaction uses microwave to heat 0.5h down at 150 degrees centigrade.Concentrate and remove AcOH, and the gained resistates is dissolved among the EtOAc (15mL), use sat.NaHCO
3Handle and extract (2 * 10mL) with EtOAc.The silica gel chromatography purifying provides title compound as white solid (0.16g, 55% productive rate).
Embodiment 141,149 and 152 is generated according to being similar to the described mode of following Ex.106 by the suitable embodiment shown in the table 1.But all these compounds also intermediate pass through to use SC by the described standard sulfuryl amine of above Ex.1 step
10Generate with the suitable direct sulfuryl amine shown in the table 1.Ex 178 uses the method for the following stated by Ex.177 and prepares.
Embodiment 106:
(R)-5-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulfamyl) picolinamide:
The developmental tube of being furnished with stirring rod be equipped with (R)-6-cyano group-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyridine-3-sulphonamide (Ex 105,82mg, 0.19mmol) and the vitriol oil (1mL).The gained mixture at room temperature stirs and spends the night.Reaction mixture is poured on about 20mL trash ice, and with gained mixture K
2CO
3Processing becomes alkalescence until mixture.Mixture CH
2Cl
2Extract (3x), and with the organic extraction salt water washing that merges, dry (MgSO
4), filter and be condensed into colorless solid.Vacuum-drying obtains 77mg (90%) analytical pure material.
The SULPHURYL CHLORIDE of listing in the table 6 is used to produce embodiment 106 and 108-110.
Embodiment 111:
(R)-4-amino-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) benzsulfamide
Comprise (R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-4-nitrobenzene sulfonamide (Ex.110,1.25g, 2.83mmol) 250mL circular base flask be equipped with tindichloride (II) dihydrate (2.72g, 12.05mmol) and EtOAc (15mL).The gained mixture uses 80 degrees centigrade of oil bath heating.After 1 hour refluxed, reaction was cooled to chamber Gentle H
2O (25mL) dilution.Add saturated NaHCO
3, cause the precipitation of gas release and solid material.The gained mixture is passed through Celite pad and reaction flask and filter cake EtOAc and H by suction strainer
2The O thorough washing.Filtrate layers separation and water layer are extracted with EtOAc.With the organism salt water washing that merges, dry (MgSO
4), filter and be condensed into toughening oil.Product is from CH
2Cl
2Precipitate in/the hexane, it is colourless to light yellow solid to obtain 973mg (84%).
Embodiment 128
R-5-chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-6-hydrazino pyridine-3-sulphonamide
Under nitrogen cleans, with R-5,6-two chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyridine-3-sulphonamide (Ex.48,0.472g, 0.00101mol) be added in the ethanol (15mL) in the 50mL 3 neck round-bottomed flasks, suspension is provided.In single part, add hydrazine hydrate (0.102g, 0.00204mol; 0.1mL).By reflux, solid all dissolves.After 90min refluxes, find muddiness, and form some solids.After other 1h, LC/MS shows that some starting raw materials are left with other and adds the 0.1mL hydrazine hydrate.After other 2h that refluxes, reaction mixture cooling and solvent under reduced pressure are removed so that solid to be provided.Solid distributes between ethyl acetate and water, filters and washes organic layer with water secondary, subsequently with the saturated sodium-chloride washing once.At MgSO
4After the last drying, solvent under reduced pressure is removed providing required product as white solid, 0.41g (88%).
Embodiment 133:(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-6-ethynyl pyridine-3-sulphonamide
The all solids reactant promptly, (R)-(Ex.35,200mg 0.46mmols) are loaded into reaction vessel to pyridine-3-sulphonamide to 6-chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) under nitrogen.In this reaction mixture, add DMF (0.5mL) and triethylamine (0.322mL), add trimethyl silyl acetylene (0.30mL) then.The gained mixture heats 3h down at 60 degrees centigrade, and this moment, all starting raw materials were consumed.Reaction mixture is cooled to room temperature and adds tetrabutyl ammonium fluoride (1mL, 1M is in THF) and the gained mixture was at room temperature stirred 30 minutes.Mixture is concentrated to remove THF and to use the ethyl acetate of gradient to carry out column chromatography to separate required product (65mg, 33.3%) with hexane (20% to 100%) subsequently.
Embodiment 129
R-5-chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyridine-3-sulphonamide:
Under nitrogen, R-5-chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-6-hydrazino pyridine-3-sulphonamide (Ex.128,0.347mg, 0.75mmol) in 50mL 3 neck round-bottomed flasks, be dissolved in the acetate (9mL), keep dissolving by adding entry (3mL).Solution is heated backflow, and (0.412mg 0.165mmol) is dissolved in solution in the 5mL water to add seven brochantites (II) this moment from feed hopper.After adding was finished, solution was by the 75min that refluxes in addition.Solution cooling and solvent are removed by vacuum.Resistates is ethyl acetate and rare (1 part: 4 parts of water) distribute between the solution of ammonium hydroxide.Organic layer dilute hydrogen ammonium oxide solution washing, 50: 50 subsequently (water: solution washing saturated EDTA).Organic layer is subsequently with the saturated nacl aqueous solution washing with at MgSO
4Last dry.Under reduced pressure remove solvent, obtain brown semisolid.Grind this semisolid with methylene dichloride, filter and obtain the 0.15g white-yellowish solid.Filtrate under reduced pressure concentrates and by the middle pressure chromatogram (ethanol in methylene dichloride; 5% dense ammonium hydroxide in ethanol) carry out chromatography, to obtain another 0.020g material, the mixture of the R of 9: 1 ratios of 0.017g (52%) and S enantiomer altogether, HPLC further splits by chirality.
Embodiment 130:
N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-4-(morpholino methyl) benzsulfamide
(0.296g 0.00101mol) is suspended among the THF (30mL) and cools off in ice-acetone bath the hydrochloride of intermediate 9.With N, (0.528mL 0.00303mol) adds suspension with single part to the N-diisopropylethylamine.(0.272g 0.00101mol) is dissolved in THF (5mL) neutralization and drops to mixture with 4-(brooethyl) benzene sulfonyl chloride.Reaction mixture stirs 30min in ice-acetone bath, be warmed to room temperature subsequently and stir 30min in addition.Suspension cools off in ice-acetone bath once more and (0.528mL is 0.00606mol) with single part of adding with morpholine.Reaction mixture stirs 30min subsequently, cools off in ice-acetone bath simultaneously.After being warmed to room temperature, reaction mixture refluxed 6h.Cooling of gained suspension and solvent under reduced pressure are removed.Resistates distributes between ethyl acetate and water.Organism washes secondary with water, and with the saturated nacl aqueous solution washing once.At MgSO
4After the last drying, solvent under reduced pressure is removed.
Gained oil is by flash chromatography (ethanol/dichloromethane; 5% dense NH in ethanol
4OH) and purifying obtains required product.Solvent under reduced pressure is removed to obtain required product as white solid, 0.17g (32% theory).This material is confirmed as about 90%R-enantiomer.
Embodiment 134:
3-(amino methyl)-N-{ (1R)-1-[1-ethyl-6-(trifluoromethyl)-1H-benzimidazolyl-2 radicals-yl] ethyl }-4-fluorobenzene sulphonamide
The 25ml round-bottomed flask is equipped with 3-cyano group-N-{ (1R)-1-[1-ethyl-6-(trifluoromethyl)-1H-benzimidazolyl-2 radicals-yl] ethyl }-4-fluorobenzene sulphonamide (Ex.27,37.4mg, 0.08mmol) and THF (2mL).Solution be cooled to 0 degree centigrade and add LAH (0.160mL, 0.32mmol).Solution becomes redness, is warmed to room temperature and stirs 5hr.To ice and EtOAc (5mL) adding reaction mixture and stirring 10mins.Water is with EtOAc extraction (3mL * 2) and with the organic phase salt water washing that merges.Organic layer filters, and purifying provides required product (11.5mg, 30%) by partly preparing HPLC for solvent evaporation and gained solid.
Embodiment 135:
(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-1-yl) ethyl) pyrimidine-5-sulphonamide
Ex.135 is prepared as follows by intermediate 9 in two steps:
Step 1:
(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-1-yl) ethyl)-2-(ethylenebis dithiocarbamate) pyrimidine-5-sulphonamide:
The 50mL round-bottomed flask is equipped with intermediate 9, and (323mg is 0.90mmol) with to wherein adding CH
2Cl
2(5mL) and triethylamine (650 μ L, 4.66mmol).Independent 50mL round-bottomed flask be equipped with 2-chloropyrimide-5-SULPHURYL CHLORIDE (217mg, 1.02mmol) and CH
2Cl
2(3mL), and with suspension be cooled to 0 degree centigrade.Drip intermediate 9 and CH
2Cl
2With the solution of triethylamine, add other 2x subsequently
1MLCH
2Cl
2With the remaining reagent of rinsing.Mixture stirs down at 0 degree centigrade.After 1 hour, (200 μ L 2.70mmol), add triethylamine (200 μ L, 6.10mmol altogether) subsequently in addition to add ethane mercaptan.After 3 hours, add 200 μ L ethane mercaptan (5.40mmol altogether) and reaction in addition and be stirred and spend the night.Mixture is at CH
2Cl
2And H
2Distribute between the O and water layer CH
2Cl
2Extract.With the organism salt water washing that merges, dry (MgSO
4), filter and concentrate.Thick foam materials is by silica gel chromatography (gradient elution; The Rf=0.31 among the EtOAc) and purifying obtains water white oil at 50: 50 hexanes:, place and crystallization (99mg, 24%) in a vacuum.1H?NMR(400MHz，DMSO-D
6)δppm1.15(t，J＝7.33Hz，3H)1.29(t，J＝7.20Hz，3H)1.49(d，J＝6.82Hz，3H)2.81-2.91(m，2H)4.37(m，2H)4.95(m，1H)7.44(m，1H)7.57(m，1H)7.96(s，1H)8.58(s，2H)9.00(m，1H)。M/Z＝459。
Step 2:
(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyrimidine-5-sulphonamide:
Comprise (R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-2-(ethylenebis dithiocarbamate) pyrimidine-5-sulphonamide (step 1,79mg, 0.17mmol) 50mL round-bottomed flask with Raney Ni (excessive) in EtOH (～slurry treatment in 5mL).The gained mixture is heated backflow.After 2 hours, LC-MS shows that sulfide changes into the desired molecule amount fully.Mixture is cooled and is filled in by the filtration over celite weak point.Flask and strainer wash with MeOH, and the filtrate that merges is condensed into solid residue.By silica gel chromatogram (gradient elution; At 20: 80 hexanes: the Rf=0.18 among the EtOAc) and purifying obtains water white oil, from CH
3CN/H
2Freeze-drying in the O solution obtains colorless solid (12mg, 17%).
Embodiment 135 also can prepare by following two step by step suddenly:
Step 1:
(R)-2-chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyrimidine-5-sulphonamide:
Comprise (777mg, 100mL circular base flask 2.17mmol) the 4N HCl/ diox (～8mL) processing of (R)-tertiary butyl 1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl carbamate.After at room temperature stirring 1 hour, the fugitive constituent vapourisation under reduced pressure.Resistates is dissolved in CH
2Cl
2(10mL) and NEt
3(1.50mL, 10.8mmol) in.Mixture is cooled to 0 degree centigrade and with 2-chloropyrimide-5-alkylsulfonyl chlorine (Beta Pharma, New Haven, CT; 513mg, 2.41mmol) a collection of adding.The gained mixture stirs down at 0 degree centigrade.After 1 hour, be reflected at CH
2Cl
2And H
2Distribute between the O.Water layer CH
2Cl
2Extract, and with the organism salt water washing that merges, dry (MgSO
4), filter and concentrate.Crude product is by silica gel chromatography (gradient elution; The Rf=0.20 among the EtOAc) and purifying obtains water white oil at 60: 40 hexanes:, slowly place and solidify (690mg).M/Z＝433。
Step 2:(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyrimidine-5-sulphonamide:
50mL circular base flask is equipped with (R)-2-chloro-N-(1-(1-ethyl-6-(trifluoro memyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyrimidine-5-sulphonamide and (generates in step 1,0.44mmol), MgO (112mg, 2.78mmol), and 10%Pd/C (92mg).Flask be evacuated with backfill with H
2(using the ball oon that fills), and add MeOH (2mL) subsequently.The gained mixture is at room temperature at 1atm H
2The following stirring.After 4 hours, reaction by suction strainer by the Celite pad, and with reaction flask and filter cake MeOH thorough washing.The filtrate that merges is concentrated, and resistates is passed through silica gel chromatography (gradient elution; The Rf=0.18 among the EtOAc) and purifying obtains water white oil at 20: 80 hexanes:.Product is from CH
2Cl
2Precipitate in/the hexane, obtain colorless solid (67mg, 38%).
Embodiment 158:(R)-5-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulfamyl)-1-methyl isophthalic acid H-pyrroles-2-methane amide
Step 1:
(R)-5-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulfamyl)-1-methyl isophthalic acid H-pyrroles-2-carboxylic acid:
Comprise (R)-methyl 5-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulfamyl)-1-methyl isophthalic acid H-pyrroles-2-carboxylicesters (Ex.40; 465mg; 1.01mmol) 50mL circular base flask be equipped with LiOH (195mg, 8.14mmol).Add THF (4mL) and H
2O (2mL), and with gained mixture vigorous stirring at room temperature.After stirring is spent the night, mixture H
2O (5mL) dilution and with dense HCl (～1mL) processing obtains the mixture of pH～1.Mixture is at EtOAc and H
2Distribute between the O and water layer extracts (2x) with EtOAc.With the organism salt water washing that merges, dry (MgSO
4), filter and concentrate, obtain colourless to brown solid (389mg, 87%).Need not any being further purified and use.
Step 2:
(R)-5-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulfamyl)-1-methyl isophthalic acid H-pyrroles-2-methane amide:
Comprising (R)-5-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulphonamide)-1-methyl isophthalic acid H-pyrroles-2-carboxylic acid (generates in step 1,389mg, 0.88mmol) 100mL circular base flask be equipped with HATU (369mg, 0.97mmol).Add dry DMF (3.0mL), (0.15mL 1.4mmol), and at room temperature stirs gained solution to add the 4-methylmorpholine subsequently.After 45 minutes, add 7N NH
3(1.0mL 7.0mmol), adds MeOH (1mL) to/MeOH subsequently in addition.Mixture at room temperature stirs.After 3 hours, reaction H
2O (25mL) dilutes and extracts (3x) with EtOAc.With the organism salt water washing that merges, dry (MgSO
4), filter and concentrate.Crude product is by silica gel chromatography (gradient elution; Rf=0.22 in 100%EtOAc) and purifying obtains colorless solid (259mg, 67%).
Embodiment 163:
(R)-4-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulfamyl) benzo acid amides
(R)-(0.50mmol) diox (3mL) obtains clear solution to benzsulfamide to 4-cyano group-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) in the 20mL penstock for Ex.163,0.21g.Be added in the 4N HCl (3mL) in the diox, form two-phase system.With the seal of tube, and, cause transforming fully with content heating 16h under 90 degrees centigrade.Reaction mixture is cooled off, and fugitive constituent is under reduced pressure removed.Be dissolved in the gained semisolid in the acetonitrile (40mL) and add powder salt of wormwood (0.077g; 1.1 equivalent).With suspension returning 30min.Fugitive constituent from suspension, remove and with resistates in ethyl acetate with just be enough to distribute between the water (about 8 water layer pH) of dissolve inorganic salts.Organic layer is separated, and wash with water once and once with the saturated nacl aqueous solution washing.After the drying, solvent under reduced pressure is removed to obtain white solid (0.16g) on sal epsom.Recrystallization is to obtain pure products from acetonitrile.(0.08g，36.2％)。
Ex.164 is as described below and prepare by Ex.126.Embodiment 165 is similarly by Ex 127 preparations.
Embodiment 164:
(R)-3-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulfamyl) pyridine 1-oxide compound
Under nitrogen cleans, (R)-(Ex.126,0.200g 0.5mmol) are dissolved in the acetate (10mL) and with solution and are heated to 85 degrees centigrade N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyridine-3-sulphonamide.With acetate (5mL), be added in 50% hydrogen peroxide in the feed hopper (0.046mL, 0.75mmol).This solution is dripped in 15min and reaction mixture was stirred 75 minutes in addition.Reaction mixture cooling and solvent and excess reagent under reduced pressure are removed.The gained resistates distributes between ethyl acetate and water.Organic layer washes twice with water, washs with saturated nacl aqueous solution subsequently.Gains are dry on sal epsom, and filtration and solvent under reduced pressure are removed to provide white semi-solid.By flash chromatography (5 to 20% ethanol/dichloromethane; The dense ammonium hydroxide of 5%v: v in ethanol) and purifying to obtain required product as white powder (0.13g, 62.8%)
Embodiment 166:
(R)-4-(chloromethyl)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) benzsulfamide
In the 100mL round-bottomed flask, (R)-(INT 9 of Boc protection, 0.543g 0.00152mol) is dissolved in the diox (15mL) tertiary butyl 1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl carbamate.(using hot rifle to carry out some heating is essential for obtaining clear solution, and room temperature is got back in cooling subsequently).In single part, be added in the 4N HCl in the diox (5mL), form two phase liquid.Reaction mixture at room temperature stirs 3h fast.Solvent under reduced pressure is removed, and is semi-solid to obtain white.The ether that adds small part, and suspension carried out supersound process.Ether is toppled over from solid, and repeat this process subsequently more than twice.Although solid is placed under vacuum to remove fugitive constituent.This solid is suspended in the tetrahydrofuran (THF) (20mL) subsequently and is reflected in ice/acetone bath and cools off.(1.059mL 6.08mmol), forms thicker suspension to drip the diisopropylethylamine that dilutes with tetrahydrofuran (THF) (5mL).(0.410g 0.00152mol) is dissolved in tetrahydrofuran (THF) (5mL) neutralization and is placed in the feed hopper with 4-(brooethyl) benzene-1-SULPHURYL CHLORIDE.After dripping content, reaction mixture is warmed to room temperature and stirs more than the 16h.Suspension is heated backflow 1h, makes the solid dissolving.Solvent under reduced pressure is removed, and will distribute between ethyl acetate and water.Organic layer washes twice with water, subsequently with the saturated nacl aqueous solution washing once.After the drying, solvent under reduced pressure is removed to obtain semisolid on sal epsom.Crude product use the gradient of 50% ethyl acetate to 100% ethyl acetate in hexane by the flash distillation column chromatography and purifying to obtain pure products.(0.34g，50％)。
Embodiment 167:
(R)-4-(cyano methyl)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) benzsulfamide
Under nitrogen cleans, (R)-(Ex.166,0.22g 0.49mmol) are dissolved in the acetonitrile (22mL) benzsulfamide 4-(chloromethyl)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl).(0.132ml 0.99mmol), washs with more slightly acetonitriles to add trimethyl silyl cyanogen from syringe.From feed hopper, add tetrabutyl ammonium fluoride (980ml, 0.98mol subsequently; 1M is in THF).Reaction mixture is heated backflow subsequently and stirs 3h, causes starting raw material by completely consumed.Reaction mixture is cooled and solvent under reduced pressure is removed.Resistates distributes between ethyl acetate and water and the organic layer water, uses the salt water washing subsequently.On sal epsom after the drying, solvent under reduced pressure be removed and will by the flash distillation column chromatography use the gradient of 50% to 100% ethyl acetate in hexane and purifying to obtain product as white solid (0.2g, 93.5%).
Embodiment 168:
(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-1-yl) ethyl)-6-hydrazino pyridine-3-sulphonamide
In 50mL 3 neck round-bottomed flasks, under nitrogen cleans, with (R)-6-chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyridine-3-sulphonamide (Ex.35,0.26g; 0.0006mol) be dissolved in the ethanol (15mL).(0.030g 0.00060mol) with single part of adding, uses more slightly washing with alcohol to hydrazine hydrate, and reaction mixture is heated backflow and keeps 6h.Solvent under reduced pressure be removed and with the gained resistates from the 2-propyl alcohol recrystallization to obtain required product (0.095g, 36.9%).
Embodiment 169:
6-amino-5-chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyridine-3-sulphonamide
With 5,6-two chloro-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) pyridine-3-sulphonamide (Ex.48,0.238g, 0.00051mol), ethanamide (0.030g, 0.00051mol), salt of wormwood (0.141g, 0.001mol) and 18-hat-6 (0.013g 0.00005mol) is added in 1.5mL acetonitrile in the 5mL microwave tube together.Manage sealed and be heated to 160 degrees centigrade of 3h.Solvent under reduced pressure is removed and the gained resistates is distributed between ethyl acetate and water.Organic layer washes secondary with water, subsequently with the saturated nacl aqueous solution washing once.After the drying, solvent is removed by vacuum on sal epsom.The gained resistates uses 100%DCM to 5% volume that has in ethanol by flash chromatography: the 15% alcoholic acid gradient in DCM of the dense ammonium hydroxide of volume and purifying are to obtain required product as beige solid (0.045g, 19.7%).
Embodiment 170:
6-amino-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-1-yl) ethyl) pyridine-3-sulphonamide:
6-chloro-N-{ (1R)-1-[1-ethyl-6-(trifluoromethyl)-1H-benzoglyoxaline-1-yl) ethyl } and pyridine-3-sulphonamide (Ex.35,0.221g, 0.00051mol) and ammonia (1.5mL, 10.50mmol; 7N is in methyl alcohol) be placed in the 5mL microwave tube.Initial, reaction is heated to 120 degrees centigrade and maintenance 2h, and the result changes into required amine considerably lessly.Be heated to 140 degrees centigrade of 2h in addition to improve transformation efficiency.After 160 degrees centigrade are heated 16h down, will react cooling and solvent and under reduced pressure be removed.Resistates distributes between ethyl acetate and water.Organic layer water extraction twice, and extract with saturated nacl aqueous solution subsequently.After the drying, solvent is removed by vacuum on sal epsom.Resistates uses 100% methylene dichloride to 15% ethanol in methylene dichloride by flash chromatography; 5%v in ethanol: the gradient of the dense ammonium hydroxide of v) and purifying to obtain required product (0.045g, 21.4%)
Embodiment 171:
N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-6-oxo-1,6-dihydropyridine-3-sulphonamide
In the 5mL penstock, 6-chloro-N-{ (1R)-1-[1-ethyl-6-(trifluoromethyl)-1H-benzimidazolyl-2 radicals-yl] ethyl } (Ex.35,0.212g 0.00049mol) are dissolved in the diox (1.5mL) pyridine-3-sulphonamide.5N sodium hydroxide solution (1mL; 0.005mol) with single part of adding, and with the seal of tube.After 150 degrees centigrade were heated 4h down, LC/MC showed almost not conversion.Reaction is heated to 170 degrees centigrade reaches other 4h.Some have changed into required product.After 170 degrees centigrade were heated other 8h down, most of starting raw materials were consumed.Suspension neutralizes by adding acetate and subsequently fugitive constituent is removed in decompression.Resistates portion of hot ethanol filters out solid.Solvent under reduced pressure is removed, and resistates distributes between ethyl acetate and small part water.Organic layer water, saturated nacl aqueous solution subsequently.After the drying, solvent under reduced pressure is removed on sal epsom.Resistates uses 100% methylene dichloride to 15% ethanol in methylene dichloride by flash chromatography; The dense ammonium hydroxide of 5%v in ethanol: v) gradient and purifying are to obtain required product (15mg, 7%).
Embodiment 173 and 174:
The product of SM 2ac ' Ex.173 of being converted to as described below and 174. steps 1 carries out step 2 and step 2 ' to produce the raceme of Ex.173 and 174 respectively, further the described condition of use Ex.97 splits to obtain Ex.173 and Ex.174 on chirality HPLC.
Step 1:
2-(6-cyano group-pyridine-3-sulfuryl amino)-N-(6-cyclopropyl-4-ethylamino-pyridin-3-yl)-propionic acid amide
With the hydrogenchloride (15mL in the Zai diox; 4M solution) at room temperature add N-[-1-[(6-cyclopropyl-4-ethylamino-pyridin-3-yl) formamyl] ethyl] the carboxylamine tertiary butyl ester (SM2ac '; 420mg, 1.2mmol) (in 10 minutes, white solid precipitates).The gained mixture at room temperature stirs 2h.Reaction mixture is concentrated.Resistates is added DCM (20mL), under the ice bath temperature, add subsequently triethylamine (1.0mL, 7.2mmol).6-cyano group-pyridine-3-SULPHURYL CHLORIDE (290mg, 1.4mmol) solution of dropping in DCM (5mL).Reaction mixture is warmed to room temperature 2h.Mixture dilutes with ethyl acetate, uses sat.aq.NaHCO
3Solution, water and salt water washing.With organic extraction drying (Na
2SO
4), filter and concentrate.Resistates is dissolved in DCM neutralization by flash chromatography (gradient of the 0-4%MeOH in chloroform) and purifying obtains title compound as light brown solid (226mg, 46% productive rate).1E?NMR(301MHz，DMSO-d
6)δppm9.36(bs，1H)，9.10(d，7＝2.2Hz，1H)，8.85(d，J＝7.4Hz，1H)，8.42(dd，J＝8.3，2.2Hz，1H)，8.32(s，1H)，8.25(d，J＝8.0Hz，1H)，7.71(s，1H)，6.53(s，1H)，4.14(t，J＝7.0Hz，1H)，3.19-3.30(m，2H)，1.96-2.08(m，1H)，1.31(d，J＝6.9Hz，3H)，1.18(t，J＝7.2Hz，3H)，0.93-1.02(m，4H)。M/z?414。
Step 2:
6-cyano group-pyridine-3-sulphonic acid [1-(6-cyclopropyl-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl)-ethyl]-acid amides
2-(6-cyano group-pyridine-3-sulfuryl amino)-N-(6-cyclopropyl-4-ethylamino-pyridin-3-yl)-propionic acid amide (step 1; 226mg; 0.55mmol) be dissolved in THF: MeOH (6: 1,7mL) in and in microwave at 120 degrees centigrade of following heating 15h (5h at interval).Reaction mixture is concentrated.Resistates is used in the 5-10%MeOH wash-out in the chloroform by flash chromatography and purifying obtains title product as white solid (97mg, 45% productive rate).1H?NMR(301MHz，DMSO-J
6)δppm?9.14(s，1H)，8.85(d，J＝2.2Hz，1H)，8.51(s，1H)，8.17(dd，J＝8.3，2.2Hz，1H)，7.95(d，J＝8.0Hz，1H)，7.42(s，1H)，4.95(q，J＝6.9Hz，1H)，4.25(q，J＝7.6Hz，2H)，2.03-2.28(m，1H)，1.44(d，J＝6.9Hz，3H)，1.30(t，J＝7.0Hz，3H)，0.89-0.98(m，4H)。M/z?396。Product mapping on chirality HPLC splits, and Ex.173 is provided.
Step 2 ': 5-[1-(6-cyclopropyl-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl)-ethyl sulfamyl]-pyridine-2-carboxylic amide:
2-(6-cyano group-pyridine-3-sulfuryl amino)-(step 1,220mg 0.54mmol) are dissolved in MeOH (4mL) and the aqueous ammonia N-(6-cyclopropyl-4-ethylamino-pyridin-3-yl)-propionic acid amide.Mixture heats 1h (5h at interval) down at 120 degrees centigrade in microwave.Reaction mixture is concentrated.Resistates is used in by flash chromatography that 5-10%MeOH wash-out in the chloroform grinds with ether/hexane subsequently and purifying obtains title product as white solid (146mg, 68% productive rate).1H?NMR(301MHz，DMSO-d
6)δppm 8.94(br..，1H)，8.86(d，J＝2.2Hz，1H)，8.56(s，1H)，8.22(dd，J＝8.3，2.2Hz，1H)，8.14(s，1H)，8.03(d，J＝8.3Hz，1H)，7.82(s，1H)，7.43(s，1H)，4.88-5.06(m，1H)，4.19-4.38(m，2H)，2.06-2.23(m，1H)，1.37(d，J＝6.9Hz，3H)，1.31(t，J＝7.2Hz，3H)，0.88-0.94(m，4H)。M/z?414。
Product is at chirality SFC (methyl alcohol/CO
2) go up the mapping fractionation, Ex.174 is provided.
Embodiment 178:
5-({ [1-(1-ethyl-1H-imidazoles [4,5-b] pyridine-2-yl)-1-methylethyl] amino } alkylsulfonyl) pyridine-2-carboxamide
(Ex.177,142mg 0.38mmols) are placed in the round-bottomed flask and to the 4M HCl (10mL) that wherein is added in the diox with 6-cyano group-N-(2-(1-ethyl-1H-imidazoles [4,5-b] pyridine-2-yl) propane-2-yl) pyridine-3-sulphonamide.Gains are at room temperature stirred and when the 4M HCL (10mL) that is added in addition in the diox, be found and only change into required product at leisure, and gains were stirred through weekend.At room temperature stir altogether after 4 days, reaction mixture is concentrated and gains is neutralized carefully and product is extracted ethyl acetate layer (in 3 * 30mL).Organism is dry on anhydrous sodium sulphate, filter and concentrate.The gained material use 50% ethyl acetate in hexane to the gradient of 15% methyl alcohol in ethyl acetate and purifying to obtain required product (26mg, 17.46%).
Embodiment 187:
(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-1-methyl isophthalic acid H-pyrroles-2-sulphonamide:
Step 1:
1-methyl isophthalic acid H-pyrroles-2--sulfinic acid lithium:
Stove exsiccant 100mL circular base flask is evacuated while hot and cools off under N2.Flask is equipped with 1-methyl isophthalic acid H-pyrroles, and (1.00mL is cooled to-78 degrees centigrade 11.3mmol) with anhydrous THF (12mL), and with gained solution.Drip the n-BuLi (2.5M in hexane; 5.0mL, 12.5mmol), and the gained mixture down stirred 5 minutes and was warmed to subsequently room temperature at-78 degrees centigrade.At room temperature stir spend the night after, mixture is cooled and gets back to-78 degrees centigrade and introduce SO
2(excessive).The gained mixture stirred 5 minutes under-78 degrees centigrade and is to be warmed to room temperature subsequently.After at room temperature 5 hours, with regard to the volatile constituent vapourisation under reduced pressure.Resistates grinds and vacuum-drying subsequently with ether, obtains brown solid.Collect the 1.76g material.Directly use and need not any being further purified.
Step 2:
(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-1-methyl isophthalic acid H-pyrroles-2-sulphonamide:
50mL circular base flask is equipped with (R)-1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl carbamic acid tertiary butyl ester, and (Int 9 of Boc protection, 236mg is 0.66mmol) with 4NHCl/ diox (3mL).Gained solution at room temperature stirred 1 hour and under reduced pressure concentrated subsequently.The gained resistates is dissolved in CH
2Cl
2(3mL) and NEt
3(500 μ L, 3.6mmol) in.Simultaneously, independent 25mL circular base flask be equipped with 1-methyl isophthalic acid H-pyrroles-2--sulfinic acid lithium (189mg, 1.25mmol), CH
2Cl
2(3mL), and H
2O (3mL).This biphasic mixture is cooled to 0 degree centigrade under vigorous stirring, and add subsequently N-chloro-succinimide (164mg, 1.23mmol).Mixture is warmed to room temperature under vigorous stirring.After 30 minutes, reaction is transferred to separatory funnel and organic layer and is discharged into and comprises the flask of protecting amine.This mixture at room temperature stirs.After at room temperature stirring was spent the night, mixture was at CH
2Cl
2And H
2Distribute between the O and water layer CH
2Cl
2Extract.With the organism drying (MgSO that merges
4), filter and concentrate.Crude product is by silica gel chromatography (gradient elution; The Rf=0.19 among the EtOAc) and purifying obtains light yellow oil at 60: 40 hexanes:.Product is from MeOH/H
2Precipitate among the O, obtain colorless solid (25mg, 9%).MJZ＝400。1H?NMR(400MHz，DMSO-D
6)δppm?1.27-1.36(m，6H)3.77(s，3H)4.28-4.34(m，1H)4.36-4.42(m，1H)4.72(m，1H)5.94(m，1H)6.62(m，1H)6.93(m，1H)7.48(m，1H)7.76(m，1H)8.00(m，1H)8.42(m，1H)。
5-({ [1-(1-ethyl-1H-imidazoles [4,5-b] pyridine-2-yl)-1-methylethyl] amino } alkylsulfonyl) pyridine-2-carboxamide
Intermediate 1
[(1R)-and 1-(ethyl of 1-ethyl-1H-benzimidazolyl-2 radicals-yl)] amine
N-ethyl-1,2-phenylenediamine (starting raw material (SM)
1H, 14.7mmol) and the D-L-Ala (2.2g 22.0mmol) is absorbed among the 6N HCl (15.0mL) and mixture was refluxed 6 days.Reaction mixture cools off in ice bath, uses 2N NaOH alkalization and extracts (3 * 50mL) with EtOAc.Organic layer washs with salt water washing (10mL), and drying and vacuum concentration obtain dark-brown thickness glue, uses silica gel and CHCl by the flash distillation column chromatography
3/ MeOH (95: 5) is as eluent and purifying obtains intermediate 1 as brown oil, 81% productive rate.1H?NMR(300MHz，CDCl
3)δ7.78-7.72(m，1H)，7.37-7.21(m，3H)，4.36-4.17(m，3H)，1.81(br，2H)，1.61(d，J＝6.9Hz，3H)，1.45(t，J＝7.1Hz，3H)。M/Z＝189
Starting raw material 1h
N-ethyl-1, the 2-phenylenediamine
(5.0g, 30.0mmol) solution in EtOH (100mL) is added in Pd (1.24g) on 10% the carbon to 1-ethyl-2-N-methyl-p-nitroaniline.Mixture in the Parr device at 50psi H
2Gas is reaction 2h down.Mixture is by filtration over celite.Diatomite washs with EtOAc, and with the organic solvent vacuum concentration that merges, obtains product as brown oil (4.0g, 100% productive rate), is directly used in next step.1HNMR(300MHz，CDCl
3)
56.72-6.68(m，4H)，3.19-3.12(m，5H)，1.28(t，J＝7.1Hz，3H)。M/Z?136。
Intermediate 2-7 shown in the table 2 according to intermediate 1 similar mode, use suitable commercially available amino acid and prepare.
Table 2
Intermediate 8
1-(the ethamine of 1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)
Intermediate 8 is according to the similar fashion that is used to prepare intermediate 1 but use the N-methyl isophthalic acid, 2-phenylenediamine (starting raw material 1i) and BOC-Ala-OH and prepare.1H?NMR(300MHz，CDCl
3)
1.57(d，3H)3.79(s，3H)4.07-4.52(m，1H)4.81(s，2H)7.10-7.69(m，3H)7.57-7.98(m，1H)。M/Z?176。
Starting raw material 1i
The N-methyl isophthalic acid, the 2-phenylenediamine
N-methyl-2-N-methyl-p-nitroaniline (3.0g; 0.05mol) be dissolved in about 120mL ethanol and become glassy yellow solution.Tetrahydrobenzene (40mL; 0.4mol) and 10% carbon on palladium (2.65g; 5mol%) sequentially with single part of adding.Gained suspension is heated and refluxes and maintenance 16h.Reaction mixture is by filtration over celite pad while hot and with the hot ethanol washing of filter cake with small part.Filtrate under reduced pressure concentrates, and obtains product as redness-brown oil, is directly used in later step.1H?NMR(300MHz，CDCl
3)：δ2.84(s，3H)3.32(s，3H)6.49-6.82(m，3H)6.78-7.01(m，1H)M/Z＝123。
Intermediate 9-16 and 25-52 as above 2 of schemes usually describe, and generate by suitable amide starting raw material 2 (SM 2) is reacted according to one of four kinds of methods with suitable cyclization agent: (1:AcOH; 2:Lawesson ' s reagent, 3:4M HCl/ diox or 4: sodium hyposulfate/aldehyde.
Method 1:AcOH
Intermediate 11;
Step I
[(1R)-and 1-(ethyl of 1-ethyl-7-methoxyl group-1H-benzimidazolyl-2 radicals-yl)] the carboxylamine tertiary butyl ester
Before deriving from step ((1R)-2-{[2-(ethylamino)-3-p-methoxy-phenyl] amino }-1-methyl-2-oxoethyl) carboxylamine tertiary butyl ester (SM 2c) (2.75mmols) is dissolved in AcOH (6mL) neutralization and is heated to 65 degrees centigrade and reaches 2h.Reaction mixture under reduced pressure is concentrated and passes through flash chromatography (30% ethyl acetate in hexane) purifying, obtains required product as white powder (180mg, 22%).Title product is carried out next step after LC-MS characterizes.
Step II
[(1R)-and 1-(ethyl of 1-ethyl-7-methoxyl group-1H-benzimidazolyl-2 radicals-yl)] amine hydrochlorate (intermediate 11)
[(1R)-1-(ethyl of 1-ethyl-7-methoxyl group-1H-benzimidazolyl-2 radicals-yl)] carboxylamine tertiary butyl ester (0.18g, 0.56mmol) and 4MHCl/ diox (3mL) be placed in the round-bottomed flask of being furnished with stirring rod and diaphragm of rubber.Reaction mixture at room temperature stirs and under reduced pressure concentrated subsequently and vacuum-drying in 40 minutes, obtains the 0.148g title compound.M/Z?219。
Method 2:Lawesson ' s reagent
Intermediate 15;
Step I
(2-{[2-(ethylamino) pyridin-3-yl] amino }-1-methyl-2-oxoethyl) carboxylamine tertiary butyl ester (SM 2g)
(0.367g 1.93mmols) is placed in the round-bottomed flask of being furnished with stirring rod and adds DCM (2mL) with Boc-Ala-OH.In the gained homogeneous phase solution, add DIEA (0.34mL, 1.93mmols) and PYBOP (1.0g, 1.93mmols).Stirred 15 minutes and slowly added subsequently with regard to the gained mixture and comprise N2-ethylpyridine-2, and 3-diamines (SM Ig) (0.24g, 1.75mmols) and another round-bottomed flask of DCM (2mL).The gained mixture at room temperature stirs and spends the night.Reaction mixture is condensed to rob.Use the ethyl acetate reconstituted solutions and wash salt water washing subsequently with water.Organic layer is gone up dry at sodium sulfate (anhydrous), filter and be condensed into solid.Use the gradient of 10% ethyl acetate to 100% ethyl acetate in hexane to use 5% methyl alcohol in ethyl acetate subsequently and the required product (0.305mg of purifying by column chromatography the solid crude product that so obtains to obtain the yellow-white powder type, 60%) 1H NMR (MeOH-d,
4): δ 7.96 (d, 1H), 7.84 (bs, 1H), 7.54 (d, 1H), 6.60 (dd, 1H), 5.04 (q, 1H), 3.42 (q, 2H), 1.50 (s, 9H), 1.48 (d, 3H), 1.28 (t, 3H).M/Z?308
Step II
[1-(3-ethyl-3H-imidazoles [4,5-b] pyridine-2-yl) ethyl] amine dihydrochloride (intermediate 15)
Will (2-{[2-(ethylamino) pyridin-3-yl] amino }-1-methyl-2-oxoethyl) carboxylamine tertiary butyl ester (0.168g, 0.54mmols) diox (3mL) and Lawesson ' s reagent (and 0.109g, 0.27mmols) be placed in the microwave tube of being furnished with stirring rod and with the gained mixture in microwave at 150 degrees centigrade of heating 2h down.This gained mixture is placed in the round-bottomed flask, is condensed into dark brown solid, reconstruct in the Zai diox is subsequently filtered, and concentrates and use 4M HCl/ diox (5mL) to carry out the protection of going of BOC group.Crude product mixture at room temperature stirs 2h and under reduced pressure concentrates, and obtains amine hydrochlorate, need not to be further purified and uses.M/Z?190。
Method 3:4M HCl/ diox
Intermediate 16:[1-(1-ethyl-1H-benzimidazolyl-2 radicals-yl)-the 1-methylethyl] amine hydrochlorate
(0.600g 1.86mmol) refluxes in 4M HCl/ diox (5.0mL) and spends the night with [1-(2-ethylamino-phenyl amino formyl radical)-1-methylethyl]-carboxylamine tertiary butyl ester (SM 2h).Solvent is evaporated to obtain title compound (0.576g), need not to be further purified and is used for next step.Analyze for NMR, (0.020g) crude product uses 2N NaOH alkalization and extracts with EtOAc on a small quantity.Organic layer is obtained product as free alkali by vacuum concentration.
1H NMR (free alkali) (300MHz, CDCl
3) δ 7.76-7.73 (m, 1H), 7.36-7.22 (m, 3H), 4.66 (q, J=7.1Hz, 2H), 3.50-3.48 (m, 2H), 1.70 (br, 3H), 1.57 (br, 3H), 1.48 (t, J=7.1Hz, 3H).M/Z203。
Method 3 ': 2M HCl in ethanol and the 4M HCl in the Zai diox
Intermediate 59:
1-(1-ethyl-1H-imidazoles [4,5-b] pyridine-2-yl)-1-methyl-ethamine; Hydrochloride
[1-(3-ethylamino-pyridine-2-base formamyl)-1-methyl-ethyl]-carboxylamine tertiary butyl ester
(SM2ai, 1.93g is 6mmol) at the 4M HCl (50mL) of N2atm low suspension in the Zai diox and 2.5M HCl (15mL) and the backflow 16h in ethanol.Solvent is evaporated with the gained solid and grinds with ether, filtration and dry to obtain required product (1.4g, 99%) under vacuum.
Method 4: sodium hyposulfate, aldehyde
Intermediate 30
(R)-and 1-(1-ethyl-5,6-dimethoxy-1H-benzimidazolyl-2 radicals-yl)-ethamine
Step 1:
(R)-[1-(1-ethyl-5,6-dimethoxy-1H-benzimidazolyl-2 radicals-yl)-ethyl]-the carboxylamine tertiary butyl ester:
With (4,5-dimethoxy-2-nitro-phenyl) ethamine (0.23g, 1mmol) and Boc-D-Ala-CHO (1mmol) solution in EtOH (4mL) or suspension are with freshly prepd 1M aq.Na for SM lae, 0.17g
2S2O
4(3mmol 3mL) handles.After 70 degrees centigrade of following reacting by heating mixture 5-12h, it is cooled to rt and uses 5N aqNH
4OH drips processing.The gained resistates extracts secondary with EtOAc.With the organic layer usefulness salt water washing of merging with at anhydrous MgSO
4Last dry and concentrated.Products therefrom uses the 35-80%EtOAc/ hexane as eluent and purifying on silica gel by flash chromatography subsequently.Productive rate: 0.37g (60%).1H?NMR(300MHz，DMSO-^6)δ：7.42(d，J＝8.5Hz，1H)，7.14(s，1H)，7.10(s，1H)，4.97(m，1H)，4.22(m，2H)，3.81(s，3H)，3.76(s，3H)，1.48(d，J＝6.9Hz，3H)，1.38(s，9H)。(M/Z＝349。
Step 2:
(R)-1-(1-ethyl-5,6-dimethoxy-1H-benzimidazolyl-2 radicals-yl)-ethamine (intermediate 30):
(R)-[1-(1-ethyl-5,6-dimethoxy-1H-benzimidazolyl-2 radicals-yl)-ethyl] (0.58mmol) (5mL, 20.0mmol) reaction obtains product as hydrochloride to the carboxylamine tertiary butyl ester with 4M HCl in diox for step 1,0.34g.Productive rate: 0.28g.M/Z?249。If step 2 use TFA/DCM (1: 1, v/v) substitute 4M HCl/ diox and carry out, obtain corresponding trifluoroacetate (as the situation of intermediate 32) so
Method 5:4N HCl/ diox and sodium hydroxide, ethanol
Intermediate 53:(R)-1-(1-ethyl-6-methoxyl group-1H-imidazoles [4,5-c] pyridine-2-yl) ethamine
Comprise thick (R)-1-(4-(ethylamino)-6-methoxypyridine-3-base is amino)-1-oxo propane-2-aminocarbamic acid tertiary butyl ester (2.13mmol at most), (SM 2ad ', 0.719g) the 100mL round-bottomed flask 4N HCl/ diox (6mL) is housed, and mixture is at room temperature stirred.， diox and excessive HCl under reduced pressure are evaporated after 2 hours.Resistates be dissolved among the anhydrous EtOH (8mL) and add solid NaOH (406mg, 10.2mmol).Mixture is placed in 80 degrees centigrade of oil baths.After 90 minutes, add other 440mg NaOH (21.2mmol is total) and continue heating.After 3 hours, will react cooling at other.Mixture under reduced pressure be concentrated and resistates at CH
2Cl
2And H
2Distribute between the O.Water layer CH
2Cl
2Extract, and with the organism salt water washing that merges, at MgSO
4Last dry, filter and be condensed into scarlet oil.This material need not to be further purified and uses.
Intermediate 60 is prepared by following method by starting raw material 2ac '.With method 5 described below ' be applied to starting raw material 2a, obtain intermediate 61.
Method 5 ' (microwave condition)
Intermediate 60:1-(6-cyclopropyl-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl)-1-methyl-ethamine:
(SM 2ac ', 696mg are added in the 4M HCl (20mL) in the diox in 2.0mmol) to [1-(6-cyclopropyl-4-ethylamino-pyridin-3-yl formamyl)-ethyl]-carboxylamine tertiary butyl ester under N2atm.At room temperature stir 2h.Solvent is removed and with resistates vacuum-drying by evaporation.Resistates is dissolved among 10%aq.NaOH (4mL) and the EtOH (10mL).Mixture heats 2h in microwave reactor under 80 degrees centigrade.Reaction mixture is concentrated.Resistates distributes between water/chloroform and uses chloroform extraction.Organic layer drying (Na
2SO
4), filter and concentrate, obtain 1-(6-cyclopropyl-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl)-ethamine as shallow brown oil.Intermediate 9,10 and 12-14 use the given specific acid amides starting raw material (SM2) of table 3 and prepare at one of intermediate 11,15 and 16 described three kinds of methods by above.
Table 3
Intermediate 17-23 generates at intermediate 17 described methods by following.
Intermediate 17:[1-(propyl group of 1-ethyl-1H-benzimidazolyl-2 radicals-yl)] amine hydrochlorate
The 25ml round-bottomed flask is equipped with the above tertiary butyl [1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)] carbamate (starting raw material 3; 0.045g, 0.17mmol) and THF (5mL).(0.25g, 0.75mmol) (18 μ L 0.19mmol) handle and at room temperature stir and spend the night solution with the n-propyl iodide with cesium carbonate.The volatile constituent vapourisation under reduced pressure.The gained resistates is by silica gel chromatography (EtOAc/ hexane 40: 60) and purifying obtains the required product of 40mg (77.65%).Be dissolved in subsequently in the 4NHCl/ diox (1.5mL) and with solution stirring 1.5 hours.Evaporating solvent, dry under high vacuum subsequently, obtain title compound with quantitative yield.
Preparation starting raw material 3:
[1-(ethyl of 1H-benzimidazolyl-2 radicals-yl)] the carboxylamine tertiary butyl ester
(1.56g, 8.24mmol) (0.91 milliliter, 8.24mmol) solution in DMF (15 milliliters) is used isobutyl chlorocarbonate (1.08 milliliters 8.24mmol) are handled down at-20 degrees centigrade with the 4-methylmorpholine with Boc-Ala-OH.After-20 degrees centigrade of following 10min, and adding o-phenylenediamine (0.89g, 8.24mmol).Reaction mixture is stirred, slowly be warmed to room temperature (1h) and stir 3h subsequently simultaneously.Solvent be evaporated and resistates at EtOAc and H
2Distribute between the O.EtOAc layer 5%NaHCO
3With salt water washing and drying.Solution is filtered, and solvent is evaporated and resistates is dissolved among the ice AcOH (15 milliliters).Solution heats 1h down at 65 degrees centigrade.Solvent be evaporated with resistates by silica gel chromatography (EtOAc/ hexane 50: 50) and purifying obtains shallow white solid (750mg, 38%).1HNMR(300MHz，DMSO-d
6)δ1.40(s，9H)，1.47(d，3H)，3.17(d，1H)，4.86(m，1H)，7.13(m，2H)，7.49(m，2H)。M/Z＝261。
Intermediate 18-20 shown in the table 4 is according to using starting raw material 3 (being used for intermediate 18 and 19) and starting raw material 4 (being used for intermediate 20) and suitable commercially available alkylogen with intermediate 17 similar modes and prepare.
Preparation starting raw material 4 (SM4):
[(1R)-and 1-(5, the ethyl of 6-two fluoro-1H-benzimidazolyl-2 radicals-yl)] the carboxylamine tertiary butyl ester
According to the mode index that is similar to starting raw material 3, except 1,2-diamines-4,5-two fluorobenzene are used for substituting the o-phenylenediamine to obtain SM4 as white solid (107mg).1H?NMR(300MHz，CDCl
3)：δ1.47(s，9H)，1.76(t，3H)，5.01(m，1H)，5.36(d，1H)，7.36-7.41(t，2H)。M/Z＝297。
Table 4
Intermediate 21:[1-(ethyl of 1-cyclopropyl-1H-benzimidazolyl-2 radicals-yl)] amine
Step I
[2-((1E)-1-[(1E ')-1-amino third-1-alkene-1-yl] fourth-1,3-diene-1-yl } amino)-1-methyl-2-oxoethyl] the carboxylamine tertiary butyl ester
(1.56g, 8.24mmol) (0.91 milliliter, 8.24mmol) at N, the solution in the dinethylformamide (DMF, 15 milliliters) is used isobutyl chlorocarbonate (1.08 milliliters 8.24mmol) are handled down at-20 degrees centigrade to Boc-Ala-OH with the 4-methylmorpholine.After-20 degrees centigrade of following 10min, and adding o-phenylenediamine (0.89g, 8.24mmol).Stirred reaction mixture slowly is warmed to room temperature (1h) simultaneously and stirs 3h subsequently.Solvent be evaporated and resistates at ethyl acetate and H
2Distribute between the O.EtOAc layer 5%NaHCO
3With the salt water washing with at Na
2SO
4Last dry.Solution is filtered, solvent is evaporated, with resistates recrystallization from EtOAc, obtain [2-((1E)-1-[(1E)-and 1-amino third-1-alkene-1-yl] fourth-1,3-diene-1-yl } amino)-1-methyl-2-oxoethyl] the carboxylamine tertiary butyl ester, and need not to be further purified and carry out next step.M/Z?279。
Step II
(2-{[2-(cyclopropyl amino) phenyl] amino }-1-methyl-2-oxoethyl) the carboxylamine tertiary butyl ester
Will be from the amine of step I, promptly [2-((1E)-1-[(1E)-and 1-amino third-1-alkene-1-yl] fourth-1,3-diene-1-yl } amino)-1-methyl-2-oxoethyl] carboxylamine tertiary butyl ester (2.07g, 7.42mmol), AcOH ((1.20ml, 29.68mmol) and MeOH (12 milliliters) be placed in 100 milliliters of round-bottomed flasks.At room temperature drip [(1-oxyethyl group cyclopropyl) oxygen base]-trimethyl silane (1.78g, 29.68mmol) and with reaction mixture under N2 atmosphere at 67-69 degree centigrade of following backflow 3h.The gained mixture use rotatory evaporator by vacuum concentration to obtain [2-({ 2-[(1-oxyethyl group cyclopropyl) amino] phenyl amino)-1-methyl-2-oxoethyl] carboxylamine tertiary butyl ester (2.69g), (M/Z363).In the 100ml round-bottomed flask, add NaBH
4(0.56g is 14.83mmol) with anhydrous THF (20 milliliters).Be cooled to 5 degrees centigrade and dropping BF
3-Et
2(2011g, 14.83mmol) afterwards, mixture is stirring 1h under 5 degrees centigrade to the O title complex under N2 atmosphere.Under 5-10 degree centigrade, in the time of 20mins, in this flask, drip the crude product be dissolved among the THF (10 milliliters) ([2-({ 2-[(1-oxyethyl group cyclopropyl) amino] phenyl } amino)-1-methyl-2-oxoethyl] the carboxylamine tertiary butyl ester).At room temperature stir 5h, backflow 2h and reclaims after the THF by distillation is cooled to room temperature and pouring in the water (50m) with mixture.Gained mixture Et
2O (2x
50Milliliter) extracts.Et
2O layer water (2 * 50 milliliters) washing and in anhydrous Na
2SO
4Last dry, use rotatory evaporator to remove Et subsequently
2O is to obtain title compound (1.2g).M/Z?319。Product is used for next cyclization step and need not to be further purified.
Step II I
[1-(ethyl of 1-cyclopropyl-1H-benzimidazolyl-2 radicals-yl)] amine hydrochlorate (intermediate 21)
(2-{[2-(cyclopropyl amino) phenyl] amino }-1-methyl-2-oxoethyl) (1.2g 7.42mmols) is dissolved in 4M HCl/ diox (10mL) neutralization and at room temperature stirs 1h to remove the BOC group carboxylamine tertiary butyl ester.Reaction mixture under reduced pressure be concentrated with vacuum-drying to obtain title compound (0.43g), M/Z 201.
Intermediate 40,41 and 43 intermediates 39 preparations by BOC protection followingly are described at intermediate 40:
Intermediate 43
[(1R)-1-(ethyl of 1-ethyl-5-pyridin-3-yl-1H-benzimidazolyl-2 radicals-yl)] amine:
Step 1:[(1R)-and 1-(ethyl of 1-ethyl-5-pyridin-3-yl-1H-benzimidazolyl-2 radicals-yl)] the carboxylamine tertiary butyl ester
Under nitrogen, and the tertiary butyl [1-(ethyl of 5-bromo-1-ethyl-1H-benzimidazolyl-2 radicals-yl)] carbamate (intermediate 39 of Boc protection, 367mg; 1mmol), and pyridyl boric acid (180mg, 1.5mmol); salt of wormwood (483mg, 3.5mmol) and (DPPF) PdCl
2(42mg 0.05mol) merges in the developmental tube of barrier film capping.Add diox (2mL) and water (0.5mL) and mixture is descended stirring 12 hours at 90 degrees centigrade.Mixture distributes and the water layer dichloromethane extraction between methylene dichloride and water.The organic layer that merges is used the salt water washing and drying on sal epsom.Solvent is removed by vacuum and material is passed through flash chromatography and purifying.
HNMR(DMSO-J
6)：1.32(t，3H)，1.38(s，9H)，1.52(d，3H)，4.30(m，2H)，5.05(m，1H)，7.47(m，1H)，7.57(d，1H)，7.65(d，1H)，7.94(s，1H)，8.09(d，1H)，8.53(d，1H)，8.92(s，1H)
Step 2:[(1R)-and 1-(ethyl of 1-ethyl-5-pyridin-3-yl-1H-benzimidazolyl-2 radicals-yl)] amine;
(170mg 0.46mmol) at room temperature stirs among the 4N HCl (3mL) in the Zai diox pyridyl benzimidazole carbamate.After when ¨, solvent is removed by vacuum, obtains crude product as HCl salt.M/Z?266。
Intermediate 52;
1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethamine [1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] amine
Step 1:
4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine
To 2-chloro-N
4-ethylpyridine-3, the 4-diamines (SM lac, 2g) solution in the adjacent manthanoate of triethyl (30mL) add HCl (12N, 1.3mL).Be reflected at rt and stir 12h down.Reaction mixture is concentrated under vacuum.Mixture uses silica gel chromatography and purifying obtains 4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridines (900mg).M/Z?181。
Step 2:4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-formaldehyde:
Under-78 degrees centigrade, add n-BuLi (2.4mL, 2.5M is in hexane) to the solution of 4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridines (500mg) in THF (14mL).Reaction mixture under this temperature, stir 45min and add subsequently DMF (1.10mL, 14.3mmol).Chloroform is used in the cancellation of gained solution with water subsequently, and (2 * 20mL) extract.With the organic layer that merges at Na
2SO
4Last dry and concentrated, obtain crude product 4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-formaldehyde and be directly used in next step as yellow solid.M/Z＝209。
Step 3:
N-[(1E)-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) methylene radical]-2-methylpropane-2-sulfinyl amine:
The solution of 4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-formaldehyde (above preparation) in methylene dichloride with 2-methylpropane-2-sulfinyl amine (518mg, 4.28mmol) and copper sulfate (4g) processing.Gained solution at room temperature stirs 18h.Reaction mixture dilutes with methylene dichloride, filters and concentrates, and obtains N-[(1E)-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) methylene radical]-2-methylpropane-2-sulfinyl amine (380mg), be directly used in next step.M/Z＝312。
Step 4:
N-[1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl]-2-methylpropane-2-sulfinyl amine:
N-[(1E)-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) methylene radical]-solution of 2-methylpropane-2-sulfinyl amine (above preparation) in THF handles down at-78 degrees centigrade with methyl-magnesium-bromide (2.4mL, 1M is in THF).The gained solution stirring is spent the night and slowly is warmed to room temperature.Reaction mixture is slowly poured into saturated solution (20mL) neutralization DCM (2 * 30mL) extractions of ammonium chloride.With the organic layer that merges at Na
2SO
4Last dry and concentrate, obtain N-[1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl]-2-methylpropane-2-sulfinyl amine is as yellow solid, is directly used in next step.M/Z＝328。
Step 5:1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethamine [1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] amine
N-[1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl]-(1.8mL 4M) handles the solution of 2-methylpropane-2-sulfinyl amine (above preparation) in MeOH (2mL) with hydrochloric acid.Gained solution is stirred and spends the night.Reaction mixture concentrates and obtains product as thickness glue.In this material, add solvent mixture MeOH/Et
2O (V/V=1: 3, about 10mL).1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethamine [1-(4-chloro-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] amine precipitates from solution as white solid.M/Z＝224。
Preparation acid amides starting raw material (SM)
2A-2z and 2aa-2aj:
Starting raw material 2a
(1.78g 9.4mmols) is placed in the round-bottomed flask of being furnished with stirring rod and to wherein adding DCM (10mL) to Boc-D-Ala-OH.In the homogeneous phase solution of gained, add DIEA (3.3mL, 19mmols) and PYBOP (4.9g, 9.4mmols).The gained mixture stirred 15 minutes and slowly add subsequently comprise the amino benzo trifluoride of N-ethyl-4-(starting raw material 1,1.74g, 8.5mmols) and another round-bottomed flask of DCM (10mL).The gained mixture at room temperature stirs and spends the night.Reaction mixture is condensed into molasse and vacuum-drying and is used for next step with its crude product form.(starting raw material 2a ") and raceme (starting raw material 2a ') prepare according to above step the S isomer of M/Z 375.2a, wherein correspondingly with starting raw material 1 and commercially available Boc-1-Ala-OH and Boc-DL-Ala-OH reaction.
Starting raw material 2b-2g begins preparation according to the mode that is similar to starting raw material 2a by the given suitable starting raw material 1b-1g of table 5.Starting raw material 2h is prepared by the amino acid and the starting raw material 1h of suitable commercially available BOC protection similarly.Raceme and L-isomer generate by the Boc-Ala-OH that use has suitable chirality.Starting raw material 2a hand 2ai is described and be prepared as follows.Starting raw material 2w uses the method for racemize Boc-Ala-OH or the following 2ah of being used for to use Boc-D-ala-OH to prepare by the method for the above-mentioned 2a of being used for, produces 2w '.
Starting raw material 2ah:
50mL circular base flask be equipped with BOC-D-Ala-OH (480mg, 2.54mmol) and add N, N '-carbonyl dimidazoles (411mg, 2.53mmol), CH
2Cl
2(3mL), and with gained solution at room temperature stir.After 75 minutes, mixture is transferred to the thick N that comprises as preparation as described in the WO2002050062
4-ethyl-6-(trifluoromethyl) pyridine-3,4-diamines (starting raw material 1aj; 446mg is in the independent 50mL circular base flask of 2.17mmol.Use other 4x
1ML CH
2Cl
2Rinsing remains reagent, and the gained mixture is placed in 45 degrees centigrade of oil baths.After 45 degrees centigrade are stirred 60 hours down, the reaction cooling.Mixture is at CH
2Cl
2And H
2Distribute between the O and water layer CH
2Cl
2Extract.With the organism salt water washing that merges, dry (MgSO
4), filter and concentrate.Crude product is by silica gel chromatography (gradient elution; At 40: 60 hexanes: the Rf=0.33 among the EtOAc) and purifying, obtain 1-(4-(ethylamino)-6-(trifluoromethyl) pyridin-3-yl amino)-1-oxo propane-2-aminocarbamic acid tertiary butyl ester as colourless to light yellow solid (397mg, 49% productive rate).Under the situation of starting raw material 2ai, reaction mixture is 60 degrees centigrade of down heating 72 hours and added other at CHCl 48 hour latter stage altogether
32-(8mL) (tert-butoxycarbonyl amino)-2 Methylpropionic acid (822mg, 4.04mmol) and CDI (665mg 4.10mmol) and with reaction mixture continues other 24 hours of heating.When this time finishes, as described in 2ah, carry out identical processing, obtain 2ai.
Starting raw material 2aj is by 1d preparation as described below:
Under N2atm under 0 degree centigrade, to 2-tert-butoxycarbonyl amino-2-methyl-propionic acid (15.5g, 76.4mmol) solution in DMF (100mL) add diisopropylethylamine (39.7mL, 229.2mmol).After stirring 5min, and HATU (32g, 84mmol).After this temperature stirs 30min, in reaction mixture, be added in N among the DMF (100mL) with intubate
3-ethyl-pyridine-2, and the 3-diamines (10.5g, 76.39mmol).Remove ice bath and further stirring 4 days under rt.Reaction mixture is concentrated, and with the EtOAc dilution, uses aq.NaHCO
3, water, salt water washing and at MgSO
4Last dry.Solution be filtered and evaporate and with resistates by the flash distillation column chromatography on silica gel, use the 80%EtOAc/ hexane to EtOAc as eluent and purifying obtains product 6.7g (27.3%).
Table 5
Starting raw material 1a-1z and 1aa-1ad are by table 6 listed commercially available material preparation and starting raw material 1aj such as WO
2002050062 is described and prepare.
Table 6
The preparation of starting raw material 1a
Step I:N-ethyl-4-nitro benzo trifluoride
3-chloro-4-nitro benzo trifluoride (1g, 4.43mmols) and ethamine (2M in THF, 12mL) is placed in the microwave tube of being furnished with stirring rod.With contents stirred, seal and in microwave, descend to heat 2 hours at 100 degrees centigrade.Reaction mixture is transferred to round-bottomed flask subsequently and concentrates, and obtains the bright orange solid.Solid distributes between ethyl acetate (300mL) and water (50mL).Organic layer salt water washing, with sodium sulfate (anhydrous) drying, filtration and vacuum-drying are to obtain the required product of 1.45g (94.66%).
Step II: the amino benzo trifluoride (starting raw material 1a) of N-ethyl-4-:
N-ethyl-4-nitro benzo trifluoride (1.94g, 8.29mmols), ethanol (25mL), 10%Pd/C (3g) and hexanaphthene (20mL) are placed in the round-bottomed flask of being furnished with stirring rod and reflux exchanger.The gained mixture is heated to 80 degrees centigrade and reaches 3h, if reaction is judged and finished based on the LC-MS monitoring.Reaction mixture is cooled to room temperature and by the filtration over celite pad.Filtrate to obtain white-yellowish solid, is used for next reaction by vacuum concentration after LC-MS characterizes.Starting raw material 1e-1h, 1m, 1o, 1q-1s, 1t, 1y, 1z, 1ae, 1af, 1ag begins preparation according to the mode that is similar to above starting raw material 1a by the given commercially available precursor of table 6, and the Step II that just is used for 1f is undertaken by handling with Fe/AcOH, with be used for 1m, the Step II of 1o uses Zn/ ammonium chloride to carry out as follows:
Step II during preparation 1f:
N
3-ethylpyridine-3,4-diamines (starting raw material 1f)
N
3-ethyl-4-nitro-pyridine-N-oxide (1.1Ig, 6mmols), acetate (30mL, 0.2M) and the Fe powder (2g 36mmols) is placed in the flask neutralization of being furnished with stirring rod and is heated to 80 degrees centigrade and reaches 4 hours.Reaction mixture is cooled and acetate evaporates on rotatory evaporator, with ammonia/methyl alcohol (2M) neutralization.After evaporation methyl alcohol, the gained material distributes between ethyl acetate and 50%aq. ammonium hydroxide.Organic layer salt water washing is at Na
2SO
4(anhydrous) goes up dry, filters and under reduced pressure concentrates to obtain title compound (420mg, 51%), need not to be further purified and is used for next step.
N-2-ethyl-3-fluoro-benzene-1,2-diamines (starting raw material 1m):
(93.57g, 66.12mmol), (4.30g 66.12mmol) adds ethyl-(2-fluoro-6-nitro-phenyl) amine (1.21g, 6.61mmol) solution in ethanol (50mL) to zinc powder with ammonium chloride.Mixture at room temperature stirs and spends the night.Reaction mixture is by the filtration over celite pad and use washing with alcohol.Filtrate is concentrated.Resistates be used in the gradient elution of the 0.10%EtOAc in the hexane by flash chromatography and purifying to obtain product as black glue (0.54g, 52% productive rate).1H?NMR(300MHz，CDCl
3)δ：6.78(m，1H)，6.50-6.43(m，2H)，3.04-2.90(m，3H)，1.15(t，J＝6.9Hz，3H)。M/Z154。
Preparation 1c
N2-ethyl-3-anisole-1,2-diamines (starting raw material 1c):
(0.68g, 3.76mmol) solution in doing THF (50 milliliters) is cooled to 0 degree centigrade and the careful LAH (15.03mmol) of adding to N-(2-amino-6-p-methoxy-phenyl) ethanamide.After backflow 30mins, mixture is cooled to room temperature and also separates with minimum quantity EtOAc and frozen water to 0 degree centigrade subsequently.Organic layer separated with solid residue by filtration wash with EtOAc.The EtOAc layer is with the salt water washing with at Na
2SO
4Last dry, filter and evaporation.Product is used for next coupling step and need not to be further purified.M/Z?166。
N-(2-amino-6-p-methoxy-phenyl) ethanamide
(1.0g 4.74mmol) is dissolved among 50 milliliters of AcOH N-(2-nitro-6-p-methoxy-phenyl) ethanamide, and (1.59g 28.43mmol) adds solution with iron subsequently.Reaction mixture at room temperature stirs and spends the night.Mixture dilutes with 50 milliliters of EtOAc, filters and evaporation.Resistates is at ethyl acetate and H
2Distribute between the O.The EtOAc layer washs until pH 9 with 1N NaOH.The EtOAc layer is with the salt water washing with at Na
2SO
4Last dry.Solution is filtered and solvent is evaporated.Products therefrom is used for the LAH reduction and need not to be further purified.M/Z?180。
N-(2-nitro-6-p-methoxy-phenyl) ethanamide
(0.80g 4.74mmol) is dissolved in the 30ml toluene 2-amino-3-nitro-6-anisole, and (0.74g 9.48mmol) adds reaction mixture with Acetyl Chloride 98Min. subsequently.Mixture is 80 degrees centigrade of following heated overnight.Resistates is at EtOAc and H
2Distribute between the O.The EtOAc layer is with the salt water washing with at Na
2SO
4Last dry.Solution is filtered and solvent is evaporated.The crude product that so obtains is carried out next step to generate N-(2-amino-6-p-methoxy-phenyl) ethanamide.M/Z?210。
Under the situation of SM Ic, need the following other step of carrying out:
2-amino-3-nitro-6 anisole:
(2.04g is 13.24mmol) with 50 milliliters of anhydrous THF to add the 2-amino-3-nitro phenol in 250 milliliters of round-bottomed flasks.With cesium carbonate (18.98g 58.26mmol) adds solution, add subsequently methyl-iodide (2.07g, 14.56mmol).Mixture at room temperature stirred 6 days.The gained mixture is filtered and washs with DCM.Solvent is removed on rotatory evaporator.Crude product is by silica gel chromatography (gradient elution; Hexane 20%) and purifying obtains title compound (1.1g, 50%) M/Z 168 EtOAc:.
Starting raw material 1b is according to beginning preparation with the similar mode of 1c by the listed commercially available precursor of table 6.
Starting raw material 1d prepares by two following step process:
Step I
N-(2-amino-pyridine-3-yl)-ethanamide
N-(2-amino-pyridine-3-yl)-ethanamide is by pyridine-2,3-diamines and diacetyl oxide, and according to Mazzini, C; Lebreton, J; Furstoss, R; Heterocycles; 45 (6); 1161 (1997) method preparation.
Step II
N
3-ethyl-pyridine-2,3-diamines (starting raw material 1d)
N
3-ethyl-pyridine-2,3-diamines be by N-(2-amino-pyridine-3-yl)-ethanamide and lithium aluminium hydride, according to Mazzini, and C; Lebreton, J; Furstoss, R; Heterocycles; 45 (6); 1161 (1997) method preparation.
Starting raw material 1i-1l, 1n, 1p begins preparation according to being similar to the described mode of above starting raw material 1a by the listed commercially available precursor of table 6.For starting raw material 1i, only step 2 (reduction ethanamide) is essential.
Preparation starting raw material 1j
N-(2,4-two fluoro-6-nitro-phenyl)-ethanamide:
2,4-two fluoro-6-nitro-aniline (3.0g 17.1mmol) is dissolved among the anhydrous THF, to wherein add pyridine (2.6rnL, 32.4mmol), add subsequently Acetyl Chloride 98Min. (2.63mL, 37.0mmol).Under rt, under N2 (g), stir and spend the night.Second day, TLC demonstration reaction was finished.Reaction mixture is concentrated, with the EtOAc dilution, and water/HCl (aq)/H
2The water washing of O/ salt is at Na
2SO
4Following dry and concentrated.Resistates carries out flash chromatography on silica gel.Productive rate: 3.9g (96%).1H?NMR(300MHz，CDCl
3)δ：8.0(brs，1H)，7.5-7.6(m，1H)，7.23-7.59(m，1H)，2.28(s，3H)。(M+1)/Z＝217.1。
Step 2:
(2,4-two fluoro-6-nitro-phenyl)-ethyl-amine:
(3.56g 16.4mmol) is dissolved in anhydrous THF neutralization and is cooled to 0 degree centigrade N-(2,4-two fluoro-6-nitro-phenyl)-ethanamide.In the gained mixture, slowly add LAH (2.49g, 65.6mmol).Subsequently at 80 degrees centigrade of following backflow 30min, then by adding several EtOAc and ice down and cancellation at 0 degree centigrade.This mixture filters on diatomite subsequently.Resistates is with EtOAc washing and concentrate and carry out flash chromatography on silica gel.Productive rate: 1.0g (35%).1H?NMR(300MHz，CDCl
3)δ：6.20-6.23(m，2H)，4.1(brs，2H)，2.92-2.94(m，2H)，2.8(brs，1H)，1.14(t，J＝7.1Hz，3H)。(M+1)/Z＝173.1。
Starting raw material 1u:
4-chloro-5-(trifluoromethyl) benzene-1, the 2-diamines
5-chloro-2-nitro-4-(trifluoromethyl) aniline with silica gel (6.692g.5% iron(ic) chloride (III) 2063mmol), gac (3.2g, 2x wt.SM) and 20mL MeOH merge.This reaction mixture is stirred and heats 10min down at 80 degrees centigrade.Begin subsequently slowly (to avoid foaming), and the single hydrazine hydrate of quick subsequently adding (4.01mL, 82.51mmol).Reaction is stirred and heats other 15min, filtered while hot subsequently.Solid is washed with MeOH and EtOAc.With filtrate merging and concentrated, obtain the 1.4276g product as light yellow solid.1H?NMR(300MHz，DMSO-D
6)
4.95(s，2H)5.41(s，2H)6.63(s，1H)6.85(s，1H)。
Starting raw material 1v:
6-chloro-N
4-ethyl pyridazine-3, the 4-diamines
By commercially available 3-chlorine furans-2, the 5-diketone prepares SM 1v in 5 steps
Step 1:4-chloro-1,2-dihydrogen dazin-3, the 6-diketone:
To 3-chlorine furans-2, the solution of 5-diketone (10g) in EtOH (200mL) adds single hydrazine hydrate (4mL) and backflow 10h.Reaction mixture concentrates and obtains 4-chloro-1,2-dihydrogen dazin-3, and the 6-diketone is directly used in next step.M/Z?146。
Step 2:3,4,6-trichlorine pyridazine:
4-chloro-1,2-dihydrogen dazin-3, the 6-diketone is at POCl
3Solution (100mL) refluxes
10h。Reaction mixture is concentrated and purifying, obtains 3,4, and 6-trichlorine pyridazine is directly used in next step.M/Z?182。
Step 3:
3,6-two chloro-N-ethyl pyridazine-4-amine
To 3,4, add ethamine (35mL, 70% aqueous solution) in the 6-trichlorine pyridazine.Reaction mixture stirs 2h and uses ethyl acetate extraction.The organic layer that merges is concentrated, obtain 3,6-two chloro-N-ethyl pyridazine-4-amine are directly used in next step.M/Z?191。
Step 4:
6-chloro-N-ethyl-3-diazanyl pyridazine-4-amine
To 3, add hydrazine (16mL) in 6-two chloro-N-ethyl pyridazine-4-amine (3.6g).Reaction mixture refluxed 2h and water (10mL) dilution.Form throw out and collection, obtain 6-chloro-N-ethyl-3-diazanyl pyridazine-4-amine, be directly used in next step.M/Z?187。
Step 5:
6-chloro-N
4-ethyl pyridazine-3, the 4-diamines
Add Raney nickel (0.2g) to the solution of 6-chloro-N-ethyl-3-diazanyl pyridazine-4-amine (500mg) in EtOH.Reaction mixture is placed 2h under nitrogen atmosphere.Reaction mixture is by filtration over celite.Organic filtrate concentrating obtains 6-chloro-N
4-ethyl pyridazine-3, the 4-diamines is directly used in next step.M/Z?172。
Starting raw material 1w is as described below and prepare 4 steps.
Starting raw material 1w:
N
3-ethyl-5-trifluoromethyl-pyridine-2, the 3-diamines:
Step 1:
N-(5-5-flumethiazine-2-yl) amsacrine
Under nitrogen atmosphere, with 2-chloro-5-trifluoromethyl-pyridine (9.07g; 0.05mol) be added in the about 30mL dimethyl sulphide in the 100mL round-bottomed flask.Amsacrine (5.3g; 0.5g; 0.06mol) and salt of wormwood (325 order powder; 13.9g; 0.10mol) wash with single part of adding with another about 30mL dimethyl sulfoxide (DMSO) in proper order.Be heated to 120 degrees centigrade reach 8h after, reaction mixture is poured into ice/waterborne, cause to form the small amount of precipitate thing.Water ether washed twice stays glassy yellow solution.It is about 4 until pH to add dense spirit of salt carefully to water layer, obtains white solid.This solid by filtration and collect and wash with massive laundering.On strainer after the drying, with solid recrystallization from the 2-propyl alcohol.M/Z=241 (300MHz, the δ ppm 3.26 of chloroform-D) (s, 3H) 7.38 (d, 1H) 7.94 (m, 1H), 8.65 (s, 1H)
Step 2:
N-(3-nitro-5-trifluoromethyl-pyridine-2-yl)-amsacrine
N-(5-trifluoromethyl-pyridine-2-yl)-amsacrine (4.8g; 0.02mol) be suspended in the about 15mL acetate in the 50mL round-bottomed flask.Be heated to about 110 degrees centigrade, make most of material dissolves become muddy slightly solution.From feed hopper, drip nitric acid and (be fuming 90%; 2.1mL), make remaining solid dissolve immediately.After adding is finished, reaction system is heated more than the 7h, and with postcooling.Yellow solution is poured into ice/waterborne, forms solid.The water gaging washing that solid is filtered and filter cake is used is to obtain white solid.Solid is recrystallization from the 2-propyl alcohol.Evaporated filtrate, and, obtain second product with the resistates recrystallize.M/Z＝285(300MHz，CDCl
3)δppm?3.58(s，3H)8.82(m，1H)8.91(m，1H)10.10(br，1H)
Step 3:N-(3-ethylamino-5-trifluoromethyl-pyridine-2-yl)-amsacrine
In the 50mL round-bottomed flask, N-(3-nitro-5-trifluoromethyl-pyridine-2-yl)-amsacrine (1.1g; 0.004mol) be suspended in about 15mL methyl alcohol.Acetonitrile (2mL; 0.04mol), ammonium acetate (0.31g; 0.004mol) and palladium (0.22g on 10% carbon subsequently; 5mol%) sequentially wash with single part of adding with some more slightly methyl alcohol.The balloon that hydrogen is filled is connected on the flask, and flask is placed under the vacuum in addition, and subsequently under nitrogen atmosphere.After the period 3, be reflected under the nitrogen atmosphere and place 16h, all starting raw materials are consumed then.Reaction mixture is used the small part methanol wash by the filtration over celite pad.There are two kinds of products: required product, and the N-of similar quantity (3-amino-5-trifluoromethyl-pyridine-2-yl)-amsacrine (simply reduce and do not have alkylating product).The middle chromatogram (ethyl acetate/hexane) of pressing obtains pure required product.M/Z＝284(300MHz，CDCl
3)
1.33(t，3H)1.64(br，1H)3.11(s，3H)3.14-3.25(m，2H)5.29(brm，1H)6.46(m，1H)7.17(s，1H)
Step 4:
N
3-ethyl-5-trifluoromethyl-pyridine-2, the 3-diamines
With N-(3-ethylamino-5-trifluoromethyl-pyridine-2-yl)-amsacrine (0.57g; 0.002mol) adding 15mL round-bottomed flask.Add about 1.0mL vitriol oil, feasible amount material dissolves.Be heated to 110 degrees centigrade, whole solid is dissolved into glassy yellow solution, the deepening a little along with the time.After about 45min, the LC/MS of aliquots containig shows that the completely dissolve and the reaction mixture of starting raw material are cooled to room temperature.In the about 20mL water in about 7g yellow soda ash adding 250mL flask; The most solid dissolving.About 125mL ether is added into as the upper strata subsequently.Reaction mixture is added the two-phase system that stirs fast carefully in batches.Layering is also washed secondary with water with ether.With the organic layer that the merges water of small part, and use the saturated nacl aqueous solution of small part to wash subsequently.Dry on sal epsom, under reduced pressure remove solvent, obtain product as white-yellowish solid.M/Z＝206(300MHz，CDCl
3) δppm1.33(t，3H)1.77(br，1H)3.10-3.22(m，2H)4.55(br，2H)6.90(d，1H)7.83-7.90(m，1H)′
Starting raw material 1aa;
4-bromo-N
1-ethyl-5-trifluoromethyl-benzene-1, the 2-diamines
Step 1:N-(4-bromo-2-nitro-5-trifluoromethyl-phenyl)-ethanamide
According to Ognyanov, V.L, et.; J.Med.Chem.; 49 (12); 3719 (2006) method is under nitrogen cleans, with 4-bromo-3-5-trifluoromethylaniline (7.2g; 0.03mol) add the diacetyl oxide (30mL) in the 100mL round-bottomed flask.At room temperature stir after the 16h, solvent under reduced pressure is removed to obtain white solid, and former state is used for denitrification step.
To in ice bath, cool off in the vitriol oil (32.5mL) adding solid N-(4-bromo-3-trifluoromethyl-phenyl)-ethanamide and with round-bottomed flask.(ca 90%, 4.1mL) is placed in the feed hopper and dropping with nitric acid.Stir under ice temperature after the other 30min, reaction is warmed to room temperature and stirs other 3h.Reaction is poured on ice and carefully adds solid sodium bicarbonate and be measured as alkalescence slightly until water.Reaction ethyl acetate extraction three times.The organic layer that merges is washed with water twice and wash once with saturated nacl aqueous solution.After the drying, solvent under reduced pressure is removed on sal epsom.The gained crude product is purifying by recrystallization from methylcyclohexane.M/Z＝328(300MHz，CDCl
3)δppm2.33(s，3H)8.53(s，1H)9.29(s，1H)10.22(br，1H)
Step 2:
4-bromo-N
1-ethyl-5-trifluoromethyl-benzene-1, the 2-diamines
The hydroboration zirconium passes through zirconium chloride (11.6g; 0.05mol) be dissolved among the THF (200mL) of 500mL round-bottomed flask and add solid sodium borohydride (7.6g subsequently; 0.2mol) and prepare.Suspension stirs 40h under nitrogen atmosphere.As required, with volume required supernatant liquid (0.1 mole of hydroborate of nominal) decant and being filled in the feed hopper from settled solid.
Under nitrogen cleans, N-(4-bromo-2-nitro-5-trifluoromethyl-phenyl)-ethanamide (0.65g: 0.002mol) be dissolved among about 30THF of 100mL round-bottomed flask.Take out supernatant liquid hydroboration zirconium solution (20mL 0.1M hydroborate; 0.002mol) and be filled in the feed hopper by syringe filter subsequently.Drips of solution is added to reaction system, produce heat release.16h is at room temperature stirred in reaction, and this moment, aliquots containig showed that acid amides and nitryl group all are reduced.Fugitive constituent is removed in decompression.To ice with ethyl acetate and add the gained resistates carefully.Layering and water wash secondary with water with twice of ethyl acetate extraction and with the organic layer that merges and wash once with saturated nacl aqueous solution.After the drying, solvent under reduced pressure is removed so that required compound to be provided on sal epsom, need not to be further purified and is used for next step.M/Z＝283(300MHz，CDCl
3)δppm1.31(t，3H)3.14(q，2H)3.61(br，2H)6.88(s，1H)6.94(s，1H)
Starting raw material 1ab:6-chloro-N '-ethyl-pyridine-3, the 4-diamines
Step 1:
4-chloro-5-nitropyridine-2-alcohol
THF (50mL) is cooled to-78 degrees centigrade, and with NH
3(gas, about 30mL) condenses in the THF solution.(9.3g heats 79.1mmol) and with mixture and remains under-35 degrees centigrade to add potassium tert.-butoxide.In independent flask, 4-chloro-3-nitropyridine is dissolved in THF (40mL) neutralization and is cooled to 0 degree centigrade.In 4-chloro-3-nitropyridine solution, add t-BuOOH (7.0mL 5M decane solution, 35.0mmol).In 30min, drips of solution added to KOt-Bu solution.Be reflected at-35 degrees centigrade and stir 0.5h down and be cooled to-78 degrees centigrade, slowly use saturated NH then
4Cl solution (20mL) cancellation.Mixture remains under the rt and ventilation is spent the night.Mixture is concentrated, filter and (3 * 10mL) washings of gained solid cold water.Vacuum-drying provides title compound as yellow solid (2.7g, 60% productive rate).1H?NMR(300MHz，DMSO-D
6)δppm?5.95(s，1H)，8.80(s，1H)。M/Z174 (M-H, observed value).
Step 2:
2,4-two chloro-5-nitro-pyridines
Under rt, 4-chloro-5-nitropyridine-2-alcohol (2.7g 15.6mmol) is suspended in the toluene (60mL), and with POCl
3(14.2mL 156mmol) adds mixture.React backflow 6h and pass through weekend 60 degrees centigrade of following heating.After cooling mixture, concentrate and remove solvent and excessive POCl
3In resistates, add toluene (2 * 20mL) and concentrate to remove excessive POCl again
3Resistates is slowly added sat.K
2CO
3(30mL), and with mixture extract (2 * 20mL) extractions with EtOAc.Dry organic phase (Na
2SO
4), filter by short silicagel pad (50/50EtOAc/ hexane) and concentrated, provide title compound as brown solid (2.2g, 75% productive rate).1H?NMR(300MHz，DMSO-D
6)δppm?8.23(s，1H)，9.18(s，1H)。M/Z 192. steps 3:
2-chloro-N-ethyl-5-nitro-pyridine-4-amine
Under 0 degree centigrade, 2, (1.7g 8.8mmol) is dissolved in THF (10mL) neutralization and slowly adds ethamine (20mmol, 2M THF solution) 4-two chloro-5-nitro-pyridines.Concentrate and obtain product.1HNMR(300MHz，DMSO-D
6)δppm?1.17(m，3H)，3.44(dq，J＝6.97，6.78Hz，2H)，7.10(s，1H)，8.51(s，1H)，8.87(s，1H)。
Step 4:
6-chloro-N '-ethyl-pyridine-3, the 4-diamines
In MeOH (80mL), dissolving from 2-chloro-N-ethyl-5-nitro-pyridine-4-amine of step C (1.6g, 8.0mmol) and in solution, add FeCl
3(1.6mmol, 5% at silica gel) and activated carbon (3.0g).Mixture is heated to 72 degrees centigrade, slowly add then hydrazine hydrate (4.0mL, 80mmol).Reaction backflow 1h.Mixture is filtered short Celite pad and resistates MeOH (4 * 20mL) washings.Filtrate is concentrated and adds entry (20mL) in liquid residue.(2 * 15mL) extract, dry (Na with EtOAC
2SO
4) and concentrate and to obtain title compound as light yellow solid (1.2g, two step 80% productive rates).1H?NMR(300MHz，DMSO-D
6)δppm?1.19(t，J＝7.16Hz，3H)，3.10(dt，J＝12.25，7.06Hz，2H)，4.75(s，2H)，5.64(s，1H)，6.28(s，1H)，7.37(s，1H)。M/Z?171。
Starting raw material 1ad:
6-cyclopropyl-N '-ethyl-pyridine-3, the 4-diamines
Steps A:
2-cyclopropyl-N-ethyl-5-nitro-pyridine-4-amine
In the 100-mL flask, add 2-chloro-N-ethyl-5-nitro-pyridine-4-amine (0.6g 3.0mmol) (generates in the step 3 of SM 1ab), cyclopropylboronic acid (0.65g, 7.5mmol) and K
3PO
4(1.92g, 15.0mmol).In mixture, add solvent (50mL, toluene=20: 1), and N2 is blasted mixture 20min, add Pd (PPh then
3)
4(0.85g, 0.75mmol).Reaction is heated to 108 degrees centigrade spends the night.After cooling, in mixture, add entry (30mL) and extract (3 * 20mL) with EtOAc.Organic phase is merged dry (Na
2SO
4) and concentrate.Silica gel chromatography (EtOAc/ hexane, 0-80% gradient) obtains title compound as solid (0.3g, 45% productive rate).1HNMR(300MHz，DMSO-D
6)δppm?0.97(s，4H)，1.21(s，3H)，2.10(s，1H)，3.43(s，2H)，6.92(s，1H)，8.30(s，1H)，8.90(s，1H)。M/Z?207。
Step 2:
6-cyclopropyl-N '-ethyl-pyridine-3, the 4-diamines
Program preparation described in the step 4 of title compound (0.25g, 100% productive rate) use SM 1ab.1H?NMR(300MHz，DMSO-D
6)δppm?0.72(s，2H)，0.75(d，J＝3.58Hz，2H)，1.20(t，J＝7.16Hz，3H)，1.82(s，1H)，3.13(dt，7＝12.39，7.09Hz，2H)，4.43(s，2H)，5.40(s，1H)，6.25(s，1H)，7.46(s，1H)。
Starting raw material 1ad:
2-chloro-N
4-ethylpyridine-3, the 4-diamines
Step 1:
N-ethyl-3-nitropyridine-4-amine
Solution to 4-chloro-3-nitropyridine (12g) adds ethamine (150mL, 70% aqueous solution) and stirs 10min down at 0 degree centigrade.(2 * 50ml) extract reaction mixture with methylene dichloride.Organic layer is concentrated, obtain N-ethyl-3-nitropyridine-4-amine, be directly used in next step.M/Z?158。
Step 2:
2-chloro-N
4-ethylpyridine-3, the 4-diamines
(12N, 50mL) solution in is heated to 90 degrees centigrade to N-ethyl-3-nitropyridine-4-amine (10g) at hydrochloric acid.In this solution, slowly add inferior tin (57g) of dichloro and gained mixture and under this temperature, keep 1h.Reaction is cooled to rt and adds entry (10mL).Form throw out and collection and obtain 2-chloro-N
4-ethylpyridine-3,4-diamines (12g).M/Z?161。
Starting raw material 1ah:
Boc-(R)-Ala-aldehyde:
(3.17g is 18.13mmol) at dried CH to commercially available (R)-(+)-2-(tert.-butoxy-carbonyl amine)-1-propyl alcohol under N2atm at 0 degree centigrade
2Cl
2Solution adding Dess-Martinperiodinane (46mL) (10g, 23.57mmol divide two portions, (and a part of earlier, after 2min, another part)).Descend to stir 45min and further under rt, stir at 0 degree centigrade-10 degrees centigrade.Analyze shown reaction at TLC and finish (2.5h) afterwards, mixture is diluted with EtOAc (250mL).To wherein adding 5N NaOH (70mL) and under rt, stirring 20min.Organic layer is separated water, salt water washing and at anhydrous MgSO
4Last dry.Solution is filtered, and evaporation and dry obtains product as the oily solid.Product stores in refrigerator.Productive rate: 2.49g (76%).1H?NMR(300MHz，CDCl
3)
9.55(s，1H)，5.09(brs，1H)，4.25-4.10(m，1H)，1.44(s，9H)，1.33(d，J＝7.14Hz，3H)。
Starting raw material 1ai:
Step 1:
N-ethyl-2-methoxyl group-5-nitropyridine-4-amine
The 250mL round-bottomed flask that comprises 2-chloro-N-ethyl-5-nitropyridine-4-amine be equipped with MeOH (25mL) and NaOMe (1.12g, 20.7mmol).Mixture is placed in 65 degrees centigrade of oil baths.After 65 degrees centigrade stirring is spent the night down, will react cooling and MeOH and under reduced pressure be removed.Resistates is at EtOAc and H
2Distribute between the O and water layer extracts with EtOAc.With the organism salt water washing that merges, dry (MgSO
4), filter and be condensed into light yellow solid (827mg, 86%).
Step 2:
N
4-ethyl-6-methoxypyridine-3, the 4-diamines
Comprise N-ethyl-2-methoxyl group-5-nitropyridine-4-amine (827mg, 250mL round-bottomed flask 4.19mmol) be equipped with tin chloride dihydrate (II) (3.82g, 16.93mmol) and EtOAc (15mL).The gained mixture is heated to 80 degrees centigrade.After 4 hours, with mixture cooling with use moisture NaHCO
3Handle the colorless solid precipitation.Mixture is passed through Celite pad by suction strainer, and with reaction flask and strainer H
2O and EtOAc thorough washing.Filtrate layers separation and water layer are further extracted with EtOAc.With the organism salt water washing that merges, dry (MgSO
4), filter and be condensed into dark red solid (465mg, 66%).
Starting raw material 1aj:
N
4-ethyl-6-trifluoromethyl-pyridine-3, the 4-diamines:
Starting raw material 1aj can prepare according to following two steps:
Step 1:
Starting raw material 1aj can pass through WO
2002050062 steps outlined and preparing.
Step 2:
In addition, it can be as described below and prepares:
Step 1:
5-bromo-2-trifluoromethyl-pyridin-4-yl-ethamine
With dropping funnel in 25min under-78 to-80 degrees centigrade under N2atm to 2.0MLDA at THF/ heptane/ethylbenzene (41.77mL, 83.54mmol) in drips of solution be added in 5-bromo-2-(trifluoromethyl) pyridine done among the THF (100mL) (18.8g, 83.54mmol).Stir down 2h at-78 degrees centigrade, in 55min, drip subsequently I 2 in THF (100mL) (21.62g, 85.21mmol).Under uniform temp, stir after the 15min, pour solution into 2.0MNa
2S2O
35H
2The mixture of O (200mL) and diethyl ether (300mL).It stirs 10min.Be separated and water is extracted with Anaesthetie Ether.With the organic layer salt water washing that merges, dry (Na
2SO
4), evaporation and dry under vacuum obtains crude product, 5-bromo-4-iodo-2-(trifluoromethyl) pyridine, and (96.7% rate of recovery, 1H NMR shows ratio 88: 12 (product and impurity) to 28.44g.
Will THF (240mL, 478mmol) above crude product 5-bromo-4-iodo-2-(trifluoromethyl) pyridine in (28.44g, 79.6mmol) and 2.0M C
2H
5NH
2In sealed tube, heated 2 days down at 70-75 degree centigrade.Reaction mixture is cooled to rt, and concentrated and resistates distributes between ethyl acetate and water.Organic layer is separated, with salt water washing and drying (Na
2SO
4).Solution is filtered, and evaporation and resistates use the 1-2%EtOAc/ hexane as eluent and purifying on silica gel by the flash distillation post.Productive rate: 15.15g (67.2%, in two steps).1H?NMR(300MHz，CDCl
3)δ：8.41(s，1H)，6.80(s，1H)，4，96(brs，1H)，3.34-3.29(m，2H)，1.35(t，J＝7.15Hz，3H)。M/Z＝268.08
Step 2:
N
4-ethyl-6-trifluoromethyl-pyridine-3,4-diamines: (starting raw material 1aj)
Stove-dry sealed tube of being furnished with magnetic stirring bar and diaphragm of rubber cools off under N2.Sealed tube is equipped with Pd
2Dba
3(5.55g, 6mmol, 20mol%), rac-BINAP (7.55g, 12.12mmol, 40mol%) and toluene (200mL).Mixture is outgased, and diaphragm of rubber is replaced with the Teflon screw-cap, and mixture is heated 30min in oil bath under 110 degrees centigrade.Solution be cooled to rt subsequently and add benzophenone imines (6.61mL, 39.5mmol), the 5-bromo-2-trifluoromethyl-pyridin-4-yl-ethamine in toluene (100mL) (8.16g, 30.32mmol), and sodium tert-butoxide (3.8g, 39.5mmol).With the mixture degassing, diaphragm of rubber is replaced by the Teflon lid, and mixture is heated 16h down at 135-140 degree centigrade.Solution is cooled to rt subsequently, dilutes with ether, filters the Celite pad and concentrate to obtain the imines affixture as deep green-brown oil, 27.24g.Add moisture 2.0M HCl (80mL) and under rt, stir 20h to this thick imines affixture in THF (242mL).Solvent is concentrated and reaction mixture distributes between EtOAc (1L) and 2.0M HCl (120mL).Water layer is separated, is cooled to 0 degree centigrade and alkalize to pH=14 with NaOH.Reaction mixture with EtOAc extract (2 * 500mL), with salt water washing and drying (Na
2SO
4).Solution is filtered, and evaporation and dry under vacuum obtains thick diamines as white-yellowish solid 4.09g (64.4%).
Pd is used in another reaction
2Dba
3(7.25g, 7.92mmol, 20mol%), rac-BINAP (9.86g, 15.84mmol), toluene (200mL), benzophenone imines (8.64mL, 51.5mmol), 5-bromo-2-trifluoromethyl-pyridin-4-yl-ethamine in toluene (100mL) (10.66g, 39.61mmol), and sodium tert-butoxide (4.94g, 51.5mmol) carry out, obtain thick imines affixture 36.47g.Obtain thick diamines 5.13g (63.17%) with THF (325mL) and 2.0M HCl (110mL) processing.
Above thick diamines (9.22g) merged and by the flash distillation post on silica gel, use the 35-40%EtOAC/ hexane as eluent and purifying to obtain 7.55g (52%, in two steps).1HNMR(300MHz，DMSO-J
6)&7.69(s，1H)，6.65(s，1H)，5.65(t，J＝4.68Hz，1H)，5.23(brs，2H)，3.21-3.12(m，2H)，1.21(t，J＝7.15Hz，3H)。M/Z＝205.0。
Preparation SULPHURYL CHLORIDE (SC):
By the synthetic 4-of aminopyridine replace-general step (SC1-SC4) of 3-pyridyl SULPHURYL CHLORIDE: 250mL circular base flask is equipped with water (30mL) and is cooled to 0 degree centigrade.(6.0mL 82.3mmol) dripped in 2 hours with thionyl chloride.Mixture slowly is warmed to ambient temperature overnight.Add CuCl (72mg, 0.73mmol) and yellow solution be cooled to 0 degree centigrade.Simultaneously, independent 100mL circular base flask is equipped with 3-aminopyrazole derivatives (15.0mmol) and dense HCl (20mL).Solution is cooled to 0 degree centigrade, and (1.49g is 21.6mmol) at H with Sodium Nitrite subsequently
2Solution among the O (15mL) dripped in 10 minutes.This mixture stirred other 15 minutes down at 0 degree centigrade, and dripped (keeping diazonium mixture body to be in 0 degree centigrade) subsequently to water/thionyl chloride solution in 10 minutes.At 0 degree centigrade after 1 hour, mixture CH
2Cl
2(2x) extract, and with the organism salt water washing that merges, dry (MgSO
4), filter and concentrate and obtain SULPHURYL CHLORIDE, need not any being further purified and use.
SC5 is according to J.Chem.Soc, and 1948,1939-1945 is described and prepare.SC
6Be prepared as follows:
Pyridine-4-SULPHURYL CHLORIDE (SC
6)
(1.101g 0.01mol) is dissolved in dense spirit of salt (the 7.5mL)+water (2mL) of 50mL 3 neck round-bottomed flasks and is cooled to-10 degrees centigrade in dry ice/acetone batch pyridine-4-mercaptan.Chlorine is introduced solution 45min by injection spray pipe, add dry ice as required to keep temperature-10 degree centigrade.In case chlorine is finished adding, (1g) slowly adds reaction mixture with lime carbonate.Reaction mixture is transferred to about 20mL chloroform subsequently, is cooled to-10 degrees centigrade.Add more calcium chloride (7g) in batches.After adding is finished, with organic layer decant from the semi-solid inorganics.Jelly is washed secondary (two portions, 20mL respectively) with chloroform subsequently.The organic layer that merges is dry on sodium sulfate.This chloroformic solution former state is used.SC
7In two steps by commercially available 2,6-lutidine-4 (1H)-ketone preparation as described below:
2,6-lutidine-4-SULPHURYL CHLORIDE
Step 1:
2,6-lutidine-4 (1H)-thioketones
Under nitrogen cleans, 2,6-lutidine-4 (1H)-ketone (5.00g, 0.04060mol) toluene (150mL) is in 500mL 3 neck round-bottomed flasks, and (16.8g 0.04mol) shifts to reaction, washes with some more slightly toluene with Lawesson ' s reagent.Suspension is heated backflow and keeps 16h.Solvent is toppled over from the gumminess yellow solid, further extracts with more a little hot toluene subsequently.Residue gumminess yellow solid is dissolved in the hot acetonitrile (ca 400mL) difficultly, and preabsorption subsequently is to silica.Use 100% methylene dichloride to 20% ethanol in methylene dichloride; 5%v in ethanol: the gradient of the dense ammonium hydroxide of v is carried out flash chromatography to obtain required product, further by recrystallization from hot water purifying so that pale yellow crystals (2.1g, 37%) to be provided.1H?NMR(300MHz，MeOH-d
4)δppm2.32-2.36(m，6H)7.14-7.17(m，2H)M/z＝140
Step 2:
2,6-lutidine-4-SULPHURYL CHLORIDE
2, (0.01008mol), dense spirit of salt (7.5mL) and water (2.0mL) are placed in the 50mL 3 neck round-bottomed flasks and are cooled to-10 degrees centigrade in dry ice/acetone batch 6-lutidine-4 (1H)-sulfo-ne for step 1,1.403g.Chlorine is introduced about 45min by injection spray pipe, adds dry ice as required with maintenance temperature-10 degree centigrade+/-5 degrees centigrade.Then, the nitrogen spraying is by this system 15min.Lime carbonate (1g) is added reaction mixture and reaction mixture is transferred to chloroform (20mL is precooled to-5 degrees centigrade) subsequently.Small part ground adds more lime carbonate (7g).After adding is finished, organic layer is toppled over from semi-solid jelly, with cold chloroform (2 * 20mL) washed twice.With the organic layer dry and filtration on sodium sulfate that merges.The filtrate former state is used and be need not to be further purified.
SC
8Preparation as described below:
Step 1:
2-picoline-4 (1H)-thioketones
The hydrate Sodium sulfhydrate (5.49g, 97.98mmol)
1(0.267g, 0.98mmol), (2.5g 19.60mmol) carries out microwave irradiation to 4-chloro-2-picoline to 0mL water together, 140 degrees centigrade of 6h with benzyl triethyl ammonium bromide in the 20mL penstock.Obtain a kind of almost yellow transparent solution like this, and some the dark solid that is positioned at the pipe bottom.This transparent yellow liquid is toppled over, and cools off in ice bath subsequently, causes solid precipitation.Yellow solid is filtered, and subsequently with the washing of small part icy water.After the dry air, this material former state is used for later step on strainer.1H?NMR(300MHz，MeOH-d
4)δppm?2.34-2.38(m，3H)7.28-7.35(m，2H)7.53-7.57(m，1H)M/z＝125
Step 2:
2-picoline-4-alkylsulfonyl muriate
(step 1,1.252g 0.01mol) are placed in the 50mL 3 neck round-bottomed flasks and are cooled to-10 degrees centigrade in dry ice/acetone batch 2-picoline-4 (1H)-thioketones in the dense spirit of salt of 7.5mL/2mL aqueous solution.Chlorine is introduced about 45min by injection spray pipe, adds dry ice as required with maintenance temperature of reaction-1 degree centigrade+/-5 degrees centigrade in acetone bath.Then, this system 15min is passed through in the nitrogen spraying.Carefully lime carbonate (1g) is added reaction mixture, in order to avoid excess foam formation.Reaction mixture is transferred in advance and is cooled to-10 degrees centigrade chloroform subsequently.Add more carbonate (7g) more carefully in batches.After adding is finished, organic layer is toppled over from semi-solid glue.This jelly washs secondary with the cold chloroform of 20mL part subsequently.The chloroform layer drying on sodium sulfate that merges be need not to be further purified with filtering with using immediately.SC9 is as described below and prepare in two steps:
Step 1:5-amino-pyridine-1-carboxylic acid methyl acid amides
To 5-amino-pyridine-2-carboxylic acid (2.0g, 14.5mmol) and CDI (2.6g, 15.9mmol) suspension in THF (20mL) adds DMF (10mL).It is muddy that reaction mixture becomes in 10min.Be added in THF (2M, 21.8mL) methylamine in and reaction mixture at room temperature stirred spend the night.Reaction mixture is concentrated.Resistates dilutes with ethyl acetate, and water is used the salt water washing subsequently, dry (Na
2SO
4), filter and concentrate.The white solid of gained is ground with cold ether, obtain 5 as white solid.Productive rate: 1.2g (55%).1H?NMR(301MHz，DMSO-O
6)δppm8.23-8.34(m，1H)，7.89(d，J＝2.8Hz，1H)，7.69(d，J＝8.5Hz，1H)，6.95(dd，J＝8.5，2.8Hz，1H)，5.90(s，2H)，2.75(d，J＝4.7Hz，3H)。(M+1)/Z＝152。
Step 2:
6-methylamino formyl radical-pyridine-3-SULPHURYL CHLORIDE
(4.1mL 56.0mmol) adds entry (22mL), keeps temperature of reaction to be lower than 5 degrees centigrade with thionyl chloride in 1h under 0 degree centigrade.Reaction mixture is warmed to 18 degrees centigrade in 20h.(0.17g 0.2mol) and with gained yellow-green solution is cooled to-5 degrees centigrade to add cupric chloride (I) in this mixture.Abreast, (1.2g 8.0mmol) is dissolved among the dense HCl (12mL) with 5-amino-pyridine-2-carboxylic acid methyl acid amides 5.In 1h, in this mixture, drip NaNO
2(1.0g, the 14.0mmol) solution in water (6mL) keep temperature of reaction-5 degree centigrade.This slurry is dropped to above mixture (thionyl chloride/water mixture) subsequently in 1h, keep between the temperature-5 and 0 degree centigrade.(annotate: the diazotization mixture should keep below-5 degrees centigrade in whole adition process).Along with the carrying out that adds, the white solid precipitation.Reaction mixture stirs another hour under being lower than 0 degree centigrade.Throw out is collected by filtration, with cold water washing and dry under vacuum, obtains title compound as light yellow solid (0.18g, productive rate: 10%).
SC10 prepares by changing the step that is used for SC1 among the WO 2007/023186, below describes in detail:
6-formamyl-pyridine-3-SULPHURYL CHLORIDE
(31.4mL 0.47mol) adds entry (182mL), keeps temperature of reaction to be lower than 5 degrees centigrade with thionyl chloride in 1h under 0 degree centigrade.Reaction mixture is warmed to 18 degrees centigrade in 20h.(0.14g 0.001mol) and with gained yellow-green solution is cooled to-5 degrees centigrade to add cupric chloride (I) in this mixture.Abreast, (10.0g 0.08mol) slowly is dissolved among the dense HCl (98mL) and weekend is passed through in stirring at room temperature with 5-amino-2-cyanopyridine.In 1h, in this mixture, drip NaNO
2(8.2g, the 0.12mol) solution in water (50mL) keep temperature of reaction-5 degree centigrade.This slurry is dropped to above mixture (thionyl chloride/water mixture) subsequently in 1h, keep between the temperature-5 and 0 degree centigrade.(annotate: the diazotization mixture should keep below-5 degrees centigrade in whole adition process).Along with the carrying out that adds, the white solid precipitation.Reaction mixture is lower than under 0 degree centigrade and is stirring another hour.Throw out is collected by filtration, with cold water washing and dry under vacuum, obtains title compound as light yellow solid (5.1g, productive rate: 27%).
Table 6
Claims (15)
1. compound with structural formula (I):
Ring A is carbocyclic ring or heterocyclic radical; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
6Group replace;
R
1Be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, diazanyl, urea groups, N, N-two (C
1-3Alkyl) urea groups, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkyloyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocylic radical, heterocyclic radical; R wherein
1Can be by one or more R on the carbon
7Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
8Group replace;
N is 0-5; R wherein
1Value can be identical or different;
R
2Be selected from C
1-6Alkyl, C
2-6Alkenyl or C
2-6Alkynyl, carbocylic radical, and heterocyclic radical; R wherein
2Can be by one or more R on the carbon
9Replace; If wherein described heterocyclic radical comprises the NH part, nitrogen can be optionally selected from R so
19Group replace;
R
3Be selected from hydrogen, C
1-6Alkyl, C
2-6Alkenyl or C
2-6Alkynyl, carbocylic radical, heterocyclic radical; R wherein
3Can be by one or more R on the carbon
11Replace; If wherein described heterocyclic radical comprises the NH part, nitrogen can be optionally selected from R so
20Group replace;
Or, in addition, R
2And R
3Can form C with the carbon that they connected
3-6The carbocyclic ring ring;
R
4Be selected from C
1-6Alkyl or carbocyclic ring; R wherein
4Can be by one or more R on the carbon
10Replace;
Ring D is fused on the have structural formula imidazoles of (I) and is 5-7 unit ring; If wherein described ring comprises-the NH-part, nitrogen can be optionally selected from R so
14Group replace;
R
5Be on carbon substituting group and be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, heterocyclic radical carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical, or two R
5Can form 5 to 8-unit's carbocyclic ring or heterocyclic rings with the carbon atom of the ring D that they connected; R wherein
5Can be by one or more R on the carbon
15Replace; If wherein described heterocyclic radical or heterocyclic ring comprise-the NH-part, nitrogen can be optionally selected from R so
16Group replace;
M is 0-5; R wherein
5Value can be identical or different;
R
7, R
9, R
11And R
15Be independently selected from halo, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl group, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical; R wherein
7, R
9, R
11And R
15Can be independently on the carbon by one or more R
17Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
18Group replace;
R
6, R
8, R
13, R
14, R
16, R
18, R
19And R
20Be independently selected from C
1-6Alkyl, C
1-6Alkyloyl, C
1-6Alkyl sulphonyl, C
1-6Alkoxy carbonyl, formamyl, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl) formamyl, benzyl, benzyl oxygen base carbonyl, benzoyl and phenyl sulfonyl;
R
10Be selected from halo, nitro, hydroxyl, amino, carboxyl, sulfydryl, sulfamyl, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkyloyl, C
1-6Alkyloyl oxygen base, N-(C
1-6Alkyl) amino, N, N-(C
1-6Alkyl)
2Amino, C
1-6Alkanoylamino, N-(C
1-6Alkyl) formamyl, N, N-(C
1-6Alkyl)
2Formamyl, C
1-6Alkyl S (O), wherein a is 0 to 2, C
1-6Alkoxy carbonyl, N-(C
1-6Alkyl) sulfamyl, N, N-(C
1-6Alkyl)
2Sulfamyl, C
1-6Alkyl sulfonyl-amino, carbocyclic ring or heterocyclic radical; R wherein
10Can be by one or more R on the carbon
12Replace; If wherein described heterocyclic radical comprises-the NH-part, nitrogen can be optionally selected from R so
13Group replace;
R
12And R
17Be selected from halo, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methyl sulfo-, ethylenebis dithiocarbamate, methyl sulfinyl, ethylsulfinyl-1 base, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxy carbonyl, N-methyl sulfamyl ,/V-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;
Or its drug acceptable salt; Prerequisite is, this compound is not the phenyl methyl of 4-methyl-N-[(1-methyl isophthalic acid H-benzimidazolyl-2 radicals-yl)] benzsulfamide.
2. according to the structural formula with structural formula (Ia) (I) compound of claim 1
R wherein
3Be hydrogen and A, D, R
1, R
2, R
4, R
5, m and n definition are as claim 1 and its drug acceptable salt.
3. according to the compound of claim 1 or 2, wherein encircling A is phenyl or pyridyl.
4. according to the compound with structural formula (I) of claim 1, be selected from
(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl)-4-fluorobenzene sulphonamide;
(R)-6-cyano group-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl) pyridine-3-sulphonamide;
(R)-5-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl) sulfamyl) picolinamide;
(R)-4-cyano group-N-(1-(1-ethyl-6-methoxyl group-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl) benzsulfamide;
(R)-6-cyano group-N-(1-(1-ethyl-6-methoxyl group-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl) pyridine-3-sulphonamide;
(R)-6-cyano group-N-(1-(1-ethyl-6-methoxyl group-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl) pyridine-3-sulphonamide;
(R)-5-(N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl) sulfamyl)-1-methyl isophthalic acid H-pyrroles-2-methane amide;
(R)-and N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-2,6-lutidine-4-sulphonamide;
(R)-N-(1-(1-ethyl-6-(trifluoromethyl)-1H-benzo [d] imidazoles-2-yl) ethyl)-2-picoline-4-sulphonamide;
6-cyano group-N-[(1R)-1-(6-cyclopropyl-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] pyridine-3-sulphonamide;
5-([(1R)-and 1-(6-cyclopropyl-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl) ethyl] amino } alkylsulfonyl) pyridine-2-carboxamide;
4-cyano group-N-{ (1R)-1-[1-ethyl-6-(trifluoromethyl)-1H-imidazoles [4,5-b] pyridine-2-yl] ethyl } benzsulfamide;
4-cyano group-N-[1-(6-cyclopropyl-1-ethyl-1H-imidazoles [4,5-c] pyridine-2-yl)-ethyl]-benzsulfamide; With
Its drug acceptable salt.
5. a pharmaceutical composition is included in desired compound with structural formula (I) in arbitrary aforementioned claim, or its drug acceptable salt and the drug acceptable carrier, thinner or the vehicle that combine.
6. be used as desired compound among the claim 1-4 of medicine with structural formula (I), or its drug acceptable salt.
7. the purposes of the desired compound with structural formula (I) of claim 1-4, or its drug acceptable salt in making medicine, described medicament are used for producing the Edg-1 antagonist action warm-blooded animal such as people.
8. the desired compound with structural formula (I) of arbitrary claim 1-4, or the purposes of its drug acceptable salt in making medicine, described medicament is used for producing antitumous effect warm-blooded animal such as people.
9. the desired compound of arbitrary claim 1-4, or the purposes of its drug acceptable salt in making medicine with structural formula (I), the disease that described medicament is used for the treatment of associated angiogenesis includes, but are not limited to, non-solid tumour such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and solid tumor and smouldering therebetween as melanoma, nonsmall-cell lung cancer, glioma, hepatocellular carcinoma, glioblastoma, thyroid carcinoma, bile duct, bone, stomach, brain/CNS, head and neck, liver, stomach, prostate gland, chest, kidney, testis, ovary, skin, uterine cervix, lung, muscle, neurone, oesophagus, bladder, lung, the uterus, vulva, uterine endometrium, kidney, colorectum, pancreas, pleura/peritonaeum, sialisterium and epidermis shape tumour.
10. one kind is used for warm-blooded animal, and the method as philtrum generation Edg-1 antagonist action comprises the desired compound with structural formula (I) to arbitrary claim 1-4 of described animals administer significant quantity, or its drug acceptable salt.
11. one kind is used for warm-blooded animal, the method as philtrum generation antitumous effect comprises the desired compound with structural formula (I) to arbitrary claim 1-4 of described animals administer significant quantity, or its drug acceptable salt.
12. the disease at the warm-blooded animal treatment associated angiogenesis of needs treatments comprises non-solid tumour, solid tumor and smoulder nonsmall-cell lung cancer, glioma therebetween, liver cell (liver) cancer, glioblastoma, thyroid carcinoma, bile duct, bone, stomach, brain/CNS, head and neck, liver, stomach, prostate gland, chest, kidney, testis, ovary, skin, uterine cervix, lung, muscle, neurone, oesophagus, bladder, lung, uterus, vulva, uterine endometrium, kidney, colorectum, pancreas, pleura/peritonaeum, the method of sialisterium and epidermis shape tumour comprises desired compound or its drug acceptable salt with structural formula (I) to arbitrary claim 1-4 of described animals administer significant quantity.
13. pharmaceutical composition that is used at warm-blooded animal such as people's generation Edg-1 antagonist action, comprise the desired compound of arbitrary claim 1-4 with structural formula (I), or its drug acceptable salt and the drug acceptable carrier, thinner or the vehicle that combine.
14. one kind is used to act on warm-blooded animal such as the anticancer pharmaceutical composition of philtrum generation, comprise the desired compound of arbitrary claim 1-4 with structural formula (I), or its drug acceptable salt and the drug acceptable carrier, thinner or the vehicle that combine.
Claim 1 is desired has the compound of structural formula (I) or a method of its drug acceptable salt 15. be used to prepare, wherein unless otherwise prescribed, variable-definition such as claim 1, this method comprises
Method a) will have the compound of structural formula (II):
React with amine with structural formula (III):
Wherein L is a displaceable group,
Then if desired:
I) compound that will have a structural formula (I) changes into the compound that another has structural formula (I);
Ii) remove any blocking group;
Iii) form drug acceptable salt.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86536406P | 2006-11-10 | 2006-11-10 | |
| US60/865,364 | 2006-11-10 | ||
| US60/895,699 | 2007-03-19 | ||
| US60/947,795 | 2007-07-03 | ||
| US60/953,838 | 2007-08-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101611018A true CN101611018A (en) | 2009-12-23 |
Family
ID=39627439
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800495750A Pending CN101611018A (en) | 2006-11-10 | 2007-11-08 | Heterocyclic sulfonamide with Edg-I antagonistic activity |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101611018A (en) |
| UY (1) | UY30705A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117131A (en) * | 2016-06-29 | 2016-11-16 | 天津市均凯化工科技有限公司 | A kind of method preparing 2 amino 3 chlorine 5 trifluoromethyl pyridines |
| CN109206323A (en) * | 2017-07-07 | 2019-01-15 | 上海现代制药股份有限公司 | A kind of preparation method of naphthylamines pharmaceutical intermediate |
| CN110845722A (en) * | 2019-10-28 | 2020-02-28 | 西北工业大学 | Carrier-free hyperbranched macromolecular polymer and preparation method thereof |
| CN114369060A (en) * | 2020-10-15 | 2022-04-19 | 杭州星鳌生物科技有限公司 | Novel indoleamine 2, 3-dioxygenase inhibitor and application thereof in preparing antitumor drugs |
-
2007
- 2007-11-08 CN CNA2007800495750A patent/CN101611018A/en active Pending
- 2007-11-09 UY UY30705A patent/UY30705A1/en unknown
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117131A (en) * | 2016-06-29 | 2016-11-16 | 天津市均凯化工科技有限公司 | A kind of method preparing 2 amino 3 chlorine 5 trifluoromethyl pyridines |
| CN106117131B (en) * | 2016-06-29 | 2018-09-04 | 天津市均凯化工科技有限公司 | A method of preparing 2- amido-3-5-trifluoro picolines |
| CN109206323A (en) * | 2017-07-07 | 2019-01-15 | 上海现代制药股份有限公司 | A kind of preparation method of naphthylamines pharmaceutical intermediate |
| CN110845722A (en) * | 2019-10-28 | 2020-02-28 | 西北工业大学 | Carrier-free hyperbranched macromolecular polymer and preparation method thereof |
| CN114369060A (en) * | 2020-10-15 | 2022-04-19 | 杭州星鳌生物科技有限公司 | Novel indoleamine 2, 3-dioxygenase inhibitor and application thereof in preparing antitumor drugs |
| CN114369060B (en) * | 2020-10-15 | 2023-11-03 | 杭州星鳌生物科技有限公司 | Indolylamine 2, 3-dioxygenase inhibitor and application thereof in preparation of antitumor drugs |
Also Published As
| Publication number | Publication date |
|---|---|
| UY30705A1 (en) | 2008-07-03 |
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